Mechanism and Synthetic Use of Paternò-Büchi

Transcription

Mechanism and Synthetic Use of Paternò-Büchi Reactions:
Spin-Mapping and Photo-Aldol Reactions
Inaugural-Dissertation
zur
Erlangung des Doktorgrades
der Mathematisch-Naturwissenschaftlichen Fakultät
der Universität zu Köln
vorgelegt von
Samir Bondock
aus Mansoura
(Ägypten)
Köln 2003
Berichterstatter:
Prof. Dr. A. G. Griesbeck
Prof. Dr. H. G. Schmalz
Tag der mündlichen Prüfung:
7. 05. 2003
Acknowledgements
I would like to thank Prof. Dr. Axel G. Griesbeck for giving me the opportunity to perform
my Ph.D in his group and for his valuable help throughout this work.
I am also grateful to Prof. Dr. H. G. Schmalz and Prof. Dr. G. Meyer for the interest they have
shown in this manuscript by accepting to act as referees.
I would like also to acknowledge Prof. Dr. M. S. Gudipati, University of Maryland, for his
help and cooperation.
I owe special thanks to the egyptian government for the Ph.D grant.
Prof. Dr. D. Döpp, University of Duisburg is thanked for providing unpublished work during
the preparation of CRC reviews.
I am indebted to all staff member of Chemistry Department, Faculty of Science, Mansoura
University, Egypt.
All my thanks go to my collegues Tamer El-Idreesy, Stefan Schiffer, Claus Miara, Nesmine
Maptue and Anna Bartoschek for the nice work atmosphere. Peter Cygon receives special
thanks for his help and friendly cooperation.
Dr. Hans Schmickler, Ms. Ingrid Hoven and Ms. Kathrin Ermer receive a special thanks not
only for NMR analyses but also for friendly reaction even when I brought ten probes every
day.
The author thanks Mr. Christof Schmitz for UV, IR and elemental analyses and Dr. Mathias
Schäfer for mass spectrometry. Dr. Johann Lex is thanked for the X-ray analyses.
Ms. Ingrid Vongerichten and Ms. Monika Boyo should not be forgotten here for their
precious help.
A last thank go to my family, my brother Ahmed and of course to my mother for their support
during theses 4 years.
List of Publications and Presentations
Publications
1.
“Spin-Directed Stereoselectivity of Carbonyl-Alkene Photocycloadditions“
Axel G. Griesbeck, Maren Fiege, Samir Bondock and Murthy S. Gudipati,
Organic Letters 2000, 2, 3623-3625.
2.
“Paternò-Büchi reactions of Allylic Alcohols and Acetates with Aliphatic Aldehydes:
Evidences for Hydrogen-Bond Activation in the Excited Singlet and Triplet States?
Axel G. Griesbeck and Samir Bondock,
J. Am. Chem. Soc. 2001, 123, 6191-6192.
3.
“Temperatur- und Viskositätsabhängigkeit der spingesteuerten Stereoselektivität von
Carbonyl-Alken-Photocycloadditionen“
Axel G. Griesbeck, Samir Bondock und Murthy S. Gudipati,
Angew. Chem. 2001, 113, 4828-4832; Angew. Chem. Int. Ed. 2001, 40, 4684-4687.
4.
“Spin-Imposed
Stereoselection
in
the
Photocycloaddition
of
cis-
and
trans-
Cyclooctene with Aliphatic Aldehydes“
Photochem. Photobiol. Sciences. 2002, 1, 81-83.
5.
“Photo
Aldol
Reactions
with
5-Methoxyoxazoles:
Highly
Regio-
and
Diastereoselective Synthesis of α-Amino-β-Hydroxy Carboxylic Acid Derivatives“
Can. J. Chem. 2003, 81, 1-5.
6.
“The
excimer
radiation
system:
a
powerful
tool
for
preparative
organic
photochemistry. A technical note“
Axel, G. Griesbeck, Nesmine Maptue, Samir Bondock and Michael Oelgemöller
,
Photochem. Photobiol. Sciences. 2003, 2, 450-451.
7.
“Photochemical Oxetane Formation: Intermolecular Reactions“
in CRC Handbook of Organic Photochemistry and Photobiology, William M.
Horspool, Phil-S. Song (Hrsg) CRC press: Boca Raton, 2003, in press.
8.
“Photochemical Oxetane Formation: Mechanism and Stereochemistry“
in CRC Handbook of Organic Photochemistry and Photobiology, William M.
Horspool, Phil-S. Song (Hrsg) CRC press: Boca Raton, 2003, in press.
9.
“Substantial
2
H-Magnetic Isotope Effects on the Diastereoselectivity of Triplet
Photocycloaddition Reactions“
J. Am. Chem. Soc. 2003, submitted.
10.
“Synthesis of quaternary α-amino β-hydroxy carboxylic acids. 1. Photo aldol reactions
of 5-methoxy oxazoles with aldehydes“
Axel G. Griesbeck , Samir Bondock and Johann Lex,
J. Org. Chem. 2003, in preparation.
11.
“Synthesis of quaternary α-amino β-hydroxy carboxylic acids. 2. Photo aldol reactions
of 5-methoxy oxazoles with α-keto esters“
Axel G. Griesbeck , Samir Bondock and Johann Lex,
J. Org. Chem. 2003, in preparation.
Posters
1.
“Spin-Mapping of [2+2]-Photocycloadditions: Concentration-, Solvent Viscosity- and
Temperature Effects“
Axel G. Griesbeck, Samir Bondock and Murthy S. Gudipati,
Gordon-Research-Conference, New London, USA July 2001
2.
Spin-Mapping
of
[2+2]-Photocycloadditions:
Concentrations,
Temperature,
and
Solvent Viscosity Effects“
Axel G. Griesbeck, Samir Bondock, Maren Fiege, and Murthy S. Gudipati,
Photochirogenesis, Osaka, Japan, September 2001
3.
“Paternò-Büchi-Reaktionen von Allylalkoholen und Allylacetaten mit Aldehyden:
Konzentrationsstudien und Spinselecktivität
“
Axel G. Griesbeck, Samir Bondock und Maren Fiege,
Meeting of the German Chemical Society, Würzburg, september 2001.
4.
“Diastereoselective Photochemical Synthesis of α-Amino-β-Hydroxy Carboxylic Acid
Derivatives by Photocycloaddition of Carbonyl Compounds to Oxazoles“
Samir Bondock and Axel G. Griesbeck,
IUPAC Conference on Photochemistry, Budapest, Hungary, July 2002.
5.
“Stereoselectivity of [2+2]-Photocycloadditions: Magnetic Isotope Effects“
Samir Bondock and Axel G. Griesbeck,
Meeting of the German Chemical Society, Mülheim/Ruhr, April 2003.
This work was carried out from May 2000 to May 2003 under the supervision of Prof. Dr.
Axel G. Griesbeck at the Institute of Organic Chemistry, University of Cologne.
Abbreviation
Ac
Acetyl
Bn
Benzyl
B.p
Boiling point (°C)
BR
Biradical
Bu
Butyl
Bui
Isobutyl
Busec
sec-Butyl
But
tert-Butyl
cc
cis,cis
CIP
Contact ion pair
Cp
Centipoise
DCC
Dicyclohexylcarbodiimide
de
Diastereomeric excess
DEPT
Distortionless Enhancement by Polarization Transfer
DMAP
N,N-Dimethylaminopyridine
DMF
Dimethylformamid
dr
Diastereomeric ratio
∆EST
Energy difference between the singlet and triplet state
EA
Ethylacetate
EIE
Equilibrium isotope effect
Et
Ethyl
F
Fluorescence intensity
F0
Initial fluorescence intensity
h
Hour
HE
n-Hexane
HFC
Hyperfine coupling
HMBC
Heteronuclear Multiple Bond Correlation
HOMO
Highest Occupied Molecular Orbital
IC
Internal conversion
i-Bu
Isobutyl
i-Pr
Isopropyl
ISC
Intersystem Crossing
kdiff
Molecular diffusion rate constant
kq
Bimolecular quenching rate constant
LUMO
Lowest Unoccupied Molecular Orbital
M
Molarity
Me
Methyl
MIE
Magnetic isotope effect
min
Minute
M.p
Melting point (°C)
Naph
Naphthyl
NOE
Nuclear Overhauser Enhancement
NOESY
Nuclear Overhauser Enhancement Spectroscopy
OAc
Acetate
o-Tol.
ortho-Tolualdehyde
PET
Photoinduced electron transfer
Ph
Phenyl
Pr
Propyl
Pri
Isopropyl
Q
Quencher
ROESY
Rotating Frame Overhauser Enhancement Spectroscopy
Rf
Retention factor
Rs
Reaction probabilty from singlet channel
Rt
Retention time
RT
Reaction probabilty from triplet channel
RT
Room temperature
S0
Ground state
S1
First excited singlet state
Sbo
Samir Bondock
S-1,4-BR
Singlet 1,4-biradical
SLR
Spin-Lattice Relaxation
SOC
Spin-Orbit Coupling
SOI
Secondary Orbital Interaction
T1
First excited triplet state
T-1,4-BR
Triplet 1,4-biradical
tc
trans,cis
TEA
Triethyl amine
THF
Tetrahydrofuran
TLC
Thin Layer Chromatography
TMEDA
Tetramethylethylenediamine
TMS
Trimethylsilyl
tt
trans,trans
ε
Molar extinction coefficient
φT
Relative triplet quantum yield
η
Viscosity
∆
Reflux
Φ
Quantum yield
λex
Excited wavelength
µ
Micro (10-6 )
τ
Lifetime
∗
[]
Excited state
Molar concentration
Contents
Abstract
I
Kurzzusammenfassung
II
1.
Introduction
1
1.1
Mechanistic studies
2
1.2
Mechanism of Paternò-Büchi reactions
3
1.3
1,n-Biradicals
5
1.4
Biradical generation and trapping
5
1.5
Lifetime of triplet 1,n-Biradicals
6
1.6
State selectivity: Singlet excited carbonyl compounds
9
1.7
Substituent effects
10
1.8
Photoinduced-electron transfer (PET) in the Paternò-Büchi reaction
11
1.9
Regioselectivity of Paternò-Büchi reactions
13
1.10
Diastereoselectivity in the Paternò-Büchi reaction
14
1.10.1
Simple diastereoselectivity
14
1.10.1.1
Paternò-Büchi reactions with 2,3-dihydrofuran and furan
14
1.10.1.2
Paternò-Büchi reactions with enamines
17
1.10.1.3
Paternò-Büchi reactions with acyclic enol ether
18
1.10.1.4
Paternò-Büchi reactions with cyclooctene
20
1.10.2
Induced diastereoselectvity
20
1.10.2.1
Induction by the carbonyl compound
20
1.10.2.2
Induction by the alkene component
21
1.11
Effect of temperature on the diastereoselectivity of Paternò-Büchi reactions 23
1.12
Effect of hydroxy groups on the stereoselectivity of Paternò-Büchi reactions 25
1.13
Synthetic applications of the Paternò-Büchi reaction
26
2.
Projected work
30
3.
Results and Discussion
32
3.1
Effect of concentration on the simple diastereoselectivity of Paternò-Büchi
reactions
32
3.1.1
Photocycloaddition of 2,3-dihydrofuran
32
3.1.1.1
Reaction with benzaldehyde
32
3.1.1.2
Reaction with acetaldehyde
33
3.1.1.3
Reaction with propionaldehyde
34
3.1.1.4
Reaction with 3- methylbutyraldehyde
36
3.1.1.5
Reaction with pivalaldehyde
37
3.1.1.6
Reaction with 3-phenylpropionaldehyde
38
3.1.2
Photocycloaddition of 2,3-dihydropyran
38
3.1.2.1
38
3.1.2.2
39
3.1.2.3
40
3.1.2.4
41
3.1.3
Photocycloaddition of cyclopentene with propionaldehyde
42
3.1.4
Photocycloaddition of 5- methyl-2,3-dihydrofuran
43
3.1.4.1
43
3.1.4.2
44
3.1.4.3
44
3.1.4.4
45
3.1.5
Synthesis of 2,2-dimethyl-2,3-dihydrofuran
46
3.1.5.1
Photocycloaddition of 2,2-dimethyl-2,3-dihydrofuran with aldehydes
47
3.1.6
Effect of concentration on simple and induced diastereoselectivity
of Paternò-Büchi reactions
49
3.1.6.1
Photocycloaddition of 2,3-dihydrofuran with 2- methylbutyraldehyde
49
3.1.6.2
Photocycloaddition of 5- methyl-2,3-dihydrofuran with
2-methylbutyraldehyde
50
3.1.7
Photocycloaddition of furan with acetaldehyde
51
3.1.8
Fluorescence quenching
52
3.1.9
Quantum yield
53
3.2
Effect of solvent polarity on the simple diastereoselectivity of
Paternò-Büchi reactions
3.2.1
Solvent polarity effect on the stereoselectivity of the 2,3dihydrofuran/propionaldehyde phototocycloaddition reaction
3.2.2
57
Effect of solvent viscosity on the simple diastereoselectivity of
3.3.1
56
Solvent polarity effect on the stereoselectivity of the 2,3dihydrofuran/acetaldehyde phototocycloaddition reaction
3.3
56
58
Solvent viscosity effect on the stereoselectvity of the benzaldehyde/2,3dihydrofuran photocycloaddition reaction
58
3.3.2
Solvent viscosity effect on the stereoselectvity of the acetaldehyde/2,3dihydrofuran photocycloaddition reaction
3.3.3
Solvent viscosity effect on the stereoselectvity of the propionaldehyde/2,3dihydrofuran photocycloaddition reaction
3.3.4
67
Effect of temperature on the simple diastereoselectivity of propionaldehyde
/2,3-dihydrofuran photocycloaddition reaction
3.5
66
Effect of temperature on the simple diastereoselectivity of
3-methylbutyraldehyde/2,3-dihydrofuran photocycloaddition reaction
3.4.5
65
Effect of temperature on the simple diastereoselectivity of acetaldehyde/2,3dihydrofuran photocycloaddition reaction
3.4.4
65
Effect of temperature on the concentration/selectivity correlation of
propionaldehyde/2,3-dihydrofuran photocycloaddition reaction
3.4.3
64
Effect of temperature on the simple diastereoselectivity of benzaldehyde/2,3dihydrofuran photocycloaddition reaction
3.4.2
62
Effect of temperature on the simple diastereoselectivity of
3.4.1
60
Solvent viscosity effect on the stereoselectvity of the 3- methylbutyraldehyde
/2,3 -dihydrofuran photocycloaddition reaction
3.4
59
69
Paternò-Büchi reaction of cis and trans-cyclooctene with
aliphatic aldehydes
74
3.5.1
Synthesis of trans-cyclooctene
74
3.5.2
Irradiation of cis-cyclooctene with propionaldehyde
74
3.5.3
Irradiation of trans-cyclooctene with propionaldehyde
76
3.5.4
Irradiation of cis-cyclooctene with acetaldehyde
77
3.6
Paternò-Büchi reaction of allylic alcohols and acetates with aldehydes
80
3.6.1
Synthesis of allylic alcohols and acetates
80
3.6.2
Simple diastereoselectivity
80
3.6.2.1
Photolysis of prenol with aldehydes
80
3.6.2.2
Photolysis of prenyl acetate with aldehydes
83
3.6.3
Spin-directed simple diastereoselectivity
86
3.6.4
Enhanced reactivity of allylic alcohols
87
3.6.5
Induced and simple diastereoselectivity with chiral allylic alcohols
88
3.6.5.1
Photolysis of mesitylol with aliphatic aldehydes
89
3.6.5.2
Photolysis of mesityl acetate with acetaldehyde
89
3.7
Diastereoselective photochemical synthesis of α-amino-β-hydroxy carboxylic
acid derivatives by photocycloaddition of carbonyl compounds to oxazoles 91
3.7.1
Synthesis of oxazole substrates
91
3.7.1.1
Synthesis of 2-methyl-5- methoxyoxazole
91
3.7.1.2
Synthesis of 4-substituted 2- methyl-5-methoxyoxazoles
92
3.7.2
Photoreactions of 2- methyl-5-methoxyoxazoles with aldehydes
94
3.7.2.1
Ring-opening of the bicyclic oxetanes 38a-f
95
3.7.2.2
Synthesis of (Z)-α,β-didehydroamino acid derivatives
97
3.7.2.3
Synthesis of methyl 1- methylisoquinoline-3-carboxylate
3.7.3
Photoreactions of 4-substituted 2- methyl-5-methoxyoxazoles
100
with aldehydes
101
3.7.3.1
Synthesis of erythro (S*,S*) α-alkylated-α-acetamido-β-hydroxy esters
108
3.7.3.2
Transacylation
122
3.7.4
Asymmetric photocycloaddition between oxazoles and chiral aldehyde
126
3.7.4.1
Synthesis of lyxo- & ribo- α-acetamido-β-hydroxy esters
128
3.8
Photo-Aldol reactions of 5- methoxyoxazoles with α-keto esters:
Selectivity pattern and synthetic route to erythro (S*,R*)
& threo (S*,S*) α-amino-β-hydroxy succinic acid derivatives
131
3.8.1
131
3.8.2
Synthesis of α-keto ester substrates
132
3.8.2.1
Synthesis of methyl trimethylpyruvate
132
3.8.2.2
Synthesis of isopropyl & tert-butyl phenylglyoxylates
132
3.8.2.3
Synthesis of (-)-menthyl phenylglyoxylate
132
3.8.3
Photocycloaddition reactions of aliphatic α-keto esters with oxazoles
133
3.8.3.1
Reaction with methyl pyruvate
133
3.8.3.2
Reaction with methyl trimethylpyruvate
138
3.8.4
Photocycloaddition reactions of aromatic α-keto esters with oxazoles
140
3.8.4.1
Reaction with methyl phenylglyoxylate
140
3.8.4.2
Reaction with ethyl phenylglyoxylate
145
3.8.4.3
Reaction with isopropyl phenylglyoxylate
149
3.8.4.4
Reaction with tert-butyl phenylglyoxylate
151
3.8.5
Asymmetric induction
157
3.8.5.1
Photoreactions of menthyl phenylglyoxylate with oxazoles 36a-f
157
3.8.6
Effect of the substituent at C-2 of the oxazole substrates on the
stereoselectivity of the photocycloaddition reactions with α-keto esters
3.8.6.1
Photocycloaddition reactions of 2-ethyl-4-methyl-5-methoxyoxazole
with α-keto esters
3.8.6.2
3.10.1
193
Synthesis of erythro (S*,R*) & threo (S*,S*) α-(2,2-dimethylpropionylamino)-β-hydroxy succinic acid derivatives 76a-f
3.10
192
Synthesis of erythro (S*,R*) & threo (S*,S*) α-isobutyrylamino-βhydroxy succinic acid derivatives 75a-f
3.9.10
189
Synthesis of erythro (S*,R*) & threo (S*,S*) α-propionylamino-βhydroxy succinic acid derivatives 74a-f
3.9.9
187
Synthesis of erythro (S*,R*) & threo (S*,S*) α-acetamido-β-hydroxy
succinic acid derivatives 73a-f
3.9.8
185
3.9.7
183
3.9.6
180
3.9.5
179
3.9.4
177
Synthesis of threo (S*,S*) α-acetamido-β-hydroxy succinic acid
derivatives 68a-f
3.9.3
177
Synthesis of erythro (S*,R*) α-acetamido-β-hydroxy succinic acid
derivatives 67a-f
3.9.2
169
Synthesis of erythro (S*,R*) & threo (S*,S*) α-amino-β-hydroxy
succinic acid derivatives
3.9.1
164
Photocycloaddition reactions of 2-tert-butyl-4- methyl-5methoxyoxazole with α-keto esters
3.9
162
Photocycloaddition reactions of 2-isopropyl-4- methyl-5methoxyoxazole with α-keto esters
3.8.6.3
161
195
Magnetic isotope effects on the diastereoselectivity of the triplet
photocycloaddition reactions
199
Synthesis of starting materials
199
3.10.1.1
Synthesis of benzaldehyde-1-d
199
3.10.1.2
Synthesis of propionaldehyde-1-d
200
3.10.1.3
Synthesis of 5-deuterio-2,3-dihydrofuran
201
3.10.1.4
Synthesis of 1-trimethylsilyloxycycloalkenes
202
3.10.2
Photoreactions of benzaldehyde & benzaldehyde-1-d with cyclic
alkenes
3.10.3
203
Photoreactions of propanal & propanal-1-d with 2,3-dihydrofuran
and 5-deuterio-2,3-dihydrofuran
207
4.
Experimental Part
213
4.1
General Remarks
213
4.2
General procedure for the photolyses of aldehydes and alkenes on
the analytical scale
4.2.1
215
General procedure for the photolyses of aldehydes and
alkenes on the preparative scale
216
4.2.1.1
Photolyses of 2,3-dihydrofuran with aldehydes
216
4.2.1.2
Photolyses of 2,3-dihydropyran with aldehydes
222
4.2.1.3
Photolysis of cyclopentene with propiona ldehyde
226
4.2.1.4
Photolyses of 5- methyl-2,3-dihydrofuran with aldehydes
227
4.3
Synthesis of 2,2-dimethyl-2,3-dihydrofuran
231
4.3.1
Photolyses of 2,2-dimethyl-2,3-dihydrofuran with aldehydes;
general procedure
233
4.4
Photolysis of 2,3-dihydrofuran with 2- methylbutyraldehyde
239
4.4.1
Photolysis of 5-methyl-2,3-dihydrofuran with
240
4.5
Photolysis of furan with acetaldehyde
241
4.6
Determination of solvent polarity effects on the stereoselectivity of
the Paternò-Büchi reaction of 2,3-dihydrofuran with aldehydes
4.7
Determination of solvent viscosity effects on the stereoselectivity
of the Paternò-Büchi reaction of 2,3-dihydrofuran with aldehydes
4.8
242
243
Determination of temperature effects on the stereoselectivity of the
Paternò-Büchi reaction of 2,3-dihydrofuran with aldehydes
243
4.9
Fluorescence quenching study
243
4.10
Quantum yield determination
243
4.11
Preparation of trans-cyclooctene
244
4.11.1
General procedure for the photolyses of aldehydes with
cyclooctene on the analytical scale
4.11.2
245
General procedure for the photolyses of aldehydes with
cyclooctene on the preparative scale
245
4.12
Synthesis of allylic alcohols and acetates
248
4.12.1
General procedure for the photolysis of propionaldehyde with
allylic substrates on the analytical scale
4.12.2
250
General procedure for the photolyses of aldehydes and allylic
substrates on the preparative scale
250
4.13
Synthesis of oxazole substrates
262
4.14
Photolyses of 2- methyl-5- methoxyoxazole with aldehydes
273
4.14.1
Ring opening of the bicyclic oxetanes; General procedure
278
4.14.2
Synthesis of (Z)-α,β-didehydroamino acid derivatives:
General procedure
283
4.14.3
Synthesis of methyl 1- methylisoquinoline-3-carboxylate
285
4.15
Photolyses of 4-substituted 2- methyl-5-methoxyoxazoles with
aldehydes
4.15.1
286
Synthesis of erythro (S*,S*) α-alkylated-α-acetamido-β-hydroxy
esters
305
4.15.2
Transacylation: General procedure
327
4.16
Photolyses of 5-methoxyoxazoles with 2-methylbutyraldehyde:
General procedure
4.16.1
329
Synthesis of lyxo- & ribo- α-acetamido-β-hydroxy esters:
General procedure
334
4.17
342
4.18.
Synthesis of α-keto ester substrates
345
4.19.
Photolyses of α-keto esters with 5-methoxyoxazoles
349
4.20
Synthesis of erythro (S*,R*) & threo (S*,R*) α-amino-β-hydroxy
succinic acid derivatives
419
4.21
Synthesis of starting materials
492
4.21.1
Preparation of benzaldehyde-1d
492
4.21.2
Preparation of propanal-1d
493
4.21.3
Preparation of 5-deuterio-2,3-dihydrofuran
493
4.21.4
Preparation of 1-trimethylsilyoxycycloalkenes
493
4.22
General procedure for photolyses of benzaldehyde &
benzaldehyde-1d with cycloalkenes
4.23
496
Photolyses of propanal & propanal-1-d with 2,3-dihydrofuran & 5deuterio-2,3-dihydrofuran
510
5.
Appendix
514
6.
Summary
516
7.
Zusammenfassung
522
8.
References
528
Abstract
___________________________________________________________________________
Abstract
The concentration dependence of the diastereoselectivity of the Paternò-Büchi reaction of a
series of cyclic enolethers, cyclooctene, allylic alcohols and acetates, respectively, with
aromatic as well as aliphatic aldehydes was studied. For most aliphatic aldehydes, a sharp
transition from low to high diastereoselectivity was observed, indicating a distinct switch
from singlet to triplet photocycloaddition with different selectivity controlling mechanisms.
1
O
RCHO*
1,2
O
O
R
O
3
RCHO*
1,2
1,2
R
low (endo/exo)
diastereoselectivity
R = Me, Et, i-Bu
O
high (endo/exo)
R = Me, Et, i-Bu, Ph
Furthermore, the effect of solvent viscosity and temperature on the spin-directed
stereoselectivity of the carbonyl-ene photocycloaddition was investigated. The variation of the
solvent viscosity over a large range resulted in a weak but significant increase in the endoselectivity of triplet benzaldehyde cycloaddition to 2,3-dihydrofuran from 82 to 91 %. For
aliphatic aldehydes, the diastereoselectivity strongly increased with increasing solvent
viscosity. The temperature dependence of the endo/exo-selectivity with aliphatic aldehydes
RCHO (R = Me, Et, i-Bu) showed characteristic non-linear behavoir with inversion points
from which activation parameters for singlet as well as the triplet photocycloaddition were
determined.
5-Methoxyoxazole derivatives were prepared and evaluated with respect to their use as diene
components in stereoselective Paternò-Büchi reaction. These oxazoles were versatile
synthetic building blocks that reacted with various photoexcited aliphatic as well as aromatic
carbonyl
compounds
with
high
regioselectvity
and
excellent
exo-diastereoselectvity.
Hydrolysis of the primary photoadducts resulted in twofold ring-opening and provided a
convenient and high yielding access to erythro (S*,S*) α-amino-β-hydroxy carboxylic acid
derivatives.
O
R1
H
N
R
H3C
O
OCH3
H
hν
H3C
N
O
I
O
R
R1
OCH3
HO
H / H 2O
AcHN
R
R1
CO2CH3
Kurzzusammenfassung
___________________________________________________________________________
Kurzzusammenfassung
Die
Konzentrationsabhängigkeit
der
Diastereoselektivität
von
Paternò-Büchi-Reaktionen
einer Reihe cyclischer Enolether, Allylalkohole und –acetate mit aromatischen bzw.
aliphatischen Aldehyden wurde untersucht. Bei den meisten aliphatischen Aldehyden wurde
ein relativ scharfer Übergang von niedriger zu hoher Diastereoselektivität registriert, der auf
einen klar ausgeprägten Wechsel zwischen Singulett- und Triplett-Photocycloaddition mit
jeweils unterschiedlichen Kontrollmechanismen hinweist.
1
O
RCHO*
1,2
O
O
R
O
3
RCHO*
1,2
1,2
R
low (endo/exo)
R = Me, Et, i-Bu
O
high (endo/exo)
R = Me, Et, i-Bu, Ph
Weiterhin wurde der Effekt von Lösungsmittelviskosität sowie Reaktionstemperatur auf die
spin-gesteuerte
Stereoselektivtiät
der
Carbonyl-En-Photocycloaddition
untersucht.
Die
Variation der Lösungsmittelviskosität über einen grossen Bereich ergab eine kleine, aber
signifikante Erhöhung der endo-Selektivität von 82% auf 91% für die Addition von TriplettBenzaldehyd an 2,3-Dihydrofuran. Im Falle aliphatischer Aldehyde stiegt die Diastereoselektivität stark mit zunehmender Lösungsmittelviskosität an. Die Temperaturabhängigkeit
der endo/exo-Selektivität aliphatischer Aldehyde RCHO (R = Me, Et, i- Bu) wies ein charakteristisches nicht-lineares Verhalten mit Inversionspunkten auf, aus dem Aktivierungsparameter sowohl für die Singulett- als auch die Triplett-Photocycloaddition ermittelt wurden.
Derivate von 5-Methoxyoxazol wurden hergestellt und auf ihre Eignung als Dienkomponenten in stereoselektiven Paternò-Büchi-Reaktionen untersucht. Diese Oxazole erwiesen
sich als vielseitige Bausteine, welche mit verschiedenen angeregten aliphatischen sowie
aromatischen Carbonylkomponenten mit hoher Regio- und exzellenter (exo)-Diastereoselektivität reagierten. Die Hydrolyse der primären Cycloaddukte führte zu einer zweifachen
Ringöffnung und ergab so einen bequemen und mit hohen Ausbeuten verlaufenden Zugang zu
erythro (S*,S*) α -Amino- β-hydroxycarbonsäurederivaten.
O
R1
H
N
R
H3C
O
OCH3
H
hν
H3C
N
O
II
O
R
1
R
OCH3
HO
H / H 2O
AcHN
R
R1
CO2CH3
1. Introduction
1. Introduction
General outlook of spin chemistry
In a recent brilliant feature article1 , Ahmed H. Zewail presented a striking and impressive
overview of the new frontier in modern chemistry-femtochemistry, which explores atomic
motions on the potential energy surface, vibrational and rotational coherence of the wave
pacets, and transition state spectra, geometry, and dynamics. Another new frontier is spin
chemistry, which monitors the behavior of angular momentum (spin) of electrons and nuclei
in chemical reactions (including coherence of spin wave pacets), spin dynamics and spin state
of evolution of reactants.
Spin chemistry is based on the fundamental and universal principle of spin conservation: all
chemical reactions are spin-selective, they are allowed only for those spin states of reactants
whose total spin is identical to that of products. Spin chemistry is unique: it introduces in
chemistry magnetic interactions. Contributing almost nothing in chemical energy, being
negligibly small and traditionally ignorable, magnetic interactions are the only ones which are
able to change electron spin of reactants and switch over the reaction between spin-allowed
and spin-forbidden channels. Ultimately, they control chemical reactivity and write a new
magnetic scenario of chemical reaction.2
Historical
The [2+2] photocycloaddition of a carbonyl compound with an alkene is termed PaternòBüchi reaction. The process described in the original publication by Paternò and Chieffi in
1909 was the addition of benzaldehyde to 2-methyl-2-butene using solar irradiation.3
Although Paternò and Chieffi suggested the correct structure for the photoproduct, it was not
until 1954 that Büchi and collaborators4 reinvestigated the reaction and confirmed
unambiguously the structure proposed originally by the Italian scientists.
O
Ph
H
O
hν
+
Ph
Scheme 1.1: Paternò-Büchi reaction of benzaldehyde with 2-methyl-2-butene.
The Paternò-Büchi reaction has become familiar to chemists interested in both the
mechanistic aspects of the photochemistry and applications in modern organic synthesis.
Since the first review of the Paternò-Büchi reaction in 19685 , several reviews have been
devoted to the mechanistic aspects and also to synthetic application. 6-9
1
1. Introduction
1.1 Mechanistic studies
The light-absorbing species responsible for Paternò-Büchi cycloaddition is usually the
carbonyl addend. The long wavelength absorption band for alkanones and alkanals appears at
280-300 nm and corresponds to a weak transition (log ε∼10-20) involving excitation of a nonbonding electron on oxygen (n,π * ) (Figure 1.1).
π*
E
n
S1
S0
T1
Figure 1.1: Molecular orbital diagram and electron occupation for ground (S0 ), first excited
singlet (S1 ), and first excited triplet states (T1 ) for carbonyl compounds.
Aromatic and other simple conjugated carbonyl compounds undergo a similar n,π * transition
at 320-350 nm. Quinones and 1,2-dicarbonyl compounds absorb in the 400-500 nm range.
Absorption data for representative carbonyl compounds is collected in Table1.1.
Table 1.1: Absorption data and excitation energies for carbonyl compounds.
Carbonyl
λ max
E (S1 )
E (T1 )
compound
(nm)
(kcal/mol)
(kcal/mol)
Butanal
280
85
78
Acetone
280
85
78
Benzaldehyde
290
82
72
Benzophenone
330
75
68
Biacetyl
420
62
56
p-Benzoquinone
456
58
50
Excitation in the short wavelength bands of these carbonyl chromophores or at higher energy
is followed by rapid non-radiative decay to the lowest vibrational level of the first excited
singlet carbonyl state (S1 ) (Figure 1.2). The half occupied molecular orbitals (e.g., n and π * ),
generated on absorption of a photon, initially have paired electron spins (Figure 1.1).
However, a more stable electronic configuration is one having unpaired or parallel spins. The
2
1. Introduction
triplet excited electronic state (T1 ) is not easily accessible through direct excitation due to spin
forbidden excitation, but is generated through intersystem crossing (ISC) (Figure 1.2).
E
kISC
S1 (nπ*)
ΦISC
hν
T1 (nπ*)
-hνF
-hνp
S0
Figure 1.2: Molecular state (Jablonski) diagram for carbonyl compounds.
1.2 Mechanism of Paternò-Büchi reactions
The early step of the reaction mechanism involves the addition of the triplet excited carbonyl
compound to the alkene and the formation of a triplet 1,4-biradical. The triplet 1,4-biradical
must undergo ISC to form a singlet 1,4-biradical, which might cleave to give the starting
material or undergo carbon-carbon bond formation to give the oxetane (see Scheme 1.2).
3
1. Introduction
ISC
*
*
*
O
O
O
+
S1
+
T1
Exciplex
hν
O
O
+
S0
O
ISC
1,4-S-BR
1,4-T-BR
O
Oxetane
Scheme 1.2: Mechanism of Paternò-Büchi reactions.
It is widely accepted, that the immediate precursors of the oxetanes are biradicals 10 whose
existance has been evidenced by chemical means11 as well as by the application of picosecond
spectroscopy. 12 Two mechanisms have been proposed to explain the low-energy pathways
leading to the biradical intermediate.10,13
(1) Nucleophilic attack initiated by the half-occupied π * -orbital of the carbonyl oxygen atom
to the unoccupied π * -orbital of an electron-deficient olefin in the plane of the molecule. This
LUMO-LUMO interaction is called “parallel approach”.
(2) An electrophilic attack initiated by the half occupied n-orbital of the carbonyl oxygen
atom to the unoccupied π * -orbital of an electron rich olefin in a perpendicular direction to the
plane of the molecule. This HOMO-HOMO interaction is called a “perpendicular approach”.
Thus, the immediate precursors of these intermediates are 3 ππ * or 3 nπ * states. From their
interaction with a suitable ground state substrate, three types of intermediates can possibly be
formed:13
(a) an exciplex with the excitation localized on one of the two partners.
(b) a neutral “conventional” biradical.
(c) an ionic biradical or radical ion pair.
4
1. Introduction
π*
.
n
.
..
π*
π*
.
π
n
.
The π
..
π
O
O
n,π*
π*
n,π*
S0
The π∗
n interaction
Perpendicular approach
S0
π* interaction
Parallel approach
Figure 1.3: Orbital interactions for the n, π* addition of carbonyl compounds to alkenes.
1.3 1,n-Biradicals
Biradicals have been proposed as reaction intermediates in thermal and photochemical
reactions since many years, but only recently were trapping reactions and direct detection
reported.14 Berson15 defined biradicals as “even-electron molecules that have one bond less
than the number permitted by the standard rules of valence”. Michl16 and Bonacic-Koutecky
defined a biradical or a biradicaloid as a molecule with an even number of electrons whose
simple MO description contains two approximately nonbonding orbitals containing only two
electrons in low energy electronic states. In a perfect biradical these orbitals are degenerate
(of exactly the same energy) whereas in a biradicaloid they are only approximately
degenerate. They represent the active space in the simple model. Wirz17 reported that the
energy difference between the singlet and the triplet state of a biradical is not more than 10
kJ/mol whereas in a biradicaloid this difference could be reach to 100 kJ/mol.
1.4 Biradical generation and trapping
Biradicals can be generated by a wide range of thermal and photochemical reactions.18
Norrish type II19,
20
reaction of aryl alkyl ketones is usually used for the production of 1,4-
biradicals as well as Paternò-Büchi reactions. Furthermore, the photoenolization of o-alkylsubstituted aromatic ketones, Norrish type I21 cleavage of aliphatic carbonyl compound after
the elimination of carbon monoxide and photoinduced nitrogen loss from azo compounds22
have been employed as source of generation of biradicals. 1,4-Paternò-Büchi biradicals have
been proposed as intermediates in the cycloaddition of triplet ketones to olefins. The 1,45
1. Introduction
biradicals were trapped directly with oxygen12,23 and sulfur dioxide.24 Freilich and Peters have
detected the 1,4-biradical from benzophenone and 1,4-dioxene which was also trapped by
oxygen to give a 1,2,4-trioxane.
O
O
Ph
Ph
hν
+
O2
O
O
O
O
O
Ph
O
O
Ph
O
Ph
Ph
λ = 525 nm
τ = 1.6 ns
Scheme 1.3: Trapping of 1,4-triplet biradical with oxygen.
1.5 Lifetime of triplet 1,n-biradicals
The lifetime of triplet 1,n-biradicals is usually determined by the intersystem crossing rate
(τBR = 1/kISC). This means, that the biradical has to stay in the triplet manifold for a defined
time, because without spin flip it can not undergo bond formation or bond cleavage. These
steps would lead to triplet excited open-shell species and thus would be highly endergonic.25
Three mechanisms operate for the interaction between singlet and triplet states of 1,nbiradicals: electron-nuclear hyperfine coupling (HFC), spin-lattice relaxation (SLR), and spinorbit coupling (SOC).26 HFC is an important control factor for biradicals with long carbon
chains between the radical centers.27 SOC plays the dominant role in biradicals with shorter
distances between the radical centers, whereas SLR seems to contribute only marginally in
general. In contrast to other mechanisms, SOC is strongly dependent on the geometry of the
triplet biradical. This was first summarized in three rules stated by Salem and Rowland 28 in
1972:
(a) SOC decreases with increasing distance between the two spin-bearing atoms. Because
there is also the possibility of through-bond interaction, not only is the actual distance
between the two radical centers important (corresponding to a conformational dependence)
but also the number of bonds (n-1).
(b) Conservation of total angular momentum could be achieved when the axes of the p
orbitals at the radical centers are oriented perpendicular to each other (see Figure1.4).
6
1. Introduction
L
L
φ
S
S
R
S´
L´
S´
´L
"singlet approach"
"triplet approach"
Figure 1.4: Singlet and triplet approach.
(c) SOC is proportional to the ionic character of the singlet state.
Summarizing these three rules, a pronounced conformational and structural dependence
should result for the lifetime of triplet 1,n-biradical.
A numerical equation for SOC was given by Doubleday et al. from calculations on
trimethylene :26
SOC = B (R) Ssin Φ
where B (R) is a function of the distance R between the radical centers, Φ is the angle
between the p orbitals at these positions, andS is the overlap integral for these orbitals.
Spin-orbit coupling (SOC) controls the rate of ISC for tetramethylene, 2-oxatetramethylene or
trimethylene triplet biradicals, i.e. strong SOC enhances the intersystem crossing rate and
lowers the lifetime of triplet biradicals. A remarkable proof for these rules are the 1,3biradical lifetimes for triplet 1,3-cyclopentadiyl (I, τ = ca. 100 ns) and for bicyclo [2.2.1]
heptane-2,7-diyl (II, τ < 100 ps).29
I
τ = 100 ns
II
τ = < 0.1 ns
Figure 1.5: Conformation of 1,3-triplet biradicals.
In contrast to rather long-lived tetramethylenes (e.g., biradical III, with τ = 190 ns),18a the 2oxatetramethylenes (preoxetane) formed during the Paternò-Büchi reaction are much shorter
lived. For the triplet biradical IV from benzophenone and dioxene, a lifetime of 1.6 ns was
determined by laser flash photolysis.23
7
1. Introduction
O
Ph
O
Ph
Ph
Ph
O
III
IV
τ = 190 ns
τ = 1.6 ns
Figure 1.6: Conformation of 1,4-triplet biradicals.
In recent publications by Michl30 and Adam31 and coworkers, these rules which help to
estimate the magnitude of SOC, were modified due to new experimental and theoretical
results. The spatial orientation of the two singly occupied orbitals has been determined to be
highly important for the biradical lifetime, whereas the through-space distance between the
radical centers plays a subordinate role and the degree of ionic contribution in the
corresponding singlet state often seems to be overestimated. This clearly indicates that for
flexible 1,4-biradicals not only one conformational arrangement is responsible for facilitating
ISC, but many. After transition from the triplet to singlet potential energy surface, immediate
product formation is expected. Thus, the ISC is expected to proceed concerted with the
formation of a new bond or the cleavage of the primary formed single bond. Recently,
conformational dependence of spin-orbit coupling (SOC) in flexible Paternò-Büchi biradicals
has been studied with high-level ab initio methods by A. Kutateladze 32 for the originally
published model system 2,3-dihydrofuran and benzaldehyde. The relevant geometrical
parameters are presented in Figure 1.7. Spin-orbit coupling was mapped out as a function of
three torsional angles: α (rotation about C1-C2 bond), β (C2-O3), and γ (O3-C4), with
conformations designated as (α, β, γ). The ab initio results revealed two distinct areas of
elevated SOC values (Figure 1.7), one corresponding to the region whereby a cisoid
conformation in the C-C-O-C fragment brings the two odd-electron orbitals closer to each
other, and the other area corresponding to the partially eclipsed conformation laking direct
overlap between the spin centers.
Figure 1.7: Selected 3-D sections of the four-dimensional SOC dependence in PB diradical.
8
1. Introduction
The largest single-triplet energy gap, approximately 2 kcal/mol, was found for a gauche
conformer (also a minimum SOC conformation). This accounts for the experimental results,
i.e. high diastereoselectivity and moderate quantum yield as well as relatively short biradical
lifetimes in comparison with the tetramethylenes. The decisive role of the oxygen in the 2oxatetramethylene radical becomes apparent in the second important area from which lower
diastereoselectivity is expected.
1.6 State Selectivity : Singlet excited carbonyl compounds
Due to rapid intersystem crossing from S1 , the aromatic carbonyl compounds used for the
investigation of product stereoselectivity reflect “pure” T1 (n,π*) photochemistry.33 The
corresponding aliphatic carbonyl compounds have a kisc about 10-fold lower and therefore
they can react from S1 as well as T1 .34 Addition of triplet quenchers moderates the reactivity
pattern. Using cyclohexene as starting material and acetaldehyde as carbonyl added in the
presence and absence of a triplet quencher (1,3-pentadiene), different endo/exo ratios were
obtained. The amount of endo diastereoisomer decreased with increasing amounts of triplet
quencher. This indicates that the reaction via the triplet biradical is highly endo selective in
contrast to analogus reaction via the singlet excited acetaldehyde. Turro and Wriede35
reported that photolysis of acetone and 1-methoxy-1-butene gave two stereoisomers of the 2methoxy oxetane. The stereoselectivity of the photoaddition was dependent on the spin state
of the reacted acetone. Singlet excited acetone gave cis oxetane predominatly, whereas triplet
excited acetone gave a mixture of cis and trans oxetanes in equal ratio.
O
O
hν
+
O
+
OCH3
OCH3
OCH3
acetone T1
1
:
1
acetone S1
4
:
1
Scheme 1.4: Photocycloaddition of acetone with 1-methoxy-1-butene.
Naphthaldehydes can be used in Paternò-Büchi reactions as singlet excited carbonyl
components.36 The reaction efficiencies and chemical yields are normaly much lower
compared to other aromatic ketones or aldehydes, but chemo- and regioselectivities are often
identical. The Paternò-Büchi reaction of 2-naphthaldehyde with 2,3-dihydrofuran is a singlet
process (as shown by triplet sensitization experiments) and gives exclusively the exodiastereoisomer.
9
1. Introduction
H
O
Ar
H
O
hν
+
Ar
O
O
H
Ar =
d.r. = endo/exo
Mesityl
> 98 : 2
α-naphthyl
< 98 : 2
β-naphthyl
< 98 : 2
Scheme 1.5: Photocycloaddition of aromatic aldehydes with 2,3-dihydrofuran.
A similar example was found for the photoaddition of 2,2-bis-isopropyl-1,3-dioxolene: the
endo/exo-ratio
is
inverted
for
oxetane
formation
when
going from triplet excited
mesitaldehyde to the singlet excited naphthaldehyde as substrate.
H
O
Ar
O
O
H
hν
+
O
O
Ar
H
Ar =
d.r. = endo/exo
Mesityl
80 : 20
α-naphthyl
17 : 83
Scheme 1.6: Photocycloaddition of aromatic aldehyde with 2,2-bis-isopropyl-1,3-dioxene.
1.7 Substituent effects
Two structural features made the conformational analysis of the spin-inversion geometries of
unsubstituted cycloalkenes straightforward: the two sites of the alkene part were well
differentiated concerning the degree of substitution and steric hindrance. Methyl-substituted
cycloalkenes, however, have two ISC-reactive sites and thus, the endo/exo ratio, drops
significantly.37 The Paternò-Büchi reaction of 1,2-dimethylcyclobutene with benzaldehyde
gave solely the exo-diastereoisomer.
Ph
CH3
CH3
O
H
+
CH3
hν
76 %
Ph
O
Ph
CH3
d.r. > 98 : 2
H
O
CH3
CH3
Scheme 1.7: Photocycloaddition of benzaldehyde with 1,2-dimethylcyclobutene.
This is exactly predicted by ISC-geometry model, because the bis-methylated site of the
cycloalkene is now sterically more demanding and the biradical combination trajectory
involves the approach from the less shielded cyclobutene plane.
10
1. Introduction
Steric hindrance can also reach a critical value during bond formation and might favor the
formation of the thermodynamically stable product. Park38 and coworkers reported, that the
photocycloaddition
of
benzaldehyde
to
2,2-diethoxy-3,4-dihydro-2H-pyran
gave
preferentially the exo-phenyl product.
O
Ph
H
OEt
+
Ph
O
CO2Et
O
hν
OEt
OH
d.r. > 98 : 2
Scheme 1.8: Photocycloaddition of benzaldehyde with 2,2-diethoxy-3,4-dihydro-2H-pyran.
1.8 Photoinduced-electron transfer (PET) in the Paternò-Büchi reaction
Another feature which might oppose the ISC-geometry model is primary photoinduced
electron transfer (PET). If this process is energetically feasible, the geometric restrictions
might be circumvented, i.e. intersystem crossing can occur at the stage of the radical ion pair
and a singlet 1,4-biradical or 1,4-zwitterion can be formed depending on the reaction
conditions. In polar solvents, the assumption of a 1,4-zwitterion as decisive intermediate is
reasonable. Both regio- and diastereoselectivity are influenced by this mechanistic scenario.
The regioselectivity is now only a consequence of a maximum charge stabilization and the no
longer a consequence of the primary interaction between the excited carbonyl compound and
alkene. Whereas 3-alkoxyoxetanes are prefentially formed from triplet excited aldehydes and
enol ethers, 2-alkoxyoxetanes result from the reaction of triplet excited ketones or aldehydes
and highly electron rich ketene silylacetals.39
O
R
H
+
H3 CO
OTMS
hν
PET
R
H3CO
+ OOTMS
R
H3CO
O
OTMS
Scheme 1.9: PET control of the regioselectivity.
In the second case, PET which gives the carbonyl radical anion and the ketene acetal radical
cation is energetically feasible.40 PET might be followed by ISC and formation of a highly
stabilized 1,4-zwitterion intermediate. By processing the photocycloaddition in a highly polar
solvent which reduces the coulombic term in the Rehm-Weller equation,41 PET becomes
compatible with radical pathways. This effect was observed with 2,3-dihydrofuran as
electron-rich substrate which gave the 3-alkoxyoxetane in high (88:12) endo-selectivity when
reacted with triplet excited benzaldehyde in unpolar solvents.
11
1. Introduction
H
3
PhCHO*
O
benzene
O
O
ISC
Ph
O
Ph
O
H
3
BR
3
PHCHO*
d.r. = 88 : 12
acetonitrile
PET
3
Ph
Ph
H
Ph
H
O
O
O
O
O
-
O
+
3
CIP
H
d.r. = 90 : 10
Scheme 1.10: PET in Paternò-Büchi reaction.
In acetonitile, however, also the corresponding 2-alkoxyoxetane was detected. The relative
amount of this product correlated with solvent polarity parameters, thus indicates PET as the
responsible mechanism. The major diastereoisomer obtained from the PET-cycloaddition of
benzaldehyde with 2,3-dihydrofuran was the exo-phenyl isomer (d.r. 90 : 10).42 Thus, a switch
from 1,4-biradical to 1,4-zwitterion path leads also to an inversion of regio- and
diastereoselectivity. A mechanism which involves a sequence of PET, formation of a contact
ion pair (CIP) and charge recombination to give a triplet 1,4-biradical43 also explains the
change in regioselectivity.
Abe and coworkers44 have also observed this stereochemical effect in the Paternò-Büchi
reaction of aromatic aldehydes with cyclic ketene acetals. The addition of benzaldehyde to the
5-silyloxy-substituted 2,3-dihydrofuran resulted in the exo-phenyl product in low yield.
Ph
O
Ph
H
hν
+
O
OTMS
O
O
OTMS
Scheme 1.11: Photocycloaddition of cyclic enolether with benzaldehyde.
Kulkarni and coworkers reported the photocycloaddition of benzaldehyde with 2,3dialkylated ascorbic acid acetonides result in the formation of two regioisomeric products.45
Both oxetanes were formed exclusively with exo-phenyl configuration. The observed regioand diastereoselectivity are in accord with the assumption of a PET process involving the
oxidation of the ascorbic derivatives and the formation of the carbonyl radical anions. In these
special cases, the 1,4-biradical and 1,4-zwitterion stabilization result in the same product
regioselectivity. The relative configuration of the products favors the assumption of a PET
process.
12
1. Introduction
O
O RO
OR
O RO
Ph
O
Ph
H
O
hν
O
+
O
O
OR
H
H
O
O
O
+
O
OR
Ph
OR
H
O
O
O
3:1
R = Me, Bu
Scheme 1.12: Photocycloaddition of benzaldehyde with 2,3-dialkylated ascorbic acid
acetonides.
1.9 Regioselectivity of Paternò-Büchi reactions
The Paternò-Büchi reaction is a powerful synthetic tool because it can be applied to a wide of
alkenes and carbonyl compounds. However, the application of the reaction is greatly limited
because the normal regioselectivity does not always satisfy the synthetic requirement. In
general, the regioselectivity of the Paternò-Büchi reaction is controlled by the substituents on
the alkenes and the type of carbonyl compound involved. The photoaddition of benzophenone
to isobutene46 gave two regioisomer in 90 : 10 ratio with preference of the oxetane that results
from the most stable biradical intermediate.
O
Ph
Ph
+
O
hν
O
+ Ph
Ph
Ph
Ph
stable
less stable
O
O
+
Ph
Ph
90 : 10
Ph
Ph
Scheme 1.13: Regioselectivity of Paternò-Büchi reaction.
This rule holds relatively weak if cycloadditions involving a pronounced degree of charge
transfer are also considered (for example, photoreactions of biacetyl). In addition,
photoreactions of aliphatic ketones and electron-deficient alkenes often lead to high yields of
2,4-disubstituted oxetanes. The photocycloaddition of acetone to 2-methyl propenenitrile give
only one regioisomer.47 The mechanism proposed for singlet addition of acetone to alkene
involves formation of an exciplex with a certain degree of charge transfer.48 These results
were rationalized in terms of a Michael addition of the electronically excited carbonyl
compound (umpolung) to acrylonitrile.6
13
1. Introduction
O
+
CN
O
CN
O -
hν
+
O
CN
CN
δ+
δExciplex
41 %
Scheme 1.14: Regioselectivity of Paternò-Büchi reaction with electron -poor alkenes.
1.10 Diastereoselectivity in the Paternò-Büchi reaction
Simple (non-induced) diastereoselectivity in general describes a selection process where two
stereogenic elements (or more) are generated in a chemical process without stereogenic
elements present already in the starting materials, whereas induced diastereoselectivity
describes a selection process where stereogenic elements are generated in a chemical process
from substrates with at least one stereogenic elements already present. Thus, in case of
Paternò-Büchi reactions, the combination of two prostereogenic substrate molecules leads to a
photoadduct with a maximum of three new stereogenic centers.
1.10.1 Simple diastereoselectivity
1.10.1.1 Paternò-Büchi reactions with 2,3-dihydrofuran and furan
The simple diastereoselectivity of Paternò-Büchi reaction of 2,3-dihydrofuran and furan with
prochiral carbonyl compounds was intensively investigated by Griesbeck and coworkers.49
They found that the [2+2] photocycloaddition of 2,3-dihydrofuran with different aliphatic
aldehydes in nonpolar solvent gave oxetanes with high regioselectivty and surprising simple
diastereoselectivities. The dihydrofuran addition to acetaldehyde resulted in a 45 : 55 mixture
of endo and exo diastereoisomer. With increasing size of the α-carbonyl substituted (Me-EtBui-But ), the simple diastereoselectivity increased with preferential formation of the endo
stereoisomer.
H
O
R
H
+
O
H
O
hν
benzene
O
O
R
H
R=
Me
Et
i-Bu
t-Bu
+
O
R
H
d.r. = endo/exo
45 : 55
58 : 42
67 : 33
91 : 9
Scheme 1.15: Photocycloaddition of aliphatic aldehydes with 2,3-dihydrofuran.
14
1. Introduction
The benzaldehyde addition, which was most intensively investigated gave a 88 : 12 mixture
of endo and exo diastereoisomers in benzene solution. Thus, the thermodynamically less
stable stereoisomers (> 1.5 kcal/mol, ab initio calculation) were formed preferentially. To
further enlarge the phenyl substituent, o-tolyl and mesitaldehyde as well as 2,4-di-tert-butyl6-methylbenzaldehyde were used and actually the diastereoselectivity did further increase.50
H
O
Ar
H
+
O
H
O
hν
benzene
O
+
Ar
O
O
H
Ar
H
Ar = d.r. = endo/exo
Ph
88 : 12
o-Tol.
92 : 8
Mes.
> 98 : 2
2,4-di-t-Bu- > 98 : 2
6-Me-Ph
Scheme 1.16: Photocycloaddition of aromatic aldehydes with 2,3-dihydrofuran.
The formation of the endo isomers can be rationalized on the basic of spin-orbit coupling
controlled geometies of the triplet 1,4-biradical.51 The conformer A and B are expected to be
similarly populated; however, ISC from A results in product formation, whereas ISC from B
leads to cleavage of the singlet biradical and formation of the starting material. Spin inversion
is coupled with a torque, which in the case of conformers A and C leads to an immediate
formation of the new C-C bond. Thus, the torque induced in conformer A rotates the large
substituent (R) over the plane and results in formation of the endo diastereoisomer. From
conformer C, preferentially the exo diastereoisomeric product is formed.
R
O
3
RCHO
O
*
H
O
H
O
O
R
H
R
H
R
O
O
O
O
H
A
R
H
ISC
endo
H
O
O
H
B
H
ISC
cleavage
C
ISC
exo
Figure 1.8: Model for endo-selective formation of oxetanes derived from 2,3-dihydrofuran.
The photocycloaddition of furan with aromatic and aliphatic aldehydes processed with
unusual high exo-diastereoselectivity to give the bicyclic oxetanes in good yield. The
diastereoselectivities (exo/endo) of the Paternò-Büchi reaction of furan with acetaldehyde,
15
1. Introduction
propionaldehyde and benzaldehyde were 19 : 1, 82 : 1 and 212 : 1, respectively. Surprisingly,
the exchange of the hydrogen in benzaldehyde by a methoxy group completely inverts the
diastereoselectivity in the photocycloaddition with furan. Further modification of the αsubstituent in the benzoyl substrates uncovered a distinct dependence of the exo/endo -ratio on
the size of this substituent. The photocycloaddition of acetophenone with furan gave only one
product, whereas a 77 : 23 mixture of diastereoisomers resulted from the addition of benzoyl
cyanide. Increasing the size of the aryl group from phenyl to mesityl in aroyl cyanides led to
an increase in exo-diastereoselectivity from 3.7 : 1 up to 16 : 1.42
H
O
1
R
R
2
R1
hν
benzene
+
O
O
O
1
2
R2
H
d.r. = exo-R1/endo-R1
R =
R =
Ph
H
212 : 1
Ph
Me
> 49 : 1
Ph
CN
3.7 : 1
Ph
CO 2Me
1:9
Ph
OMe
1 : 19
Mes
CN
t-Bu
CO 2Me
16 : 1
< 1 : 49
Scheme 1.17: Paternò-Büchi reaction of furan.
As already described for the dihydrofuran case, ISC from conformer A and C are expected to
lead to endo and exo diastereoisomer, respectively. An alternative explaination for the high
exo-selectivity in the furan-aldehyde photocycloaddition could be an enlarged lifetime of the
singlet
1,4-biradical
which
is
formed
after
ISC.
However,
this
concept
predicts
thermodynamic control for the formation of all cycloaddition products, whether, they are
formed from triplet excited aldehydes or ketones, ester, etc. In addition to that, an interaction
between the allylic and the exocyclic radical in the 1,4-biradical (as depicted in strucure C)
must be crucial for the dominance of this biradical geometry for rapid ISC. This effect can be
described as secondary orbital interaction which facilitates intersystem crossing by means of
an increase in spin-orbit coupling.
16
1. Introduction
R
O
O
3
RCHO
*
O
H
H
O
O
R
H
R
O
H
O
O
O
R
H
H
ISC
A
O
R
O
H
H
H
ISC
B
cleavage
endo
ISC
C
exo
Figure 1.9: Model for exo- selective formation of oxetanes derived from furan.
1.10.1.2 Paternò-Büchi reactions with enamines
In the last decade, there were many report on the reaction of acyclic olefins with asymmetric
carbonyl compounds which procceed with high simple diastereoselectivity. Bach52 and
coworkers investigated the photocycloaddition of N-acyl enamine with benzaldehyde and
noticed
that
the
reaction
proceeds
with
excellent
regioselectivity
and
good
diastereoselectivity. Also, the thermodynamically less stable cis isomer prevailed similar to
the endo selectivity in the case of 2,3-dihydrofuran.
O
Ph
H
O
O
hν
R CH CN
3
N
Ph
+
O
N
R
+
Ph
R
O
O
R=
H
Bn
Pr
N
d.r. = cis/trans
79 : 21
89 : 11
> 90 : 10
Scheme 1.18: Photocycloaddition of benzaldehyde with enamide.
Recently, Bach and coworker reported, that the photocycloaddition of α-alkyl-substituted ene
carbamates to benzaldehyde afforded 3-aminooxetanes in moderate to good yields (46-71%).
An increase in the steric bulk of the alkyl substituent R shifted the diastereomeric ratio
cis/trans in the direction of the thermodynamically less stable cis-product (29 : 71 for R =
Me) up to (57 : 43 for R = cyclohexyl).53
17
1. Introduction
O
+
Ph
R
H
O
O
hν
BOC CH C N
3
N
Ph
N
BOC
+
BOC
Ph
R
R
Bn
Bn
Bn
R=
Me
Et
i-Pr
Ch x
H
N
d.r. = cis/trans
29 : 71
34 : 66
54 : 46
57 : 43
87 : 13
Scheme 1.19: Photocycloaddition of benzaldehyde with enamide.
1.10.1.3 Paternò-Büchi reactions with acyclic enol ether
Alkenes with moderate oxidation potentials were investigated by the Bach group in the last
decade.54 They have intensively studied the complex stereoselectivity of the Paternò-Büchi
reaction of acyclic trialkyl silylenol ethers with aromatic aldehydes and developed an
impressive set of synthetic applications.55 A series of photocycloaddition reactions of
benzaldehyde to trimethylsilyl (TMS) enol ethers showed a stereoselectivity trend which at
the first sight was in contradiction to the rules described above, i.e. the thermodynamically
more stable trans steroisomers (with respect to the C-substituent at C-2 and C-3) were formed
preferentially and the trans/cis ratio increases with increasing size of the C-3 substituent.
O
+
Ph
H
R
OTMS
O
O
hν
benzene
+
Ph
OTMS
Ph
R
R=
Me
Et
i-Pr
t-Bu
Ph
R
OTM S
d.r. = cis/trans
30 : 70
17 : 83
12 : 88
9 : 91
8 : 92
Scheme 1.20: Paternò-Büchi reactions of benzaldehyde with silylenol ether.
The stereoselectivity might in these cases be attributed to a memory effect from the approach
geometry between the triplet excited benzaldehyde and the alkene as depicted in Figure 1.10.
18
1. Introduction
Ph
O
Ph
O
H
OTMS
R
OTMS
H
R
ISC
ISC
O
O
R
Ph
R
Ph
OTMS
OTMS
trans
cis
Figure 1.10: Mechanistic scenario for the formation of cis and trans oxetanes.
Abe and coworkers have also observed this stereochemical effect in the Paternò-Büchi
reaction of p-cyanobenzaldehyde with thiosilylketene acetals.56
O
+
Ar
H
MeS
OSiR3
O
hν
CH3CN
OSiR3
Ar
Ar = p-CN-C6H4
O
+
Ar
SMe
SiR3 =
O SiR3
SMe
d.r. = cis/trans
t
SiBu Me2
20 : 80
SiMe3
18 : 82
Scheme 1.21: Photocycloaddition of ketene-O,S-acetal with p-cyanobenzaldehyde.
Abe rationalized the formation of the thermodynamically more stable trans isomer due to the
interaction between the electronically excited carbonyl and the sulfur atom, this interaction
favors the formation of conformer (A) than (B). The sulfur-derived control of trans isomer
formation is depicted in Figure 1.11.
Ar
Ar
.
O.
H
S
Me
O
or
.O
OTMS R3SiO
SMe
Ar
Ar
H
OSiR3
MeS
H
O
H
MeS
(B)
OSiR3
(A)
ISC
ISC
O
Ar
.
O
OSiR3
Ar
SMe
cis
OSiR3
SMe
trans
Figure 1.11: Sulfur control regio- and stereoselectivity.
19
1. Introduction
1.10.1.4 Paternò-Büchi reactions with cyclooctene
Recently, cyclooctene was used as an olefinic substrate in Paternò-Büchi reaction with
different carbonyl compounds. The simple diastereoselectivity was moderate. In all cases,
there were two diastereoisomers (cis and trans oxetanes) with moderate diastereomeric ratio.
Butanal,57 1,4-naphthoquinone,58 1,4-benzoquinone59 and acetone 60 were applied as the
carbonyl compounds with cis-cyclooctene. The authors rationalized the cis/trans selectivity
on the basis of the formation of triplet 1,4-biradical which has a relatively long lifetime in
order to allow rotate around C-C bond and hence led to formation of the transdiastereoisomer.
O
H , hν
O
+
O
CH 3CN
d.r.= 35 : 65
O
, hν
O
+
O
O
d.r.= 50 : 50
o
O , hν
+
benzene
O
O
O
d.r.= 75 : 25
O
O
, hν
benzene
O
O
+
O
O
d.r.= 67 : 33
Scheme 1.22: Paternò-Büchi reactions with cyclooctene.
1.10.2 Induced diastereoselectivity
There are many reviews7,8 in the literature on the induced-diastereoselectivity of the PaternòBüchi reaction using chiral reaction partners. In principle, one can induce diastereoselectivity
through using chiral carbonyl compounds or chiral olefins.
1.10.2.1 Induction by the carbonyl compound
The first report concerning an asymmetric Paternò-Büchi reaction with a chiral carbonyl
component was reported in 1979 by Gotthardt and Lenz. 61 The photocycloaddition of the
enantiomerically pure (-)-menthyl ester of phenylglyoxylic acid with 2,3-dimethyl-2-butene
gave the oxetane with a diastereomeric excess of only 37%.
20
1. Introduction
O
OR*
Ph
O
hν
benzene
+
O
+
Ph
Ph
CO2R*
CO2R*
O
R*OH =
d.r. = 76 : 24
HO
Scheme 1.23: Photocycloaddition of chiral phenylglyoxylates with tetramethylethylene.
Oppenländer and Schönholzer studied the diastereofacial differentiation in the Paternò-Büchi
reaction
using
4-(S-)-isopropyl-2-benzoyl-2-oxazoline
(prepared
from
condensation
of
phenylglyoxylic acid with (S)-valinol) as a chiral auxiliary.62 The [2+2] photocycloaddition
gave a mixture of diastereoisomeric l-and u-oxetanes with equal amounts.
O
O
Ph
O
hν
benzene
+
N
O
+
Ph
N
Ph
N
O
O
u-oxetane
l-oxetane
d.r. = 50 : 50
Scheme 1.24: Paternò-Büchi reaction of a benzoyloxazoline with tetramethylethylene.
The unique behavior of chiral phenyl glyoxylates was demonstrated by Scharf and
coworkers.63 Despite the fact that in all cases the stereogenic centers are localized in the
alcohol part of the α-keto ester and therefore remarkably far away from the reactive triplet
excited carbonyl group, the induced diastereoselectivities were exceedingly high, e.g. >98%,
in the photocycloaddition of 1,3-dioxole with 8-phenylmenthol as the the chiral auxiliary.
H
O
O
OR*
Ph
+
hν
benzene
O
O
O
O
Ph
O
H
CO2R*
d.r. = >98 : 2
R*OH =
Ph
HO
Scheme 1.25: Asymmetric induction in Paternò-Büchi reaction.
1.10.2.2 Induction by the alkene component
The induced diastereoselectivity in the Paternò- Büchi reaction using stereogenic center in the
olefin was recently investigated by Bach and coworkers in the photocycloaddition for chiral
silylenolethers with benzaldehyde.64 The substituent RL at the stereogenic center attached to
21
1. Introduction
the γ-position of the silyl enolether were varied in order to evaluate the influence of steric
bulk and electronic effect. In accordance with the 1,3-allylic strain model65 the facial
diastereoselectivity was best with large (RL = t-Bu, SiMe2 Ph) and polar (RL = OMe)
substituents at the γ-position of the silyl enolether (d.r. up to 95 : 5).
H
O
R
hν
benzene Ph
OTMS
+
Ph
H
But
H
O
R
t
Bu
O
+
R
t
Bu
Ph
OTMS
OTMS
a
b
R=
Et
i-Pr
Ph
t-Bu
d.r. (a : b)
61 : 39
70 : 30
71 : 29
95 : 5
Scheme 1.26: Photocycloaddition of benzaldehyde with silylenol ether.
Several efforts, made by Bach and coworkers to apply chiral auxiliaries in N-acyl enamines
that facilitated a facial differentiation in 1,4-biradical intermediate, failed. In all cases, they
obtained a racemic mixture of oxetanes with moderate diastereoselectivity.66
O
R
+
Ph
H
O
hν
R
CH 3CN Ph
N
N
R
Ph
N
O
O
O
O
+
O
O
(a)
(b)
R=
Ph
Bn
O
d.r. (a : b)
65 : 35
19 : 81
Scheme 1.27: Photocycloaddition of benzaldehyde with a chiral enamide.
Moreover,
the
photocycloaddition
of
axially
chiral
racemic
N-acyl
enamine
67
benzaldehyde yielded predominantly oxetanes with moderate diastereomeric excess.
O
O
O
+
Ph
H
hν
N
CH 3CN
Ph
N
O
de. 62 %
Scheme 1.28: Photocycloaddition of benzaldehyde with chiral acylenamine.
22
with
1. Introduction
1.11 Effect of temperature on the diastereoselectivity of Paternò-Büchi reactions
The temperature dependence of the auxiliary-induced diastereoselectivity was intensively
studied by Scharf group.68 In the Paternò-Büchi reaction of the chiral phenylglyoxylates with
electron-rich cycloalkenes, the diastereomeric oxetanes are formed endo-phenyl selective in
high chemical yields. Scharf et al. observed a striking temperature dependence of the facial
selectivity which resembled the isoselectivity reactions investigated by Giese69 in carbene and
simple radical reactions. In addition to isoselectivity points, however, inversion temperatures
were discovered at which the influence of the reaction temperature on the degree of
stereoselectivity was inverted.
H
O
O
OR*
Ph
+
O
hν
benzene
O
O
H
O
Ph
H CO2R*
Oxetane A
R*OH =
HO
O
Ph
, HO
+
O
O
O
Ph
H CO2R*
Oxetane B
Ph
, HO
Scheme 1.29: Photocycloaddition of chiral phenylglyoxylates with 2,2-dimethyl-1,3-dioxole.
A straightforward mechanistic interpretation of this phenomenon in Paternò-Büchi reaction is
the assumption of a two-stage process with one stage predominately determined by the
activation entropy term and the other by the activation enthalpy. At the inversion temperature,
the selectivity determining step changes from entropy to enthalpy determined and thus also
the temperature/selectivity behavoir. No inversion temperatures were detected for simple
diastereoselectivity. Actually, the diastereoselectivity of the second bond formation is more
than 98% in all cases investigated by Scharf et al. This clearly results from a process at stage
(2) that can not be influenced by temperature effects on stage (1). From the analysis of simple
and induced diastereoselectivities, as well as from the temperature dependence of the facial
diastereoselectivity, a reaction mechanism results which described the origin of product
stereochemistry as a subtle combination of facial approach, biradical conformational
equilibration, retrocleavage, and C-C bond formation. A simple kinetic picture for this
scenario is shown in scheme 1.30. The endo/exo (simple) selectivity (endo-Ph selectivity)
results from the last step in the reaction sequence, i.e., after spin-inversion from several
possible biradical conformers, the exo- and endo-diastereoisomers (with already determined
facial selectivity) are formed in competition with C-O bond cleavage. Whether or not singlet
biradicals are involved in this process is still an open question. In any case, the lifetimes for
these species are expected to be extremely short, and bond rotations cannot compete with C-C
23
1. Introduction
bond formation or C-O bond cleavage. Thus, the simple diastereoselectivity maps the ISC
geometry for the triplet 1,4-biradicals.
O
O
+
O
hν
OR*
Ph
Ph
O
O
COOR*
+
O
O
O
O
Ph
Oxetane A
Ph
O
O
O
O
COOR*
Oxetane B
COOR*
Oxetane A
O
Starting materials
O
O
O
Oxetane B
COOR*
O
Ph
2. Selection Stage
1. Selection stage
Scheme 1.30: The two-stage model for the Paternò-Büchi reaction.
Recently, Adam and coworker investigated the Paternò-Büchi reaction of cis-cyclooctene as
well as trans-cyclooctene with triplet carbonyl partners.70 They reported an unprecedent
temperature-dependent diastereoselectivity in the [2+2] photocycloaddition of benzophenone
with cis and trans cyclooctenes. They document the unusual case, that the lower-energy
substrate diastereoisomer (cis-cyclooctene) affords, with increasing temperature the higherenergy product diastereoisomer (trans-oxetane). These unprecedented experimental facts on
the [2+2] photocycloaddition of the diastereomeric cyclooctenes with benzophenone were
rationalized in terms of a consistent mechanism: (i) The cis-cyclooctene displays a remarkable
temperature dependence, in that the trans-oxetane is favored with increasing temperature; (ii)
for trans-cyclooctene, the trans geometry is preserved in trans-oxetane cycloadduct over a
broad temperature range of 180 °C; (iii) the extent of trans to cis isomerisation in the
cycloaddition with trans-cyclooctene increase with temperature.
24
1. Introduction
O
Ph
hν
Ph
O
hν
O
Ph
Ph
Ph
Ph
T °C
-95
-20
100
d.r. (cis : trans)
98 : 2
45 : 55
20 : 80
Scheme 1.31: Paternò-Büchi reaction of benzophenone with cis- and trans-cyclooctenes.
1.12 Effect of hydroxy groups on the stereoselectivity of Paternò-Büchi reactions
The first study of the effect of the hydroxy group on the Paternò-Büchi reaction of substituted
norbornene with biacetyl was reported by Sauers and coworker.71 The addition of biacetyl to
norbornene is highly exo selective, whereas the syn-7-tert-butyl derivative showed inverted
exo-selectivity. Introduction of a hydroxy group at the 7-syn-position of norbornene reinverts
the diastereoselectivity: in this case, the exo-adduct is formed with de >97%. The later effect
could be due to the hydrogen bonding forces between the hydroxy function and the electronrich π* system orient the reactive species on the exo-face of the molecule.
O
H
+
H
R
hν
benzene
R
H
O
O
R
+
O
O
R=
H
t-Bu
OH
d.r. (exo : endo)
>96 : 4
<3 : 97
>97 : 3
O
Scheme 1.32: Photocycloaddition of norbornene with biacetyl.
The Paternò-Büchi reaction between 2-furylmethanol derivatives and benzophenone was
recently reported by DÀuria and coworkers.72 They explained the regio- and stereoselectivity
of the reaction by assuming a controlling function of both the substituent on the 2furylmethanol derivatives and the hydroxy group in order to favor the approach of the
carbonyl group towards a prochiral face of the furan. They have also reported that no
photoadduct was obtained when the hydroxy group is protected by alkylation.
25
1. Introduction
Ph
O
R
+
Ph
Ph
O
Ph
hν
benzene
O
O
OH
OH
R
small d.r. for
R = Et, i-Pr
Scheme 1.33: Photocycloaddition of 2-furylmethanols with benzophenone.
More recently, Adam reported that hydrogen bonding directed regio and diastereoselectivity
of the [2+2] photocycloaddition of benzophenone to chiral allylic alcohols.73 The PaternòBüchi reaction of electronically excited benzophenone with chiral allylic alcohols afforded
only one regioisomer of the diastereomeric threo, erythro-oxetanes. Hydrogen bonding
between the allylic alcohol and the incoming triplet excited benzophenone as an attractive
interaction
accounts
for
the
marked
regio-
and
the
threo-diastereoselectivity.
The
diastereoselectivity was reduced in the presence of protic solvents (due to competition
intermolecular hydrogen bonding) and disappeared when the hydroxy group is protected by
silyl ether which can not serve as hydrogen-bonding donor.
OX
O
Ph
OX
OX
O
hν
benzene Ph
+
Ph
Ph
Ph
X=
Solvent
H
C6D 6
H
O
+
Ph
d.r. (threo : erythro)
C6D 6/CD3COD (1:1)
t
SiMe Bu C6D6
90 : 10
69 : 31
52 : 48
Scheme 1.34: Paternò-Büchi reaction of allylic alcohols with benzophenone.
1.13 Synthetic applications of the Paternò-Büchi reaction
Kubota and coworkers found that irradiation of propanal in the presence of 1,3cyclohexadiene produced the corresponding oxetanes in a 4:1 ratio.74 These adduct were
thought to occur via an attack of the first excited singlet state of propanal to the diene. The
synthesis of (E)-6-nonen-1-ol, a component of the sex pheromone of the Mediterranean fruit
fly, applied this process as the first step.75 Hydrogenation and metal catalyzed [2+2]
cycloreversion gave aldehyde, which then was easily converted to the target molecule by
reduction.
26
1. Introduction
H
H
O
hν
EtC HO
O
+
Et
H
Et
H
4 :1
H
1. H2, PtO2(EtOH)
O
Et
H
H
2. [Rh (CO) 2Cl]2
O
LiAlH4
OH
Scheme 1.35: Synthesis of (E)-6-nonen-1-ol.
Schreiber and coworkers have used the photocycloadduct of furan and carbonyl compound as
the key intermediate for the synthesis of complex molecules.76 Schreiber was the first to
recognize that the bicyclic adducts formed in these reactions could be unmasked under acidic
conditions to afford threo aldol products of 1,4-dicarbonyl compounds. This strategy has been
exploited in the synthesis of a variety of novel natural products.
hν
R
O
R
1
R CHO
OH
R1
H
H
O
R
O
R= H, alkyl, aryl, R3Sn
R
R1
O
R
O
R
R1= alkyl
Scheme 1.36: Synthesis of threo β-hydroxy ketone.
An application of this strategy is the synthesis of the antifungal metabolite (±)-avenaciolide,77
shown in Scheme 1.37. The photoadduct was hydrogenated and hydrolyzed to give the
aldehyde. Reaction of the aldehyde with vinyl magnesium bromide and subsequent
manipulation afforded another aldehyde, which could be transformed via ozonolysis,
epimerization of the dialdehyde and acidification of the dialdehyde acetonide to a protected
bis-lactol. Oxidation and methylenation then afforded the desired target.
27
1. Introduction
H
C8H17
hν
O
C8H17CHO
O
O
HO
OH
H
CHO
C8H17
C8H17
O
O
O
O
C8H17
1. H 2
2. H +
H3CO
O
O
C8H17
OHC
O
O
OCH3
Scheme 1.37: Synthesis of (±)-avenaciolide.
Scharf and coworkers have explored the 2,3-dihydrooxazole-carbonyl photocycloaddition for
asymmetric synthesis. Irradiation of chiral α-keto ester with 2,2-dimethyl-3-N-acetyl-2,3dihydrooxazole gave two regioisomeric oxetanes which under solvolysis yield erythro sugars
and erythro α-amino carbohydrates.78
O
O R*
Ph
O
O
+
O
hν
N
Ac
Ph
O
N
CO2R* Ac
+
O
Ph
Ac
N
O
CO2R*
R* = (-)-8-phenyl-menthyl
H
O
H
O
H
Ph
NH2
OH
H
Ph
OH
OH
O
OR*
O
OR*
Scheme 1.38: Synthesis of erythro sugars and erythro α-amino carbohydrates.
Recent investigations from the Bach group were focused on enamides as substrates. The
resulting 3-aminooxetanes were used for the synthesis of chiral 1,2-aminoalcohols.79 The
photocycloaddition of N-vinyl formamide and benzaldehyde gave 3-aminooxetane, which
was converted to pseudoephedrine in a single step by treatment with LiAlH4 .
O
hν
NHCHO PhC HO Ph
OH
NHCHO
LiAlH4
86 %
Ph
NHCH3
Scheme 1.39: Synthesis of pseudoephedrine.
Bach and coworkers have been also developed the total synthesis of the antifungal agent (±)preussin via the photocycloaddition of benzaldehyde with 2,3-dihydropyrrole. The ring
28
1. Introduction
opening of the photoadduct gave a hydroxypyrrolidine which after hydrogenolysis gave the
enantiomerically pure target molecule (+)-preussin.80
H
N
C9H19
H
O
hν
PhCHO
C9H19
+
N
H CO CH
2
3
Ph
H3CO2C
O
Ph
53 %
C9H19
N
H
CO2CH3
12 %
H 2 [Pd (OH) 2]
(MeOH)
91 %
HO
C9H19
N
CO2CH3
Ph
LiAlH4
(THF)
91 %
HO
Ph
N
Scheme 1.40: Synthesis of (+)-preussin.
Recently, Griesbeck and Fiege published the photocycloaddition of an oxazole to carbonyl
compounds as a convenient route for the synthesis of erythro α-amino-β-hydroxy ketones.
Irradiation of 2,4,5-trimethyloxazole with benzaldehyde gave the bicyclic oxetane with highly
exo-diastereoselectivity. The bicyclic oxetane is highly sensitive to hydrolysis and underwent
twofold ring opening to give erythro- α-acetamido-β-hydroxy ketone.81
H
N
CH3
hν
O
CH 3
O
H3C
H
H3C
N
O
Ph
O
CH3
H+/H2O
CH3
Ph
Scheme 1.41: Synthesis of erythro α-acetamido-β-hydroxy ketone.
29
HO
AcHN
Ph
CH3
COCH3
2. Projected work
___________________________________________________________________________
2. Projected work
To the best of our knowledge, there was no detailed investigation on the connection between
spin state and stereoselectivity in [2+2]-photocycloadditions. At first, I decided to study the
concentration dependence of the simple diastereoselectivity of the Paternò-Büchi reaction of
electron-rich cycloalkenes with aliphatic as well as aromatic aldehydes in order to evaluate
the difference of stereoselectivity between singlet and triplet photoreaction. In addition, I
proposed to investigate the effect of solvent polarity as well as solvent viscosity on the spinselectivity of the photocycloaddition reaction of 2,3-dihydrofuran with aldehydes. The
unusual
nonlinear
temperature
dependence
of
the
stereoselectivity
of
Paternò-Büchi
photocycloadditions of electron-rich cycloalkenes with chiral phenylglyoxylates served as the
basis for the development of the isoinversion principle by Scharf and coworkers.68 The
influence of the excited-state spin multiplicity was not observed in these studies because
substrates with high ISC rates were used and thus exclusive bimolecular triplet reactions were
expected.82 Thus, I intended to study the effect of temperature on simple diastereoselectivity
in the singlet and the triplet photocycloaddition reaction of 2,3-dihydrofuran with aldehydes.
O
R
R
H
+
R= Ph, Me,
Et, Bu i
O
hν
+
O
O
O
R
O
Effect of concentration on d.r. ?
Effect of solvent viscosity on d.r. ?
Effect of temperature on d.r. ?
In the light of recent research activities in the field of enantioselective cyclooctene
photoisomerisation83 and diastereoselective photocycloaddition, 70 I became interested in spindirected effects on both the addition of electronically excited carbonyl compounds and the
photoisomerisation process of cyclooctene. In a previous study by Jones et al., it was shown
that the stereoselectivity of the Paternò-Büchi reaction with cis-cyclooctene is indeed
influenced by the substrate concentration, but no further conclusions were drawn concerning
the mechanism of the spin-inversion process from the triplet 1,4-biradical.57 Triplet excited
aliphatic aldehydes with ET
in the 80 kcal/mol range are capable of cis-trans
photoisomerisation of cyclooctenes wheras the singlets have energies that are too low for
singlet-singlet energy transfer. It was thus of interest to study whether aliphatic aldehydes
show spin-selectivity with respect to the cis/trans oxetane ratio and/or the endo/exo-selectivity
relevant for the cis-photoadduct.
30
2. Projected work
___________________________________________________________________________
O
R
H
H
O
H
hν
(Z)
cc
R= Me, Et
O
+
R
H
tc
O
H
O
+
R
H
tt
R
hν
R
H
H
R= Me, Et
(E)
Effect of concentration on d.r. ?
Do Z-E-isomerisation influence on d.r. ?
The concept of hydrogen-bonding as a tool for directing photochemical reactions has been
reported for intermolecular [2+2] and [4+2] cycloadditions.73,84 However, there was yet no
conclusion about the effect of hydrogen bonding on the excited singlet and triplet states. I
investigated the Paternò-Büchi reaction of allylic alcohols and acetates with aldehydes to test
the influence of hydrogen bonding on the excited singlet and triplet state. The study addressed
the following questions:
(a) is there a specific spin-directing effect connected with hydrogen bonding?,
(b) do hydrogen-bonding interactions influence induced as well as non-induced “simple”
diastereoselectivity?,
(c) does hydrogen-bonding effect the rate of the Paternò-Büchi reaction?
OR2
O
R
+
H
hν
benzene
R1
OR2
OR2
R1
O
+
R1
O
R
R
R= Ph, Me,
1
Et, Bu i
R = H, CH 3
degree of regioselectivity ?
R2= H, Ac
degree of diastereoselectivity ?
In a second part, I studied synthetic applications of the Paternò-Büchi reaction of aldehydes
and α-ketoesters with oxazoles, a reaction which has been developed in this research group in
the last years. A series of interesting starting materials from the chiral pool of amino acids
should be synthesized and transformed photochemically into bicyclic oxetanes. The
selectivity of these reactions and further transformations of these highly interesting and
reactive products were to be investigated in order to examplify the importance of this
synthetic pathway.
O
R1
R
H2N
1
N
R
CO2 H
H3C
O
H
OCH3
H3C
hν
R1 = H, Me, Et, n-Pr, i-Pr, i-Bu, sec-Bu
N
O
H
O
R
R
1
HO
H / H2O
OCH3
Diastereoselectivity ?
31
Ac HN
R
R1
CO2CH3
Diastereoselectivity ?
3. Results & Discussion
3. Results and Discussion
3.1 Effect of concentration on simple diastereoselectivity of Paternò-Büchi reactions
In order to evaluate the differences in simple diastereoselectivity of the Paternò-Büchi
reaction in the singlet versus the triplet channel, the concentration dependence of the [2+2]
photocycloaddition of aldehydes with electron-rich cycloalkenes was investigated. As alkene
reagents, 2,3-dihydrofuran, 2,3-dihydropyran, cyclopentene, 5-methyl-2,3-dihydrofuran, 2,2dimethyl-2,3-dihydrofuran and furan were used. As aliphatic aldehydes I used acetaldehyde,
propionaldehyde,
3-methylbutyraldehyde, pivalaldehyde, 3-phenylpropionaldehyde and 2-
methylbutyraldehyde. Benzaldehyde was applied as an aromatic aldehyde.
3.1.1 Photocycloaddition of 2,3-dihydrofuran
3.1.1.1 Reaction with benzaldehyde
It is well known that aromatic aldehydes exhibit high intersystem crossing rates and quantum
yields and thus exclusively react via their first excited triplet states in intermolecular
photocycloaddition. 37,49 On irradiation of a benzene solution of benzaldehyde 1a and 2,3dihydrofuran 2, two cycloadducts exo-3a and endo-3b were formed in a 12 : 88 ratio with
high yield.
H
O
Ph
H
1a
+
O
H
O
hν
benzene
O
Ph
O
2
H
+
Ph
O
exo-3a
H
endo-3a
Scheme 3.1: Photocycloaddition of benzaldehyde with 2,3-dihydrofuran.
Both substrates (1a and 2) were applied in a 1:1 ratio over a broad concentration range,
showing no significant effect on the simple (endo/exo) diastereoselectivity (see Figure 3.1)
32
100
endo-selectivity (%)
95
90
85
80
benzaldehyde+
2,3-dihydrofuran
75
0,01
0,1
1
log [2,3-dihydrofuran]
Figure
3.1:
Concentration/selectivity
profile
of
the
benzaldehyde/2,3-dihydrofuran
photocycloaddition.
The relative configuration of the diastereoisomers exo-3a and endo-3a were deduced from
their 1 H-NMR spectra on the basis of the aromatic ring current effect by the phenyl group. H5 in the exo-diastereoisomer absorbs at higher field (4.64 ppm) compared with the endoisomer (5.05 ppm) due to the shielding effect of the benzene ring (see Table 3.1).
Table 3.1: Chemical shift (δ ppm ) of H-1, H-5 and H-7 for exo-3a and endo-3a.
H
5 O
1 7
O
Ph
H
endo-3a
Compound
H-1
H-5
H-7
exo-3a
5.50
4.64
5.41
endo-3a
5.51
5.05
5.80
3.1.1.2 Reaction with acetaldehyde
The lifetimes of the first excited singlet state of aliphatic aldehydes are in the 1-2 ns range.85
Thus, appropriate trapping reagents can intercept these singlets in diffusion-controlled
bimolecular
processes.
The
addition
of
2,3-dihydrofuran
to
electronically
excited
acetaldehyde in benzene at a wide range of substrate concentrations afforded two
diastereoisomers exo-3b and endo-3b. The diastereomeric ratios were determined by GC and
NMR analyses.
33
H
O
H
hν
benzene
+
O
O
+
O
2
1b
H
O
O
H
H
endo-3b
exo-3b
Scheme 3.2: Photocycloaddition of acetaldehyde with 2,3-dihydrofuran.
Figure 3.2 shows the effect of concentration variation on the endo/exo diastereoselectivity of
acetaldehyde/2,3-dihydrofuran photocycloaddition. At higher concentrations the selectivity
switched to 42 : 58 wheras at lower concentration the selectivity reached 76 : 24 with
preferential formation of the endo diastereoisomer.
80
75
endo -selectivity (%)
70
65
60
55
50
45
acetaldehyde+
2,3-dihydrofuran
40
1E-3
0,01
0,1
1
10
Figure
3.2:
profile
of
the
acetaldehyde/2,3-dihydrofuran
photocycloaddition.
3.1.1.3 Reaction with propionaldehyde
Photolysis of an equimolar ratio of propionaldehyde and 2,3-dihydrofuran in benzene solution
gave the two diastereoisomers exo-3c and endo-3c.
H
O
H
1c
+
O
H
O
hν
benzene
O
+
O
2
H
exo-3c
O
H
endo-3c
Scheme 3.3: Photocycloaddition of propionaldehyde with 2,3-dihydrofuran.
The diastereomeric ratios of the photoadducts were strongly affected by the concentration of
substrate. Figure 3.3 displays the effect of concentration variation on the endo/exo
diastereoselectivity of the propionaldehyde/2,3-dihydrofuran photocycloaddition. In the low
concentration region (< 0.02 M), the diastereoselectivity reached a plateau with an endo/exo
34
ratio of ca. 85 : 15. Likewise, in the high concentration region (>0.8M) the
diastereoselectivity become constant with ca. 1: 1 endo/exo ratio. The diastereomeric ratios
were determined by GC and 1 H-NMR analyses. Figure 3.4 shows the GC trace of the exo- and
endo-diastereoisomers of the photocycloaddition of propionaldehyde with 2,3-dihydrofuran at
different substrate concentrations. The exo-isomer has low retention time compared with the
endo-isomer.
endo
endo
90
85
exo
endo
endo -selectivity(%)
80
75
exo endo
70
exo endo
propionaldehyde +
2,3-dihydrofuran
65
endo
endo
exo
60
exo
55
exo
50
exo
45
1E-3
0,01
0,1
1
1M
Figure 3.3: Concentration/selectivity profile Figure
of
the
0.5M
3.4:
0.125M
GC
0.1M
trace
0.05M
0.01M
analysis
of
0.0025M
the
propionaldehyde/2,3-dihydrofuran propionaldehyde/2,3-dihydrofuran
photocycloaddition.
photocycloaddition.
The relative configuration of the photoadducts were established by nOe measurements. The
exo-diastereoisomer shows strong nOe enhancements between H-1 and CH3 group. This
phenomena is illustrated in Figure 3.5, which summarizes the pertinent nOe data recorded for
the diastereoisomer exo-3c. The endo-diastereoisomer did not show significant nOe
enhancements between the CH3 group and the proton H-1.
7 O
5
H 1
O
nOe
Figure 3.5: NOE interaction in bicyclic oxetane exo-3c.
Furthermore, the chemical shift of the proton H-1 is distinctly different in either pair of
bicyclic oxetane diastereoisomers exo-3c and endo-3c. It resonates at lower field in the endoisomer (δ = 4.75 ppm) and at higher field in the exo-isomer (δ = 4.51 ppm) (see Table 3.2).
35
Table 3.2: Chemical shift (δ ppm ) of H-1, H-5 and H-7 for exo-3c and endo-3c.
Compound
H-1
H-5
H-7
exo-3c
4.51
5.25
4.31
endo-3c
4.75
5.34
4.60
3.1.1.4 Reaction with 3-methylbutyraldehyde
The [2+2] photocycloaddition of electronically excited 3-methylbutryaldehyde with 2,3dihydrofuran in benzene afforded the two diastereoisomers exo-3d and endo-3d.
H
O
H
+
1d
O
H
O
hν
benzene
O
+
O
2
H
exo-3d
O
H
endo-3d
Scheme 3.4: Photocycloaddition of 3-methylbutyraldehyde with 2,3-dihydrofuran.
Analogous to acetaldehyde and propionaldehyde, the diastereomeric ratios endo/exo were
strongly influenced by the concentration of substrates. The diastereomeric ratios were
determined by using GC and
1
H-NMR analyses. Figure 3.6 shows the effect of concentration
variation on the endo/exo diastereoselectivity of the 3-methylbutyraldehyde/2,3-dihydrofuran
photocycloaddition. In the low concentration region (< 0.01M) the diastereoselectivity
reached a plateau with an endo/exo ratio of ca. 87 : 13. At high concentration the selectivity
switched to 53 : 47. The structure of the photoadducts were established using 1 H-NMR and
13
C-NMR analyses.
Figure 3.7 shows the GC trace of the exo- and endo- diastereoisomers of the
photocycloaddition of 3-methylbutyraldehyde with 2,3-dihydrofuran at different substrate
concentrations. Analogous to propionaldehyde/2,3-dihydrofuran photoadducts, the exo-isomer
has low retention time compared with the endo-isomer.
36
endo
endo
exo
90
endo
85
endo
e n d o-selectivity(%)
80
exo
75
exo
70
65
3-Methylbutraldehyde +
2,3-dihydrofuran
60
exo endo
exo
endo
55
exo
50
0,01
0,1
1
1M
0.5M
0.25M
0.05M
0.0125M
0.005M
Figure 3.6: Concentration/selectivity profile Figure 3.7: GC trace analysis of the 3of
the
3-methylbutyraldehyde/2,3- methylbutyraldehyde/2,3-dihydrofuran
dihydrofuran photocycloaddition.
photocycloaddition.
3.1.1.5 Reaction with pivalaldehyde
Pivalaldehyde,
when
irradiated
in
the
presence
of
2,3-dihydrofuran,
delivered
the
diastereoisomer exo-3e and endo-3e in moderate yield.
H
O
+
H
O
hν
benzene
O
+
O
2
1e
H
O
H
O
H
endo-3e
exo-3e
Scheme 3.5: Photocycloaddition of pivalaldehyde with 2,3-dihydrofuran.
Interestingly, the diastereomeric ratios of the photoadducts were depended only little on the
concentration of substrate (see Table 3.3).
Table 3.3: Concentration dependence on simple diastereoselectivity of the pivalaldehyde/2,3dihydrofuran photocycloaddition reaction.
Conc. (M)
d.r. (exo : endo)
1
54.1 : 45.9
0.5
51.0 : 49.0
0.125
50.0 : 50.0
37
3.1.1.6 Reaction with 3-phenylpropionaldehyde
Irradiation of a benzene solution of
equimolar amount of 2,3-dihydrofuran and 3-
phenylpropionaldehyde afforded two diastereoisomers exo-3f and endo-3f.
H
O
Ph
H
hν
benzene
+
O
O
Ph +
O
2
1f
H
O
Ph
O
H
H
endo-3f
exo-3f
Scheme 3.6: Photocycloaddition of 3-phenylpropionaldehyde with 2,3-dihydrofuran.
Figure 3.8 displays a linear correlation between the endo-selectivity and concentration, i.e. the
endo-selectivity increases with decreasing substrate concentration. The diastereomeric ratio
endo/exo at 1M was 50 : 50 and 70 : 30 at 0.125 M. The structure of the photoadducts were
identified using
1
13
H-NMR,
C-NMR and DEPT analyses. The diastereomeric ratios were
1
determined by using GC and H-NMR analyses.
endo-selectivity(%)
70
65
60
3-phenylpropionaldehyde +
2,3-dihydrofuran
55
50
1
Figure
3.8:
profile
of
the
3-phenylpropionaldehyde/2,3-
3.1.2 Photocycloaddition of 2,3-dihydropyran
Photolysis of benzaldehyde with 2,3-dihydropyran in benzene afforded two diastereoisomers
exo-5a and endo-5a in moderate yield with high regio- and stereoselectivity.
H
O
Ph
H
1a
hν
benzene
+
H
O
O
+
O
O
4
Ph
H
exo-5a
O
H
endo-5a
Scheme 3.7: Photocycloaddition of benzaldehyde with 2,3-dihydropyran.
38
Ph
The diastereomeric ratios were constant over a wide range of concentration similar to the
reaction with 2,3-dihydrofuran (see Figure 3.9). The diastereomeric ratios were determined by
using GC and NMR analyses. The strucure of the photoadducts were identified from 1 H-NMR
and 13 C-NMR analyses.
100
endo-selectivity(%)
80
benzaldehyde +
2,3-dihydropyran
60
40
20
0
0,01
0,1
1
log [2,3-dihydropyran]
Figure
3.9:
profile
of
the
benzaldehyde/2,3-dihydropyran
photocycloaddition.
The photoaddition of electronically excited acetaldehyde to 2,3-dihydropyran in benzene gave
two diastereoisomers exo-5b and endo-5b.
H
O
H
+
1b
O
H
O
hν
benzene
O
+
O
O
H
4
H
endo-5b
exo-5b
Scheme 3.8: Photocycloaddition of acetaldehyde with 2,3-dihydropyran.
The diastereomeric ratios endo/exo were substantially dependent on the concentration of
substrate. When the substrate concentration was lowered from 1 to 0.002 M, a distinct
increase in the amount of endo-diastereoisomer was obtained. Figure 3.11 shows the GC trace
of the exo- and endo-diastereoisomers of the photocycloaddition of acetaldehyde with 2,3dihydropyran
at
different
substrate
concentrations.
In
contrast
to
2,3-dihydrofuran
photocycloaddition, the endo-isomer has low retention time compared with the exo-isomer of
the 2,3-dihydropyran photocycloaddition.
39
endo
76
exo
74
72
70
acetaldehyde +
2,3-dihydropyran
68
endo
endo
exo
endo
exo
66
exo
64
0,01
0,1
1
0.1M
1M
0.01M
0.002M
Figure 3.10: Concentration/selectivity profile Figure 3.11: GC trace analysis of the
of
the
acetaldehyde/2,3-dihydropyran acetaldehyde/2,3-dihydropyran
photocycloaddition.
photocycloaddition.
Irradiation of propionaldehyde with 2,3-dihydropyran in benzene gave the bicyclic oxetanes
exo-5c and endo-5c in concentration-dependent ratios.
H
O
H
1c
O
hν
benzene
+
H
O
+
O
O
4
H
exo-5c
O
H
endo-5c
Scheme 3.9: Photocycloaddition of propionaldehyde with 2,3-dihydropyran.
In contrast to the results with 2,3-dihydrofuran, the selectivity curve was much less steeper
and showed a non-linear behavoir in the region between 1M and 0.01M (see Figure 3.12). The
diastereomeric ratios were determined by high resolution 1 H-NMR measurements of the crude
product mixtures and the structure of the products were elucidated by their 1 H-NMR and
13
C-
NMR spectral data. Figure 3.13 shows the GC trace of the exo- and endo-diastereoisomers of
the photocycloaddition of propionaldehyde with 2,3-dihydropyran at different substrate
concentrations. Analogous to acetaldehyde/2,3-dihydropyran photoadducts, the endo-isomer
has low retention time compared with the exo-isomer.
40
endo exo
80
endo
78
endo-selectivity(%)
76
74
72
70
exo
68
propionaldehyde +
2,3-dihydropyran
66
64
endo
62
exo
60
58
0,01
0,1
1
1M
0.1M
0.002M
Figure 3.12: Concentration/selectivity profile Figure 3.13: GC trace analysis of the
of
the
propionaldehyde/2,3-dihydropyran propionaldehyde/2,3-dihydropyran
photocycloaddition.
photocycloaddition.
The [2+2] cycloaddition of 3-methylbutyraldehyde with 2,3-dihydropyran afforded the two
diastereoisomers exo-5d and endo-5d .
H
O
H
1d
hν
benzene
+
H
O
O
+
O
O
H
4
exo-5d
O
H
endo-5d
Scheme 3.10: Photocycloaddition of 3-methylbutyraldehyde with 2,3-dihydropyran.
Figure 3.14 displays the effect of concentration variation on the endo/exo diastereoselectivity
of the 3-methylbutyraldehyde/2,3-dihydropyran photocycloaddition. At high concentration
(1M) the diastereomeric ratio endo/exo was moderate (60 : 40) while at low concentration
(0.002M) the endo-selectivity dominated (72 : 28).
41
72
endo-selectivity(%)
70
68
66
3-methybutyraldehyde +
2,3-dihydropyran
64
62
60
58
0,01
0,1
1
Figure 3.14: Concentration/selectivity profile of the 3-methylbutyraldehyde/2,3-dihydrofuran
photocycloaddition.
3.1.3 Photocycloaddition of cyclopentene with propionaldehyde
Cyclopentene,
when
irradiated
with
propionaldehyde
in
benzene,
gave
also
two
diastereoisomers exo-7b and endo-7b.
H
O
H
H
O
hν
benzene
+
6
1c
O
+
H
H
exo-7c
endo-7c
Scheme 3.11: Photocycloaddition of cyclopentene with propionaldehyde.
The diastereomeric endo/exo ratios were slightly depended on the substrate concentration.
62
61
endo-selectivity(%)
60
59
58
57
propionaldehyde +
cyclopentene
56
55
54
53
1
log [cyclopentene]
Figure
3.15:
profile
photocycloaddition.
42
of
the
propionaldehyde/cyclopentene
3.1.4 Photocycloaddition of 5-methyl-2,3-dihydrofuran
It was already documented that alkyl-substituted cycloalkenes react with electronically
excited
carbonyl
compounds
with
moderate
in
comparison
with
unsubstituted cycloalkenes due to the additional steric hindrance by the extra alkyl group. To
further understand this concept, the concentration effect on the stereoselectivity of the
photoaddition of 5-methyl-2,3-dihydrofuran with aldehydes was studied.
Irradiation of benzaldehyde with 5-methyl-2,3-dihydrofuran in benzene afforded two
diastereoisomers exo-9a and endo-9a.
H
O
Ph
+
H
O
hν
benzene
O
+
Ph
Ph
O
8
1a
H
O
O
endo-9a
exo-9a
Scheme 3.12: Photocycloaddition of benzaldehyde with 5-methyl-2,3-dihydrofuran.
The diastereomeric ratio endo/exo (60 : 40) was independent on the concentration of the
substrate. The diastereomeric ratios were determined using GC and 1 H-NMR analyses (see
Figure 3.17). The structure of the photoadducts were identified from 1 H-NMR and
13
C-NMR
analyses.
100
80
60
40
endo
endo
benzaldehyde +
5-methyl-2,3-dihydrofuran
20
5.60 5.59
5.58
5.57
5.56 5.55
5.54
0,1
5.66
1
5.64
5.62
5.53
5.52 5.51 5.50
(ppm)
5.49
5.48 5.47
5.46
5.45 5.44
1M
endo
0
0,01
exo
exo
5.60
5.58
5.56
(ppm)
5.43
5.42
exo
5.54
5.52
5.50
5.48
5.46
5.64
5.63
5.62
5.61
5.60
5.59
5.58
endo
5.66 5.65 5.64 5.63
5.62 5.61 5.60 5.59
0.05M
5.57
5.56 5.55 5.54
(ppm)
5.53
5.52
0.1M
5.58 5.57 5.56 5.55
(ppm)
5.51
5.50
5.49
5.48
5.47
exo
5.54 5.53 5.52
5.51 5.50 5.49 5.48
5.47 5.46
0.01M
log [5-methyl-2,3-dihydrofuran]
Figure
of the benzaldehyde/5-methyl-2,3-
benzaldehyde/5-methyl-2,3-dihydrofuran
photocycloaddition.
43
3.17:
1
Figure 3.16: Concentration/selectivity profile
H-NMR
analysis
of
the
The photocycloaddition of electronically excited acetaldehyde to 5-methyl-2,3-dihydrofuran
gave the two diastereoisomers exo-9b and endo-9b.
H
O
H
+
O
hν
benzene
O
+
O
8
1b
H
O
O
endo-9b
exo-9b
Scheme 3.13: Photocycloaddition of acetaldehyde with 5-methyl-2,3-dihydrofuran.
The diastereomeric ratios endo/exo were completely inverted when processing from high to
low concentration. At high concentration (1 M) the endo/exo selectivity was 38 : 62 and
changed to 62 : 38 at low concentration (0.025 M) (see Figure 3.19).
65
60
55
50
40
exo
endo
45
acetaldehyde +
4.70
4.68
4.66
4.64
4.62
4.60
4.58
endo
4.56
(ppm)
4.54
4.52
4.50
4.48
4.46
4.44
46.6
46.4
exo
1M
exo
endo
46.2
46.0
45.8
45.6
(ppm)
45.4
45.2
45.0
44.8
44.6
44.4
0.25M
endo
exo
35
0,1
4.66
1
4.64
4.62
4.60
the
4.56
(ppm)
4.54
4.52
4.50
4.48
4.46
4.44
4.65 4.64 4.63
4.62 4.61 4.60 4.59
4.58 4.57 4.56 4.55
(ppm)
4.54 4.53 4.52
4.51 4.50 4.49 4.48
4.47 4.46
0.05M
0.1M
of
4.58
1
3.19:
H-NMR
analysis
of
the
acetaldehyde/5-methyl-2,3- acetaldehyde/5-methyl-2,3-dihydrofuran
photocycloaddition.
Irradiation of propionaldehyde with 5-methyl-2,3-dihydrofuran gave the two diastereoisomers
exo-9c and endo-9c.
H
O
H
1c
+
O
H
O
hν
benzene
O
+
O
8
O
exo-9c
endo-9c
Scheme 3.14: Photocycloaddition of propionaldehyde with 5-methyl-2,3-dihydrofuran.
44
The diastereomeric endo/exo ratio was 50 : 50 at high concentration (1M) and shifted to
higher endo-selectivity by lowering the substrate concentrations. The endo/exo ratio was 67 :
33 at 0.01M. Figure 3.20 shows the concentration/selectivity profile of the photocycloaddition
of 5-methyl-2,3-dihydrofuran with propionaldehyde.
68
66
64
62
endo
exo
endo
exo
60
58
4.60
endo
4.59
4.58
56
4.57
4.56
4.55
4.54 4.53
4.52
4.51
(ppm)
4.50
4.49
4.48 4.47
4.46
1M
4.45
4.44
4.43
4.42
46.0
45.9
45.8
45.7
45.6
45.5
45.4
endo
exo
45.3
45.2
(ppm)
45.1
45.0
44.9
44.8
44.7
0.25M
44.6
44.5
44.4
44.3
exo
54
52
50
4.59
propionaldehyde +
4.57
4.56
4.55
4.54
4.53
4.52
4.51
(ppm)
4.50
4.49
4.48
4.47
4.46
4.45
4.44
4.43
4.60
4.59
4.58
4.57
4.56
4.55
0.1M
4.54
4.53
4.52 4.51
(ppm)
4.50
4.49
4.48
4.47
4.46
4.45
4.44
4.43
0.05M
exo
48
4.59
0,01
4.58
endo
0,1
4.58
4.57
4.56
1
4.55
4.54
4.53
4.52
4.51
(ppm)
4.50
4.49
4.48
4.47
4.46
4.45
4.44
4.43
0.01M
of
the
3.21:
1
H-NMR
analysis
of
the
propionaldehyde/5-methyl-2,3- propionaldehyde/5-methyl-2,3-dihydrofuran
photocycloaddition.
The
[2+2]-photocycloaddition
of
with
afforded the mixture of exo-9d and endo-9d.
H
O
H
1c
+
O
H
O
hν
benzene
O
+
O
8
O
exo-9c
endo-9c
Scheme 3.15: Photocycloaddition of 3-methylbutyraldehyde with 5-methyl-2,3-dihydrofuran.
At high concentration (1M) the endo/exo selectivity was 51: 49. By lowering the
concentration of the substrate (0.01M) the selectivity switched constantly to 68 : 32 ( see
Figure 3.23).
45
70
68
66
endo
64
endo
exo
exo
62
4.90 4.89 4.88 4.87
60
4.86 4.85 4.84 4.83 4.82
endo
4.81 4.80 4.79 4.78
(ppm)
4.77 4.76 4.75 4.74
0.5M
4.73 4.72 4.71 4.70
4.87
4.86
4.85
4.84
endo
4.83
4.82
4.81
4.80
4.79
(ppm)
4.78
4.77
4.76
0.125M
exo
4.75
4.74
4.73
4.72
4.71
exo
58
56
4.87
54
4.86
4.85
4.84
4.83
4.82
4.81
4.80
4.79
(ppm)
4.78
4.77
4.76
4.75
50
4.72
4.71
4.87
4.86
4.85
4.84
4.83
4.82
4.81
4.80
4.79
(ppm)
4.78
4.77
4.76
4.75
4.74
4.73
4.72
4.71
exo
4.860
0,01
4.73
0.025M
3-methylbutraldehyde +
52
4.74
0.1M
endo
0,1
4.850
4.840
4.830
4.820
4.810
4.800
4.790
(ppm)
4.780
4.770
4.760
4.750
4.740
4.730
4.720
0.01M
1
Figure 3.22: Concentration/selectivity profile Figure 3.23:
of
the
1
H-NMR analysis of the 3-
3-methylbutyraldehyde/5-methyl-2,3- methylbutyraldehyde/5-methyl-2,3-
3.1.5 Synthesis of 2,2-dimethyl-2,3-dihydrofuran
2,2-Dimethyl-2,3-dihydrofuran was not commercially available and was prepared according
to a literature procedure as depicted in scheme 3.16.86 To improve the yield of the primary
substrate, 2-methyl-4-penten-2-ol 10, two different methods were used. The first method
required the Grignard addition of allyl magnesium bromide to acetone in ether87 and the
second method used Luche reaction which required the addition of allyl bromide to acetone in
DMF and in the presence of zinc dust.88 The second reaction gave appreciable higher yields.
Bromination of 2-methyl-4-penten-2-ol 10 in ether gave 2-methyl-4,5-dibromo-2-pentanol
which in situ underwent dehydrobromination by refluxing with quinoline to give 2,2dimethyl-4-bromotetrahydrofuran
11.
Distillation
of
2,2-dimethyl-4-bromotetrahydrofuran
over KOH pellets furnished the two regioisomers 2,2-dimethyl-2,5-dihydrofuran 12 and 2,2dimethyl-2,3-dihydrofuran 13. The 1 H-NMR spectra of the products revealed that the ratio of
these regioisomers is 1 : 1.5 with preferential formation of the 2,2-dimethyl-2,3-dihydrofuran
13. The two regioisomers 12 and 13 were successfully separated by column chromatography.
The structure of the isolated products were identified using 1 H-NMR and
analyses.
46
13
C-NMR spectral
O
Br
+
O
Zn, DMF
Mg, ether
40 %
OH
+ Br
60 %
10
Br
Br
Br 2, ether
N
OH
OH
10
O
-HBr
Br
11
Br
KOH
O
+
reflux
11
O
O
12
13
Scheme 3.16: Synthesis of 2,2-dimethyl-2,3-dihydrofuran.
3.1.5.1 Photocycloaddition of 2,2-dimethyl-2,3-dihydrofuran with aldehydes
In order to estimate if there is a correlation between spin selectivity and steric effects on the
simple diastereoselectivity of the Paternò-Büchi reaction, the photocycloaddition of 2,2dimethyl-2,3-dihydrofuran 13 with aliphatic and aromatic aldehydes was studied.
H
H
R
O
O
O
H
+
O
hν
benzene
O
13
R
R +
O
H
H
endo-14a-f
exo-14a-f
R=Ph,o-Tol, Et, i-Pr, i-Bu, t-Bu
Scheme 3.17: Photocycloaddition of 2,2-dimethyl-2,3-dihydrofuran with aldehydes.
Table 3.4: Simple diastereoselectivity in the Paternò-Büchi reaction of 2,2-dimethyl-2,3dihydrofuran with aldehydes.
Entry
Conc. (M)
R=
% exo-14
% endo-14
1
0.1
Ph
14
86
2
0.1
o-Tol
13
87
3
1.0
Et
38
62
4
0.1
Et
26
74
5
0.1
i-Pr
35
65
6
0.1
i-Bu
30
70
7
0.1
t-Bu
18
82
47
Firstly, both benzaldehyde and o-tolualdehyde were used as triplet precursor of the
photocycloaddition with 2,2-dimethyl-2,3-dihydrofuran. The endo/exo selectivity was high in
both cases (see Table 3.4, entry 1&2). From concentration studies, we have already learned
that aliphatic aldehydes can react from both singlet and triplet excited state. The
photocycloaddition of the electronically excited singlet state of propionaldehyde (1M) to 2,2dimethyl-2,3-dihydrofuran gave a moderate endo/exo selectivity (62 : 38) whereas the triplet
excited state of propionaldehyde (0.1M) reacted highly endo -selective (74 : 26) (see Table
3.4, entry 3&4). Interestingly, the diastereomeric ratios exhibit a slightly increasing trend in
favor of the endo-isomers with increasing steric demand of the R-substituent (Et, i- Pr, i- Bu, tBu) of the aldehyde. The diastereomeric ratio of the photoadducts were determined from 1 HNMR and the structure of the products were identified from
1
H-NMR and
13
C-NMR spectral
analyses. The relative configuration of the diastereoisomers exo-14c and endo-14c were
unambiguously determined from NOE difference measurement. In the exo-14c isomer,
irradiation of a methyl hydrogen protons at 1.51 ppm leads to nuclear Overhauser
enhancements of both methyl protons signal at 1.22 ppm and methine proton signal, H-7 at
4.16 ppm. In the endo-14c, irradiation of a methyl protons signal at 1.45 ppm leads to nuclear
Overhauser enhancements of the intensity of the methyl protons signal at 1.14 ppm (see
Figure 3.24).
0.73 ppm
4.16 ppm
0.83 ppm
7 OH
4.40 ppm H 1
1.51 ppm
4.38 ppm H
7 O
4.70 ppmH 1
O
1.45 ppm
O
1.14 ppm
1.22 ppm
exo-14c
endo-14c
Figure 3.24: NOE interactions in bicyclic oxetanes exo-14c and endo-14c.
48
CH3
CH3
(c) irradiation of CH3 at 1.22 ppm
H-4
(c) irradiation of CH3 at 1.14 ppm
H-5
H-4
H-1
(b) irradiation of CH3 at 1.51 ppm
CH3
H-7
(b) irradiation of CH3 at 1.45 ppm
H-4
CH3
H-4
(a) no irradiation
(a) no irradiation
Figure 3.25: NOE difference spectra (300 Figure 3.26: NOE difference spectra (300
MHz, CDCl3 ) of exo-14c.
MHz, CDCl3 ) of endo-14c.
3.1.6 Effect of concentration on simple and induced diastereoselectivity of Paternò-Büchi
reactions
In order to determine the difference between simple and induced diastereoselectivity in singlet
and triplet reactions, the concentration dependence of the photocycloaddition reaction of a
chiral aldehyde with 2,3-dihydrofuran and 5-methyl-2,3-dihydrofuran, respectively, was
investigated.
3.1.6.1 Photocycloaddition of 2,3-dihydrofuran with 2-methylbutyraldehyde
2-Methylbutyraldehyde is commerically avaliable and was applied in the Paternò-Büchi
reaction. The photolysis of 2-methylbutyraldehyde with 2,3-dihydrofuran was performed in
benzene at a wide range of concentrations. Two diastereoisomers exo-3g and endo-3g were
obtained in good yield.
H
O
H
1g
+
O
H
O
hν
benzene
O
+
O
2
H
exo-3g
O
H
endo-3g
Scheme 3.18: Photocycloaddition of 2-methylbutyraldehyde with 2,3-dihydrofuran.
49
The asymmetric induction was negligible (i.e. the diastereomeric excessess for both endo- and
exo-isomers was 50 : 50); this might be a reason of the small difference in substituent size at
the stereogenic center. The simple endo/exo diastereoselectivity was affected by the change of
the concentration of the substrate. The results are shown in Figure 3.27: at high alkene
concentration (1M), the simple endo/exo selectivity was low (47 : 53). In the low
concentration region (0.025 M), the endo-selectivity became dominant (71 : 29).
75
70
65
60
55
50
2,3-dihydrofuran
45
0,1
1
Figure 3.27: Concentration/selectivity profile of the 2-methylbutyraldehyde/2,3-dihydrofuran
photocycloaddition.
3.1.6.2 Photocycloaddition of 5-methyl-2,3-dihydrofuran with 2-methylbutyraldehyde
Irradiation of 2-methylbutyraldehyde with 5-methyl-2,3-dihydrofuran in benzene furnished
the two diastereoisomers exo-9g and endo-9g.
H
O
H
1g
+
O
H
O
hν
benzene
O
+
O
8
O
exo-9g
endo-9g
Scheme 3.19: Photocycloaddition of 2-methylbutyraldehyde with 5-methyl-2,3-dihydrofuran.
Again, the asymmetric induction was low and not affected by change of the concentration of
the substrate. The simple endo/exo-selectivity at 1M was low (52 : 48), increased by dilution
and switched to 63 : 37 at 0.025M (see Figure 3.28).
50
64
62
60
58
56
54
52
0,1
1
Figure 3.28: Concentration/selectivity profile of the 3-methybutyraldehyde/5-methyl-2,3dihydrofuran photocycloaddition.
3.1.7 Photocycloaddition of furan with acetaldehyde
The results of the concentration study of the photocycloaddition of aldehydes with electron
rich-cycloalkenes have prompted me to investigate the concentration effect also on the
stereoselectivity of the furan/acetaldehyde photocycloaddition. Irradiation of acetaldehyde
with furan in benzene furnished two diastereoisomers exo-16b and endo-16b.
H
O
H
1b
+
O
hν
benzene
H
O
O
15
+
H
exo-16b
O
O
H
endo-16b
Scheme 3.20: Photocycloaddition of acetaldehyde with furan.
Table 3.5: Simple diastereoselectivity of the photocycloaddition reaction of furan with
acetaldehyde.
Conc. (M)
% exo
% endo
10
92
8
1
86
14
0.1
64
36
Surprisingly, the diastereomeric exo/endo ratios were also dependent on the concentration of
the substrate (Table 3.5). At high concentration (10M) the simple exo/endo selectivity was 92
: 8 wheras at low concentration (0.1M) it decreased to 64 : 36. The diastereomeric ratios were
determined from the 1 H-NMR analysis of the crude reaction mixture.
51
3.1.8 Fluorescence quenching
Fluorescence quenching is the most valuable method for determining the probability of
carbonyl singlets participation in bimolecular reaction. This measurement uses the intensities
of fluorescence (band maxima) in the presence of varying concentrations of a potential
quencher and leads to data correlation resolved by the Stern-Volmer equation.
F0 /F = 1+ kq τ [Q]
Where F0 : unquenched fluorescence intensity
F : quenched fluorescence intensity
kq : bimolecular quenching rate constant
τ : lifetime of the carbonyl singlet
[Q] : molar concentration of quencher
Solutions of propanal (0.2M) with various concentrations of 2,3-dihydrofuran as quencher
(0.02-1M) were measured in benzene; both benzene and 2,3-dihydrofuran showing negligible
fluorescence. Solutions were placed in 3 cm2 quartz cells after deoxygenated by nitrogen
bubbling for 30 sec and the fluorescence spectra were recorded. The excitation wavelength
was 310 nm, the intensity of the emission (F) at the maximum (∼400 nm) for propanal was
compared to the intensity (F0 ) in the abscence of quencher. A Stern-Volmer plot was drawn of
F0 /F versus molarity of quencher, and the slope determined at least from four points using
linear portion of the curve. The results are shown in Figure 3.29 & 3.30.
0.00 M 2,3-Dihydrofuran
0.02 M
0.04 M
0.06 M
0.08 M
0.10 M
0.50 M
1.00 M
400
1,4
300
1,3
250
y = 0.9981 + 3.87143 x
200
F0/F
Rel.fluorescence intensity
350
1,2
150
1,1
100
50
1,0
0
320
340
360
380
400
420
440
460
480
500
0,00
520
0,02
Figure
3.29:
Fluorescence
0,04
0,06
0,08
0,10
0,12
[2,3-Dihydrofuran]
Wavelength/nm
quenching
of Figure
3.30: Stern-Volmer plot for the
propionaldehyde 0.2M with 2,3-dihydrofuran fluorescence
(0.02–1.00 M) in benzene at 25°C.
quenching
with 2,3-dihydrofuran.
52
of
propionaldehyde
By applying the lifetime of singlet excited state of propanal (τs = 1.8 ns),85 a bimolecular
quenching rate constant of kq = 2.15 x 109 m-1 s-1 was determined. This result clearly shows
that the reactivity of singlet excited state of propanal in the photocycloaddition reaction is
high and only a factor 5 away from the diffusion limit.
3.1.9 Quantum yield (Φ
Φ)
The quantum yield of the photocycloaddition of benzaldehyde with 2,3-dihydrofuran in
benzene was determined by using a merry-go-round apparatus 89 with valerophenone as
chemical actinometer.90 The product composition was measured as a function of time by GC
analysis. The conversion of starting material is plotted as a function of time as shown in
Figure 3.31.
100
Valerophenone
Benzaldehyde
98
96
% Starting material
94
92
90
88
86
84
82
80
78
76
74
72
70
0
2
4
6
8
10
12
14
16
18
Time(min.)
Figure 3.31: The relationship between conversion of the starting material versus time for the
chemical actinometer and the benzaldehyde/2,3-dihydrofuran system.
The best-fit line for benzaldehyde had a slope -1.43 and for valerophenone a slope of -1.004
resulted. By using the following equation.
slope (valerophenone)
slope (benzaldehyde)
=
Φ (valerophenone)
Φ (Paternò-Büchi reaction)
The quantum yield for the triplet photocycloaddition of benzaldehyde with 2,3-dihydrofuran
(Φ = 0.48) was determined. The quantum yield is in agreement with literature value for the
photocycloaddition of benzaldehyde with tetramethylethylene (Φ = 0.53).91
Due to the long lifetimes of the excited triplet carbonyl states, the high concentration of the
excited triplet state quencher 2,3-dihydrofuran, and because the slopes are compared in the
low conversion region, the method is reliably, albeit uni- and bimolecular photochemistry is
compared herein.
53
Mechanistic analysis
Spin-directed stereoselectivity has been already reported for the photolyses of azoalkenes92 as
well as for Yang cyclization processes following intramolecular hydrogen abstractions.93 In
these cases, however, high diastereoselectivities were observed for singlet reactions and low
selectivities for sensitized (triplet) processes. The inverse behavoir, as described herein for the
cycloalkene photocycloadditions to aliphatic aldehydes, can be rationalized as follows:
In triplet Paternò-Büchi reactions 1,4-triplet biradicals are generated, which have to undergo
intersystem crossing in order to convert into closed-shell products. Obviously, this process
requires severe geometrical restrictions and, following the “Griesbeck model”,51 leads to high
endo-selectivity. The surprising result is the stereoselectivity of the singlet process: very low
selectivities were determined even for the reaction of pivalaldehyde with 2,3-dihydrofuran (50
: 50 at high concentration), which gave a 95 : 5 diastereomeric ratio in the triplet channel.
Thus, the stereoselectivity of the Paternò-Büchi reaction of singlet excited aldehydes which
most likely involves conical intersections is not sensitive with respect to carbonyl
substituents. The reaction sequence behind the concentration/selectivity plots is given in
scheme 3.21.
A
hν
ISC
1
A*
3
A*
+B
C
+B
D
C 0 = (endo-exo)/100
for pure singlet reaction
D0 = (endo-exo)/100
for pure triplet reaction
Scheme 3.21: Mechanistic scenario for singlet and triplet reaction.
The bimolecular photocycloaddition steps resulting in the “spin-characteristic” products C
and D competes with unimolecular processes, the ISC to give the triplet excited carbonyl (
Φ ISC ca. 0.3-0.5 for aliphatic aldehydes) and the photophysical deactivation of the triplet state.
From the correlation shown in the above scheme, C0 and D0 were estimated and the D/C+D
ratio plotted versus the concentration of the trapping reagent B. Nonlinear curve fitting led to
the equation y = [D0 -C0 /1 + (x/x0 )p ] + C0 with y = D/(C+D) and x = B. For the
photocycloaddition of propionaldehyde with 2,3-dihydrofuran, the values x0 = 0.09 and
were determined (see Figure 3.32).
54
p
= 1.9
1,0
calcd.
0,8
exptl.
D/(D+C)
isospin selectivity
0,6
0,4
0,2
0,0
propionaldehyde+
2,3-dihydrofuran
[B 0]
0,01
0,1
1
[B]
Figure
3.32:
Experimental
and
calculated
concentration/selectivity
profile
of
the
propionaldehyde/2,3-dihydrofuran reaction.
The concentration B0 (x0 ) corresponds to a spin (singlet/triplet) selectivity of zero. These
values were characteristic for every substrate combination and represent the specific kinetic
data. Qualitatively, for carbonyls with shorter lived excited singlets (e.g. aromatic aldehydes),
the B0 value shiftes to higher concentrations, wheras a change in bimolecular rate constants of
the cycloaddition steps alters the sigmoidal behavoir of the curve.
Spin selectivity for furan/acetaldehyde photocycloaddition can be explained as depicted in
scheme 3.22. At high concentration, the first excited singlet state was quenched rapidly with
furan to give high exo-adduct wheras at low concentration the singlet excited state undergo
ISC to triplet excited state which has relatively long lifetime and then SOC controls geometry
of triplet 1,4-biradical.51
O
hν
H
*
O
1
3
O.
ISC
.
O.
.
H
H
H
τ =1.5−2 ns
O
O
H
H
O
O
O
O
H
exo-16b
H
endo-16b
Scheme 3.22: Mechanistic scenario of furan/acetaldehyde photocycloaddition.
55
3.2 Effect of solvent polarity on the simple diastereoselectivity of Paternò-Büchi
reactions
To
get
more
information
on
the
surprising
concentration
effect
of
the
simple
diastereoselectivity of [2+2] photocycloaddition, solvent polarity effects of the Paternò-Büchi
reaction of 2,3-dihydrofuran with aldehydes were studied. As a polar protic solvent, methanol
was used, and both acetonitrile and tetrahydrofuran were used as polar aprotic solvent. In
addition, n-hexane and benzene were applied as nonpolar solvent.
3.2.1 Solvent polarity effect on the stereoselectivity of the 2,3-dihydrofuran/
propionaldehyde photocycloaddition reaction
The photocycloaddition of propionaldehyde with 2,3-dihydrofuran was investigated in
different types of solvent and with a wide range of concentration (1-0.0125M). The
diastereomeric exo/endo ratios of the photoadducts were determined by using GC and 1 HNMR analyses. Figure 3.33 shows solvent polarity effects on the concentration/selectivity
profile of the propionaldehyde/2,3-dihydrofuran photocycloaddition. At singlet conditions, i.e.
at high concentration range, the endo-selectivity was low in the nonpolar solvent n-hexane,
and increased with increasing polarity of the solvent. In contrast to the results for the singlet
reaction, for the triplet reaction (i.e. at low concentration) the endo-selectivity was dominant
in the nonpolar solvent benzene whereas polar solvents (methanol and acetonitrile) gave
moderate endo-selectivity.
85
benzene
n-hexane
acetonitrile
THF
MeOH
80
75
70
65
60
55
50
propionaldehyde +
2,3-dihydrofuran
45
40
35
0,1
1
Figure
3.33: Solvent polarity effect on the concentration/selectivity profile of the
propionaldehyde/2,3-dihydrofuran photocycloaddition.
56
3.2.2 Solvent polarity effect on the stereoselectivity of the 2,3-dihydrofuran/acetaldehyde
photocycloaddition reaction
Next, the effect of solvent polarity on the stereoselectivity of the photocycloaddition of
acetaldehyde with 2,3-dihydrofuran was investigated in three solvents (tetrahydrofuran,
acetonitile and methanol). The results depicted in Figure 3.34 show, that the endo-selectivity
in polar solvents (methanol and acetonitrile) was higher than in the less polar tetrahydrofuran
solvent at high concentration. By lowering the concentration, the endo-selectivity increases
parallel with increasing solvent polarity. Surprising, THF showed nearly no concentration
effect on the diastereoselectivity in contrast to the propionaldehyde/2,3-dihydrofuran
photocycloaddition reaction.
74
72
acetonitrile
THF
MeOH
70
endo-selectivity(%)
68
66
64
62
60
58
acetaldehyde +
2,3-dihydrofuran
56
54
52
50
48
46
0,1
1
Figure
3.34: Solvent polarity effect on the concentration/selectivity profile of the
acetaldehyde/2,3-dihydrofuran photocycloaddition.
Comment
The results of solvent polarity effect suggest that the spin-multiplicity of the excited
aldehydes, singlet or triplet, may play an important role for determining the stereoselectivities.
The important findings from solvent polarity experiments in the photoreactions of 2,3dihydrofuran with acetaldehyde and propionaldehyde are as follows:
(a) polar solvents favor the formation of endo-diastereoisomers under singlet condition.
(b) nonpolar solvents also favor the formation of endo-diastereoisomers under triplet
condition.
This results can be explained as follows: At singlet condition, the mechanism of PaternòBüchi reactions procced via conical intersections or exciplex which it might be favored in
polar solvents than in nonpolar solvent. At triplet condition, SOC controls the geometry of the
triplet 1,4-biradical. In polar solvents, there is a competition between biradical formation and
photoinduced electron transfer (PET).42 The PET is favored in polar solvents, so the endo57
selectivity decreased while the biradical dominants in nonpolar solvent and hence the endoselectivity increased.
3.3 Effect of solvent viscosity on simple diastereoselectivity of Paternò-Büchi reactions
The detection of solvent viscosity dependence on the stereoselectivity of the Paternò-Büchi
reaction was essential for demonstrating the difference in simple diastereoselectivites in
singlet and in triplet routes. As a model system for this study, the photocycloaddition reaction
of 2,3-dihydrofuran with four aldehydes was investigated.
3.3.1 Solvent viscosity effect on the stereoselectivity of the benzaldehyde/2,3dihydrofuran photocycloaddition reaction
The photocycloaddition of benzaldehyde with 2,3-dihydrofuran was firstly investigated as a
typical triplet reaction with concentration-independent diastereoselectivity.
H
O
Ph
H
+
O
hν
20°C, 1M
O
Ph
O
2
1a
H
O
H
exo-3a
+
Ph
O
H
endo-3a
Table 3.6: Viscosity dependence of the diastereoselectivity of the Paternò-Büchi reaction of
2,3-dihydrofuran (1M) with benzaldehyde (1M) at 293K.
Solvent
η [p]
n-hexane
0.0033
1.8 x 1010
2.9 x 1010
82 : 18
acetonitrile
0.0036
1.6 x 1010
2.6 x 1010
82 : 18
n-heptane
0.0041
1.4 x 1010
2.3 x 1010
85 : 15
methanol
0.0060
9.8 x 109
1.6 x 1010
84 : 16
ethanol
0.012
4.8 x 109
7.9 x 109
86 : 14
n-propanol
0.023
2.5 x 109
4.1 x 109
90 : 10
n-butanol
0.029
2.0 x 109
3.3 x 109
87 : 13
n-octanol
0.085
6.9 x 108
1.1 x 109
89 : 11
glycol
0.20
2.9 x 108
4.7 x 108
83 : 17
1,2-propanediol
0.56
1.0 x 108
1.6 x 108
87 : 13
1,4-butanediol
0.89
6.6 x 107
1.1 x 108
91 : 9
kdiff[a] [M-1 sec-1 ] k`Diff[b] [M-1 sec-1 ]
endo/exo[c]
[a] kdiff= 2 x 105 T/η. [b] k`Diff= 8 x RT/2000η.95 [c] Determined by means of NMR
spectroscopic analysis of the crude product mixture.
58
The variation of the solvent viscosity over a wide range (η = 0.3 to 89 cp)94 resulted in a weak
but significant increase in endo-selectivity from 82% to 91% (Table 3.6, Figure 3.38).
3.3.2 Solvent viscosity effect on the stereoselectivity of the acetaldehyde/2,3dihydrofuran photocycloaddition reaction
The simple diastereoselectivity of the photocycloaddition reaction of acetaldehyde with 2,3dihydrofuran (1M substrate concentration) highly influenced by changing the viscosity of the
solvent.
H
O
H
+
O
hν
20°C, 1M
O
+
O
2
1b
H
O
H
O
H
endo-3b
exo-3b
2,3-dihydrofuran (1M) with acetaldehyde (1M) at 293K.
Solvent
η [p]
kdiff[a][M-1 sec-1 ]
k`Diff[b] [M-1 sec-1 ]
endo/exo[c]
n-hexane
0.0033
1.8 x 1010
2.9 x 1010
40.0 : 60.0
acetonitrile
0.0036
1.6 x 1010
2.6 x 1010
41.6 : 58.4
n-heptane
0.0041
10
1.4 x 10
10
2.3 x 10
44.4 : 55.6
methanol
0.0060
9.8 x 109
1.6 x 1010
44.4 : 55.6
ethanol
0.012
4.8 x 109
7.9 x 109
44.7 : 55.3
n-propanol
0.023
2.5 x 109
4.1 x 109
46.1 :53.9
n-butanol
0.029
2.0 x 109
3.3 x 109
46.5 : 53.5
n-octanol
0.085
6.9 x 108
1.1 x 109
47.0 : 53.0
glycol
0.20
2.9 x 108
4.7 x 108
50.3 : 49.7
1,2-propanediol
0.56
1.0 x 108
1.6 x 108
53.6: 46.4
1,4-butanediol
0.89
6.6 x 107
1.1 x 108
63.5 : 36.5
[a] kdiff= 2 x 105 T/η. [b] k`Diff= 8 x RT/2000η.95 [c] Determined by means of GC analysis.
The endo/exo selectivity in the low viscous solvent n-hexane was 40 : 60 and increased by
increasing solvent viscosity and switched to 63 : 37 in 1,4-butanediol (Table 3.7). The
diastereomeric ratios endo/exo were determined by using GC analysis (Figure 3.35).
59
exo
exo
endo
endo
exo
endo
endo
exo endo
endo
exo
exo
n-hexane
acetonitrile
n-octanol
glycol
1,2-propanediol 1,4-butanediol
Figure 3.35: GC trace analysis of the diastereoselectivity of acetaldehyde/2,3-dihydrofuran
photocycloaddition as a function of solvent viscosity.
3.3.3 Solvent viscosity effect on the stereoselectivity of the propionaldehyde/2,3dihydrofuran photocycloaddition reaction
The photoaddition of propionaldehyde to 2,3-dihydrofuran was performed in different
solvents and with 1M concentration of both substrates.
H
O
H
1c
+
O
H
O
hν
20°C, 1M
O
+
O
2
H
exo-3c
O
H
endo-3c
The variation of the solvent viscosity over a large range (η = 0.3 to 1500 cp) resulted in a
substantional increase in endo selectivity from 45.3 % to 80.2 % (Table 3.8, Figure 3.36).
Table 3.8 shows, that the endo-selectivity changes slightly when going from n-hexane to nbutanol and jumps to moderate selectivity in glycol and is again dramatically increased in
glycerol.
60
2,3-dihydrofuran (1M) with propionaldehyde (1M) at 293K.
Solvent
η [p]
n-hexane
0.0033
1.8 x 1010
2.9 x 1010
45.3 : 54.7
acetonitrile
0.0036
1.6 x 1010
2.6 x 1010
45.3 : 54.7
n-heptane
0.0041
1.4 x 1010
2.3 x 1010
48.6 : 51.4
methanol
0.0060
9.8 x 109
1.6 x 1010
49.6 : 50.4
ethanol
0.012
4.8 x 109
7.9 x 109
50.4 : 49.6
n-propanol
0.023
2.5 x 109
4.1 x 109
52.1 : 47.9
n-butanol
0.029
2.0 x 109
3.3 x 109
53.6 : 46.4
n-octanol
0.085
6.9 x 108
1.1 x 109
57.5 : 42.5
glycol
0.20
2.9 x 108
4.7 x 108
59.0 : 41.0
1,2-propanediol
0.56
1.0 x 108
1.6 x 108
60.6: 39.4
1,4-butanediol
0.89
6.6 x 107
1.1 x 108
72.6 : 27.4
glycerol
15.0
3.9 x 106
6.3 x 106
80.2 : 19.8
Kdiff[a][M-1 sec-1 ] k`Diff[b] [M-1 sec-1 ]
endo/exo[c]
exo endo
endo
endo
endo
exo
exo
endo
exo
exo
n-hexane
Figure
n-octanol 1,2-propanediol1,4-butanediol glycerol
3.36: GC trace analysis of the diastereoselectivity of propionaldehyde/2,3-
dihydrofuran photocycloaddition as a function of solvent viscosity.
61
3.3.4 Solvent viscosity effect on the stereoselectivity of the 3-methylbutyraldehyde/2,3dihydrofuran photocycloaddition reaction
The irradiation of 2,3-dihydrofuran in presence of 3-methylbutyraldehyde gave two
diastereoisomers, the ratio of which was influenced by changing the solvent viscosity.
H
O
H
+
O
1d
H
O
hν
20°C, 1M
O
+
O
2
O
H
H
endo-3d
exo-3d
2,3-dihydrofuran (1M) with 3-methylbutyraldehyde (1M) at 293K.
Solvent
η [p]
kdiff[a][M-1 sec-1 ]
k`Diff[b] [M-1 sec-1 ]
endo/exo[c]
n-hexane
0.0033
1.8 x 1010
2.9 x 1010
48.8 : 51.2
acetonitrile
0.0036
1.6 x 1010
2.6 x 1010
51.2 : 48.8
n-heptane
0.0041
10
1.4 x 10
10
2.3 x 10
51.2 : 48.8
methanol
0.0060
9.8 x 109
1.6 x 1010
51.7 : 48.3
ethanol
0.012
4.8 x 109
7.9 x 109
51.8 : 48.2
n-propanol
0.023
2.5 x 109
4.1 x 109
52.4 : 47.6
n-butanol
0.029
2.0 x 109
3.3 x 109
53.5 : 46.5
n-octanol
0.085
6.9 x 108
1.1 x 109
55.7 : 44.3
glycol
0.20
2.9 x 108
4.7 x 108
62.2 : 37.8
1,2-propanediol
0.56
1.0 x 108
1.6 x 108
65.4: 34.6
1,4-butanediol
0.89
6.6 x 107
1.1 x 108
73.5 : 26.5
The results in Table 3.9 display, that the endo/exo selectivity changes slightly when going
from n-hexane to ethanol and increased by increasing solvent viscosity and were switched to
73.5 : 26.5 in 1,4-butanediol.
62
endo
exo
endo
endo
exo
endo
exo
exo
endo
exo
n-hexane
acetonitrile
n-octanol 1,2-propanediol 1,4-butanediol
Figure 3.37: GC trace analysis of the diastereoselectivity of 3-methylbutyraldehyde/2,3dihydrofuran photocycloaddition as a function of solvent viscosity.
The results of the viscosity dependence on the diastereoselectivity of the photocycloaddition
reaction of 2,3-dihydrofuran with aliphatic aldehydes suggest that the differences in endo/exo
selectivity in the singlet reaction are more pronounced than in the triplet reactions (see Figure
3.38).
3,5
3,0
Selectivity Increase
benzaldehyde
2,5
acetaldehyde
propionaldehyde
2,0
3-methylbutraldehyde
1,5
1,0
0,5
1
10
log
100
η (cP)
Figure 3.38: Viscosity dependence (normalized) of the Paternò-Büchi reaction of 2,3dihydrofuran with aldehydes (1M) at 293 K.
63
Comment
The results of the viscosity studies can be explained as follows:
An increase in solvent viscosity should favor the triplet channel as a result of a reduction in
the diffusion rate limit (about 4 orders of magnitude in the viscosity range).95 Thus, the
viscosity of the medium only slightly influences the diastereoselectivity of the triplet
photocycloaddition (k3 ) which is controlled by the geometry of 2-oxatetramethylene triplet
1,4-biradical.32,51 The influence of the solvent viscosity on the diastereoselectivity of singlet
reactions which can be estimated from the correlation in Figure 3.38 is more distinct.
The
shape
of
concentration/diastereoselectivity
correlations
as
well
as
the
viscosity/diastereoselectivity correlations reflects the different kinetic contribution to this
complex reaction scenario (Scheme 3.23). Recognize that the difference to Scheme 3.21 is
that identical products are now formed via the singlet as well as the triplet path, only with
different C/D-composition. The endo/exo selectivity is controlled by the geometry of the
conical intersections for the singlet reaction96 and by the optimal ISC-geometry of the 2oxatetramethylene biradical 3 (OTM) for the triplet path reaction. 51
O
H
R
1 O*
hν
O
R
k1
kISC
R
H
1a-d
3 O*
R
+
O
H
endo-3a-d
O
2
O
k2
H
H
O
O
2
3
O
exo-3a-d
R
R
H
O
R
H
O
H
k3
O
endo-3a-d
H
+
O
R
O
exo-3a-d
OTM
Scheme 3.23: Mechanistic scenario for singlet and triplet reaction.
3.4 Effect of temperature on the simple diastereoselectivity of Paternò-Büchi reactions
The effect of temperature on the diastereoselectivity has recently been observed and its
influence is not uniform: On increasing the reaction temperature the diastereoselectivity may
decline, but it can also be constant or even increase. Scharf et al. intensively investigated the
effect of temperature on facial selectivities in the triplet photocycloaddition reaction of
electron-rich cycloalkenes with chiral phenyl glyoxylates.68 It was thus of interest to study the
influence of excited-state spin multiplicity (singlet versus triplet) at different temperatures on
64
the simple diastereoselectivity of the [2+2] photocycloaddition reaction of 2,3-dihydrofuran
with prochiral aldehydes.
3.4.1 Effect of temperature on the simple diastereoselectivity of benzaldehyde/2,3dihydrofuran photocycloaddition reaction
Firstly, the temperature dependence of the simple diastereoselectivity of the Paternò-Büchi
reaction was studied for the triplet reaction between benzaldehyde and 2,3-dihydrofuran. No
influence was detected, within the error margin (see Table 3.10). The results of the
temperature dependence of the simple diastereoselectivity in the triplet reaction suggest that
the reaction is soley controlled by the activation entropy.
H
O
Ph
H
1a
+
O
hν
n-hexane, 1M
H
O
O
Ph
O
2
+
H
exo-3a
Ph
O
H
endo-3a
Table 3.10: Temperature dependence of the diastereoselectivity of the Paternò-Büchi reaction
of 2,3-dihydrofuran (1M) with benzaldehyde (1M) in n-hexane.
Entry
T (°C)
d.r. (endo : exo)[a]
1
0
90.9 : 9.1
2
-10
90.0 : 10.0
3
-15
91.1 : 8.9
4
-25
88.0 : 12.0
4
-32
87.8 : 12.2
6
-42
90.5 : 9.5
7
-52
90.4 : 9.6
8
-61
86.2 : 13.8
9
-72
89.9 : 10.1
10
-78
90.2 : 9.8
[a] Determined by means of 1 H-NMR spectroscopic analysis of the crude product mixture.
3.4.2
Effect
of
temperature
on
the
correlation
of
propionaldehyde/2,3-dihydrofuran photocycloaddition reaction
In the next experiment, the concentration dependence of the [2+2] photocycloaddition
reaction at different temperatures was investigated with the standard system propionaldehyde
65
and 2,3-dihydrofuran. This substrate combination was used primarily to determine the
different simple diastereoselectivities of singlet and triplet photocycloadditions.97
25°C
10°C
-14°C
-78°C
80
endo-selectivity(%)
75
70
65
60
55
propionaldehyde +
2,3-dihydrofuran
50
45
0,01
0,1
1
Figure
3.39:
Temperature
effect
on
the
profile
of
the
propionaldehyde/2,3-dihydrofuran photocycloaddition in n-hexane.
In the temperature region between –14 and +25 °C, the diastereoselectivity/concentration
correlation showed only small changes, whereas at lower (-78 °C) temperatures the point of
isospinselectivity is shifted significantly to higher concentrations (see Figure 3.39). This shift
is not yet a proof for nonlinear temperature dependence, but a clear indication that not only
the
concentration,
but
also
the
temperature
influences
the
of
photocycloadditions with carbonyl compounds which can react from initial S1 and T1 states.
3.4.3 Effect of temperature on the simple diastereoselectivity of acetaldehyde/2,3dihydrofuran photocycloaddition reaction
The temperature dependence of the endo/exo-selectivity of Paternò-Büchi reaction of
acetaldehyde with 2,3-dihydrofuran was investigated at constant concentration (1M) in order
to evaluate the difference in spin selectivity in singlet and in triplet reaction. With decreasing
temperature, the endo-selectivity decreased in the region from +25 °C to –32 °C, and was
inverted at –37°C (see Table 3.11 and Figure 3.40).
H
O
H
1b
+
O
hν
n-hexane, 1M
2
H
O
+
O
H
exo-3b
66
O
O
H
endo-3b
of 2,3-dihydrofuran (1M) with acetaldehyde (1M) in n-hexane.
Entry
T (°C)
1
25
53.2 : 46.8
2
0
48.6 : 51.4
3
-10
46.3 : 53.7
4
-15
45.5 : 54.5
5
-25
41.0 : 59.0
6
-32
41.5 : 58.5
7
-42
45.5 : 54.5
8
-52
50.0 : 50.0
9
-61
51.4 : 48.6
10
-72
57.9 : 42.1
11
-78
58.3 : 41.7
[a] Determined by means of GC and NMR spectroscopic analysis of the crude product
mixture.
Furthermore, Figure 3.40 shows the strongest deviation from linearity with an inversion
temperature at –37°C. For this specific reaction, we have already detected from concentration
studies that the acetaldehyde triplet adds to 2,3-dihydrofuran with high endo selectivity (up to
75%) wheras the singlet gives the same products with moderate exo selectivity (up to 65%).
Thus, the temperature correlation can be interpreted qualitatively as follows: at room
temperature under high concentration conditions, the cycloadducts 3b were formed with low
exo selectivity, predominantly through the singlet channel. This selectivity increases with
decreasing temperature (as intuitively expected) and reaches an inversion point at –37°C
(Figure 3.40). At this point, the triplet reactivity gains sufficient influence to increase the endo
selectivity. The rate of the intersystem crossing process (kISC) is expected to be nearly
temperature-independent.98
3.4.4 Effect of temperature on the simple diastereoselectivity of 3-methylbutyraldehyde
/2,3-dihydrofuran photocycloaddition reaction
In
contrast
to
photocycloaddition
the
of
results
of
acetaldehyde,
the
temperature
dependence
of
the
3-methylbutyraldehyde with 2,3-dihydrofuran showed a positive
67
deviation from linearity with an inversion temperature at –28°C. In addition, the endo/exo
selectivity was altered slightly by lowering the temperature (see Table 3.12 and Figure 3.40).
H
O
H
O
hν
H
+
n-hexane, 1M
O
O
2
1d
O
+
O
H
H
endo-3d
exo-3d
of 2,3-dihydrofuran (1M) with 3-methylbutyraldehyde (1M) in n-hexane.
Entry
T (°C)
1
25
51.8 : 48.2
2
0
52.7 : 47.3
3
-10
52.8 : 47.2
4
-15
53.4 : 46.6
5
-25
53.6 : 46.4
6
-32
53.4 : 46.6
7
-42
52.7 : 47.3
8
-52
51.7 : 48.3
9
-61
51.0 : 49.0
10
-72
50.9 : 49.1
11
-78
50.6 : 49.4
[a] Determined by means of GC and NMR spectroscopic analysis of the crude product
selectivity change (rel. to room temp.)
mixture.
1,4
1a
1c
1b
1d
1,3
+
+
+
+
2
2
2
2
1,2
1,1
1,0
0,9
0,8
-80
-60
-40
-20
0
20
40
T (°C)
Figure 3.40: Temperature dependence (normalized) of the Paternò-Büchi reaction of 2,3dihydrofuran with aldehydes in n-hexane (1M both of substrate).
68
3.4.5 Effect of temperature on the simple diastereoselectivity of propionaldehyde/2,3dihydrofuran photocycloaddition reaction
The
results
of
the
temperature
dependence
of
simple
of
the
photocycloaddition reaction of propionaldehyde (1M) with 2,3-dihydrofuran (1M) was
surprising. The
endo selectivity increased gradually with decreasing the temperature and no
inversion temperature was detected (see Table 3.13 and Figure 3.40).
H
O
H
1c
hν
n-hexane
+
O
H
O
O
+
O
2
O
H
H
endo-3c
exo-3c
of 2,3-dihydrofuran with propionaldehyde at (1M & 5M) in n-hexane.
Entry
T (°C)
d.r. (endo : exo)[b]
1
25
45.3 : 54.7
47.7 : 52.3
2
0
48.4 : 51.6
43.8 : 56.2
3
-10
50.5 : 49.5
41.4 : 58.6
4
-15
54.6 : 45.4
37.3 : 62.7
5
-25
56.6 : 43.4
35.7 : 64.3
6
-32
57.4 : 42.6
37.1 : 62.9
7
-42
58.9 : 41.1
42.2 : 47.8
8
-52
61.5 : 38.5
48.0 : 52.0
9
-61
61.7 : 38.3
52.4 : 47.6
10
-72
63.2 : 36.8
58.1 : 41.9
11
-78
63.6 : 36.4
63.3 : 36.7
[a] 1M, [b] 5M.
This selectivity reversal could be detected for both acetaldehyde and 3-methylbutyraldehydeadditions to 2,3-dihydrofuran in a temperature region that is experimentally accessible. A
marginal change in activation parameter, however, “catapults” this effect out of the
experimental window (+40 to –78 °C). This might have been the reason why I did not detect
an inversion effect in the propionaldehyde photocycloaddition. If this assumption is true, a
change
in
substrate
concentration
might
shift
the
inversion
region
back
into
the
experimentally accessible range. Thus, the temperature dependence of propionaldehyde/2,3-
69
dihydrofuran system at 5M (both substrates) was measured, and indeed an inversion point at –
27°C was detected (see Table 3.13& Figure 3.42).
25°C
-32°C
exo
endo
exo
endo
5.190
5.180
5.170
5.160
5.150
5.140
5.130
5.120
5.110
5.100
5.090
5.080
5.070
5.060
5.050
5.170
5.160
5.150
5.140
5.130
5.120
5.110
(ppm)
25°C
5.20
5.19
5.18
5.17
5.16
5.15
5.14
endo
exo
5.13
5.12
5.11
5.10
5.09
5.08
5.07
5.06
5.05
5.04
5.03
5.02
5.160
5.150
5.140
(ppm)
1
5.070
5.060
5.050
5.040
5.030
5.130
5.120
5.110
exo
5.100
(ppm)
5.090
5.080
5.070
5.060
5.050
1M
1M
Figure 3.41:
5.080
-32°C
endo
5.21
5.090
5M
5M
5.22
5.100
(ppm)
H-NMR analysis of propionaldehyde/2,3-dihydrofuran photocycloaddition
reaction at 1M and 5M.
0,6
0,5
0,4
ln (endo/exo)
0,3
0,2
0,1
0,0
-0,1
-0,2
-0,3
2 + 1c (1M)
2 + 1c (5M)
-0,4
-0,5
-0,6
-0,7
0,0032
0,0036
0,0040
0,0044
0,0048
0,0052
-1
1/T (K )
Figure 3.42: Eyring plots of the Paternò-Büchi reaction of 2,3-dihydrofuran 2 with
propionaldehyde 1c at 1M and 5M in n-hexane.
Presumably, in this case an increase in concentration led to a low-temperature shift of the
inversion region (Figure 3.42). The reverse should be observed in reactions with their
inversion points at low temperatures; which could be shifted to higher temperature with
concentration variation.
In order to determine kinetic parameters out of the experimental results, we simulated the
curves shown in Figure 3.42 in collaboration with Dr. Gudipati. The simulations have been
carried out based on the following considerations: the amount of product Pj formed, which in
70
the present case is either the exo or endo oxetane 3 from the singlet and triplet channels, is
given by equation (1):
− Ej
P j = Aj • e RT (1)
with the four channels (j) being exo (j = 1) and endo (j = 2) from the singlet state, as well as
exo (j = 3) and endo (j = 4) from the triplet state of the aldehyde. As the lifetime of the S1
state of aliphatic aldehydes is of the order of ~1 ns,85 the reaction probability from the singlet
channel is further restricted by molecular diffusion in order to encounter the reaction partner
during the lifetime of the singlet state in diluted solutions. Under such conditions the
photophysical deactivation processes compete with the photochemical channels. Thus, in
dilute solutions, the probability of reaction from the singlet channel (RS) decreases and the
probability of triplet population (φ T ) increases. On the other hand, when the concentrations of
the aldehyde and olefin are increased, though one expects reaction from the singlet channels
to dominate, in reality other processes like collisional quenching of the excited singlet and
triplet aldehyde by the ground-state aldehyde can not be ignored. If the temperature is
lowered, then diffusion controlled diminution of the reaction from the singlet channel is to be
expected. Due to the ca. 200 times longer lifetime of the T1 state of the aldehyde (200-400
ns)85 the reaction probability (RT ) from the triplet channel should be less dependent on the
temperature. From previous studies we know that at concentrations above 1M, the reaction
takes place only through the singlet channel at room temperature. Normalized temperature
dependent reaction probabilities from the singlet and triplet channels with respect to room
temperature (300 K) can be approximated by equation (2a & 2b). Here n reflects the nonlinearity of the temperature dependent contributions from molecular diffusion, viscosity and
concentration.
RS = (T/300K)n
(2a)
RT = (1-RS) φ T
(2b)
From the concentration studies at 300K, we know the endo/exo ratios for pure singlet and
pure triplet channels.97 By using this information we can reduce the number of parameters as
follows:
300K
endo / exo
S
P2 A2
=
=
•e
P1 A1
− ( E2 − E1 )
300 R
 S 300K • A1 

E1 = E2 + 300R • ln  endo/ exo
A2


(3)
(4)
similarly, for the triplet channel:
71
 S 300K • A3 

E3 = E4 + 300R • ln  endo/ exo
A4


(5)
Thus, the temperature-dependent overall endo/exo ratio ∑ is given by equation (6).
Σ Tendo / exo =
RS P2 +(1− Rs) ΦTP4
RS P1 + (1 − R S )ΦTP3
(6)
The simulated endo/exo selectivity using these eight parameters for 1M and 5M
concentrations of propionaldehyde and dihydrofuran are shown in Figure 3.43.
0,8
0,6
ln(endo/exo)
0,4
0,2
0,0
-0,2
1c.1M
1c.5M
1c.1M
1c.5M
-0,4
(exp)
(exp)
(simulation)
(simulation)
-0,6
-0,8
0,0035
0,0040
0,0045
0,0050
-1
1/T (K )
Figure 3.43: Simulation of temperature dependence of the Paternò-Büchi reaction of 2,3dihydrofuran 2 with propionaldehyde 1c at 1M and 5M.
The reliability of the present simulations (notwithstanding the high number of parameters)
comes from the fact that after fitting the experimental data from 5M solutions, all the other
parameters were fixed and only n and φ T were varied to simulate the curve for the 1M data. It
should be noted that these variable parameters are not independent, but are highly correlated
with each other.
Table 3.14: Simulation parameter of the photocycloaddition of propionaldehyde with 2,3dihydrofuran at 1M and 5M.
Conc.
E1 [a]
E2
E3
E4
A1
A2
A3
A4
n
φT
5M
157
8992
-12.5
5.8
0.054
1.599
0.057
0.327
8.99
0.0079
1M
„
„
„
„
„
„
„
„
0.88
0.9975
[a] J/Mol.
72
The qualitative interpretation of the “selectivity-inversion” is as follows: from the singlet
channel the activitation barrier for the formation of the exo product is much smaller than for
the endo product. However, the pre-exponential factor for the endo product is larger than for
the exo product. With decreasing temperature, the exponential part dominates and more exo
product is formed than the endo product.
The situation is completely different for triplet channel, namely, the formation of both the
endo and exo products has almost no barrier whereas the pre-exponential factors favor the
formation of the endo product. Due to the lack of activation barrier for both the products, one
should expect no temperature dependence of endo/exo ratio from the triplet channel. This has
been experimentally proven, as discussed earlier, in the case of photocycloaddition of
benzaldehyde (1a) with 2 (vide supra). If in this case the reaction probabilities RS and RT were
not temperature dependent, then one should not observe any „selectivity inversion“. The
temperature dependent reaction probabilities RS and RT are reflected in the values n and φ T .
For the 5M data, n is large, reflecting faster decrease in the reaction probability (RS) from the
singlet channel. This may be due to quenching of the excited singlet aldehyde molecule by the
ground-state aldehydes. Similarly, the relative triplet quantum yield, φ T , is very small,
implying that at higher concentrations the majority of the excited singlet aldehyde molecules
undergo reaction or get deactivated. For the 1M data, n is small and the value RS decreases
less steeply with temperature and (1-RS) increases correspondingly from the initial value of 0
at 300 K. Simultaneously, the relative triplet population φ T is predicted to be close to unity.
Thus, both singlet and triplet channels compete with each other at 1M concentration. With
decreasing temperature, the triplet contribution increases. Due to larger endo/exo selectivity
from the triplet channels (5.6)97 with decreasing temperature, the total endo/exo ratio
increases steadily.
The simulations do not indicate an abrupt change in the selectivity correlation like in
isoinversion curves,68 but a inversion region as described by Hale and Ridd.99
73
___________________________________________________________________________
3.5 Paternò-Büchi reactions of cis and trans cyclooctene with aliphatic aldehydes
3.5.1 Synthesis of trans-cyclooctene
Trans-cyclooctene was not commercially available and was prepared by photoisomerisation
of cis-cyclooctene using dimethylisophthalate as a sensitizer.100 Another method was applied
to improve the yield.101 In this method, trans-cyclooctene was obtained by irradiation of a
solution of Cu2 Cl2 in a 2.6 fold excess of cis-cyclooctene at 250 nm for 24h. Unisomerized
cis-cyclooctene was removed in vacuo and the Cu(I) salts were successively extracted with
aqueous ammonia and cyanide. Separation of trans from cis was accomplished by taking
advantage of the better solubility of trans-cyclooctene in aqueous silver nitrate solution.
hν
hν
Cu 2Cl2
CO2 CH3
(E)-17
(Z)-17
(Z)-17
CO2CH3
Scheme 3.24: Synthesis of trans-cyclooctene.
3.5.2 Irradiation of cis-cyclooctene with propionaldehyde
The [2+2]-cycloaddition of propionaldehyde with cis-cyclooctene in benzene afforded three
products with high chemoselectivity.
H
O
H
hν
benzene
+
H
O
H
1c
(Z)-17
H
O
+
O
+
H
cc-18
tc-18
H
tt-18
Scheme 3.25: Paternò-Büchi reaction of cis-cyclooctene with propionaldehyde.
The relative configurations of the cis-fused oxetanes cc-18 and tc-18 were determined by
proton and carbon chemical shift comparison with literature data57,70,74 and CH-COSY. The
assignment of the configuration of the trans-fused product tt-18 resulted from a comparison
of chemical shift data of the oxetane ring hydrogen and carbon resonates with the structurally
related tc-18 (see Table 3.15 & experimental section).
74
___________________________________________________________________________
Table 3.15: Comparison of the
1
H-NMR chemical shift (δ ppm ) of Ha of cyclooctene-
propionaldehyde photoadducts with cyclohexadiene-propionaldehyde photoadducts.
H
H
H
O
O
O
H
H
O
O
Compound
H
a
δ ppm ( H )
Ha
H Ha
Ha
H
Ha
H
H
Ha
cc-18
cc
tt-18
tc-18
tc
4.63
4.63
4.25
4.13
3.89
When the substrate concentration was lowered from 5M to 0.01M, a distinct sharp increase in
the relative amount of trans-fused oxetane tt-18
resulted between 3 and 1M concentration
(Figure 3.44 & 3.45).
45
rel.composition (%)
40
35
tt-18
tc-18
cc-18
30
tc
cc cc
tc
25
tt
85.8
85.6 85.4
84.8 84.6
20
15
tt
tt
85.2 85.0
cc
tc
84.4 84.2 84.0
83.8 83.6
(ppm)
83.4 83.2
83.0 82.8
82.6 82.4
82.2 82.0
86.0 85.8
85.6 85.4
84.8 84.6
10
0,01
cc cc tc
tt
86.0
0,1
1
85.8 85.6 85.4
84.4 84.2 84.0 83.8
(ppm)
83.6 83.4
3M
tc
tc tt
tc
tt
85.2 85.0
4M
propionaldehyde +
cis-cyclooctene
cc
83.2 83.0
82.8 82.6
cc
tt
82.4 82.2
cc
tc
tt
85.2 85.0
84.8 84.6 84.4
84.2 84.0
(ppm)
83.8 83.6 83.4
83.2 83.0
82.8 82.6
82.4 82.2
86.4 86.2 86.0 85.8 85.6
85.4 85.2 85.0 84.8 84.6
84.4 84.2 84.0 83.8 83.6
(ppm)
83.4 83.2 83.0 82.8 82.6
82.4
1M
2M
10
concentration of cis-cyclooctene (Mol/l)
Figure 3.44: Concentration dependence of the Figure 3.45:
photocycloaddition of propionaldehyde to cis- stereoismers
cyclooctene.
13
C-NMR analysis of
of
the
propionaldehyde
cycloaddition to cis-cyclooctene.
Additionally, the ratio between the cis-fused exo and endo-configurated diastereoisomers cc18 and tc-18 did respond to changes in concentrations in a similar fashion as already
determined for less complicated cases, i.e. the Paternò-Büchi reaction of aliphatic aldehydes
to cyclic enol ether. At high substrate concentrations preferentially singlet reactivity was
observed with low (simple) endo/exo-selectivity whereas at low concentrations the endodiastereoisomer dominated with a limiting endo/exo ratio of 58 : 42.
75
___________________________________________________________________________
Fluorescence quenching of propionaldehyde by cis-cyclooctene was observed and from the
concentration dependence (Stern-Volmer analysis) the bimolecular quenching rate constant of
2.2 x 108 m-1 s-1 was determined (Figure 3.46 & 3.47).85
0.00
0.02
0.04
0.06
0.08
0.10
0.50
1.00
450
1,05
1,04
350
300
1,03
y = 1.00333 + 0.4 x
250
F0/F
Rel.fluorescence intensity
400
M cyclooctene
M
M
M
M
M
M
M
200
1,02
150
1,01
100
50
1,00
0
320
340
360
380
400
420
440
460
480
500
520
0,00
0,02
0,04
Wavelength/nm
Figure
3.46:
Fluorescence
0,06
0,08
0,10
0,12
[cyclooctene]
quenching
of Figure
3.47: Stern-Volmer plot for the
propionaldehyde (0.2M) by cis-cyclooctene fluorescence
(0.02 – 1.00 M) in benzene at 25°C.
quenching
of
propionaldehyde
by cis-cyclooctene.
The change from the singlet-determined to triplet determined stereoselectivity occurs parallel
to the increase in trans-isomer tt-18 formation indicating that the triplet 1,4-biradical involved
in the photocycloaddition of the triplet excited aldehyde to (Z)-17 preferentially converts to
the singlet potential energy hypersurface at points which essentialy differ from the
corresponding reaction channel involving the singlet excited carbonyl species. It was also
striking to find that only one out of the two possible diastereoisomeric trans-fused oxetanes
was formed: only isomer tt-18 was detected and none (i.e.< 5 %) of the ct-isomer. The low
content of tt-18 at high substrate concentrations (Figure 3.44) indicated that this product is
predominantly formed via the triplet 1,4-biradical. Thus, the diastereoselectivity of the triplet
photocycloaddition path in the reaction of propionaldehyde to cis-cyclooctene is remarkably
higher for the formation of trans-fused products than as for the formation of cis-fused
products.
3.5.3 Irradiation of trans-cyclooctene with propionaldehyde
In order to compare this selectivity behavoir with the reactivity of trans-cyclooctene ((E)-17),
the product pattern of the photocycloaddition of propionaldehyde to mixtures of (Z)-17 and
(E)-17 with increasing amounts of the trans-isomer was investigated.
76
___________________________________________________________________________
H
O
H
hν
benzene
+
H
O
O
+
H
1c
(E)-17
H
O
+
H
cc-18
H
tc-18
tt-18
Scheme 3.26: Paternò-Büchi reaction of trans-cyclooctene with propionaldehyde.
The oxetane compositions of the photoadducts were detected from 2M starting material
concentration; the results are depicted in Figure 3.48.
tt-18
tc-18
cc-18
45
rel.composition (%)
40
35
30
25
20
15
0
25
50
75
100
% t r a n s- c y c l o o c t e n e
Figure 3.48: Photocycloaddition of propionaldehyde with a mixture of cis & transcyclooctene.
Figure 3.48 shows that, even from high proportions of trans-17, only the tt-18 isomer was
detected and none of ct-18. This shows that the 1,4-triplet biradicals preceding the formation
of tt-18 are identical from cis-17 and trans-17. The selectivity values have been corrected to
low conversions and thus the appearance of tt-18 is not connected to cis-trans isomerisation
of cis-17 under the reaction conditions.
3.5.4 Irradiation of cis-cyclooctene with acetaldehyde
Analogous to propionaldehyde, the photocycloaddition of cyclooctene with acetaldehyde
furnished three diastereoisomers cc-19, tc-19 and tt-19.
H
O
H
hν
benzene
+
H
O
H
1b
(Z)-17
H
O
+
O
+
H
cc-19
tc-19
Scheme 3.27: Paternò-Büchi reaction of cis-cyclooctene with acetaldehyde.
77
H
tt-19
___________________________________________________________________________
Again, the relative configurations of the photoadducts were unambiguously assigned from the
1
H-NMR spectroscopy of the crude reaction mixture and reconfirmed by comparison with
data from cyclohexene-acetaldehyde photoadduct (Table 3.16).
Table 3.16: Comparison of the
1
H-NMR chemical shift (δ ppm ) of Ha of cyclooctene-
acetaldehyde photoadducts with cyclohexene-acetaldehyde photoadducts.
H
H
H
O
H
H
O
O
O
O
Compound
Ha
H
a
δppm ( H )
H
cc-19
cc
4.94
4.94
Ha
H
Ha
H
Ha
H
Ha
tt-19
tc-19
tc
4.44
4.55
4.36
Under high concentration conditions (> 3M) less than 10 % of tt-19 was formed beside a 1 : 1
mixture of cc-19 and tc-19, wheras under low concentration conditions (< 0.05M) 62 % of tt19 was observed together with 38 % of a 2 : 1 mixture of cc-19 and tc-19 (Table 3.17). Thus,
the tt-isomer is formed by singlet/triplet photocycloaddition of 1b to trans-cyclooctene as
well as by triplet photocycloaddition of 1b to cis-cyclooctene.
Table 3.17: Concentration dependence of the diastereoselectivity of the acetaldehyde/ciscyclooctene photocycloaddition reaction.
Conc. (M)
d.r. (cc-19 : tc-19 : tt-19)[a]
5
45.6 : 46.9 : 7.5
3
46.4 : 41.9 : 11.7
2
43.7 : 37.4 : 18.9
1
46.3 : 32.8 : 20.9
0.5
45.6 : 31.2 : 23.2
0.1
43.3 : 26.3 : 30.4
0.05
39.6 : 22.0 : 38.4
0.025
40.6 : 21.2 : 38.2
The results indicate a moderate but still significant spin correlation effect in the Paternò-Büchi
reaction of cyclooctenes with aliphatic aldehydes; the exo-diastereoisomers tc-18, tc-19 were
formed with similar probablity than the endo-diastereoisomers cc-18, cc-19 in the singlet
78
___________________________________________________________________________
manifold of the excited carbonyl species, whereas the triplet excited aldehydes preferred the
formation of the endo-diastereoisomeres cc-18, cc-19 and the trans-fused products tt-18, tt19.
cis-17
3 O
trans-17
*
3 O
*
R
H
R
R
H
O
H
H
O
H
3
H
3
BRc
H
BRt
H
O
O
H
R
R
H
cc-18,19
R
tt-18,19
Scheme 3.28: Mechanistic scenario for the cyclooctene triplet photocycloaddition reaction
from (Z)- and (E)-17.
The preference of endo-isomers in triplet photocycloaddition reaction can be rationalized on
the basis of the already described spin-orbit coupling (SOC) model which controls
intersystem crossing geometries favorable for product formation from the triplet 1,4-biradical
intermediate,51 a concept which has recently been corroborated by a profound ab initio
study.32 Following the classical “ 90° rule ” as originally described in the Salem rules,28 the
triplet 2-oxatetramethylene biradical intermediate 3 BRc (Scheme 3.28) is expected to prevail
due to minimized steric interactions between the substituent R and the localized hydrogen
atom at C-4. The radical-radical combination is coupled to a torque (indicated by the curved
arrow) leads to the endo-(cc) diastereoisomer. In competition with this process, bond rotation
about the central C-C single bond driven by release of gauche strain generates the isomeric
triplet biradical intermediate
3
BRt which exhibits a similar orbital orientation minimizing
steric interactions. In this case, however, the formation of the trans-trans-diastereoisomer is
largely preferred because the biradical conformer
3
BRt preceding the terminating bond
formation has an optimal substituent orientation. The alternative structure leading to the ctisomer is reasonably expected to be much higher in energy due to severe steric replusion
between the R group and the trans-cyclooctene ring.
79
___________________________________________________________________________
3.6 Paternò-Büchi reactions of allylic alcohols and acetates with aldehydes
The following questions were addressed in this investigation: (a) is there a specific spindirecting effect connected with hydrogen-bonding, (b) do hydrogen-bonding interactions
influence induced as well as noninduced (simple diastereoselectivity) of the Paternò-Büchi
reaction?, (c) does hydrogen-bonding effects the rate of the Paternò-Büchi reaction?
The role of hydrogen-bonding interactions in the Paternò-Büchi reaction of allylic alcohols
can be easily tested by comparison of the free alcohols with O-protected substrates, i.e. the
corresponding acetates.
3.6.1 Synthesis of allylic alcohols and acetates
Two allylic alcohols were used in this study, prenol 21, which was commercially available
and mesitylol 22 which was prepared via reduction of mesityl oxide in dry ether with
LiAlH4 .102
O
OH
LiAlH4
ether
20
22
Scheme 3.29: Synthesis of mesitylol.
Stirring of an equimolar ratio of prenol as well as mesitylol with acetic anhydride in the
presence of catalytic amount of pyridine at room temperature, respectively, led to formation
of the corresponding allylic acetates 23103 and 24,104 in high yields.
OAc
OH
(CH 3CO) 2O
R
R
pyridine
21 R= H
23 R= H
22 R= CH 3
24 R= CH 3
Scheme 3.30: Synthesis of prenyl acetate and mesityl acetate.
3.6.2 Simple diastereoselectivity
3.6.2.1 Photolysis of prenol with aldehydes
As a typical triplet precursor, benzaldehyde 1a was irradiated in benzene in the presence of
prenol 21. Additionally, three aliphatic aldehydes (acetaldehyde 1b, propionaldehyde 1c & 3-
80
___________________________________________________________________________
methylbutyraldehyde 1d) which can react either from their singlet as well as triplet excited
states were applied (all substrate 0.1M).
OH
OH
O
R
hν
benzene
0.1M
+
H
OH
1a-d
O
O
+
R
R
21
cis-25a-d
trans-25a-d
Scheme 3.31: Paternò-Büchi reaction of prenol with aldehydes.
Table 3.18: Simple diastereoselectivity of the photocycloaddition of 1a-d with 21.
Entry
R
d.r. (cis : trans)[a]
Yield (%)
A
Ph
> 97 : 3
80
B
Me
81 : 19
85
C
Et
86 : 14
86
D
Bui
83 : 17
82
The structure of oxetanes were assigned on the basis of the spectroscopic analyses (1 H-NMR
and
13
C-NMR) and mass spectra. In the 1 H-NMR spectrum, the hydrogen on the carbon α to
oxygen of an oxetane ring has a chemical shift 4.00 - 4.45 ppm which in good agreement with
the data reported by Arnold.105 The mass spectra of compound 25a and 25c support the
oxetane structure but are not conclusive for their structure. The molecular ion peaks are not
observed (usual situation for oxetanes)106 and the most important fragmentation is cleavage to
OH
6.0
Figure 3.49:
5.5
5.0
1
spectrum of 25a.
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
2.7632
2.8941
Ph
1.0515
0.9550
0.8461
0.8776
4.7570
6.5
17.0171
O
Ph
7.0
27.6760
OH
O
7.5
42.0784
63.2423
89.4098
87.7541
139.3931
133.3567
130.0674
128.3532
128.1115
127.3862
124.9394
0.6708
1.3894
3.9060
3.8815
3.8663
3.8413
3.7076
3.6934
3.6674
3.6532
4.6367
4.6264
4.6122
5.4841
7.2552
7.2498
7.2287
prenol and a charged carbonyl fragment, the latter then undergoing further decomposition.
1.0
0.5
140
130
120
110
H-NMR (300 MHz, CDCl3 ) Figure 3.50:
100
13
spectrum of 25a.
81
90
80
(ppm)
70
60
50
40
30
20
C-NMR (75 MHz, CDCl3 )
17.5519
15.5153
27.6687
39.3898
63.1178
85.2341
87.7322
1.1939
1.1915
1.1729
1.1332
1.0122
3.7365
3.7149
3.6963
3.6748
3.6331
3.6189
3.5930
3.5788
4.5388
4.5172
4.4962
4.4746
4.3801
4.3654
4.3585
4.3438
___________________________________________________________________________
OH
OH
O
4.8
4.4
4.0
Figure 3.51:
3.6
1
3.2
2.8
(ppm)
2.4
2.0
1.6
2.6419
5.4823
2.1607
0.9005
0.9973
Integral
O
1.2
0.8
90
85
80
75
70
65
13
H-NMR (300MHz, CDCl3 ) Figure 3.52:
spectrum of 25b.
60
55
50
(ppm)
45
40
35
30
25
20
15
C-NMR (75MHz, CDCl3 )
spectrum of 25b.
From all substrate combinations, the cis-oxetanes were formed as the major diastereoisomers
in good yields. The relative configurations of the major diastereoisomers were unambiguously
determined from the NOE effects which were detected for one of the gem-methyl groups at
the oxetane ring by saturation of both methine hydrogens at C-2 and C-4 of 25c (Figure 3.53
& 3.54). NOE enhancements were also detected for the methylene hydrogens of the
hydroxymethyl and the ethyl substituents at C-2 and C-4 by saturation of the second methyl
group. The pseudoaxial methyl group at C-3 (δ = 0.83 ppm) is shifted upfield by ca. 0.2 ppm
with respect to the other methyl (δ = 0.98 ppm).
4.00 ppm
H
H
4.10 ppm
CH3
CH2-OH
H3C-H2C
0.63 ppm
O
3.41 ppm
CH3
0.83 ppm
Figure 3.53: NOE-effects for oxetane 25c.
The diastereomeric values were nearly identical for the three aliphatic aldehydes but higher
with benzaldehyde (> 97 : 3) (Table 3.18).
82
___________________________________________________________________________
CH3
CH 3
CH3
H4
H2
CH2OH
CH2 CH 3
Figure 3.54: NOESY (300 MHz, CDCl3 ) spectrum of compound 25c.
3.6.2.2 Photolysis of prenyl acetate with aldehydes
Analogous to prenol, the [2+2] photocycloaddition reaction of prenyl acetate with aldehydes
in benzene afforded two diastereoisomers cis-26a-d and trans-26a-d in good yield.
OAc
O
R
1a-d
H
OAc
hν
benzene
0.1M
+
23
OAc
O
O
+
R
R
cis-26a-d
trans-26a-d
Scheme 3.32: Paternò-Büchi reaction of prenylacetate with aldehydes.
83
___________________________________________________________________________
Table 3.19: Simple diastereoselectivity of the photocycloaddition of 1a-d with 23.
Entry
R=
d.r. (cis : trans)[a]
Yield (%)
A
Ph
93 : 7
75
B
Me
77 : 23
80
C
Et
81 : 19
83
D
Bui
80 : 20
85
The chemical structure of compounds 26a-d were established by IR, 1 H-NMR,
13
C-NMR and
mass spectrometry. The 1 H-NMR showed signals at δ 4.53 and 4.64 ppm indicated two
methine hydrogens on carbons α of oxetanes ring. The
13
C-NMR spectra of compounds 26a-d
showed signal at δ 39 ppm for the quaternary carbon confimed the regioselective addition of
aldehydes to prenyl acetate. In the IR spectra, the peak at 1710 cm-1 suggests the presence of
(C=O) carbonyl ester group.
Interestingly, the diastereomeric cis/trans
ratio of compounds 26a-d
slightly decreased by
OAc
6.5
6.0
Figure 3.55:
5.5
1
spectrum of 26a.
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
20.8778
17.1270
27.4489
3.1182
2.9851
3.1232
Ph
1.7933
0.9960
1.0000
Integral
5.2924
7.0
42.4227
O
Ph
7.5
64.7954
OAc
O
8.0
84.4429
89.3878
128.1188
127.4375
125.0054
139.2905
170.9156
0.6812
1.3953
2.0781
4.7156
4.6994
4.6926
4.6764
4.2518
4.2341
4.2283
4.2175
5.4694
7.3380
7.3189
7.2738
7.2611
7.2518
7.2400
7.2356
comparison with compounds 25a-d (Table 3.19).
170
1.0
160
150
140
130
spectrum of 26a.
84
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
20.8338
17.5226
15.5813
27.1486
39.8440
65.2203
85.1389
84.3843
170.8863
1.2087
1.2038
1.1871
1.0333
2.0369
4.5491
4.5275
4.5065
4.4898
4.4756
4.4643
4.4501
4.2136
4.1994
4.1744
4.1597
4.1332
4.1078
4.0936
4.0681
___________________________________________________________________________
OAc
OAc
O
4.8
4.4
4.0
Figure 3.57:
3.6
1
3.2
2.8
(ppm)
2.4
2.0
1.6
2.7402
5.6531
3.0874
2.0537
1.8544
Integral
O
170
1.2
160
150
140
130
spectrum of 26b.
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of 26b.
Conclusion I
The regioselectivity of the Paternò-Büchi reaction with prenol as well as prenyl acetate is high
and corresponds to the classical biradical stablization concept.107 The comparison shows that
hydrogen-bonding effects are not responsible for controlling the product regioselectivity. The
simple diastereoselectivity is moderately high for aliphatic aldehydes reacting with prenol and
very high for benzaldehyde with prenol. Comparing these numbers with prenyl acetate shows,
that hydrogen-bonding effects might slightly increase the simple diastereoselectivity, but also
other reasons like steric effects might explain the marginal differences.
From the numbers in Table 3.18 & 3.19, one can unambiguously derive that the triplet excited
carbonyl state reacts highly cis-selective with prenol and prenyl acetate. This effect strongly
resembles the pronounced endo-selectivity which was observed for the Paternò-Büchi
reaction of aromatic aldehydes with cycloalkenes. This contrathermodynamic selectivity is
again rationalized by the assumption of spin-orbit coupling (SOC) controlled intersystem
crossing (ISC) geometries at the stage of the triplet 1,4-biradical (1,4- 3 BR). Optimal φ-values
for strong SOC are in the range of 90° ± 10°. This model presupposes conformational mobilty
at this intermediate stage in contrast to the reaction of singlet excited carbonyl states where
conical intersections guide the substrates to the cycloaddition products nearly barrier-free.51 A
view along the central C-C bond of the intermediate triplet 1,4-biradical (Figure 3.59) shows
the relevant contribution to this high degree of stereocontrol: increasing gauche interactions
are expected for biradical approach from the same half space as the hydroxymethyl or
acetoxymethyl group, respectively.
85
___________________________________________________________________________
.........................
O
.........................
φ
OR2
R
R
R1
H
H
CH3
H3C
1,4-3BR
Figure 3.59: Simple diastereoselecectivity: triplet 1,4-biradical geometries from prenol
substrates.
Thus, the approach of the two radical centers is expected to proceed preferentially as shown in
Figure 3.59 leading to the cis-diastereoisomer. An additional internal hydrogen-bonded
between the primary hydroxy group and the oxygen atom at position 2 of the 1,4- 3 BR slightly
increases this conformational preference.
3.6.3 Spin-directed simple diastereoselectivity
In order to evaluate the differences in simple diastereoselectivity of the Paternò-Büchi
reaction in the singlet and in the triplet channel, the concentration dependence of the reaction
of propionaldehyde with prenol and prenyl acetate was investigated. As already described for
analogous reactions with 2,3-dihydrofuran as alkene component, the spin profile of a
bimolecular photochemical reaction can be traced by variation of substrate concentrations
provided that the lifetime of the excited singlet state allows diffusion-controlled processes.
This is the case of aliphatic aldehydes which have lifetimes in the 1-2 ns range.85
% cis-diastereoisomer 25c, 26c
95
90
85
80
75
70
65
0,01
prenol + EtCHO
prenyl acetate + EtCHO
0,1
alkene [Mol/l]
1
Figure 3.60: Concentration dependence of the propionaldehyde photocycloaddition with
prenol and prenyl acetate.
86
___________________________________________________________________________
At higher alkene concentration (alkene and aldehyde were used in equimolar concentrations)
the simple cis/trans-stereoselectivity is identical (ca. 2 : 1) with both substrates prenol and
prenyl acetate. In the low concentration region, the selectivity increases constantly to values >
9 : 1 always with the prenol reactions being slightly more selective.
Conclusion II
The curvature of the spin map indicates, that very high selectivities are expected for “pure”
triplet reactions, whereas the singlet excited carbonyls only give moderate selectivities. This
perfectly corresponds to the results on the spin-directed Paternò-Büchi reaction with cyclic
alkenes and clearly shows that the SOC-determined ISC-geometry model is a powerful
rationale for explaining simple diastereoselectivites originating from 1,4-triplet biradical
combination.
3.6.4 Enhanced reactivity of allylic alcohols
Competition experiments were performed in order to examine the difference in reactivity
comparing free and O-protected allylic alcohols. As a standard olefin, 2,3-dihydrofuran in
equimolar concentrations (1.0M) as the aldehyde and the acylic alkene was applied.
OR1
OR1
O
R
+
H
+
O
1
23 R = Ac
1
:
1
:
O
O
+
R
21 R1= H
2
1
hν
benzene
25
R1= H
26
R1= Ac
R
O
3
1
Scheme 3.33: Competition experiments.
Table 3.20: Results of competition experiment.
Entry
R=
R1 =
Conc. (M)
25,26 : 3[a]
A
Ph
H
1.0
47 : 53
B
Et
H
1.0
55 : 45
C
Et
H
0.01
60 : 40
D
Et
Ac
1.0
13 : 87
Firstly, benzaldehyde was applied as precursor to a triplet excited carbonyl state: from the
ratio of prenol-cycloadduct 25a and the adduct with dihydrofuran 3, it was concluded that the
87
___________________________________________________________________________
alkenes have similar reactivities toward triplet excited carbonyls (Table 3.20, entry A). In a
second
experiment,
propionaldehyde
was
used
in
high
(1.0M)
and
low
(0.01M)
concentrations in order to trace spin effects. The triplet reactivity of propionaldehyde was
slightly higher with prenol than with 2,3-dihydrofuran, an effect which vanished with
increasing amount of singlet-derived products (Table 3.20, entry B,C). When prenyl acetate
was applied, the adduct 26c was observed in minor quantities and the dihydrofuran adduct
prevailed. Thus, the reactivity difference between prenol and prenyl acetate is about a factor 3
which can originate either from hydrogen bonding interactions or simply from the electronic
deactivation of the alkene.
3.6.5 Induced and simple diastereoselectivity with chiral allylic alcohols
3.6.5.1 Photolysis of mesitylol with aliphatic aldehydes
When the aliphatic aldehydes, which gave moderate simple diastereoselectivities with prenol,
were irradiated with mesitylol, only one cis-diastereoisomers were obtained in high (induced)
threo-diastereoselectivities (>95 : 5) from the NMR analysis of the crude reaction mixture.
This result is fitted well with the results published by Adam in the photocycloaddition of the
triplet excited benzophenone with chiral allylic alcohols.73
OH
O
R
1b-d
H
OH
hν
benzene
1M
+
22
O
R
threo-27b-d
d.r. > 95 : 5
Scheme 3.34: Paternò-Büchi reaction of mesitylol with aliphatic aldehydes.
The chemical structure of the compounds 27b-d were assigned by 1 H-NMR and
analyses. Again, the
13
13
C-NMR
C-NMR spectrum showed a signal at δ 40.0 ppm for the quaternary
carbon and confirmed the regiochemical addition of mesitylol to aldehydes. The IR spectra of
compounds 27b-d exhibit a broad absorption bands at 3300 cm-1 to the free OH group.
88
OH
3.6
Figure 3.61:
3.2
1
2.8
(ppm)
2.4
2.0
1.6
8.8270
15.1271
3.4024
2.9554
2.9545
3.4146
2.4637
O
1.0344
1.0072
Integral
1.0000
4.0
17.7204
OH
O
4.4
27.1632
24.6212
39.1920
67.0517
90.4793
89.0654
1.6250
1.5672
1.5417
1.5310
1.5168
1.5094
1.5070
1.4849
1.4604
1.4261
1.3698
1.1372
1.1039
1.0181
0.9951
0.9746
0.8575
0.8325
0.8075
4.1935
4.1724
4.1680
4.1465
3.9285
3.9006
3.8545
3.8364
3.8159
3.7948
3.7874
3.7742
3.7669
3.7473
___________________________________________________________________________
1.2
0.8
90
85
80
75
70
65
13
spectrum of 27c.
60
55
50
45
(ppm)
40
35
30
25
20
15
10
spectrum of 27c.
3.6.5.1 Photolysis of mesityl acetate with acetaldehyde
In contrast to mesitylol, when the mesityl acetate was reacted with acetaldehyde, a mixture of
all four diastereoisomers resulted, and the threo/erythro-selectivity for the cis-isomers
dropped.
OAc
O
H
1b
OAc
hν
benzene
1M
+
24
OAc
O
56
O
+
threo-28b
:
OAc
25
O
+
threo-28b
:
OAc
O
+
erythro-28b erythro-28b
12
:
7
Scheme 3.34: Paternò-Büchi reaction of mesityl acetate with acetaldehyde.
The relative configuration of the four stereoisomers of compound 28b was assigned by
comparing the chemical shifts of the methine hydrogen in the oxetane ring with the literature
data from Adam group.73a,b
Conclusion III
In light of the mechanistic picture shown in Figure 3.59, an increase in bulk of the
hydroxyalkyl chain is expected to lead to an increase in simple diastereoselectivity due to
increasing steric interaction in one half-space of the ISC-reactive conformer. This effect was
also apparent for the corresponding allylic acetate and thus is not coupled with hydrogenbonding interactions and also vanishes in the singlet manifold (Figure 3.60). When allylic 1,389
___________________________________________________________________________
strain operates (as in substrates 22 & 24), an additional selectivity increase is observed which
is connected with hydrogen-bonding interaction with singlet as well as triplet excited carbonyl
states prior to bond formation. Surprisingly, also the induced (threo) stereoselectivity was also
high with aliphatic aldehydes. This fact, in contrast to the simple diastereoselectivity, cannot
be explained by assuming SOC-determined ISC-geometries, because at the given substrate
concentrations a noticeable amount of singlet reactivity must be assumed (Scheme 3.36). Also
this singlet path gives rise to high selectivity and thus hydrogen bonding interaction in the
singlet as well as triplet channel prior to bond formation is most probably.
OR2
R
3
OR2
O
3
+
H
R3
R1
O
R1
1
O
+
H
R1
OR2
R3
OR2
R3
O
R1
O
R1
3
high simple d.s. for R3 = H
high simple and induced d.s.
for R3 =CH3 and R2 =H
low simple d.s. for R = H
high simple and induced d.s.
for R3 =CH3 and R2 =H
Scheme 3.36: Mechanistic scenario for singlet and triplet Paternò-Büchi reaction of allylic
alcohols and acetates.
90
___________________________________________________________________________
3.7 Diastereoselective photochemical synthesis of α-amino-β
β -hydroxy carboxylic acid
derivatives by photocycloaddition of carbonyl compounds to oxazoles
The interest in α-amino-β-hydroxy acids, a class of primary metabolites, is based on their
biological activity as enzyme inhibitors and as starting materials for the synthesis of complex
molecules.108 For example, β-hydroxy tyrosine and β-hydroxy phenylalanine derivatives are
found as parts of clinically important glycopeptide antibiotics, which include teicoplanin,
ristocetin, actaplanin A4696 and A33512b.109 The “photoaldol route” has been initially
developed by Schreiber et al. as a powerful photochemical tool for the synthesis of threo βhydroxy carbonyls compounds.110 Recently, Griesbeck and Fiege reported on the first
example of oxazole-carbonyl photocycloaddition as an efficient route to erythro α-amino-βhydroxy ketones.81 It was thus of interest to extend the photo aldol route to the synthesis of αamino-β-hydroxy acids which could be accessible via photocycloaddition reaction of 5methoxy oxazoles with carbonyl compounds.
3.7.1 Synthesis of oxazole substrates
3.7.1.1 Synthesis of 5-methoxy-2-methyl oxazole
5-Methoxy-2-methyl oxazole was prepared from glycine via protection as the glycine methyl
ester hydrochloride, followed by acylation with acetyl chloride in the presence of triethyl
amine to give 31 which upon heating with POCl3 in chloroform afforded oxazole 32 in good
yield.111,112
H2N
(i) 0-10°C
+ CH3OH/SOCl2 (ii) ∆, 3h.
CO2H
-
+
ClH3N
30
29
O
-
+
ClH3N
CO2CH3
CO2CH3
+
Cl
TEA/CHCl3
0°C, 30 min.
AcHN
CO2CH3
31
30
AcHN
CO2CH3
POCl3/CHCl3
∆, 6h.
31
N
H3C
O
OCH3
32
Scheme 3.37: Synthesis of 5-methoxy-2-methyl oxazole.
The structure of compound 32 was established on the basis of spectroscopic data. For
example, the IR spectrum showed two absorption bands at 1589 and 1625 cm-1 correspond to
91
___________________________________________________________________________
the presence of C=N and C=C groups, respectively. The 1H-NMR spectrum shows the
N
7.2
6.8
6.4
6.0
H3C
5.2
4.8
4.4
(ppm)
4.0
13.8744
OCH3
O
3.2861
3.0000
O
5.6
58.4147
N
OCH3
0.9683
Integral
H3C
97.7757
152.0226
160.4545
2.2730
3.7938
5.8691
olefinic hydrogen resonance at 5.87 ppm.
3.6
3.2
2.8
2.4
2.0
160
150
140
130
120
Figure 3.63: 1H-NMR spectrum (300 MHz, Figure 3.64:
13
110
100
90
(ppm)
80
70
60
50
40
30
20
10
C-NMR spectrum (75 MHz,
CDCl3) of 32.
CDCl3) of 32.
3.7.1.2 Synthesis of 4-substituted 2-methyl-5-methoxy oxazoles
A convenient method for the synthesis of 5-methoxy oxazoles with additional substituents at
position C-4 is the reaction of an N-acetyl-L-aminoacid methyl ester with PCl5 as dehydrating
agent following a Robinson-Gabriel synthesis as shown in Scheme 3.38.113,114,115
R
H2N
R
CO2H
+ CH3OH/SOCl2
(i) 0-10°C
(ii) ∆, 3h.
-
+
ClH3N
R= Me, Et, n-Pr, i-Pr,i-Bu, sec-Bu
33a-f
R
-
+
ClH3N
+
34a-f
R
O
CO2CH3
CO2CH3
Cl
TEA/CHCl3
0°C, 30 min.
AcHN
CO2CH3
35a-f
34a-f
R
R
AcHN
CO2CH3
PCl5/CHCl3
∆, 15min.
35a-f
N
H3C
O
36a-f
Scheme 3.38: Synthesis of 4-substituted 2-methyl-5-methoxy oxazoles.
92
OCH3
___________________________________________________________________________
Table 3.21: Characteristic properties of 4-substituted 2-methyl-5-methoxy oxazoles.
1
H-NMR[a]
Compound
R=
36a
Me
3.83
36b
Et
36c
13
C-NMR[b]
B.p10 torr (°C)
Yield (%)
111.2
61-63
60
3.77
117.1
64-67
74
n-Pr
3.77
115.6
75-78
68
36d
i-Pr
3.75
121.1
71-73
65
36e
i-Bu
3.74
114.8
86-88
70
36f
sec-Bu
3.79
119.9
89-93
75
[a] chemical shift of OCH3 in ppm, [b] chemical shift of C-4 in ppm.
The chemical structures of compounds 36a-f were established on the basis of rigorous
spectroscopic (UV, IR, 1H-NMR,
13
C-NMR) and elemental analyses. The UV spectra of 5-
methoxy-2-methyl oxazoles exhibit one major band of strong intensity at 245-270 nm. Alkyl
substitution on oxazole ring has little effect on the position and intensity of this band. The IR
spectrum of 2,4-dimethyl-5-methoxy oxazole 36a shows a strong band at 1555-1598 cm-1
which was assigned to the –N=C-O ring stretching frequency. This band is shifted to higher
frequency when an additional alkyl substituent is introduced to the oxazole ring either in C-2
or C-4 position. In the 1H-NMR spectra of 5-methoxy oxazoles, the methoxy group absorbs at
around 3.7 ppm and the CH3 at position C-2 absorbs at 2.00 ppm. The
13
C-NMR spectra of
14.0795
13.5594
21.6689
26.4526
61.1911
115.5625
154.5646
151.8834
0.8585
0.8340
0.8090
1.5741
1.5496
1.5246
1.4996
1.4751
1.4511
2.2588
2.2348
2.2314
2.2265
2.2088
3.7747
oxazoles showed two signals at 152 and 154 ppm assigned to the C-2 and C-5, respectively.
N
N
OCH 3
7.0
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
1.0
160
150
140
130
120
CDCl3) of 36c.
O
OCH 3
3.0152
2.8191
7.5
1.8151
H3C
Integral
O
4.9820
H3C
110
13
CDCl3) of 36c.
93
100
90
80
(ppm)
70
60
50
40
30
20
10
14.0650
13.5449
21.6544
26.4381
61.1766
___________________________________________________________________________
N
H3C
75
70
65
60
55
50
OCH 3
O
45
40
(ppm)
35
30
25
20
15
10
5
Figure 3.67: DEPT spectrum (75 MHz, CDCl3) of 36c.
3.7.2 Photoreactions of 5-methoxy-2-methyl oxazole with aldehydes
First of all, the photoreactions (λex = 300 nm) of aldehydes (0.05M) with 5-methoxy-2-methyl
oxazole (0.05M) were performed in 50 mL benzene at 10°C. In all cases, exo-selective (>98 :
2) formation of the 4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-enes 38a-f was observed in medium
yields (Table 3.22).
H3C
H
O
N
O
OCH3
+
R
H
hν
benzene
H3C
37a-f
32
N
O
R
O
H
OCH3
38a-f
Scheme 3.40: Paternò-Büchi reaction of 5-methoxy-2-methyl oxazole with aldehydes.
Table 3.22: Results of the photocycloaddition of 32 with 37a-f.
Compound
R=
d.r. (exo : endo)[a]
Yield (%)[b]
38a
Ph
>98 : 2
87
38b
β-Naph
>98 : 2
85
38c
BnCH2
>98 : 2
87
38d
Et
>98 : 2
90
38e
i-Pr
>98 : 2
86
38f
i-Bu
>98 : 2
88
[a] based on the integration of characteristic signals in the 1H-NMR spectra of the crude
product mixture; [b] yield (%) based on conversion of the oxazole.
The formation of the acid-labile bicyclic oxetanes 38a-f was proven by the characteristic 13CNMR signals of the orthoester carbon (δC ca. 124 ppm). The stereochemical assignment of the
94
___________________________________________________________________________
bicyclic oxetanes 38a-f was performed on the basis of 1H-NMR analysis (especially the strong
ring current induced upfield-shift for the aryl-substituted products 38a and 38b (Table 3.23).
Table 3.23: Chemical shift (δppm) of H-1 and C-5 for compounds 38a-f.
Compound
R=
H-1
C-5
38a
Ph
4.58
122.9
38b
β-Naph
4.62
123.1
38c
BnCH2
4.87
124.5
38d
Et
5.04
124.6
38e
i-Pr
4.92
124.6
38f
i-Bu
4.97
124.7
3.7.2.1 Ring opening of the bicyclic oxetanes 38a-f
The primary photoadducts 38a-f were hydrolytically unstable and underwent twofold ring
opening to give the α-acetamido-β-hydroxy esters 39a-f. The diastereomeric ratio of the ring
opened products was identical to the diastereomeric ratio of the oxetane precursors except for
39d (Table 3.24).
H
H3C
N
O
R
O
H
H+/H2O
HO
AcHN
OCH3
R
CO2CH3
39a-f
38a-f
Scheme 3.40: Synthesis of erythro (2S*, 3S*) α-acetamido-β-hydroxy esters.
Table 3.24: Diastereomeric ratio of the compounds 39a-f.
Compound
R=
d.r. (erythro : threo)[a]
Yield (%)[b]
39a
Ph
>98 : 2
70
39b
β-Naph
>98 : 2
75
39c
BnCH2
>98 : 2
65
39d
Et
95 : 5
72
39e
i-Pr
>98 : 2
78
39f
i-Bu
>98 : 2
74
product mixture, [b] yield (%) of the isolated mixture of diastereoisomers.
95
___________________________________________________________________________
In order to elucidate the relative configuration of the photoaldol adducts 39a-f, N-acetyl
threonine methyl ester 39g was prepared.116 Figure 3.68 displays the X-ray analysis of
compound 39g.
Figure 3.68: X-ray analysis of threo-39g.
Furthermore, the relative configuration of methyl esters of phenylserine 39a117 and βhydroxyleucine118 were already elucidated in the literature and, by comparison with our data,
the erythro (S*, S*) configuration for the major diastereoisomers of 39a-f was established
(Table 3.25).
Table 3.25: Comparsion of NMR spectra of compounds 39d-f with similar known
compounds.
Compound
HO
3
HO
HO
HO
2
δppm
AcHN
CO2CH3
AcHN
CO2CH3
AcHN
CO2CH3
HO
AcHN
CO2CH3
[a]
AcHN
CO2CH3
118
39g
Lit.
4.87
4.35
4.84
3.45
4.18
4.16
3.73
56.5
54.3
56.8
57.6
54.0
65.3
69.8
61.8
67.3
77.2
39d
39e
H-2
4.88
4.75
H-3
4.01
C-2
C-3
39f
[a] Prepared from (2S*,3R*) threonine.
96
___________________________________________________________________________
The structural assignments of compounds 39a-f were made on the basis of spectroscopic data.
The IR spectra of compounds 39a-f showed characteristic absorption bands for hydroxy,
amino, amide and ester groups at 3400, 3320, 1670 and 1720 cm-1, respectively. The
13
C-
NMR spectra clearly showed resonances which correspond to the carbinol C-3 at 65.3 ppm.
Moreover, there appeared two signals at 169.1 and 169.6 ppm pointing out the presence of
11.5155
23.1048
28.5991
56.5100
52.5907
65.3228
169.5750
169.0695
1.0833
1.0593
1.0348
1.0264
2.0751
2.0286
1.9928
4.9056
4.8944
4.8782
4.8669
4.0357
4.0245
4.0201
4.0088
4.0034
3.9926
3.9882
3.9770
3.9334
3.7688
CON and COO, respectively.
HO
HO
AcHN
CO 2CH3
7.0
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
CO 2CH3
4.8672
7.6164
4.0976
1.2109
0.9535
Integral
AcHN
2.0
1.5
1.0
170
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of 39c.
CDCl3) of 39c
3.7.2.2 Synthesis of (Z)-α
α, β -didehydroamino acid derivatives
Dehydroamino acids have recently become a topic of increasing interest as important
constituents of many fungal metabolites with antibiotic or phytotoxic properties such as nisin
and subtilin.119 In addition, dehydroamino acids are versatile precursors for the asymmetric
synthesis of amino acids and peptides.120 Acid-catalyzed water elimination from the αacetamido-β-hydroxy esters 39 gave the (Z)-α,β-didehydroamino acid derivatives
preferentially.
HO
R
AcHN
+
H/CH2Cl2
CO2CH3
H
CO2CH3
R
NHAc
40a-d
39
Scheme 3.41: Synthesis of (Z)-α, β-didehydroamino acid derivatives.
97
___________________________________________________________________________
Table 3.26: Diastereomeric ratio of the products 40a-d.
Compound
R=
d.r. (Z : E)
Yield (%)
40a
Ph
>98 : 2
80
40b
Et
97 : 3
75
40c
i-Pr
95 : 5
78
40d
i-Bu
93 : 7
83
The relative configurations of the major and the minor diastereoisomers of the compound 40d
were unambiguously determined by NOE and ROESY analyses at -63°C. The amide proton
signal overlaped and exchanged with the deuterium atom from CDCl3 and was not available
for NOE measurement at room temperature. At –63°C the NH signal was lowfield-shifted to
7.58 ppm and could be used for saturation experiments.
CO2CH3
major H
CO2CH3
minor
H
NHAc
NHAc
(Z)
(E)
Figure 3.71: NOE interaction of the major and minor diastereoisomer of compound 40d.
By irradiation of the amide proton at 7.75 ppm, NOE enhancement was observed for the vinyl
proton at 6.95 ppm for the minor diastereoisomer E-40d. In the major diastereoisomer Z-40d,
no enhancement of the vinyl proton signal at 6.75 ppm was observed by irradiation the amide
proton at 7.58 ppm (Figure 3.72).
98
___________________________________________________________________________
(c) irradiation of NH at 7.58 ppm
CH=
(b) irradiation of NH at 7.75 ppm
NH
CH=
(a) no irradiation
NH
CH=
Figure 3.72: The NOE difference spectra (300 MHz, CDCl3) of Z & E - 40d.
The constitution of the compounds 40a-d was established by 1H-NMR and
13
C-NMR
analyses. The 1H-NMR spectra of these compounds show the olefinic hydrogen at around 6.7
ppm and the
13
C-NMR spectra show two singlets at around 165 and 168 ppm indicating the
presence of two conjugated carbonyl groups.
99
H
27.8152
23.3978
22.4748
22.3795
37.8001
52.3270
125.2764
138.1770
168.3296
165.1209
0.9074
0.8854
1.7812
1.7592
1.7366
1.7146
1.6921
2.0893
3.7463
3.7419
6.8398
6.7267
6.7027
6.6787
___________________________________________________________________________
CO 2CH 3
H
CO 2CH 3
NHAc
7.0
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
7.7570
0.9694
1.9125
1.4581
3.0000
0.6286
0.7429
Integral
NHAc
1.5
1.0
170
160
150
140
1
130
Figure 3.73: H-NMR spectrum (300 MHz, Figure 3.74:
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of 40d.
CDCl3) of 40d.
3.7.2.3 Synthesis of methyl 1-methyl isoquinoline-3-carboxylate
Compound 40a when treated with POCl3 in methylene chloride afforded methyl 1-methyl
isoquinoline-3-carboxylate 41 in good yield via a Bischler-Napieralski cyclization.
CO2CH3
H
NHAc
CO2CH3
POCl3/CH2Cl2
N
40a
41
CH3
Scheme 3.42: Synthesis of methyl 1-methyl isoquinoline-3-carboxylate 41.
The structure of compound 41 was confirmed by spectroscopic analysis and by comparsion
with literature data.121 For example, the 1H-NMR spectrum showed two singlets at 2.99, 3.99
ppm attributed to methyl and methoxy groups, respectively. In the
13
C-NMR spectrum two
signals at 159.4 and 166.5 ppm indicated the presence of conjugated C=N and COOMe
groups, respectively.
100
CO 2CH3
CO 2CH3
N
N
8.5
8.0
7.5
7.0
6.5
6.0
(ppm)
5.5
5.0
4.5
4.0
2.9576
2.8779
CH3
1.8171
0.9689
0.1544
0.9409
0.9533
Integral
CH3
9.0
22.6579
52.8471
140.3747
135.4884
130.7048
129.4228
128.7341
125.8039
123.0274
159.3922
166.5348
2.9927
2.9913
3.9909
8.1503
8.1478
8.1444
8.1272
8.1243
8.1214
8.1184
8.1155
8.0312
7.9161
7.9083
7.8892
7.8848
7.7158
7.7099
7.7045
7.6947
7.6845
7.6786
7.6727
___________________________________________________________________________
3.5
3.0
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of 41.
CDCl3) of 41.
3.7.3 Photoreactions of 4-substituted 2-methyl-5-methoxyoxazoles with aldehydes
In order to extend the versatility of 5-methoxyoxazole-carbonyl photocycloaddition as an
synthetic approach to α-alkylated-α-amino-β-hydroxy carboxylic acid derivatives, the
Paternò-Büchi reaction of 4-substituted 2-methyl-5-methoxyoxazoles with aliphatic and
aromatic aldehydes was investigated. The substituents R1 at position C-4 of the oxazole were
varied in order to evaluate the influence of steric bulk and possible electronic effects.
Analogous to 32, photolysis of aliphatic or aromatic aldehydes in presence of oxazole
substrates 36a-f gave the bicyclic oxetanes 42aa-ff with high regio- and stereoselectivity.
R1
H3C
O
36a-f
OCH3
H
O
N
+
R
H
37a-f
hν
benzene
H3C
N
O
O
R
R1
OCH3
42aa-ff
Scheme 3.43: Paternò-Büchi reaction of aldehydes with oxazole substrates 36a-f.
101
___________________________________________________________________________
Table 3.27: Diastereoselectivity of the photocycloaddition of 36a-f with 37a-f.
Compound
R=
R1 =
d.r.(exo : endo)[a]
Yield (%)[b]
42aa
Ph
Me
>98 : 2
85
42ab
Ph
Et
>98 : 2
84
42ac
Ph
n-Pr
>98 : 2
86
42ad
Ph
i-Pr
73 : 27
80
42ae
Ph
i-Bu
87 : 13
78
42af
Ph
sec-Bu
85 : 15
81
42ba
β-Naph.
Me
>98 : 2
79
42ca
BnCH2
Me
>98 : 2
87
42cd
BnCH2
i-Pr
81 : 19
86
42da
Et
Me
>98 : 2
90
42db
Et
Et
>98 : 2
92
42dc
Et
n-Pr
>98 : 2
95
42dd
Et
i-Pr
>98 : 2
88
42de
Et
i-Bu
>98 : 2
84
42df
Et
sec-Bu
>98 : 2
87
42ea
i-Pr
Me
>98 : 2
90
42eb
i-Pr
Et
>98 : 2
87
42ec
i-Pr
n-Pr
>98 : 2
85
42ed
i-Pr
i-Pr
>98 : 2
83
42ee
i-Pr
i-Bu
>98 : 2
80
42ef
i-Pr
sec-Bu
>98 : 2
83
42fa
i-Bu
Me
>98 : 2
84
42fb
i-Bu
Et
>98 : 2
84
42fc
i-Bu
n-Pr
>98 : 2
80
42fd
i-Bu
i-Pr
81 : 19
81
42fe
i-Bu
i-Bu
>98 : 2
85
42ff
i-Bu
sec-Bu
89 : 11
83
product mixture, [b] yield (%) based on conversion of the oxazole.
From the results in Table 3.27, one can clearly notice that the exo-selectivity of the
photoadducts was exceedingly high (>98 : 2) except for the benzaldehyde additions to
102
___________________________________________________________________________
oxazole substrates with bulky substituents R1. Again, the formation of the acid-labile bicyclic
oxetanes 42aa-ff was proven by the significant 13C-NMR signals of the orthoester carbon (δc
ca. 124.5 ppm). The relative configuration of compound 42aa was unambiguously assigned
from NOE measurement. Irradiation of the methine hydrogen at 5.23 ppm leads to nuclear
Overhauser enhancement of a methyl signal at 2.03 ppm which clearly confirmed the exo-Ph
configuration of the bicyclic oxetane. Figure 3.77 summarizes the NOE data recorded for
compound 42aa.
OCH3
Ph
CH
CH3
OCH3 3.55
ppm
CH3
2.03
5.23 ppmH
O
N
ppm H3C O
Figure 3.77: NOESY (300 MHz, CDCl3) spectrum of 42aa.
Moreover, the stereochemical assignment was performed on the basis of 1H-NMR analysis
(especially the strong ring current-induced upfield-shift for the C-1 and C-3 methyl groups in
the aryl-substituted, see e.g. Table 3.28).
Table 3.28: 1H-NMR chemical shifts of the methyl protons on exo-42ad & endo-42ad.
H
a
H3C
N
O
Ph
Ph b
CH3
O
a
c
CH3
OCH3
exo-42ad
H3C
N
O
H
b
CH3
O
c
CH3
OCH3
endo-42ad
δ / ppm
a
CH3
b
CH3
exo-42ad
2.00
0.55
0.73
endo-42ad
1.67
0.93
0.98
103
c
CH3
___________________________________________________________________________
The chemical structures of the photoadducts 42aa-ff were established on the basis of the
spectroscopic data. For example, the 1H-NMR spectrum of compound 42ac showed three
singlets at 2.00, 3.54 and 5.17 ppm corresponding to CH3 at position C-3, OCH3 and CH at
position C-7, respectively. In the 13C-NMR spectrum, there are three signals characteristic for
the oxetane ring at 79.0, 89.9 and 124.6 ppm attributed to C-1, C-7 and C-5, respectively. The
H 3C
3
H 7 Ph
2 6O 1
N
O
5 OCH3
4
H 3C
3
7.0
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
O
16.3798
15.0465
14.1454
29.6393
5 OCH3
2.7713
1.2095
2.1653
3.0000
2.6293
0.9222
5.9565
Integral
7.5
51.2575
H 7 Ph
2 6O 1
N
4
8.0
78.9926
89.8639
137.1148
128.1994
128.1847
126.4046
124.6464
165.0916
0.6606
0.6370
1.2268
1.2082
2.1172
2.1128
1.9703
3.6895
3.6542
3.6498
5.2715
7.3429
7.3179
7.3135
signal for C-3 appears down-field shifted at 165.0 ppm (Figure 3.78 & 3.79).
1.0
0.5
160
150
140
130
120
1
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of 42ac.
CDCl3) of 42ac.
The 1H-NMR spectrum of compound 42ae showed doublets at 0.58 and 0.69 ppm due to the
isopropyl group and confirmed the exo-Ph configuration of the photoadduct. In addition, there
are three singlets at 2.12, 3.66 and 5.25 ppm corresponding to CH3, OCH3 and CH of the
oxetane ring, respectively. In the 13C-NMR spectrum, the characteristic signals for the oxetane
H
7.0
6.5
6.0
5.5
5.0
H 3C
4.5
4.0
(ppm)
3.0
2.5
2.0
1.5
N
O
23.7787
23.6982
22.9583
15.0685
35.6171
51.2721
78.7362
Ph
CH3
O
CH3
OCH 3
4.8563
3.4671
3.1444
2.2446
2.8598
3.0000
3.5
160
1.0
150
140
130
CDCl3) of 42ae.
90.4427
137.1734
134.3310
129.6206
128.8807
128.3459
128.2140
128.1701
126.8075
124.7563
164.6741
CH3
OCH 3
0.8814
11.639
Integral
7.5
H
CH3
O
3.3100
N
O
H 3C
Ph
2.1246
2.1202
2.1157
1.2037
1.1861
1.1685
1.1425
0.9167
0.9123
0.9084
0.8947
0.8913
0.8864
0.8834
0.7159
0.6939
0.6096
0.5871
3.6694
3.6655
3.6615
5.2598
7.3213
7.3164
7.3115
ring resonate at 78.7, 90.4 and 124.7 ppm due to C-1, C-7 and C-5, respectively.
120
13
CDCl3) of 42ae.
104
110
100
90
(ppm)
80
70
60
50
40
30
20
___________________________________________________________________________
The IR spectrum of compound 42af showed a strong absorption band at 1620 cm-1 attributed
to the presence of a C=N group. The mass spectrum showed the base peak at m/z 105 due to
the retrocleavage of the photoadduct and formation of the benzoyl cation (PhCO+). The 1HNMR spectrum showed an upfield-shifted triplet signal at 0.31 ppm corresponding to CH3
group attached to CH and again strongly supported the exo-configuration of the bicyclic
oxetane. In the
13
C-NMR spectrum, one can clearly show the facial selectivity of the
photoadduct is about 50 : 50 with each carbon appears as a signal pair with the same intensity
H
6.0
4.0
3.0
2.0
32.0568
32.0128
23.4711
23.1707
14.9879
12.9367
11.7499
11.5228
11.3177
Ph
CH3
O
CH3
OCH 3
6.2772
3.3581
1.5852
1.2256
OCH 3
N
O
51.0963
82.9704
90.7943
90.7650
137.2906
137.1587
134.3456
129.6279
128.8880
128.2140
128.0822
128.0235
127.8844
127.7598
126.3753
126.3533
124.7270
165.2162
H 3C
CH3
3.8994
5.0
0.9089
0.8830
0.8595
0.7390
0.7243
0.7169
0.5249
0.5029
0.3408
0.3163
0.2918
CH3
0.9996
7.2237
7.0
H
Ph
O
3.0000
2.4855
N
O
H 3C
2.1329
2.1236
1.9997
1.9894
3.6910
3.6797
3.6772
5.3132
5.2769
7.4266
7.4232
7.3174
7.2400
(Figure 3.82 & 3.83).
1.0
0.0
160
150
140
130
120
(ppm)
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of 42af.
CDCl3) of 42af.
The chemical structure of compound 42ca was established on the basis of 1H-NMR and 13CNMR analyses. In the 1H-NMR spectrum, there are three singlets absorbing at 1.18, 1.94 and
3.42 ppm corresponding to the CH3 at position C-1, CH3 at position C-3, and OCH3,
respectively. In addition there appears a doublet of doublet signal at 4.15 ppm due to the CH
of the oxetane ring. The
13
C-NMR spectrum revealed, three signals for the oxetane ring at
73.4, 87.9 and 124.5 ppm attributed to C-1, C-7, and C-5, respectively (Figure 3.84 & 3.85).
105
Ph
O
CH3
7.5
H 3C
7.0
6.5
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
14.9073
12.1162
O
N
O
CH3
OCH3
3.1047
3.1016
1.7009
2.4794
0.8841
OCH3
8.5561
Integral
8.0
H
3.0000
N
O
33.9688
30.6063
27.9471
Ph
H
H 3C
45.0819
51.2721
73.4397
87.8860
140.7483
140.1842
128.4265
128.3239
128.2873
128.1627
128.1188
126.1262
125.9430
124.5438
164.8425
2.9043
2.8788
2.7432
2.7407
2.7388
2.7363
2.7202
2.7172
2.7148
2.7123
2.7099
2.6903
2.0153
2.0129
1.2473
1.2454
3.4916
3.4891
4.2469
4.2326
4.2155
4.2008
7.3061
7.3037
7.2145
7.1548
7.1504
___________________________________________________________________________
2.0
1.5
1.0
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of 42ca.
CDCl3) of 42ca.
The structural assignment of compound 42dc was based on the IR spectrum, mass spectrum
and NMR analyses. The IR spectrum showed a strong absorption band at 1615 cm-1 attributed
to a C=N, and a weak absorption band at 1110 cm-1 due to a C-O bond. The mass spectrum
showed the base peak at 57 corresponding to the (CH3CH2CO+) which results after retro
cycloaddition of the photoadduct. The 1H-NMR spectrum revealed a doublet of doublet signal
at 4.03 ppm attributed to the CH of the oxetane ring. The
13
C-NMR spectrum showed three
triplet signals at 16.8, 24.9, and 28.3 ppm due to the presence of three methylene groups. In
addition three further signals in the aliphatic range (8.9, 14.2, 14.8 ppm) and the OCH3 group
N
O
H 3C
OCH 3
28.2621
24.9435
50.8253
76.3627
90.5013
124.3167
164.5495
1.9482
1.9424
1.5765
1.5579
1.5520
1.5451
1.5393
1.2082
1.1954
1.1876
1.1842
1.1724
1.1636
0.8295
0.8237
0.8085
0.7992
0.7899
0.7845
H
CH3
8.9149
H 3C
CH3
O
16.8779
14.7681
14.2260
H
N
O
3.4000
3.3936
4.0514
4.0455
4.0318
4.0255
4.0186
4.0049
3.9990
appears at 50.8 ppm.
20
10
CH3
O
CH3
OCH 3
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
10.863
2.9874
5.6234
2.9578
3.0000
1.0068
Integral
benzene
1.0
0.5
160
150
140
130
CDCl3) of 42dc.
120
13
110
90
80
(ppm)
70
60
50
40
30
CDCl3) of 42dc.
106
100
___________________________________________________________________________
The constitution of compound 42df was established by IR, mass spectrum and NMR analyses.
The IR spectrum showed absorption bands at 987 and 1605 cm-1 attributed to a C-O bond and
a C=N bond, respectively. In the mass spectrum, the molecular ion peak did not appear and
the most important fragments correspond to the retrocycloaddition to oxazole and
propionaldehyde which decompose to further fragment. The 1H-NMR spectrum showed two
singlets at 2.00 and 3.47 ppm due to the presence of CH3 and OCH3, respectively. In addition,
the oxetane ring signal absorbs at 4.16 ppm. The
13
C-NMR spectrum confirmes the facial
selectivity induced by chiral oxazole 36f is about 50 : 50 as shown from the intensity of the
carbon signals. Furthermore, the characteristic signals of the oxetane ring appear at 80.5, 90.9
H
7.5
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
O
32.0495
31.7857
24.9435
24.7677
24.7238
23.5443
14.8707
13.9476
12.9074
11.9038
11.5009
9.0614
9.0101
50.8399
80.5090
90.9042
benzene
OCH3
28.645
3.7039
4.3216
3.0931
3.0000
OCH 3
1.0935
7.0
N
O
H 3C
1.7479
N
O
H
O
Integral
H 3C
124.5732
165.1576
164.9085
1.9963
1.9860
1.6980
1.3605
1.3527
1.3458
0.8888
0.8727
0.8668
0.8565
0.8497
0.8428
0.8276
0.8173
0.7963
0.7884
0.7747
3.4309
3.4294
4.3625
4.3551
4.3336
4.3257
4.3179
4.2958
4.2885
and 124.5 ppm corresponding to C-1, C-7, and C-5, respectively (Figure 3.88 & 3.89).
1.0
0.5
220
200
180
160
CDCl3) of 42df.
140
13
120
100
(ppm)
80
60
40
20
0
CDCl3) of 42df.
The 1H-NMR spectrum of compound 42fe showed singlets at 2.00 and 3.44 ppm attributed to
CH3 and OCH3, respectively. In addition a doublet of doublet signal for one proton at 4.25
ppm corresponding to the CH of the oxetane ring. In the
13
C-NMR spectrum, there are two
triplets at 34.2 and 40.7 ppm indicating the presence of two methylene groups. In addition,
three signals appear at 76.3, 88.3, and 124.5 ppm due to C-1, C-7, and C-5, respectively
(Figure 3.90& 3.91).
107
H 3C
O
N
O
OCH3
40
15.0025
50
CH3
CH3
CH3
H
40.7011
34.2765
24.1963
23.9985
23.9033
23.3538
23.0901
21.6396
CH3
51.0084
76.2967
88.2889
124.5805
164.1906
3.4617
3.4553
2.0139
2.0075
1.6646
1.6441
1.5402
1.5344
1.5270
1.5197
1.5167
1.3605
1.3556
1.3326
1.3247
0.9030
0.8966
0.8810
0.8751
0.8550
0.8486
0.8413
0.8330
0.8281
0.8197
0.8139
4.3032
4.2929
4.2885
4.2674
4.2576
4.2527
___________________________________________________________________________
CH3
CH3
H
H 3C
CH3
N
O
O
OCH 3
CH3
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
21.489
3.1868
2.6508
1.8473
7.0
3.4919
7.5
3.0000
0.9131
Integral
benzene
1.0
0.5
160
150
140
1
130
120
13
110
100
90
(ppm)
80
70
60
30
20
CDCl3) of 42fe.
CDCl3) of 42fe.
3.7.3.1 Synthesis of erythro (S*,S*) α-alkylated-α
α-acetamido-β
β -hydroxy esters
Analogous to 38a-f, hydrolysis of the bicyclic oxetanes 42aa-ff resulted in twofold ringopening and provided a convenient and a high yielding access to erythro (S*,S*) α-alkylatedα-acetamido-β-hydroxy esters 43aa-ff. In most cases, the diastereomeric ratio of the opened
products matched the diastereomeric ratio of the bicyclic oxetanes.
H
H3C
N
O
O
R
1
R
HO
H+/H2O
AcHN
OCH3
R
R1
CO2CH3
43aa-ff
42aa-ff
Scheme 3.44: Synthesis of erythro (S*,S*) α-alkylated-α-acetamido-β-hydroxy esters.
The erythro (S*,S*) configuration of compound 43df was unambiguously determined by
single crystal X-ray analysis as depicted in Figure 3.92.
Figure 3.92: X-ray analysis of erythro-43df: without and with hydrogen-bonds.
108
___________________________________________________________________________
Table 3.29: Diastereomeric ratio of compounds 43aa-ff.
Compound
R=
R1 =
d.r.(erythro
Yield (%)[b]
: threo)[a]
43aa
Ph
Me
>98 : 2
65
43ab
Ph
Et
93 : 7
73
43ac
Ph
n-Pr
90 : 10
58
43ad
Ph
i-Pr
90 : 10
48
43ae
Ph
i-Bu
90 : 10
58
43af
Ph
sec-Bu
92 : 8
40
43ba
β-Naph.
Me
>98 : 2
48
43ca
BnCH2
Me
85 : 15
55
43cd
BnCH2
i-Pr
>98 : 2
55
43da
Et
Me
>98 : 2
70
43db
Et
Et
95 : 5
65
43dc
Et
n-Pr
92 : 8
55
43dd
Et
i-Pr
95 : 5
68
43de
Et
i-Bu
>98 : 2
70
43df
Et
sec-Bu
90 : 10
67
43ea
i-Pr
Me
>98 : 2
70
43eb
i-Pr
Et
88 : 12
71
43ec
i-Pr
n-Pr
85 : 15
68
43ed
i-Pr
i-Pr
93 : 7
73
43ee
i-Pr
i-Bu
90 : 10
59
43ef
i-Pr
sec-Bu
96 : 4
68
43fa
i-Bu
Me
>98 : 2
55
43fb
i-Bu
Et
93 : 7
66
43fc
i-Bu
n-Pr
>98 : 2
68
43fd
i-Bu
i-Pr
>98 : 2
62
43fe
i-Bu
i-Bu
92 : 8
45
43ff
i-Bu
sec-Bu
90 : 10
73
product mixture, [b] yield (%) of the isolated mixture of diastereoisomers.
109
___________________________________________________________________________
The mechanism of the ring opening process of bicyclic oxetanes is illustrated in Scheme 3.45.
The first step is probably the protonation of the oxetane-oxygen atom followed by opening of
the oxetane ring. Then attack of water to the carbenium ion, protonation of the nitrogen atom
of the oxazole and the second ring opening follows. Thus, ring opening of the bicyclic
oxetanes procceeded with retention of configuration to give the erythro (S*,S*) α-alkylatedα-acetamido-β-hydroxy esters 43aa-ff.
H
H3C
N
O
R
O
R1
H
H3C
OCH3
H
H
O
N
O
R
R
HO
1
H3C
OCH3
R
R1
N
O
OCH3
42aa-ff
H
HO
HO
R
1
AcHN
R
CO2CH3
R
H3C
N
O
R
O
43aa-ff
1
OCH3
H
H
HO
H
H-
O
H shift
H3C
R1
N
O
H
R
O
OCH3
H
Scheme 3.45: Proposed mechanism for the formation of erythro (S*,S*)-α-alkylated-αacetamido-β-hydroxy esters 43aa-ff.
Structural assignment of the photoaldol adduct
The relative configurations of the compounds 43aa-ff were assigned by using
13
C-NMR
analysis and also by comparison with similar compounds in the literature.122 In the 13C-NMR
spectra of these compounds, there is a striking difference between erythro and threo isomers.
Both C-2 and C-3 resonate upfield in erythro-isomer in compared with the corresponding
threo-isomer. This phenomena fits well with the results reported by Heathcock who used 13CNMR as a tool for the assignment of the configuration of β-hydroxy carbonyl compounds
(Table 3.30).123
110
___________________________________________________________________________
Table 3.30: Characterisitic 13C-NMR signals (δ ppm) of photoaldol products in (CDCl3).
Compound
R1 =
R=
erythro
threo
C-2
C-3
C-2
C-3
43af
Ph
sec-Bu
71.9
74.9
82.3
83.9
43ca
BnCH2
Me
75.1
75.6
86.2
87.2
43dc
Et
n-Pr
70.1
78.0
86.1
88.7
43df
Et
sec-Bu
69.2
70.3
78.4
86.9
43ea
i-Pr
Me
68.3
71.0
83.3
90.0
In order to account for the difference in the
13
C-NMR shifts in erythro and its epimers, I
suggest the predominance of a conformation stabilized by an intramolecular hydrogen bond
between the hydroxy and amide group (see X-ray structure of compound 43df). Figure 3.93
shows that such an effect is clearly manifested in the erythro and threo pairs. However, in the
threo-isomer, there is a gauche interaction between R & R1 substituents which weakens the
the hydrogen bond and might be also responsible for the deshielding effect of C-2 & C-3. If
this assumption is true, one should also note the anti conformation between the R and R1 in
the erythro-isomer resulting in a higher field shift of C-2 and C-3 in comparsion with the
threo-isomer. In fact, this was proven experimentally. Thus, the 13C-NMR shifts of the C-2 &
C-3 in the photoaldol adducts erythro & threo should unambiguously show correct trends and
corroborated the proposed relative configurations.
R1
H
R1
O
H
R
O
H3CO
R
H
N
O
erythro-isomer
H
O
H3CO
N
O
O
H
H
threo-isomer
Figure 3.93: Newman projection of the erythro & threo-isomers.
The constitutions of the products 43aa-ff were established on the basis of IR, mass spectrum,
NMR analyses and elemental analysis. For example, the IR spectrum of compound 43aa
displayed absorption bands at 3350, 3220, 1720 and 1680 cm-1 corresponding to OH, NH,
COO and CON groups, respectively. Scheme 3.46 summarizes the fragmentation pattern of
the mass spectrum of compound 43aa.
111
___________________________________________________________________________
COOMe
Me
NHCOMe
OH
Ph
m/z =192
COOMe
NHCOMe
- Me
OH
H
OH
Ph
Ph
m/z =251
NHCOMe
Me
COOMe
NHCOMe
H
-P
hC
HO
H
H
- (COOMe)
Me
m/z =236
- H2
m/z =144
COOMe
Me
NHCOMe
- (COOMe)
Me
Ph
H
Me
Ph
m/z =249
- MeCONH2
COOMe
Ph
O
C
-(
O
Ph
H
Me
-O
m/z =160
OH
Me
Ph
OC
OH
CH m/z =161
m/z =90
m/z =107
m/z =107
HO
Ph
O
MeOOC
Me
MeOOC
McLafferty rearrangement
N
COOMe - MeCONH2
H Me
m/z =191
- OH
OH
m/z =251
COOMe
- CO
m/z =79
Ph
-
Ph
OC
OH
m/z =192
HO
H
- H2
H
e)
- OMe
Ph
MeOOC
OH
m/z =133 HO
m/z =131
- C2H2
M
O
-H
OH
Ph
- H2
m/z =51
Ph
MeOOC
m/z =251
O
m/z =144
N
H
HO
m/z =77
NHCOMe
Me
O
m/z =190
O
COOMe
NHCOMe - PhCO
O
m/z =192
O
Ph
- (COOMe)
Ph
O
- H2
Me
Me
m/z =192
m/z =133
Ph
m/z =131
Scheme 3.46: Fragmentation pattern of compound 43aa.
In the 1H-NMR spectrum, there are four singlets at δ 1.22, 2.14, 3.79 and 4.06 ppm attributed
to CH3, CH3CO, OCH3 and CHOH, respectively. The 13C-NMR showed the disappearence of
the orthoester signal and the formation of new signals at δ 47.6, 49.6, 169.9 and 179.4 ppm
corresponding to C-2, C-3, CON and COO, respectively (Figure 3.94 & 3.95).
112
HO
7.5
6.5
6.0
5.5
5.0
4.0
3.0
2.5
2.0
13.4641
23.4271
52.9790
49.0671
47.6899
CO2CH3
3.0743
2.9792
3.0000
3.5
133.4666
128.4265
128.2580
127.5694
Ph
AcHN
4.5
(ppm)
169.9632
179.4280
CO2CH 3
0.9474
7.0
1.2268
HO
4.5338
Integral
8.0
2.1241
Ph
AcHN
8.5
3.7943
4.0637
7.3296
7.3135
___________________________________________________________________________
1.5
1.0
220
0.5
200
180
160
140
13
120
100
(ppm)
80
60
40
20
0
CDCl3) of 43aa.
CDCl3) of 43aa.
The IR spectrum of compound 43ca showed two strong absorption bands at 1735 and 1690
cm-1 indicating the presence of ester and amide groups, respectively. In addition, there are two
broad bands at 3420 and 3270 cm-1 attributed to OH and NH groups, respectively. The 1HNMR spectrum revealed three singlets at δ 1.35, 2.05, 3.76 ppm corresponding to CH3,
CH3CO, and OCH3, respectively. The carbinol hydrogen absorbs at δ 4.68 ppm (dd, J = 11.2,
13
3.1Hz). The
C-NMR spectrum shows signals at δ 75.0, 89.9, 165.2 and 174.3 ppm
HO
6.0
5.5
5.0
4.5
(ppm)
4.0
3.0
2.5
2.0
1.5
220
200
180
160
CDCl3) of 43ca.
19.6470
14.2407
32.9505
31.9322
52.6127
75.0001
83.9008
CO2CH3
2.9423
3.0776
2.3204
1.5133
1.2229
3.5
141.0047
128.4265
128.3239
126.0749
165.2308
174.3220
2.9043
2.8799
2.8529
2.7858
2.7589
2.7393
2.7310
2.7114
2.6849
2.0261
1.9816
1.9595
1.9541
1.9331
1.9287
1.3522
3.7620
3.0000
0.9609
Integral
0.7792
6.5
Ph
AcHN
CO2CH3
6.8820
7.0
HO
Ph
AcHN
7.5
4.7029
4.6833
4.6794
4.6573
5.2994
7.2900
7.2880
7.2807
7.2400
7.2170
corresponding to C-2, C-3, CON, and COO, respectively (Figure 3.96 & 3.97).
140
13
120
100
(ppm)
80
60
40
20
0
CDCl3) of 43ca.
The mass spectrum showed the molecular ion peak at m/z 279 which strongly supports the
structure of compound 43ca. The fragmentation pattern are summarized in scheme 3.47.
113
___________________________________________________________________________
COOMe
Me
NHCOMe
Me
- (COOMe)
OH
H
H
2
Ph
OH
COOMe
Me
NHCOMe
Ph
m/z =261
m/z =279
NHCOMe
OH
Me
NHCOMe
- OMe
H
Ph
-P
hC
H
m/z =220
CO
COOMe
NHCOMe - H2O
Ph
m/z =246
- (COOMe)
m/z =188
NHCOMe
Ph
m/z =202
MeO
MeOCHN
O
- PhCH2CH2CHO
Me
MeOOC
Me
NHCOMe
O
CO
Me
NHCOMe
e)
M
- MeCO
MeOOC
NHCOMe
m/z =113
m/z =145
Ph
O
-(
m/z =279
Me
- Me OH
-M
e
O
H
Me
NHCOMe
MeOOC
m/z =130
NH
m/z =86
m/z =102
- C2H2
m/z =91
O
O
m/z =65
O
Me
H
OH
m/z =91
-
Me
Ph
HO
N
COOMe - MeCONH2
H Me
m/z =279
Ph
MeOOC
Me
COOMe
O
Me
-
MeOOC
COOMe
- CO
Me
m/z =220
m/z =220
Ph
m/z =133
m/z =105
Scheme 3.47: Fragmentation pattern of compound 43ca.
The constitution of compound 43da was confirmed by IR and NMR analyses. Analogous to
the compounds mentioned above, there are four distinct absorption bands in the infrared
spectrum at 3330, 3260, 1720 and 1685 cm-1 attributed to OH, NH, ester and amide groups,
respectively. The 1H-NMR spectrum revealed three singlets at δ 1.53, 1.95 and 3.71 ppm
corresponding to CH3, CH3CO and OCH3, respectively. In addition, there is a low-field signal
at δ 4.14 ppm for the carbinol proton. In the 13C-NMR spectrum, there are signals resonate at
δ 63.5, 69.9, 169.3 and 171.6 ppm for C-2, C-3, CON, and COO, respectively (Figure 3.98 &
3.99).
114
HO
6.0
AcHN
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
220
200
180
160
CDCl3) of 43da.
26.2182
23.3319
17.1929
11.8452
CO2CH3
3.0821
2.9791
0.8233
2.7876
1.0659
2.7702
0.8062
CO 2CH 3
0.7366
Integral
6.5
52.8838
HO
AcHN
7.0
63.4548
69.9087
171.6701
169.3625
1.9571
1.7606
1.7435
1.7366
1.7190
1.7122
1.6642
1.5495
1.5309
1.0509
1.0269
1.0029
3.7110
4.1499
4.1430
4.1131
4.1058
6.2193
___________________________________________________________________________
140
13
120
100
(ppm)
80
60
40
20
0
CDCl3) of 43da.
It was possible to separate the two diastereoisomers of compound 43dc, i.e. erythro (S*,S*)
and threo (S*,R*) by chromatographic purification. The relative configurations of both
diastereoisomers were established on the basis of NMR analyses:
There are two main differences in the 1H-NMR spectra of erythro- and threo-isomer:
(a) both acetyl and methoxy groups in the threo-isomer absorb at δ 1.95 and 3.69 ppm,
respectively, while in the erythro-isomer, this absorption is shifted downfield to 2.00 and 3.77
ppm; (b) the carbinol proton of the erythro-isomer resonates at a much higher field (δ = 4.24
ppm, dd, J = 11.6, 2.1 Hz) than in the threo-isomer which absorbs at δ 4.34 ppm, dd, J = 10.1,
3.5 Hz.
In the
13
C-NMR spectrum, there are also two main differences between the erythro- and
threo-isomers: (a) in the erythro-isomer, both C-2 and C-3 resonate at higher field δ 69.1 and
70.3 ppm than in the threo-isomer which resonate at δ 78.4 and 86.9 ppm, respectively; (b)
the carbonyl of amide and ester appears for the erythro-isomer at 169.4 and 172.3 ppm wheras
at 165.1 and 174.5 ppm, respectively in the threo-isomer (see Figure 3.100, 3.101, 3.102 and
3.103).
115
HO
AcHN
CO2CH 3
3.0
2.5
2.0
1.5
1.0
180
170
160
150
140
130
100
90
(ppm)
80
70
60
50
40
30
18.1233
13.9183
12.0136
20
10
86.9923
HO
AcHN
AcHN
CO2CH 3
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
2.0213
3.7103
6.5288
3.1506
3.7297
3.3856
1.1702
3.0000
0.8871
5.5
CO2CH 3
threo-43dc
Integral
threo-43dc
6.0
13
110
165.1136
174.5052
2.2926
2.2171
1.9517
1.7308
1.6847
1.6725
1.4864
1.4550
1.4428
1.4148
1.0455
1.0210
0.9961
0.9931
0.8687
0.8452
0.8212
3.6988
4.3453
4.3335
4.3115
4.2997
HO
6.5
120
CDCl3) of erythro-43dc.
CDCl3) of erythro-43dc.
7.0
26.6138
24.4820
3.6598
6.0765
1.5882
1.4936
0.9031
1.3904
1.3786
3.0000
1.2123
3.5
22.8557
17.8669
14.3213
14.2700
11.3324
4.0
(ppm)
36.0420
4.5
52.2757
5.0
78.4139
5.5
3.1454
0.8696
6.0
CO2CH 3
erythro-43dc
0.8368
Integral
erythro-43dc
6.5
33.3534
HO
AcHN
7.0
53.1548
70.3409
69.1981
172.3294
169.4944
4.2488
4.2420
4.2101
4.2033
3.7683
2.8882
2.8583
2.8495
2.8441
2.8196
2.8073
2.7838
2.7598
2.1451
2.1388
2.1206
2.1138
2.0962
2.0893
2.0104
1.7949
1.7660
1.7513
1.7239
1.7087
1.6480
1.6240
1.5990
1.5251
1.5006
1.4864
1.4771
1.4619
1.4516
1.4384
1.4129
1.2753
1.2581
1.2513
1.2341
1.0357
1.0117
0.9877
0.8854
0.8624
6.4147
___________________________________________________________________________
170
1.0
160
150
140
130
CDCl3) of threo-43dc.
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of threo-43dc.
The constitution determination of the compound 43dd was based on IR, mass spectrum and
NMR analyses. The IR spectrum showed absorption bands characteristic for OH, NH, CON
and COO at 3335, 3210, 1745 and 1675 cm-1, respectively. The mass spectrum showed the
base peak at m/z 130 due to the formation of methyl propioacetate. Scheme 3.48 illustrates the
fragmentation pattern of compound 43dd.
116
___________________________________________________________________________
Me COOMe
COOMe
NHCOMe - i-Pr
NHCOMe - (COOMe)
NHCOMe
Me H
OH
OH
H
OH
Et
Et
Et
m/z =231
m/z =172
m/z =188
COOMe
Me
NHCOMe
- H2
Me
m/z =172
COOMe
Me
Me
H
COOMe
Me
N CO
NHCOMe - EtCO
- Me
NHCOMe
Me
O
Me
O
Me
Et
Et
m/z =172
Me
-E
tC
H
O
H
Me
H
m/z =214
O
Me
OH
Et
H
COOMe
Me
- MeCONH2
m/z =172
- MeCH=CH2
MeO
MeOCHN
H
OH
i-Pr
Me
O
- MeOH
O
Me
-H
m/z =140
m/z =172
2O
Et
Et
- (COOMe)
Me
Me
MeOOC
Me
Me
m/z =154
-
OH
Me
Me
Et
m/z =130
MeOOC
Et
MeOOC
Me
Me
m/z =95
COOMe
COOMe
COOMe
- EtCHO
O
Me
Et
O
- Et
m/z =101
Me
m/z =231
Et
O
m/z =73
O
COOMe
Et
MeOOC
m/z =231
COOMe - CO
m/z =229
HO
N
H
Me
m/z =229
m/z =112
m/z =130
NHCOMe
NHCOMe
- (COOMe)
Me
Me
m/z =164
Me
Me
m/z =105
Scheme 3.48: Fragmentation pattern of compound 43dd.
In the 1H-NMR spectrum, there are two singlet signals at δ 4.04, 3.79 ppm indicating the
presence of CH3CO and OCH3, respectively. In addition, at δ 4.52 and 6.45 ppm, there are
two signals corresponding to CHOH and NH, respectively. The
13
C-NMR spectrum shows
signals at δ 69.9, 73.5, 169.7 and 171.8 ppm attributed to C-2, C-3, CON, and COO,
respectively.
117
HO
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
CO 2CH 3
3.5174
6.4537
1.3988
3.4843
1.4238
3.0000
1.1061
0.9877
Integral
AcHN
CO 2CH 3
0.9077
6.5
28.2547
26.8043
25.1120
18.5995
17.1929
12.0503
HO
AcHN
7.0
52.9717
73.4544
69.8648
171.7654
169.6922
3.7963
3.6508
3.6273
3.6043
2.2059
2.1839
2.1785
2.1584
2.1525
2.1339
2.1280
2.0477
1.6421
1.6181
1.6035
1.5922
1.5795
1.5682
1.5530
1.5442
1.5290
1.5055
1.0627
1.0387
1.0152
0.9917
0.8526
0.8296
4.5579
4.5525
4.5192
4.5133
6.4495
___________________________________________________________________________
170
1.0
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
10
CDCl3) of 43dd.
CDCl3) of 43dd.
The constitution of compound 43de was elucidated by 1H-NMR and
13
C-NMR analyses. In
the 13C-NMR spectrum, both C-2 and C-3 resonate at lower field in compared with the spectra
of the compounds mentioned above indicating the threo-configuration of compound 43de.
The 1H-NMR spectrum shows two singlets at δ 3.70 and 1.96 ppm corresponding to OCH3
and CH3CO, respectively. In addition, there appears a doublet of doublet signal at 4.22 ppm
14.3249
11.4386
24.5516
24.4198
23.0572
22.6982
42.0088
52.2794
77.9560
87.8091
164.9195
174.9411
1.9620
1.7092
1.6642
1.6407
1.4614
1.4448
1.4168
1.4002
1.0446
1.0201
0.9956
0.9035
0.8815
0.8222
0.8002
3.7022
4.2351
4.2234
4.2013
4.1896
dd, J = 10.8, 3.5 Hz for the CHOH.
HO
HO
CO2CH3
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
170
160
150
140
130
CDCl3) of threo-43de.
CO 2CH 3
3.2485
7.3526
3.5122
1.3423
5.8533
2.9514
0.8925
7.0
3.0000
AcHN
Integral
AcHN
120
13
110
100
90
(ppm)
70
60
50
40
30
20
CDCl3) of threo-43de.
118
80
___________________________________________________________________________
Moreover, the CH-COSY correlation supported the chemical structure of compound 43de as
depicted in Figure 3.108.
C11
C3
C8&C9 C7 C10 C5
C6
C4
H3
H11
5
HO
HN
10
3
8
4
6 7
9
2 COOMe
1 11
O
H10
`6 H6
H4HH`4
H7
H9 H8
H5
Figure 3.108: HMQC spectrum (300 MHz, CDCl3) of threo-43de.
The constitution of compound 43fd was established by IR and NMR analyses. The IR
spectrum showed four strong absorption bands at 3452, 3310, 1725 and 1685 cm-1
corresponding to the OH, NH, COO and CON groups, respectively. The 1H-NMR spectrum
showed singlets at δ 2.04, 3.78 and 6.43 ppm attributed to CH3CO, OCH3 and NH,
respectively. The carbinol proton appears at δ 4.73 ppm with doublet of doublet multiplicity
(dd, J = 11.2, 2.1 Hz). The
13
C-NMR spectrum showed signals at δ 65.9, 73.5, 169.6 and
171.8 pm corresponding to C-2, C-3, CON and COO, respectively. Figure 3.111 shows the
HMQC spectrum which also confirmes the NMR assignments.
119
28.1449
25.2073
25.0974
23.8008
20.4602
18.6801
17.0318
41.6169
52.9644
65.8723
73.5350
171.8020
169.6409
2.0408
1.8400
1.8278
1.7739
1.7661
1.7249
1.7171
1.6936
1.6882
1.6843
1.6755
1.6500
1.6392
1.0059
0.9824
0.9378
0.9158
0.9021
0.8805
0.8423
0.8198
3.7889
3.6199
3.5969
3.5739
4.7318
4.7229
4.6955
4.6931
4.6857
6.4250
___________________________________________________________________________
HO
HO
AcHN
7.0
6.5
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
17.036
1.1936
2.1561
3.4258
1.1452
3.0000
0.9864
6.0
CO 2CH 3
CO 2CH 3
0.8925
Integral
AcHN
1.5
1.0
0.5
170
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of 43fd.
CDCl3) of 43fd.
C5&C12
C8 C7 C9 C10
C6
C11
C3
C4
H3
H11
H8
6
5
HO
3
HN
2 COOMe
1 11
4 9
8 10
H12
O
H 5 H4
12
7
H6&H7
H10 H9
Figure 3.111: HMQC spectrum (300 MHz, CDCl3) of 43fd.
Analogous to compound 43de, the relative configuration of compound 43ff was assigned by
using the down-field shift of both C-2 and C-3 as guide for the threo-isomer. The constitution
120
___________________________________________________________________________
of compound threo-43ff was established on the basis of IR, mass spectrum and NMR
analyses. The IR spectrum revealed bands at 3335, 3225, 1735 and 1680 cm-1 attributed to
OH, NH, COO, CON groups, respectively. The mass spectrum showed the base peak at m/z
255 due to (M+-H2O). In the 1H-NMR spectrum, there are signals at δ 4.40, 3.66 and 1.97
ppm corresponding to CHOH, OCH3 and CH3CO, respectively. The
13
C-NMR spectrum
displayed signals at δ 82.7, 84.6, 165.8 and 174.8 ppm related to C-2, C-3, CON and COO,
respectively. Figure 3.114 shows the HH-COSY spectrum of the off-digonal cross peak which
HO
AcHN
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
170
1
160
150
140
130
CDCl3) of threo-43ff.
CO2CH3
14.724
1.7950
1.2364
2.5002
3.2944
0.8955
6.5
3.0000
CO2CH 3
Integral
7.0
38.3873
37.8452
26.6002
26.4903
25.9922
23.8824
23.8604
21.9191
14.5421
14.0439
12.3590
HO
AcHN
7.5
52.4160
52.3940
84.6345
82.7005
165.8034
4.4110
4.4021
4.3757
4.3674
3.7135
3.6944
3.6767
3.6743
3.6645
3.6601
3.6395
1.9688
1.9595
1.9488
1.9350
1.7435
1.7328
1.6980
1.5844
1.5550
1.2244
1.2004
0.9417
0.9202
0.9099
0.9055
0.8879
0.8839
0.8624
0.8511
0.8399
0.8281
0.8149
0.8061
0.7899
174.7700
correctly correlated the coupled protons.
120
13
110
100
90
(ppm)
70
60
50
40
30
20
CDCl3) of threo-43ff.
121
80
___________________________________________________________________________
H12
H13
H6&H7&H8
&H10&H11
H3
H4H9H`4 H5
H3
H12
6
7
5
3
HN
2 COOMe
1 12
4 9 10
8 11
O
H6&H7&H8
&H10&H11
H4H9H`4 H5
H13
13
HO
Figure 3.114: HH-COSY spectrum (300 MHz, CDCl3) of threo-43ff.
3.7.3.2 Transacylation
In order to test the stability of the photoaldol adducts, compounds 43da, 43dc and 43fc were
stirred in CHCl3 in the presence of catalytic amount of conc. HCl at r.t. for 24 h.
HO
R
1
AcHN
R
CO2CH3
AcO
R
H2N
R1
CO2CH3
H+/CHCl3
43da, 43dc & 43fc
44da, 44dc & 44fc
Scheme 3.49: Transacylation.
Thin layer chromatograpy revealed a new spot in addition to the spot of starting material. The
result of 1H-NMR analysis indicated that there are a pair of each signals with only small
differences in chemical shifts for each proton except for the signal of carbinol hydrogen.
These signals were strongly different (about 1.0 ppm). The carbinol proton in the starting
122
___________________________________________________________________________
material resonates at higher field than in the new compound. So, I assumed that this may be
related to a migration of the acetyl group from amino to hydroxy (i.e transacylation). This
assumption was supported by chemical shift comparsion of the carbinol hydrogen with similar
compounds in literature (Table 3.31 ).124,125
Table 3.31: Comparison of carbinol 1H-NMR signals of compounds 43da & 44da with
similar known compounds in the literature.
HO
AcHN
δ / ppm
AcO
HO
H2N
CO2CH3 H3CO
CO2CH3
AcO
HO
H3CO
CO2CH3
AcO
CO2H
CO2CH3
43da
44da
Lit.124
Lit.124
Lit.125
4.15
5.25
3.60
5.12
4.01
CO2H
Lit.125
5.29
The constitution of compounds 44da, 44dc and 44fc were confirmed by NMR analyses. For
example, the 1H-NMR spectrum of compound 44da showed a signal at δ 5.25 ppm related to
CHOAc. In the
C-NMR spectrum, C-3 resonates at lower field δ 75.1 in comparsion with
13
HO
HO
AcO
43da
AcHN
CO2CH3
44da
CO 2CH 3
H2N
43da
CO 2CH 3
44da
44da
44da
44da
44da
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
3.1495
2.2905
1.1184
1.3986
3.4792
0.6116
0.5691
2.4866
1.3018
1.2277
3.0000
0.8289
0.5804
0.7620
Integral
6.5
44da
44da
44da
44da
7.0
26.2255
23.3685
23.1780
20.9510
19.9840
17.2076
11.8598
10.1822
+
H2N
CO2CH3
53.3160
52.9131
AcO
+
AcHN
69.9527
63.4768
63.3962
75.0953
171.6848
170.5639
169.3552
168.6666
2.2083
1.9654
1.7744
1.7670
1.7499
1.7430
1.7259
1.7186
1.6759
1.5589
1.0593
1.0353
1.0108
0.9045
0.8888
0.8648
0.8404
3.8183
3.7203
4.1563
4.1489
4.1190
4.1117
5.2529
5.2436
5.2167
5.2069
6.2026
that in 43da (Figure 3.115 & 3.116).
170
1.0
160
150
140
130
Figure 3.115: 1H-NMR (300 MHz, CDCl3) Figure 3.116:
spectrum of compounds 43da & 44 da.
120
13
110
100
90
(ppm)
80
70
60
50
40
30
10
C-NMR (75MHz, CDCl3)
spectrum of compounds 43da & 44 da.
123
20
___________________________________________________________________________
Scheme 3.50 illustrates the suggested mechanism for transacylation via formation of an
oxazolidine ring intermediate.
H
O
HO
N
H
+
H
R
R1
CO2CH3
+ HO
HO
N
H
H
R
O
R1
CO2CH3
O+
R
N
H
R1
CO2CH3
H shift
43da, 43dc & 43fc
AcO
R
H2N
R1
CO2CH3
+
H-
H
O
R
O
+N
H
44da, 44dc & 44fc
+
H
R1
CO2CH3
Scheme 3.50: Proposed mechanism for transacylation.
In contrast to the result with the photoaldol adducts in acidic medium, treatment of compound
43dc with aqueous NaOH (10%) led to a cleavage process with the formation of compound
45. The formation of this product was rather unexpected and may be probably formed via
nucleophilic substitution by hydroxyl group.
HO
AcHN
NaOH (10%)
CO2CH3
AcHN
43dc
OH
CO2CH3
45
Scheme 3.51: “ Retro-aldol“ reaction of compound 43dc.
The structure determination of compound 45 was based on spectroscopic analysis, elemental
analysis and X-ray analysis. The IR spectrum showed strong absorption bands at 3400, 3250,
1730 & 1685 cm-1 corresponding to OH, NH, COO & CON groups, respectively. The 1HNMR spectrum showed the disappearence of the carbinol signal at 4.12 ppm. In the 13C-NMR
spectrum, there is a new signal at 82.5 ppm related to a quaternary carbon attached to n-Pr,
CON &COO groups.
124
6.0
5.5
5.0
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
16.2919
13.8231
22.9509
40.0418
53.1914
82.5456
172.1756
171.2086
3.1800
1.0258
1.0558
1.9846
3.2001
3.0000
4.5
OH
CO2CH3
AcHN
0.9025
0.9620
Integral
6.5
1.9742
1.8175
1.8023
1.7979
1.7822
1.7666
1.7612
1.7484
1.5065
1.4810
1.4595
1.4560
1.4462
1.4345
1.4217
1.3272
1.3037
1.2826
1.2797
1.2699
1.2469
0.9349
0.9104
0.8859
OH
CO2CH3
AcHN
7.0
3.7786
4.8199
6.3525
___________________________________________________________________________
1.0
180
170
160
150
140
130
13
120
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of 45.
CDCl3) of 45.
Moreover, the elemental analysis confirmed the molecular formular C8H15NO4 of the
compound 45. The structure determined by single crystal X-ray analysis of compound 45 is
shown in Figure 3.119.
Figure 3.119: X-ray analysis of compound 45.
The regioselectivity of the Paternò-Büchi reaction of aldehydes with oxazoles is high (>99 :
1) and corresponds to the classical biradical stablization concept. Wheras the high exoselectivity of the photocycloaddition of electronically excited aldehydes to the C-4
unsubstituted oxazole 32 is analogous to the furan case, the high diastereoselectivity for the
trisubstituted oxazoles 36a-f deserves further explanation. In the triplet photocycloaddition
reaction to cycloalkenes,37 ring alkylation leads to a decrease in selectivity and in some case
even to selectivity inversion due to the interference with the spin-orbit coupling geometries.51
This is obviously not the case for the oxazoles 36a-f which indicates that the secondary orbital
interaction model originally applied for the benzaldehyde-furan reaction is operating.42
Scheme 3.52 shows the triplet 1,4-biradical conformers A-C with reactive spin-orbit coupling
geometries.32 If most of the spin inversion process is directed through the channel C, high
125
___________________________________________________________________________
exo-selectivity is expected. The endo-contribution from A becomes only relevant for bulky
groups R and R1 (as for 42ad-42af).
R
O
O
3
R
N
RCHO*
1
O
H
R1
N
O
O
H
R
N
R
1
R
H
O
O
O
R
O
O
O
H
N
N
H
R1
R
A
ISC
R1
B
N
R1
ISC
ISC
C
cleavage
endo
exo
Scheme 3.52: Mechanistic scenario for oxazole-carbonyl photocycloaddition.
3.7.4 Asymmetric photocycloaddition between oxazoles and chiral aldehyde
The oxazole-carbonyl photocycloaddition reaction provides a method for the addition of an
enolate equivalent (oxazole) to an aldehyde which allows access to erythro-aldol products as
described above. In the light of the above results photochemical asymmetric synthesis of
oxazoles appeared interesting and worth of study. Thus, the photocycloaddition of 4substituted 2-methyl-5-methoxyoxazoles 36a-f with 2-methylbutyraldehyde as a chiral
carbonyl component was investigated. Irradiation of 2-methylbutyraldehyde in benzene in the
presence of oxazole substrates 36a-f afforded a 1.12 : 1 mixture of the diastereomeric
products with high exo-selective (> 99 : 1) and in good yields.
R1
N
H3C
+
O
36a-f
H
OCH3
R1 H
R1 H
O
hν
benzene H3C
1g
N
N
O
O
OCH3
+
H3C
O
O
46a-f
OCH3
Scheme 3.53: Photocycloaddition reaction of 2-methylbutyraldehyde with 36a-f.
The results in Table 3.32 show that the facial selectivity decreased with increasing size of
substituent on the oxazole ring. The high exo-selective (relative face selectivity) in
combination with the poor diastereotopic face selectivity with regard to the chiral aldehyde
was expected on the basis of the results from previous studies.
126
___________________________________________________________________________
Table 3.32: Diastereoselectivity of the photocycloaddition of 1g with 36a-f.
Compound
R1 =
d.r.[a]
Yield (%)
46a
Me
63 : 37
75
46b
Et
56 : 44
80
46c
n-Pr
55 : 45
65
46d
i-Pr
47 : 53
84
46e
i-Bu
50 : 50
76
46f
sec-Bu
40 : 60
79
product mixture, [b] yield (%) based on converted oxazole.
The stereochemical assignments of the bicyclic oxetanes 46a-f were based on the
configuration of their hydrolysis products, i.e. the aldol type adducts 47a-f which were easily
formed due to the instabilty of the bicyclic oxetanes 46a-f under the isolation conditions. The
constitution of the photoadducts were elucidated by NMR analyses. For example, in the 1HNMR spectrum of compound 46a (R1 = Me), three singlets at δ 3.79, 1.98 and 1.24 ppm
appeared corresponding to OCH3, CH3 at position C-3 and CH3 at position C-1, respectively,
whereas these signals in the corresponding diastereoisomer (both exo-isomers) resonate at δ
13
3.65, 2.23 and 1.26 ppm. The
C-NMR spectrum showed one signal at δ 124.1 ppm
indicating the presence of the orthoester carbon. At this point, the relative configuration of
H
H
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
O
1.0
170
0.5
160
150
140
130
spectrum of 46a.
5 1 .1 3 2 9
4 0 .7 6 7 1
3 6 .7 8 9 2
3 6 .2 4 7 1
2 4 .8 1 1 7
2 3 .8 5 2 0
1 4 .8 6 3 4
1 4 .0 8 6 8
1 3 .9 4 7 6
1 3 .6 7 6 6
1 2 .3 4 3 3
1 2 .2 9 2 0
1 0 .7 6 1 0
1 0 .1 2 3 6
9 .6 6 9 4
6 0 .9 8 6 0
9 2 .5 5 2 5
7 3 .5 4 2 3
O
H3C
O
OCH 3
OCH3
19.934
4.1890
1.5
+
O
H3C
OCH3
3.1311
3.4711
3.0000
7.0
O
OCH 3
Integral
7.5
O
H3C
N
N
3.8670
4.9351
+
O
O
H
H
N
N
H3C
1 2 4 .1 2 6 3
3.7919
3.7762
3.4480
3.4465
2.2328
2.2274
2.2235
2.2177
1.9972
1.9948
1.9884
1.9826
1.9796
1.9208
1.9159
1.9120
1.9061
1.2684
1.2616
1.2542
0.8771
0.8717
0.8678
0.8634
0.8570
0.8497
0.8438
0.8335
0.8281
0.8247
0.8198
0.8095
0.7933
0.7889
1 6 5 .0 6 2 3
both diastereoisomer is unknown.
120
13
spectrum of 46a.
127
110
100
90
(p p m)
80
70
60
50
40
30
20
10
C-NMR (75 MHz, CDCl3)
___________________________________________________________________________
3.7.4.1 Synthesis of lyxo-& ribo- α-acetamido-β
β-hydroxy esters
The bicyclic oxetanes 46a-f possesses an inherent potential as precursors to lyxo-& ribo- αacetamido-β-hydroxy esters. Acid treatment of the bicyclic oxetanes 46a-f afforded a mixture
of two diastereoisomers which could not be separated by preparative thick layer
chromatograpy.
O
O
H+/H2O
N
N
H3C
CO2CH3
R1 H
R1 H
+
OCH3
H3C
O
O
1
NHAc
H
OH
R
H3C
OCH3
H
Et
46a-f
lyxo-47a-f
CO2CH3
R1
AcHN
+
HO
H
H3C
H
Et
ribo-47a-f
Scheme 3.54: Ring opening of bicyclic oxetanes 46a-f.
Table 3.33: Diastereomeric ratio of the photo aldol adducts 47a-f.
Compound
R1 =
d.r. (lyxo : ribo)[a]
Yield (%)[b]
47a
Me
62 : 37
75
47b
Et
56 : 44
80
47c
n-Pr
55 : 45
73
47d
i-Pr
47 : 53
69
47e
i-Bu
49 : 51
80
47f
sec-Bu
38 : 62
74
[a] based on the integration of characteristic signals in the 1H-NMR spectra of the product
mixture, [b] yield (%) of the crude mixture of diastereoisomers.
The results for the photo aldol adducts are summarized in Table 3.33. The diastereomeric
ratio of the ring-opened products matched the diasteremeric excessess of the precursor
oxetanes. From the previous studies, the relative configuration of C-2 and C-3 was anticipated
to be erythro- (S*,S*), since the precursor bicyclic oxetanes have exo-configurations. The
relative configuration of C-3 and C-4 of the products 47a-f was determined on the basis of
1
H-NMR coupling constants between the hydrogens on C-3 and C-4 in each diastereoisomer
following Karplus126 curve analysis. According to Karplus correlation, the coupling constant
of two trans vicinal protons (having a dihedral angle of about φ = 180°) is expected to be in
the range of 9-12 Hz. The coupling constant of the two protons of C-3 and C-4 in the major
diastereoisomer was found to be 3J = 9.1 Hz which is consistent with the trans configuration
and assignable to xylo-isomer (R*,R*,S*) wheras the minor diastereoisomer had 3J = 6.1 Hz
which established the ribo-configuration (S*,S*,S*).
128
___________________________________________________________________________
The constitutions of compounds 47a-f were determined on the basis of IR, NMR analyses.
For example, the IR spectrum of compound 47c showed absorption bands at 3455, 3330, 1720
and 1685 cm-1 attributed to OH, NH, COO and CON groups, respectively. The
1
H-NMR
spectrum showed two doublets, one at δ 4.2 ppm (d, J = 9.1 Hz) assigned to the xylo-isomer
and the second at δ 4.33 ppm (d, J = 6.9 Hz), attributed to the ribo-isomer. In the
13
C-NMR
spectrum, there are signals at δ 78.6, 89.8, 165.1 and 174.7 ppm corresponding to C-2, C-3,
CO 2C H 3
Pr
H
52.4223
52.4076
35.0530
34.8699
34.5036
33.9322
26.8189
26.1230
18.0134
17.6618
15.8450
15.3102
14.5337
14.5117
14.1747
14.1015
11.1492
10.4899
78.6043
78.2307
89.8273
88.9922
165.1136
174.8202
174.6956
CO 2 CH 3
NHAc
OH
H 3C
3.7208
3.7149
1.9801
1.9713
1.5393
1.5280
1.5192
1.5094
1.4976
1.4888
1.4780
1.2419
1.2175
1.1935
1.1685
1.1469
0.9593
0.9544
0.9378
0.9324
0.9192
0.9118
0.8947
0.8878
0.8697
0.8628
4.3355
4.3125
4.2067
4.1763
CON and COO, respectively.
AcHN
+
Pr
HO
H
H
H 3C
Et
CO 2CH 3
H
Pr
Et
lyxo-47c
ribo-47c
CO 2 CH 3
NHAc
H
AcHN
OH
H 3C
+
H
Pr
HO
H
H 3C
Et
H
Et
lyxo-47c
ribo-47c
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
24.944
4.7810
5.6930
5.9424
4.4168
5.5220
0.8055
1.0000
Integral
xylo ribo
1.0
180
170
160
150
140
130
Figure 3.122: 1 H-NMR (300 MHz, CDCl3 ) Figure 3.123:
spectrum of 47c.
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
10
spectrum of 47c.
In the 1 H-NMR spectrum of compound 47f, there are two downfield signals at δ 4.42 ppm, (d,
J = 6.9 Hz, 1H) and δ 4.16 ppm, (d, J = 9.2 Hz, 1H) attributed to the carbinol protons of riboand xylo-isomers, respectively. The
13
C-NMR spectrum showed signals at δ 82.4, 88.9, 174.4
CO 2CH 3
+
H
Bu
HO
H 3C
Et
H
H
H 3C
5.5
5.0
CO 2 CH 3
NHAc
AcHN
OH
+
H
4.0
(ppm)
3.5
3.0
2.5
2.0
180
1.0
170
160
150
140
130
Figure 3.124: 1 H-NMR (300 MHz, CDCl3 ) Figure 3.125:
spectrum of 47f.
H
Et
ribo-47f
2.4492
8.1319
8.4893
79.291
10.957
7.6409
1.5
s ec
H
H 3C
lyxo-47f
4.5
Bu
HO
Et
1.0000
6.0
s ec
ribo-47f
Integral
6.5
Bu
Et
lyxo-47f
7.0
CO 2CH 3
s ec
H
20.098
H 3C
AcHN
2.6900
OH
88.9116
82.4796
52.2025
52.0853
37.6829
37.3093
37.2141
37.0749
34.4010
33.8882
26.6504
26.3061
26.2255
25.9691
16.2699
15.4860
15.4567
14.2773
13.9989
13.9257
12.5118
12.3653
12.1675
12.1162
12.0430
11.9404
11.0979
CO 2CH 3
NHAc
H
12.094
s ec
0.6637
Bu
174.4173
4.4222
4.3992
4.1641
4.1332
3.7105
3.7037
3.6939
2.3969
1.9977
1.9884
1.9860
1.9825
1.9762
1.1548
1.1479
1.1317
1.1244
1.0382
0.9608
0.9539
0.9388
0.9324
0.9255
0.9192
0.9084
0.9040
0.9006
0.8942
0.8868
0.8795
0.8628
0.8535
0.8467
0.8364
0.6640
0.6419
179.7504
and 179.8 ppm corresponding to C-2, C-3, CON and COO, respectively.
spectrum of 47f.
129
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
10
___________________________________________________________________________
The lack of facial selectivity in the addition of oxazoles to the excited state of a chiral
aldehyde is in contrast to the normal aldol reaction.127 This feature of the photoreaction
suggests a mechanism that is insensitive to the substitution pattern on the chiral aldehyde.
One such mechanism is depicted in Scheme 3.53.
3
R1
k1
O*
H3C
H
ISC
O
N
H3C
O
R1 H
R1
N
N
H3C
O
OCH3
O
O
OCH3
OCH3
R1 H
R1
N
k2
H3C
ISC
O
O
OCH3
N
H3C
O
O
OCH3
Scheme 3.53: Mechanism of the photoaddition of a chiral aldehyde to oxazoles.
The reaction between an triplet excited aldehyde and the oxazole procceds with initial carbonoxygen bond formation to produce the two biradical species shown above. The k1/k2 -ratio
represents the amount of induced diastereoselectivity. The asymmetric induction comes from
the difference in the distance between the stereocenter of incoming aldehyde and C-5 of
oxazole substrates. The top attack (k1 ) is slightly favor than the bottom attack (k2).
A stereogenic center adjacent to the carbonyl is now in a 1,4-relationship to the newly formed
stereogenic center at the acetal carbon and is expected to exert little influence as a
stereocontrol device. Two stereogenic centers are present in these intermediates, but the
stereogenic center at the acetal carbon is expected to completely dictate the stereochemical
outcome of the biradical bond formation. In each case ring closure will produce a cis ring
fusion with an exo-substituted side chain, as in the reaction of achiral aldehydes. The
stereogenic center on the side chain is unrelated to the outcome of biradical closure and has
minimal influence, stereochemicaly, on the initial acetal formation.
130
___________________________________________________________________________
3.8 Photo-Aldol reactions of 5-methoxyoxazoles with α-keto esters: Selectivity pattern
and synthetic route to erythro (S*,R*) & threo (S*,S*) α-amino-β
β -hydroxy succinic acid
derivatives
Photochemical cycloaddition between oxazoles and aldehydes affords, with remarkably high
regio- and stereoselectivity, 7-exo substituted derivatives of 2-aza-4,6-dioxa-bicyclo[3.2.0]
hept-2-enes. Exploring the utility of these highly functionalized compounds for the synthesis
of amino acids derivatives seems attractive. The photocycloaddition of oxazoles to α-keto
esters appeared to me interesting, not only for mechanistic studies but also from a synthetic
point of view, where the photoadducts represent bulding blocks for the synthesis of β-hydroxy
aspartic acid derivatives which are known as naturally occuring amino acids.128
3.8.1 Synthesis of 2-substituted 4-methyl-5-methoxyoxazoles
Treatment of L-alanine methyl ester hydrochloride with different acid chlorides (propionyl
chloride, isobutyrolyl chloride and pivaloyl chloride) in the presence of TEA afforded the
amides which cyclized to 2-substitued 4-methyl-5-methoxyoxazoles 49a-c when heated with
PCl5.129
O
-
+
ClH3N
CO2CH3
34a
+
R
TEA/CHCl3
0°C, 30 min.
Cl
ROCHN
48a-c
R= Et, i-Pr, t-Bu
ROCHN
CO2CH3
CO2CH3
PCl5/CHCl3
∆, 30min.
48a-c
N
R
OCH3
O
49a-c
Scheme 3.54: Synthesis of 2-substituted 4-methyl-5-methoxy oxazoles 49a-c.
Table 3.34: Characteristic properties of 2-substituted 4-methyl-5-methoxy oxazoles 49a-c.
1
H-NMR[a]
Compound
R=
49a
Et
3.78
49b
i-Pr
49c
t-Bu
13
C-NMR[b]
B.p10 torr (°C)
Yield (%)
156.1
80-83
75
3.78
159.2
94-97
80
3.79
161.2
100-102
78
[a] chemical shift of OCH3 in ppm, [b] chemical shift of C-2 in ppm.
The chemical structures of the compounds 49a-c were established on the basis of
spectroscopic data (UV, IR, 1H-NMR, 13C-NMR) and elemental analyses. The UV spectra of
the 2-substitued 4-methyl-5-methoxy oxazoles 49a-c exhibit one major band of strong
131
___________________________________________________________________________
intensity at 245-270 nm. The IR spectra showed strong bands at 1555-1598 cm-1 assigned to
the –N=C-O ring stretching frequency. The
13
C-NMR spectra showed that alkyl substitution
at C-2 deshield C-2 in the order t-Bu > i-Pr > Et as depicted in Table 3.34.
3.8.2 Synthesis of α-keto ester substrates
3.8.2.1 Synthesis of methyl trimethylpyruvate
Methyl trimethylpyruvate was prepared from the commercially available methyl tert-butyl
ketone via oxidation with KMnO4 in the presence of sodium hydroxide to give the α-keto acid
followed by refluxing with methanol in the presence of conc. H2SO4.130
O
O
KMnO4
NaOH (10%)
O
CO2H
CH3OH/H2SO4
∆, 3h.
O
O
50
Scheme 3.55: Synthesis of methyl trimethylpyuvate.
3.8.2.2 Synthesis of isopropyl & tert-butyl phenylglyoxylates
Both isopropyl and tert-butyl phenylglyoxylates were prepared following a procedure
described by Neckers131 from the reaction of phenyl glyoxylic acid with isopropyl alcohol as
well as tert-butyl alcohol in presence of DCC/DMAP as coupling reagent. The products were
isolated as colorless oils after column chromatography.
O
OH
OH
Ph
+
O
DCC/DMAP
Benzene
O
Ph
O
O
51
O
O
OH
OH
Ph
+
DCC/DMAP
Benzene
O
O
Ph
O
52
Scheme 3.56: Synthesis of isopropyl and tert-butyl phenylglyoxylates.
3.8.2.3 Synthesis of (-)-menthyl phenylglyoxylate
Treatment of phenyl glyoxylic acid with (-)-menthol at -15°C in the presence of coupling
reagents (oxalyl chloride, DMF/CH3CN) following the Stadler procedure afforded the (-)menthyl phenylglyoxylate 53 in high yields.132
132
___________________________________________________________________________
COCl
O
OH
Ph
, DMF/CH3CN
Pyridine, -15°C
Ph
O
COCl
+ HO
O
OR*
O
53
R*=
Scheme 3.57: Synthesis of (-)-menthyl phenylglyoxylate 53.
The structure of the menthyl phenylglyoxylate 53 was confirmed on the basis of the
spectroscopic analysis (UV, IR, 1H-NMR,
13
C-NMR) and elemental analysis. The UV
spectrum showed two absorption bands, one with low intensity at 353 nm and the other with
high intensity at 300 nm. The IR spectrum showed two strong signals at 1735 and 1680 cm-1
indicating the presence of two carbonyl groups (C=O & OC=O), respectively.
3.8.3 Photocycloaddition reactions of aliphatic α-keto esters with oxazoles 36a-f
3.8.3.1 Reaction with methyl pyruvate
Photolysis of methyl pyruvate with oxazole substrates 36a-f in benzene using a Rayonet
photoreactor (λ = 350 nm) at 10 °C afforded the bicyclic oxetanes 55a-f with high regio- and
stereoselectivity in good yields.
O
R1
N
H3C
+
O
O
H3C
OCH3
CH3
O
36a-f
hν
benzene
H3C
54
H3C
O
N
O
CO2CH3
R1
OCH3
55a-f
Scheme 3.58: Photoreaction of methyl pyruvate with oxazoles 36a-f.
Table 3.35: Results of the photocycloaddition of methyl pyruvate to oxazole substrates 36a-f.
Compound
R1 =
Yield (%)[b]
55a
Me
>98 : 2
85
55b
Et
>98 : 2
87
55c
n-Pr
>98 : 2
90
55d
i-Pr
>98 : 2
92
55e
i-Bu
>98 : 2
84
55f
sec-Bu
>98 : 2
88
product mixture, [b] based on the degree of conversion of the oxazole.
133
___________________________________________________________________________
The relative configuration of the bicyclic oxetane 55a was unambiguously determined from
NOE effects which were detected for the CH3 group at C-3 by saturation of both methyl
hydrogens at C-7 and the methoxy hydrogens at C-5.
OCH3 OCH3
CH3
CH3 CH3
1.44 ppm
H3C
2.08 ppm
H3C
O
N
O
CO2CH3
CH3
OCH3
CH3
3.56 ppm
Figure 3.126: NOESY spectrum (300 MHz, CDCl3) of compound 55a.
The formation of acid-labile bicyclic oxetanes were proven by the characteristic
13
C-NMR
signals of the orthoester at δ ca. 124.0 ppm. The structure determination of the photoadducts
55a-f were based on IR, mass spectra and NMR analyses. For example, the IR spectrum of
compound 55a showed absorption bands at 1735 and 1610 cm-1 attributed to COO, C=N
groups, respectively. The 1H-NMR spectrum showed five singlets at δ 1.22, 1.44, 2.08, 3.56
and 3.78 ppm corresponding to CH3 at C-1, CH3 at C-7, CH3 at C-3, OCH3 at C-5 and OCH3
of the ester group, respectively. In the
13
C-NMR spectrum, the signals of the oxetane ring
resonate at δ 76.0, 88.7 and 123.9 ppm due to C-7, C-1 and C-5, respectively. Additionally,
there appeared two signals at low field δ 166.2 and 171.5 ppm attributed to C-3 and the COO
group.
134
H 3C
6.0
5.5
5.0
4.5
3.5
3.0
2.5
2.0
18.9511
14.8780
14.5850
52.4076
51.8362
76.0037
88.6772
123.9505
1.2219
171.5236
166.2344
CH 3
OCH 3
3.1100
3.2107
3.2222
3.0000
4.0
CO 2CH 3
O
N
O
H 3C
OCH 3
3.2094
6.5
1.4428
H 3C
CH 3
Integral
7.0
2.0835
CO 2CH 3
O
N
O
H 3C
3.5582
3.7762
___________________________________________________________________________
1.5
220
200
180
160
140
120
(ppm)
13
100
(ppm)
80
60
40
20
0
spectrum of 55a.
spectrum of 55a.
The mass spectrum showed the major peak at m/z = 170 corresponding to (M+-COOMe). The
fragmentation pattern is depicted in Scheme 3.59.
N
O
H 3C
-(CO2Me)
CH3
H 3C
H3C
CO2CH3
O
N
O
H3C
OCH3
m/z = 229
O
CH3
O
N
O
H 3C
OCH3
CH3
H
-C
O
CO2CH3
-CH2=C=O
CH3
O
O
m/z = 146
m/z = 188
OCH3
N
m/z = 86
-(CH3CO)
N
CH3
H3C
-CH2=CHCO2CH3
CH3
OCH3
CN
3
CH3
CO2CH3
OCH3
N
O
m/z = 127
m/z = 170
m/z = 170
CO2CH3
H 3C
OCH3
-CH3CN
H 3C
-(CH3CO)
-(M
eO
CO
)
H 3C
m/z = 68
OCH3
H3C
m/z = 84
O
O
H3C
CH3
-CH3
O
CH3
O
O
m/z = 102
O
-CO
O
m/z = 87
CH3
O
m/z = 59
-OCH3
O
O
-CO
H3C
H3C
O
m/z = 71
m/z = 43
Scheme 3.59: Fragmentation pattern of compound 55a.
Figure 3.129 shows the HMBC-spectrum of the bicyclic oxetane 55a which clearly correlates
the protons with the corresponding carbon atoms and further assignes the chemical structure
of compound 55a.
135
___________________________________________________________________________
C10&C13
C9 C3
C7
C5
C8 C11&C12
C1
H10 H13
8
12 3
H3C
H3C
2 6O
N
O
4
9 10
7 CO2CH3
1 11
CH3
5 OCH3
13
H12
H8 H11
Figure 3.129: HMBC spectrum (300 MHz, CDCl3) of compound 55a.
The 1H-NMR spectrum of compound 54d showed two doublets at δ 0.82 ppm (d, J = 6.6 Hz,
3H) and 1.20 ppm (d, J = 6.6 Hz, 3H) corresponding to the two methyl protons of the
isopropyl group. In addition, there appeared four singlets at δ 1.55, 2.13, 3.63 and 3.79 ppm
attributed to CH3 at C-1, CH3 at C-3, OCH3 at C-5 and OCH3 of the ester group. The
13
C-
NMR spectrum revealed signals at δ 82.8, 90.7 and 124.0 ppm due to C-1, C-7 and C-5 of the
oxetane ring, respectively. Both C-3 and carbonyl ester resonate at δ 166.4 and 171.2 ppm,
respectively.
136
19.1855
16.8999
16.4091
14.6363
27.4929
52.2611
51.3307
82.8020
90.1936
124.0603
166.3883
171.7727
2.1412
2.1393
1.5515
1.4737
1.2880
1.2650
1.2449
1.2234
1.2038
1.0118
0.9897
0.8487
0.8266
3.7953
3.6366
___________________________________________________________________________
benzene
H 3C
7.5
H 3C
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
CO 2CH 3
O
OCH 3
3.1970
3.0416
1.2186
3.2975
3.3518
3.0000
7.0
N
O
OCH 3
Integral
H 3C
H 3C
CO 2CH 3
O
2.9652
N
O
1.0
170
160
150
140
130
120
110
13
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of 55d
spectrum of 55d.
Compound 55f was analyzed by 1H-NMR and
13
C-NMR spectroscopy. In the 1H-NMR
spectrum at δ 1.47, 2.07, 3.57 and 3.77 ppm, there appeared four singlets attributed to CH3 at
C-1, CH3 at C-2, OCH3 at C-5 and OCH3 of the ester group, respectively. In addition, there
appeared a triplet at δ 0.76 and a doublet at δ 0.89 ppm assigned to the CH3 group attached to
CH2 and CH3 attached to a CH group, respectively. The 13C-NMR spectrum revealed signals
H3C
7.5
6.5
5.5
5.0
4.5
4.0
(ppm)
3.5
2.5
2.0
1.5
1.0
170
160
150
140
130
spectrum of 55f.
34.8113
34.3058
23.9912
23.7714
19.2808
14.8267
13.1052
12.6730
12.0430
11.3031
52.4369
51.4772
83.4833
OCH3
3.0275
4.2191
0.6438
1.0927
1.1456
3.5489
1.5153
2.5700
3.0
CO2CH3
O
N
O
H 3C
OCH 3
6.0
90.3548
124.2362
124.2215
165.8315
H3C
3.0000
0.9745
1.3749
2.6016
7.0
171.9485
CO 2CH 3
O
Integral
H 3C
N
O
2.0879
2.0756
1.6632
1.6475
1.4830
1.4756
1.4697
1.4237
1.4012
1.3997
0.9177
0.8957
0.8007
0.7928
0.7884
0.7806
0.7635
0.7409
3.7713
3.7296
3.7150
3.7056
3.6777
3.6723
3.6670
3.5754
3.5719
at δ 83.5, 90.5 and 124.2 ppm for the C-1, C-7 and C-5 of the oxetane ring, respectively.
120
13
spectrum of 55f.
137
110
100
90
(ppm)
80
70
60
50
40
30
20
___________________________________________________________________________
3.8.3.2 Reaction with methyl trimethylpyruvate
In contrast to methyl pyruvate, photolysis of methyl trimethylpyruvate in the presence of
oxazole substrates afforded the bicyclic oxetanes 56a-f with exo-tert-butyl substituent at
position C-7. The diastereomeric ratio was significantly affected by the size of alkyl groups at
position C-4 of the oxazole substrates.
O
R1
N
H3C
+
O
OCH3
H3CO2C
H3C
H3C
O
CH3
36a-f
CH3
O
hν
benzene
H3C
N
O
O
CH3
CH3
R1
CH3
OCH3
56a-f
50
Scheme 3.60: Photoreaction of methyl trimethylpyruvate with oxazoles 36a-f.
Table 3.36: Results of the photocycloaddition reaction of methyl trimethylpyruvate with
oxazole substrates 36a-f.
Compound
R1 =
Yield (%)[b]
56a
Me
>98 : 2
80
56b
Et
>98 : 2
75
56c
n-Pr
>98 : 2
68
56d
i-Pr
49 : 51
79
56e
i-Bu
63 : 37
84
56f
sec-Bu
56 : 44
89
The exo-tert-butyl configuration of the bicyclic oxetane 56a was determined by NOE
measurement. Irradiation of a methyl protons of the tert-butyl group at 1.11 ppm led to NOE
enhancement of both signals of CH3 on C-1 at 1.48 ppm and OCH3 group on C-5 at 3.55 ppm
(see Figure 3.134).
138
___________________________________________________________________________
CH3
OCH3
CH3 1.11
CH3
O
OCH3
3.71 ppm
H3C
H3 C
O O
N
O
CH3
CH3
OCH3
CH3
ppm
1.48 ppm
3.55 ppm
CH3
H3C
CH3
Figure 3.134: NOESY (300 MHz, CDCl3) spectrum of compound 56a.
The chemical structure determination of the bicyclic oxetanes 56a-f was based on IR, NMR
analyses and mass spectrometry. For example, the infrared spectrum of compound 56a
showed strong absorption bands at 1735 and 1620 cm-1 indicating the presence of COO and
C=N groups, respectively. Again, the mass spectrum of the bicyclic oxetane did not show the
molecular ion peak but peaks which were characteristic for retro-cycloaddition to oxazole and
methyl trimethylpyruvate. The 1H-NMR spectrum of compound 56a showed five singlets at
δ1.11, 1.48, 2.01, 3.54 and 3.71 ppm attributed to the tert-butyl group, CH3 at C-1, CH3 at C3, OCH3 at C-5 and OCH3 of ester group, respectively. The
13
C-NMR spectrum revealed
signals at δ 80.6, 97.3 and 118.7 ppm corresponding to C-1, C-7 and C-5 of the oxetane ring,
respectively. In addition, there appeared two signals at δ 167.8 and 173.3 ppm assigned to C-3
and the carbonyl methyl ester, respectively.
139
O
6.0
5.5
4.5
4.0
3.5
3.0
2.5
2.0
O
27.2951
26.0937
26.0790
25.9105
15.5959
33.9248
51.6677
51.3161
80.6922
80.6482
CH3
CH3
OCH3
10.282
2.9041
2.9725
OCH 3
5.0
97.2702
118.7492
173.3038
167.8095
N
O
H 3C
3.2298
6.5
1.0955
CH3
CH 3
Integral
7.0
CH3
CH3
H3CO2C
3.0000
N
O
1.4731
CH3
CH3
H3CO2C
H 3C
1.9551
3.7086
3.7061
3.5430
___________________________________________________________________________
170
1.5
160
150
140
130
120
110
(ppm)
13
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of 56a.
spectrum of 56a.
3.8.4 Photocycloaddition reactions of aromatic α-keto esters with oxazoles 36a-f
In order to evaluate the influence of steric as well as electronic factors on the stereoselectivity
of the Paternò-Büchi reaction of oxazoles with aromatic α-keto esters, the photocycloaddition
of 4-substituted oxazoles with different types of alkyl phenylglyoxylates was investigated.
3.8.4.1 Reaction with methyl phenylglyoxylate
Photolysis of equimolar amounts of methyl phenylglyoxylate and an oxazole in benzene at
350 nm furnished mixture of diastereoisomers exo-58a-f and endo-58a-f in good yields.
O
R1
N
H3C
+
O
36a-f
OCH3
O
Ph
CH3
hν
benzene
O
H3CO2C
O
N
H3C
O
Ph
R1
OCH3
+
H3C
exo-58a-f
57
Ph
O
N
O
CO2CH3
R1
OCH3
endo-58a-f
Scheme 3.61: Photoreaction of methyl phenylglyoxylate with oxazole substrates 36a-f.
The exo/endo diastereomeric ratios of the photoadducts 58a-f were slightly affected by
changing the alkyl substituent of the oxazole substrates (see Table 3.37).
140
___________________________________________________________________________
Table 3.37: Results of the photocycloaddition reaction of methyl phenylglyoxylate with
Compound
R1 =
Yield (%)[b]
58a
Me
79 : 21
86
58b
Et
77 : 23
79
58c
n-Pr
75 : 25
78
58d
i-Pr
71 : 29
85
58e
i-Bu
72 : 28
89
58f
sec-Bu
74 : 26
90
The bicyclic oxetanes 58a-f were formed with moderate simple diastereoselectivity favoring
the exo-Ph products. In most examples, the diastereomeric exo and endo oxetane products
were separated by preparative chromatography after treatment with 1% TEA/CH2Cl2. No side
products were formed except the inevitable pinacol formation, which is due to hydrogen
abstraction of the photoexcited methyl phenylglyoxylate and its subsequent addition to
another substrate molecule. In order to determine the prefered mode of diastereofacial attack
of methyl phenylglyoxylate to the chiral oxazole 36f, a NOESY experiment was performed
with the isolated endo-Ph bicyclic oxetane 58f. Saturation of the methyl hydrogen at 1.22 ppm
led to an enhancement of the aromatic proton signal at 7.51 ppm assigned the lk-attack (lk =
like) of the methyl phenyglyoxylate whereas irradiation of the methylene proton at 2.09 ppm
led to enhancement of the aromatic proton at 7.51 ppm assigned to ul-attack (ul = unlike) of
methyl phenylglyoxylate to the chiral oxazole (see Figure 3.137).
141
___________________________________________________________________________
OCH3 OCH3
CH3
de.= 58 : 42
7.51 ppm
H
H3C
CH3
OCH3
O
CO 2CH3
N
O
H3 C
O
2.09 ppm
CO2CH3
O
1.22 ppm
CH3
CH3
N
H
CH3
7.51 ppm
OCH 3
CH3
CH3 CH3
CH
CH
Figure 3.137: NOESY spectrum (300 MHz, CDCl3) of endo-58f.
Scheme 3.62 displays the formation of the two diastereoisomers of the bicyclic oxetanes from
the lk-attack and ul-attack of methyl phenylglyoxylate to the chrial oxazole 36f.
3 O*
lk
3 O*
O
Ph
CH3
O
lk
H3C
OCH3
O
ul
H3C
O
OCH3
CH3
ul
CO2CH3
Ph
N
O
H3C
O
Ph
N
O
endo (a : b)
de. 58 : 42
N
OCH3
O
Ph
O
CO2CH3
endo-(b)
endo-(a)
Scheme 3.62: lk- and ul- attack of methyl phenylglyoxylate to the chiral oxazole.
The assignment the relative configuration of the two diastereoisomers was possible by 1HNMR analysis, which showed two main differences between the exo-Ph and the endo-Ph
diastereoisomers in the 1H-NMR spectra: (a) the methyl protons at C-3 in the exo-Ph isomer
absorb at 2.00 ppm, while in the endo-Ph isomer this absorption is shifted upfield to 1.70 ppm
due to shielding effect of the benzene ring; (b) the methoxy protons at C-5 in the exo-Ph
142
___________________________________________________________________________
isomer is shielded by the benzene ring and resonates at much higher field (δ = 3.00 ppm) than
the methoxy protons in the endo-Ph isomer which absorb at δ = 3.67 ppm.
The constitutions of the bicyclic oxetanes 58a-f were elucidated on the basis of NMR
analyses. For example, the 1H-NMR spectrum of exo-58a showed four singlets at δ 2.03,
2.08, 3.05 and 3.73 ppm attributed to CH3 at C-1, CH3 at C-3, OCH3 at C-5 and OCH3 of the
ester group, respectively. The 13C-NMR spectrum revealed signals at δ 80.9, 90.9 and 121.7
H3CO2C
N
O
H 3C
H3CO 2C
Ph
O
CH3
H 3C
OCH3
7.5
6.5
6.0
5.5
5.0
(ppm)
4.5
4.0
3.5
3.0
2.5
170
2.0
160
150
140
130
spectrum of exo-58a.
16.2955
28.1339
53.2281
52.1988
Ph
O
CH 3
OCH 3
2.9389
3.0100
3.2965
3.0000
7.0
N
O
exo-ph
7.3652
4.5388
Integral
exo-ph
8.0
80.4468
90.9079
135.2540
134.3054
128.5583
127.7195
126.1335
125.8954
121.7747
169.5860
168.7179
2.0763
2.0283
3.0505
3.7377
7.5165
7.5145
7.3499
7.3254
7.3205
7.3161
7.3142
7.3054
7.2975
7.2035
ppm due to C-1, C-7 and C-5 of the oxetane ring, respectively.
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
In the 1H-NMR spectrum of compound 58c, the methyl protons at C-3 resonates at higher
field (δ = 1.66 ppm) influenced by the ring current effect of the benzene ring and assigned to
the endo-Ph configuration of the bicyclic oxetane. In addition, the two methoxy groups absorb
at δ 3.64 and 3.73 ppm. The 13C-NMR spectrum revealed signals at δ 81.6, 91.0, 123.7, 165.2
and 169.8 ppm attributed to C-1, C-7, C-5, C-3 and the carbon of carbonyl ester, respectively.
143
Ph
N
O
H 3C
Ph
CO2CH3
O
N
O
H 3C
OCH3
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
17.0098
14.3359
14.2626
14.2480
31.6466
52.7226
51.9095
OCH3
1.5
3.4752
2.0744
3.3260
1.1364
Integral
3.0000
2.9108
7.0
CO2CH3
O
endo-ph
3.8662
2.5083
endo-ph
7.5
81.6445
91.0287
127.6793
126.4119
123.7527
135.1002
165.2308
169.8680
1.9992
1.9801
1.9620
1.9522
1.9434
1.9355
1.9130
1.8968
1.6642
1.3424
1.3257
1.3228
1.3184
1.3071
1.2988
0.8908
0.8663
0.8418
3.7287
3.6371
7.2645
7.2400
7.2385
7.2287
7.1993
___________________________________________________________________________
1.0
170
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of endo-58c.
CDCl3) of endo-58c.
The 1H-NMR spectrum of endo-58e revealed two doublets at δ 0.79 ppm (d, J = 6.6 Hz, 3H)
and 0.92 ppm (d, J = 6.6 Hz, 3H) indicating the presence of an isopropyl group. Again, the
methyl protons at C-3 resonate at higher field at δ 1.72 ppm confirming the endo-Ph
configuration of the bicyclic oxetane. Further prove of the endo-Ph configuration came from
the chemical shift of OCH3 group at C-5 (3.69 ppm) indicating that the phenyl group is distant
from OCH3 group. The 13C-NMR spectrum showed signals at δ 81.8, 90.9 and 123.8 ppm due
to C-1, C-7 and C-5 of the oxetane ring, respectively. Both C-3 and carbonyl ester resonate at
Ph
N
O
H 3C
CO 2CH 3
N
O
H 3C
OCH 3
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
170
160
150
140
130
120
110
(ppm)
CDCl3) of endo-58e.
24.2622
24.1743
23.0022
14.2846
37.1921
OCH3
0.5769
3.1640
3.1017
3.3980
1.1733
1.3910
3.0000
2.9983
Integral
2.2179
3.4301
7.0
CO2CH3
O
endo-Ph
7.5
52.7153
51.9241
Ph
O
endo-Ph
81.7983
90.9408
135.2247
130.0381
128.8587
127.9283
127.7232
126.3533
123.7966
164.7180
169.8680
2.0922
2.0771
2.0452
2.0300
1.7293
1.6426
1.6171
1.5956
1.5696
0.9265
0.9050
0.8217
0.7997
3.7664
3.6919
7.3091
7.2846
7.2821
7.2694
7.2400
lower field at δ 164.7 and 169.9 ppm, respectively.
13
100
90
(ppm)
80
70
60
50
40
30
20
CDCl3) of endo-58e.
In the 1H-NMR spectrum of endo-58f, three singlets appeared at δ 1.70, 3.71 and 3.77 ppm
related to CH3 at C-1, OCH3 at C-5 and OCH3 of the ester group, respectively. The 13C-NMR
spectrum revealed signals at δ 86.3, 92.3 and 123.9 ppm assigned to C-1, C-7 and C-5 of the
144
___________________________________________________________________________
oxetane ring, respectively. Moreover, from the intensity of the signals it was detected that the
9.0
8.5
8.0
7.5
2.9797
3.0000
7.0
6.5
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.5
34.7820
34.5475
24.3062
24.0278
14.2480
13.2957
12.1455
11.5961
52.8911
52.8178
51.8582
92.3034
86.3110
86.2890
135.3200
135.2687
127.7452
127.7012
126.7709
126.7196
123.9871
123.9651
170.1830
170.1317
165.5532
165.2015
endo-Ph
2.0003
3.1672
Integral
endo-Ph
H 3C
OCH 3
CO2CH3
OCH3
2.0362
1.6322
3.4235
H 3C
Ph
O
N
O
CO 2CH 3
0.5468
0.9051
2.9931
1.6951
Ph
O
N
O
2.0908
1.9360
1.7621
1.7508
1.7092
1.2243
1.2023
0.9613
0.9368
0.9118
0.8839
0.8687
0.8673
0.8628
0.8408
3.7742
3.7722
3.7086
3.7066
7.5138
7.4967
7.4913
7.4869
7.3228
7.3203
7.2958
7.2939
7.2792
7.2400
facial selectivity of the photoadduct was low (de. 58 : 42).
1.0
0.5
220
200
180
160
140
13
120
100
(ppm)
80
60
40
20
0
CDCl3) of endo-58f.
CDCl3) of endo-58f.
3.8.4.2 Reaction with ethyl phenylglyoxylate
Analogous to methyl phenylglyoxylate, irradiation of ethyl phenylglyoxylate in benzene in
the presence of the oxazole substrates afforded two diastereoisomers exo-60a-f and endo-60af in good yields with preferential formation of the exo-Ph photoadducts.
O
R1
N
H3C
+
O
O
Ph
OCH3
36a-f
hν
benzene
O
C2H5O2C
O
N
H3C
O
Ph
R
OCH3
exo-60a-f
59
1
+
H3C
Ph
O
N
O
CO2C2H5
R1
OCH3
endo-60a-f
Scheme 3.63: Photoreaction of ethyl phenylglyoxylate with oxazole substrates 36a-f.
The exo/endo diastereoselectivity of the photoadducts was slightly changed by increasing the
size of the alkyl substituent of the oxazole substrates. Comparing the diastereoselectivity of
the photoadducts from methyl phenylglyoxylate and ethyl phenylglyoxylate showed that the
exo/endo diastereoselectivity slightly decreased in case of ethyl phenylglyoxylate than for
methyl phenylglyoxylate.
145
___________________________________________________________________________
Table 3.38: Results of the photocycloaddition reaction of 59 with 36a-f.
Compound
R1 =
Yield (%)[b]
60a
Me
73 : 27
89
60b
Et
72 : 28
85
60c
n-Pr
70 : 30
78
60d
i-Pr
67 : 33
75
60e
i-Bu
65 : 35
90
60f
sec-Bu
66 : 34
76
product mixture, [b] based on conversion of the oxazole.
The exo-Ph and endo-Ph bicyclic oxetane diastereoisomers were separated by preparative
chromatography although the separation was not always fully successful. The relative
configurations of the two separated isomers of compound 60d were deduced from NOESY
studies. The endo-Ph diastereoisomer shows strong NOEs effect between the methyl protons
at C-3 and aromatic phenyl protons at C-7. This phenomenon is illustrated in Figure 3.147
which summarizes the NOE data recorded for the endo-Ph-60d. The exo-Ph isomer showed a
strong nuclear Overhauser enhancement of the aromatic protons signal when both methoxy
protons at 3.54 ppm and methyl protons at 0.85 ppm were irradiated (see Figure 3.146).
OCH3
CH3
7.81 ppm
C2H5O2C
H3 C
N
O
O
CH3
CH3
0.85 ppm
CH3
CH3
OCH 3
3.72 ppm
OCH2
CH
Figure 3.146: NOESY (300 MHz, CDCl3) spectrum of exo-60d.
146
CH3
___________________________________________________________________________
OCH3
CH3
CO 2C2H5
7.50 ppm
1.77 ppm
OCH2
H3 C
N
O
O
CH3
1.23 ppm
CH3
OCH3
CH3
CH3
CH3
CH
Figure 3.147: NOESY (300 MHz, CDCl3) spectrum of endo-60d.
The constitutions of the bicyclic oxetanes 60a-f were confirmed by the 1H-NMR and
13
C-
NMR analyses. For examples, the 1H-NMR spectrum of endo-60b showed two triplets at δ
0.93 (t, J = 7.5 Hz, 3H), 1.27 (t, J = 7.4 Hz, 3H) indicating the presence of two ethyl groups.
In addition, there appeared two singlets at δ 1.72, 3.69 ppm attributed to methyl protons at C3 and methoxy protons at C-5, respectively and confirmed the endo-Ph configuration of the
bicyclic oxetane. The
13
C-NMR spectrum revealed signals at δ 81.9, 90.9 and 123.8 ppm
attributed to C-1, C-7 and C-5 of the oxetane ring, respectively. Moreover, there appeared two
down-field shifted signals at δ 165.4 and 169.3 ppm related to C-3 and carbonyl ester group,
respectively.
147
Ph
Ph
7.5
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
14.2920
14.0282
8.0211
22.5627
3.0733
2.5707
7.0
4.0259
OCH 3
1.9739
4.0039
Integral
8.0
OCH 3
endo-Ph
endo-Ph
8.5
CO 2C2H5
O
N
O
H 3C
1.1003
1.1600
3.0172
H 3C
CO 2C2H5
O
3.0000
N
O
51.9095
61.8871
81.9449
90.9555
135.2101
127.8917
127.6426
126.9027
126.4266
123.7746
169.3039
165.3993
2.1922
2.1070
2.0820
2.0595
2.0345
1.8738
1.8498
1.8258
1.8018
1.7225
1.2959
1.2719
1.2484
0.9579
0.9334
0.9084
3.6929
4.2625
4.2591
4.2385
4.2366
4.2145
4.2131
4.1905
7.5045
7.4991
7.4766
7.4722
7.3110
7.3086
7.2841
7.2821
7.2713
___________________________________________________________________________
1.0
0.5
170
160
150
140
130
110
13
Figure 3.148: 1H-NMR (300 MHZ, CDCl3) Figure 3.149:
spectrum of endo-60b.
120
100
90
(ppm)
80
70
60
50
40
30
20
10
There are two main differences in the 1H-NMR spectra of the exo-Ph and endo-Ph
diastereoisomers of compound 60d: a) the methyl protons of the isopropyl group in the exoPh isomer resonate upfield-shifted at δ 0.66 (d, J = 6.6 Hz, 3H), and 0.84 (d, J = 6.6 Hz, 3H)
while in the endo-Ph isomer the corresponding signals appear at δ 0.84 (d, J = 6.6 Hz, 3H)
and 1.22 (d, J = 6.8 Hz, 3H); b) the methyl protons at C-3 absorb at higher field in the endoPh isomer in comparsion with the exo-Ph isomer. The
13
C-NMR spectrum revealed, that the
methine carbon of isopropyl group in the exo-Ph isomer resonate at higher field (δ = 25.9
ppm) than in the endo-Ph isomer which resonates at δ 27.8 ppm. This phenomena is related to
the ring current effect of the benzene ring which was often used as a tool for the assignement
C2H5O2C
H 3C
N
O
H 3C
OCH 3
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
16.5483
15.9109
14.7242
14.2260
25.9179
51.5505
Ph
O
OCH 3
1.5
3.2002
2.8595
2.9548
1.2522
2.8966
3.0000
2.5923
7.0
N
O
exo-ph
2.9249
Integral
1.8507
7.5
61.5501
C2H5O2C
Ph
O
exo-ph
8.0
86.0106
92.8675
123.2545
134.7998
168.2783
166.0367
2.0815
1.7210
1.6984
1.6764
1.6539
1.3218
1.2978
1.2743
0.8643
0.8423
0.6870
0.6645
3.7208
4.3502
4.3262
4.2562
4.2322
7.8209
7.7998
7.7944
7.3634
7.3615
7.3443
7.3375
of the relative configuration of the bicyclic oxetanes.
1.0
0.5
160
150
140
130
spectrum of exo-60d.
120
110
13
100
80
70
60
50
40
30
20
148
90
(ppm)
Ph
Ph
O
N
O
H 3C
CO 2C2H5
N
O
H 3C
17.4273
17.3468
14.2919
13.9330
27.7639
51.8142
61.9896
85.6663
92.2814
127.6719
126.6756
123.8772
135.3712
169.6262
165.4286
1.3051
1.2811
1.2571
1.2439
1.2214
0.8648
0.8428
1.7724
2.2950
2.2730
2.2509
3.7135
4.3213
4.2694
4.2615
4.2459
4.2380
4.2219
4.2140
4.1979
4.1905
7.4873
7.4829
7.3144
7.2900
7.2718
7.2488
7.2400
___________________________________________________________________________
CO 2C2H5
O
OCH 3
endo-ph
OCH 3
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.5
3.3090
3.1747
3.1852
3.0110
1.1866
3.0000
2.0338
3.5041
1.9683
Integral
endo-ph
1.0
170
160
150
140
130
120
110
13
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of endo-60d.
The IR spectrum of compound 60e showed two strong absorption bands at 1740 and 1620 cm1
attributed to the COO and C=N groups, respectively. The 1H-NMR spectrum showed two
singlets at δ 1.72 and 3.69 ppm attributed to methyl protons at C-3 and methoxy protons at C5, respectively, and confirmed the endo-Ph configuration. In the
13
C-NMR spectrum, at δ
81.6, 90.8 and 123.8 ppm, there signals appeared corresponding to C-1, C-7 and C-5 of the
Ph
6.0
5.5
5.0
4.5
4.0
(ppm)
3.0
2.5
2.0
24.2256
24.1450
22.9436
14.2846
14.0355
37.2580
51.8948
CO2C2H5
O
OCH3
3.2632
1.2060
1.9529
3.3127
0.7599
4.3986
3.0197
1.3706
3.5
61.8431
81.6884
90.8163
135.2980
129.9649
128.8294
127.8331
127.6499
126.3533
123.7820
N
O
endo-Ph
1.9999
6.5
164.6814
OCH 3
2.4884
3.5555
7.0
169.2893
H 3C
endo-Ph
7.5
2.1887
1.7268
1.6563
1.6299
1.6093
1.5833
1.3948
1.3463
1.2944
1.2708
1.2468
0.9197
0.8976
0.8139
0.7923
Ph
CO 2C2H5
O
3.0000
H 3C
N
O
3.6949
4.4359
4.4119
4.3370
4.3130
4.2390
4.2331
4.2155
4.2096
4.1915
7.2762
7.2738
7.2606
7.2400
oxetane ring, respectively.
1.5
1.0
170
160
150
140
130
spectrum of endo-60e.
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
3.8.4.3 Reaction with isopropyl phenylglyoxylate
The [2+2]-photocycloaddition of the electronically excited triplet state of isopropyl phenylglyoxylate with the oxazole substrates 36a-f afforded two diastereoisomer of the bicyclic
oxetanes 61a-f in high chemical yields.
149
___________________________________________________________________________
O
R1
N
H3C
+
O
OCH3
36a-f
O
Ph
hν
benzene
O
PriO2C
O
N
H3C
O
Ph
R1
OCH3
exo-61a-f
51
CO2Pri
Ph
+
H3C
N
O
O
R1
OCH3
endo-61a-f
Scheme 3.64: Photoreaction of isopropyl phenylglyoxylate with oxazole substrates 36a-f.
The exo-Ph / endo-Ph diastereomeric ratios exhibited a strong trend disfavoring the endo-Ph
isomers with increasing steric demand of the R1 substituent (Me, Et, n-Pr, i-Bu, sec-Bu and iPr) of the oxazole substrates (see Table 3.39). Interestingly, the exo-Ph diastereoisomer is still
favored even with the bulky isopropyl substituent.
Table 3.39: Results of the photocycloaddition reaction of isopropyl phenylglyoxylate with
Compound
R1 =
Yield (%)[b]
61a
Me
67 : 33
85
61b
Et
66 : 34
87
61c
n-Pr
63 : 37
80
61d
i-Pr
51 : 49
90
61e
i-Bu
56 : 44
86
61f
sec-Bu
55 : 45
84
product mixture, [b] based on conversion of the oxazole.
The exo-Ph and endo-Ph diastereoisomers of the bicyclic oxetanes 61a-f were separated by
preparative chromatography. The relative configurations of the photoadducts were assgined
from the 1H-NMR chemical shift comparsion of the methyl protons at C-3 in both the exo and
endo-isomers similar to the results described above. The chemical structure of the bicyclic
oxetanes were elucidated by the 1H-NMR and 13C-NMR analyses. For example, the 1H-NMR
spectrum of compound 61a showed two doublets at δ 1.20 (d, J = 6.2 Hz, 3H), 1.28 (d, J = 6.2
Hz, 3H) indicating the presence of an isopropyl group. In addition, at δ 1.50, 1.69 and 3.67
ppm, three singlets appeared related to CH3 at C-1, CH3 at C-3 and OCH3 at C-5, respectively,
and confirmed the endo-Ph configuration. In the 13C-NMR spectrum, three signals appeared at
δ 78.5, 90.5 and 123.7 ppm attributed to C-1, C-7 and C-5 of the oxetane ring, respectively.
150
8.0
7.5
1.4397
7.0
6.5
6.0
5.5
5.0
4.5
(ppm)
4.0
21.6836
21.5737
15.7937
14.3139
52.0413
69.9087
78.4505
90.4573
168.6300
165.2894
1.6882
1.5075
1.2954
1.2831
1.2626
1.2248
1.2043
135.1148
127.9283
127.5767
126.4632
126.4412
126.4266
123.7014
CH3
endo-Ph
OCH 3
2.2400
4.0386
Integral
endo-Ph
H 3C
CH3
OCH 3
3.6216
3.0096
4.3680
3.9046
H 3C
CO 2Pri
Ph
O
N
O
CO 2Pri
3.0000
Ph
O
N
O
3.6670
5.1158
5.0947
5.0736
5.0531
5.0320
7.4913
7.4854
7.4805
7.3326
7.3056
7.3032
7.2787
7.2767
7.2709
7.2400
___________________________________________________________________________
3.5
3.0
2.5
2.0
1.5
170
160
150
140
130
120
110
13
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of endo-61a.
3.8.4.4 Reaction with tert-butyl phenylglyoxylate
Analogous to isopropyl phenylglyoxylate, irradiation of tert-butyl phenylglyoxylate in
benzene in the presence of the oxazole substrates 36a-f delivered two diastereoisomers of the
bicyclic oxetanes 62a-f in high chemical yields.
O
R1
N
H3C
+
O
O
Ph
OCH3
36a-f
hν
benzene
O
ButO2C
O
N
H3C
O
Ph
R1
OCH3
exo-62a-f
52
CO2But
Ph
+
H3C
N
O
O
R1
OCH3
endo-62a-f
Scheme 3.65: Photoreaction of tert-butyl phenylglyoxylate with oxazole substrates 36a-f.
Table 3.40: Results of the photocycloaddition reaction of tert-butyl phenylglyoxylate with
Compound
R1 =
Yield (%)[b]
62a
Me
69 : 31
85
62b
Et
67 : 33
87
62c
n-Pr
61 : 39
80
62d
i-Pr
53 : 47
90
62e
i-Bu
55 : 45
86
62f
sec-Bu
55 : 45
84
151
___________________________________________________________________________
Again, the exo-Ph/ endo-Ph diastereoselectivities of the photoadducts decreased by increasing
size of the substituent at C-4 of the oxazole substrates 36a-f, albeit the exo-Ph isomer is still
favored (see Table 3.40).
The two diastereoisomers of the bicyclic oxetanes could be separated by preparative
chromatography. The relative configuration of the endo-Ph bicyclic oxetane 62a was clearly
assigned by NOESY measurements. Irradiation of the methyl hydrogen protons at 1.67 ppm
led to an enhancement of the intensity of the phenyl protons signal at 7.48 ppm. Also,
irradiation of the phenyl protons at 7.48 ppm led to an enhancement of the intensity of both
the methyl signal at 1.53 ppm and the tert-butyl protons signal at 1.44 ppm (see Figure 3.158).
1.44 ppm
O
7.48 ppm
1.67 ppm H3C
N
O
O
CH3
CH3
CH3
O
CH3 1.53
ppm
OCH3
CH3
CH3
CH3
CH3
H3C
Figure 3.158: NOESY (300 MHz, CDCl3) spectrum of endo-62a.
The constitutions of compounds 62a-f were determined by IR, mass spectroscopy and NMR
analyses. For example, the IR spectrum of compound 62a showed two strong absorption
bands at 1615 and 1725 cm-1 corresponding to the C=N and COO group, respectively. The
mass spectrum showed the base peak at m/z 276 due to [M+ - (CH3)3 C], in addition there are
two peaks at m/z 127 and 206 related to retrocycloaddition to give 2,4-dimethyl-5152
___________________________________________________________________________
methoxyoxazole and tert-butyl phenylglyoxylate. Scheme 3.66 summarizes the fragmentation
pattern of the compound 62a.
N
O
H3C
CO2CH3
O
H3C
H3C
-C
H
m/z = 333
-(CH3)3CCN
- (C
H
CH3
N
O
H3C
OCH3
H3C
m/z = 274
CO2CH3
-CN
CH3
OCH3
OCH3
CO2CH3
O
CH3
m/z = 86
OCH3
CH3
OCH3
m/z = 169
CN
) 3C
H3
-( C
OCH3
N
-(CH3)3CCO)
N
CH3
H3C
H3C
m/z = 276
m/z = 250
H3C
CH3
O
N
O
N
O
H3C
CH3
m/z = 274
m/z = 292
H3C
-(PhCO)
O
[C16H20O5]
3)
3C
O
O
H3C
O
H3C
3 CN
Ph
Ph
N
O
H3C
OCH3
Ph
Ph
-(CO2Me)
CH3
-(M
eO
CO
)
Ph
H3C
OCH3
H3C
CH3
m/z = 110
m/z = 84
-CH2=CHCO2CH3
O
O
Ph
CH3
O
-CH3
O
O
-CO2
Ph
-CO
Ph
O
O
m/z = 164
m/z = 149
m/z = 105
m/z = 77
-OCH3
O
O
-CO
-CO
Ph
Ph
O
m/z = 133
m/z = 105
m/z = 77
There are two main differences in the 1H-NMR spectra between the exo-Ph and the endo-Ph
diastereoisomer of compound 62a: (a) the methyl protons at C-3 in the exo-Ph isomer absorb
at 2.07 ppm, while in the endo-Ph isomer this absorption is shifted upfield to 1.67 ppm due to
the shielding effect of the benzene ring; (b) the methyl protons at C-1 in the exo-Ph isomer are
shielded by the benzene ring and resonate at a much higher field (δ = 1.04 ppm) than in the
endo-Ph which absorbs at 1.52 ppm. The
13
C-NMR spectra of both the exo- and endo-Ph
isomers revealed signals at δ 78.8, 91.1 and 123.4 ppm attributed to C-1, C-7 and C-5 of the
oxetane ring, respectively. Figure 3.163 shows the DEPT spectrum of the compound endo62a which clearly displayes the CH and CH3 groups.
153
CH 3
OCH 3
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.0
220
200
180
160
140
8.0
7.5
6.5
6.0
135.4481
127.4558
126.5914
123.6977
167.9743
165.1832
CH 3
5.5
5.0
4.5
(ppm)
N
O
H 3C
OCH 3
14.9293
14.8560
14.3139
27.9251
51.8069
60
40
20
0
CO 2But
O
CH 3
OCH 3
endo-Ph
3.0000
7.0
80
Ph
2.3122
4.2773
Integral
CO 2But
O
endo-Ph
100
(ppm)
4.0
3.1590
3.1307
9.2891
N
O
1.6740
1.5270
1.4428
3.6679
H 3C
13
120
7.4922
7.4756
7.4717
7.4697
7.4653
7.2944
7.2890
7.2748
7.2694
7.2616
7.2562
7.2400
Ph
82.9778
78.7655
3.0524
8.6009
1.5
3.5
3.0
2.5
2.0
1.5
220
200
180
160
140
13
120
100
(ppm)
N
O
H 3C
180
160
140
120
15.8634
14.3177
O
CH3
endo-Ph
200
27.9142
51.9938
127.7709
127.4559
126.5915
CO2But
Ph
OCH3
100
(ppm)
80
60
40
Figure 3.163: DEPT (75MHz, CDCl3) spectrum of endo-62a.
154
20
80
60
40
20
0
220
15.8706
14.3176
6.5
3.0418
3.0000
7.0
27.9141
7.5
51.9937
8.0
CH3
OCH3
83.1426
78.2344
8.5
Ph
exo-Ph
2.2516
0.5249
4.1845
Integral
exo-Ph
91.0727
135.5251
128.2287
127.9430
127.4521
126.5877
126.3533
123.4010
167.3919
166.2344
1.0436
1.4639
ButO2C
O
N
H 3C
O
Ph
90.4976
ButO2C
O
N
H 3C
O
2.0741
3.6224
7.6764
7.6705
7.6480
7.6436
7.3718
7.3693
7.3443
7.3336
7.2400
___________________________________________________________________________
0
___________________________________________________________________________
Proving the chemical structure of compound 62b was based on NMR analyses. Analogous to
compound 62a, there are also two main differences in the 1H-NMR spectra between the exoand the endo-Ph diastereoisomers. The 1H-NMR spectrum of the exo-Ph isomer showed a
triplet (J = 7.5 Hz, 3H) at higher chemical shift (δ = 0.72 ppm) related to the methyl group
attached to the methylene group and assigned to the exo-Ph configuration. Additionally, there
appeared three singlets at δ 1.47, 2.09 and 3.65 ppm attributed to the tert-butyl, methyl, and
methoxy groups, respectively. In the 1H-NMR spectrum of the endo-Ph isomer, the chemical
shift of the methyl protons of ethyl group is shifted downfield to 0.92 ppm, whereas the
chemical shift of the methyl protons at C-3 is shifted upfield to 1.70 ppm. The
13
C-NMR
spectra of both the exo-Ph and endo-Ph diastereoisomers revealed signals characteristic for
the oxetane ring at δ 81.9, 91.3 and 123.3 ppm corresponding to C-1, C-7 and C-5,
OCH 3
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
1.5
1.0
220
0.5
200
180
160
140
13
7.5
H 3C
OCH 3
6.5
6.0
5.5
5.0
80
7.4131
27.9397
27.8738
21.8374
14.8341
51.6091
60
40
20
0
135.6569
127.6792
127.4521
126.6243
123.7746
N
O
O
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.5
220
1.0
200
180
160
OCH 3
3.4012
9.2968
endo-Ph
3.0000
7.0
100
(ppm)
CO2But
Ph
2.2464
5.1642
Integral
endo-Ph
8.0
168.0952
165.3041
CO2But
O
1.3246
1.2974
2.9569
H 3C
2.1814
2.1780
2.1442
2.0962
2.0737
2.0629
2.0487
1.9292
1.9052
1.8817
1.7073
1.4408
0.9657
0.9413
0.9163
3.6978
7.4810
7.4584
7.4540
7.2963
7.2939
7.2694
7.2576
7.2400
N
O
120
spectrum of exo-62b.
spectrum of exo-62b.
Ph
82.8825
81.9742
3.1717
1.1790
1.2747
10.970
2.0
28.0643
27.8958
27.8592
22.5846
14.3139
8.1530
6.5
OCH 3
51.8801
7.0
3.0888
3.0000
3.7432
Integral
2.0380
7.5
Ph
exo-Ph
exo-Ph
8.0
91.3804
135.4518
128.2214
127.8990
126.4632
123.3571
167.4725
166.2418
1.7009
1.6049
1.4653
1.2635
1.2390
1.2160
0.7512
0.7267
0.7017
ButO2C
O
N
H 3C
O
Ph
90.9628
83.0803
81.6958
ButO2C
O
N
H 3C
O
2.0947
3.6513
7.3522
7.3380
7.3316
7.3252
7.3198
7.3047
7.3027
7.2880
7.2400
respectively.
140
13
120
100
(ppm)
60
40
20
0
155
80
___________________________________________________________________________
The structure elucidation of both the exo- and endo-Ph diastereoisomer of compound 62d was
based on their NMR analyses. Analogous to 62a, there are two main differences between the
exo- and endo-Ph isomers in the 1H-NMR spectra: (a) the methyl protons of the isopropyl
group in the exo-isomer appears at 0.68 and 0.84 ppm, while in the endo-isomer, this
absorption is shifted downfield to 0.87 and 1.26 ppm; (b) the methyl protons at C-3 in the
exo-isomer resonates at 2.09 ppm, while in the exo-isomer this absorption is shifted to 1.75
ppm due to shielding effect of the benzene ring. In the 13C-NMR spectra of both the exo- and
endo-isomers, the signals at 85.8, 92.6 and 123.2 ppm correspond to C-1, C-7, and C-7 of the
oxetane ring, respectively. In addition, the methine carbon of exo-isomer appears at 25.9 ppm,
ButO2C
O
N
H 3C
O
ButO2C
O
N
H 3C
O
Ph
OCH 3
10
9
8
6
5
4
3
2
1
170
0
160
150
140
130
120
11
10
9
8
90
(ppm)
80
70
60
16.6801
15.9842
14.8047
28.0863
25.9911
50
40
30
20
7
(ppm)
135.8840
127.5620
127.4595
126.8368
123.8406
N
O
5
4
3
OCH3
2.7493
8.9116
3.3231
3.0455
0.9640
3.0000
6
2
1
0
220
200
180
160
CO2But
O
endo-Ph
1.8891
3.9259
12
168.4541
165.2162
OCH 3
Integral
13
13
100
Ph
H 3C
endo-Ph
14
2.3910
2.3685
2.3464
2.3244
2.3024
1.7572
1.4521
1.2557
1.2331
0.8707
0.8486
3.7169
7.4893
7.4839
7.4663
7.4609
7.4565
7.3213
7.2983
7.2934
7.2914
7.2738
7.2557
7.2508
7.2400
7.2322
CO 2But
O
N
O
H 3C
110
Ph
51.5285
8.0722
0.9171
2.9522
2.6770
2.5934
3.0000
7
(ppm)
27.8005
27.5735
17.6984
17.3834
14.3139
11
51.7629
12
85.4465
83.0291
13
OCH 3
92.4426
14
Ph
exo-Ph
2.8732
1.7202
Integral
exo-Ph
85.7909
82.9192
92.6184
135.4811
128.6023
128.0162
127.4375
126.8295
123.1959
167.1355
165.6923
0.8482
0.8261
0.7027
0.6806
1.5363
2.0903
3.7228
7.8317
7.8248
7.8038
7.7989
7.3708
7.3531
7.3463
7.3409
7.2400
while in the endo-isomer this absorption is shifted to 27.6 ppm.
140
13
120
100
(ppm)
60
40
20
0
156
80
___________________________________________________________________________
3.8.5 Asymmetric induction
Phenyl glyoxylates derived from chiral alcohols were already described to be excellent
substrates for the photocycloaddition to a variety of alkenes.63 Depending on the facial bias
exerted by the auxiliary they yield the corresponding oxetanes with modest to excellent
diastereomeric excesses. It was thus of interest to study the asymmetric induction in the
Paternò-Büchi reaction of 5-methoxyoxazoles 36a-f with (-)-menthyl phenylglyoxylate.
3.8.5.1 Photoreactions of menthyl phenylglyoxylate with 5-methoxyoxazoles
When (-)-menthyl phenylglyoxylate was irradiated in benzene in the presence of 5methoxyoxazoles 36a-f at 350 nm, mixtures of the exo- and endo-Ph diastereoisomers 63a-f
were formed in high chemical yields.
R1
N
H3C
O
36a-f
O
+
O
Ph
OCH3
R*=
R*
hν
benzene
O
53
R*O2C
O
N
H3C
O
Ph
R1
OCH3
CO2R*
Ph
+
H3 C
exo-63a-f
N
O
O
R1
OCH3
endo-63a-f
Scheme 3.67: Photocycloaddition of (-)-menthyl phenylglyoxylate with 5-methoxyoxazoles
63a-f.
Table 3.41: Results of the photocycloaddition reaction of menthyl phenylglyoxylate with 5methoxyoxazoles 36a-f.
Compound
R1 =
(exo : endo)[a]
de. exo-Ph
de. endo-Ph
Yield (%)[b]
63a
Me
76 : 24
55 : 45
54 : 46
85
63b
Et
69 : 31
53 : 47
53 : 47
92
63c
n-Pr
66 : 34
56 : 44
52 : 48
84
63d
i-Pr
54 : 46
60 : 40
58 : 42
73
63e
i-Bu
64 : 36
52 : 48
53 : 47
92
63f
sec-Bu
55 : 45
56 : 44
55 : 45
85
[a] based on the integration of characteristic signals in the 1H-NMR spectrum of the crude
products mixture, [b] yield (%) based on the degree of conversion of the oxazole.
Interestingly, the substituent R1 in the oxazole substrates 36a-f has significant influence on
both the simple exo/endo diastereoselectivity and and also facial selectivity of the
photoadducts. The simple exo/endo diastereoselectivity decreased with increasing steric
demand of the substituent R1 like the non-induced photocycloaddition of achiral alkyl
157
___________________________________________________________________________
phenylglyoxylates with 36a-f. The facial selectivities of the photoadducts for both exo-and
endo-isomers were low and slightly influenced by increasing size of R1 groups in oxazole
substrates. The low facial selectivity of the photoadducts is similar to furan-menthyl
phenylglyoxylate photoadducts which were described by Scharf and coworker.63 The
relatively low diastereomeric excess values observed for both the exo- and the endo-Ph
diastereoisomers might be due to the fact that the bond formation proceeds in an early
transition state at high energy of the diabatic reaction coordinate. Another reason for the lack
of facial selectivity could be related to the excited menthyl phenyl glyoxylate which attacks
the oxazole ring in an exo- or endo-fashion and might lead to partial cancellation of the
inducing effect of the chiral auxiliary.
The relative configurations of the four stereoisomers of the photoadduct 63a were determined
on the basis of the chemical shifts comparsion of the methyl protons at C-1, OCH3 at C-5 and
also the chemical shift of the orthoester carbon (see Table 3.42).
Table 3.42: NMR chemical shifts of the four stereoisomers of compound 63a.
Compound
R*O2C
O
N
H3C
O 5
δ ppm
exo-(a)
a
CH3
Ph
1 a
CH3
OCH3
N
H3C
O
5
a
1 CH3
*
R O2C
O
OCH3
Ph
CO2R*
Ph
H3C
N
O
O
1a
CH3
5 OCH3
H3C
N
O
Ph
5
O
a
1 CH3
OCH3
CO2R*
exo-(b)
endo-(a)
endo-(b)
1.04
1.13
1.53
1.55
OCH3
3.63
3.61
3.64
3.65
C-5
122.9
123.1
123.4
123.5
By use of preparative chromatography both the exo- and the endo-Ph isomers could be
separated. The relative configuration of the major exo-Ph diastereoisomer of compound 63a
was determined unambiguously via NOE spectroscopy. Significant effects were observed for
aromatic phenyl protons ( δ = 7.66 ppm ) by irradiation of the methyl protons ( δ = 1.04 ppm )
and the methoxy protons at 3.63 ppm.
158
___________________________________________________________________________
OCH3
CH3
CH3
CH3
H3C
CH3
O
O O
N
O
H3C
7.66 ppm
CH3 1.04
CH3
ppm
CH3
OCH 3
3.63 ppm
OCH
Figure 3.172: NOESY (300 MHz, CDCl3) spectrum of exo-63a.
Structure elucidation of the bicyclic oxetanes 63a-f was based on the NMR analyses. For
example, the 1H-NMR spectrum of compound 63a revealed three singlets at δ 1.04, 2.05 and
3.63 ppm corresponding to the methyl protons at C-1, CH3 at C-3 and OCH3 at C-5,
13
respectively, and confirmed the exo-Ph configuration. In the
C-NMR spectrum, at δ 79.4,
91.8, 123.7, 166.3 and 168.8 ppm, five signals appeared which were attributed to C-1, C-7, C-
34.5632
31.7941
26.0141
23.5820
22.3440
21.1352
16.4175
15.4358
15.3186
52.2988
47.2001
41.0758
79.3673
76.5689
91.8503
135.8412
128.7792
128.4203
126.6181
123.7025
168.6750
166.2869
2.1530
2.1339
2.0462
1.8645
1.8287
1.6828
1.6691
1.6602
1.6353
1.6255
1.6142
1.4731
1.4364
1.0362
0.8374
0.8339
0.8158
0.8104
0.6615
0.6385
3.6268
4.7944
4.7793
4.7577
4.7430
4.7210
4.7063
7.6524
7.6480
7.3708
7.3683
7.3438
7.3419
7.3331
7.3277
7.2400
5, C-3 and COO group, respectively.
CH3
CH3
H3C
H3C
O CH3
O CH3
Ph
Ph
8.5
H3C
CH3
8.0
7.5
6.5
6.0
5.5
5.0
1
CH3
OCH 3
4.5
4.0
(ppm)
3.5
3.2598
0.9696
1.3074
3.5771
2.9697
3.7190
2.3249
7.7733
3.3617
3.0000
1.2584
7.0
O O
N
O
OCH 3
2.0567
0.3950
4.2644
Integral
H3C
O O
N
O
3.0
2.5
2.0
1.5
1.0
0.5
220
200
180
160
Figure 3.173: H-NMR (300 MHz, CDCl3) Figure 3.174:
140
13
120
80
60
40
20
0
159
100
(ppm)
___________________________________________________________________________
C23
C24
C21 C14
C9
C25
C17&C18
C15 C19&C20
C11 C16
H23 H24&25
C10 C12 C13
H9
16
12
13 14
15
11 10
9 O
17
24
23
H21
18
25
H19
H15
8 7
22
O O
2 6 1 20
19 3 N
O 5
O 21
4
H16&17&18
Figure 3.175: HMQC (300 MHz, CDCl3) spectrum of exo-63a.
The IR spectrum of compound 63c showed strong absorption bands at 1630 and 1735 cm-1
characteristic for the C=N and COO groups, respectively. The 1H-NMR spectrum showed two
singlets at δ 2.06 and 3.67 ppm attributed to CH3 at C-3 and OCH3 group, respectively, and
assigned to the exo-Ph configuration. The 13C-NMR spectrum revealed signals at δ 81.9, 91.8
and 123.2 ppm corresponding to C-1, C-7 and C-5 of the oxetane ring, respectively. In
addition, two signals appeared down-field shifted at δ 165.4 and 168.3 ppm due to C-3 and
CO group, respectively.
160
34.1593
31.4048
30.6942
25.5735
23.2513
21.9546
20.6360
16.3578
16.0135
14.8560
14.1747
51.7410
46.6935
40.7890
81.8862
76.0037
91.8126
135.3126
129.8916
128.8733
128.3825
128.0016
126.3313
123.2399
168.3516
165.4433
4.8101
4.7954
4.7734
4.7587
4.7371
4.7224
3.6689
2.0604
1.9184
1.9046
1.8953
1.8811
1.8596
1.6730
1.6642
1.6573
1.6245
1.5011
1.4932
1.4854
1.4736
1.4619
1.4540
1.4496
1.4447
1.1856
1.1744
1.1435
0.8604
0.8388
0.7933
0.7698
0.7105
0.6209
0.5979
7.7161
7.7102
7.6882
7.6838
7.3732
7.3482
7.3429
7.2400
___________________________________________________________________________
CH3
CH3
H3C
O CH3
H3C
Ph
H3C
O O
N
O
O CH3
Ph
OCH3
O O
N
O
H3C
exo-Ph
OCH3
8.0
7.0
6.0
5.0
3.1034
3.4550
3.7490
4.8775
3.9728
3.1884
1.2858
11.365
4.0434
3.6751
3.0000
1.2890
4.1024
1.9298
0.2700
Integral
exo-Ph
4.0
3.0
2.0
1.0
0.0
220
200
180
160
140
120
(ppm)
13
100
(ppm)
80
60
40
20
0
spectrum of exo-63c.
The 1H-NMR spectrum of compound 63f showed two singlets at δ 2.05 and 3.73 ppm due to
CH3 at C-3 and OCH3 at C-5, respectively, and were assigned to the exo-Ph configuration. In
13
the
C-NMR spectrum, three signals at δ 86.5, 93.1 and 123.3 ppm appeared which were
attributed to C-1, C-7 and C-5 of the oxetane ring, respectively. In addition, both C-3 and CO
CH3
H3C
H3C
OCH3
7.0
6.0
O O
N
O
OCH 3
5.0
4.0
(ppm)
3.0
2.0
3.0491
9.4369
3.6962
6.4208
2.8417
1.4391
2.5616
4.9203
3.0000
exo-Ph
0.9599
3.5977
1.9768
Integral
8.0
51.6531
46.6203
40.9502
34.1300
32.6795
31.4414
25.2585
23.3026
23.0535
21.9620
20.6433
15.8303
14.8267
12.0869
11.2371
Ph
H 3C
exo-Ph
9.0
75.6814
O CH3
Ph
O O
N
O
86.5014
CH3
O CH3
H 3C
93.0946
135.2540
128.6609
128.0089
127.3056
123.3058
167.8388
165.0916
3.7365
2.0536
1.9688
1.6764
1.6681
1.6426
1.6353
1.6255
1.4751
1.4653
1.4384
1.4257
1.4168
1.4036
1.3943
1.3821
1.3728
1.3581
1.0955
1.0578
0.8859
0.8648
0.8433
0.7698
0.7463
0.6846
0.6567
0.6337
4.9301
4.9154
4.8934
4.8787
4.8572
4.8425
7.8175
7.8106
7.7900
7.7851
7.3722
7.3580
7.3541
7.3502
7.3473
7.2400
resonate at lower field at δ 165.1 and 167.8 ppm, respectively.
1.0
220
0.0
200
180
160
spectrum of exo-63f.
140
13
120
100
(ppm)
80
60
40
20
0
spectrum of exo-63f.
3.8.6 Effect of the substituent at C-2 of the oxazole substrates on the stereoselectivity of
the photocycloaddition with α-keto esters
The successful explanation of the strong endo preference for a large number of Diels-Alder
reactions has been usually considered as an example of secondary orbital interaction (SOI).133
Recently, Griesbeck et al. reported that the exo preference for the triplet carbonyl
photocycloaddition to dienes could also be related to secondary orbital interactions that
161
___________________________________________________________________________
facilitates intersystem crossing by means of an increase in spin-orbit coupling.42 In order to
clarify the role of secondary orbital interactions in controlling the stereoselectivity of the
triplet carbonyl-diene photocycloadditions, the Paternò-Büchi reaction of 5-methoxyoxazoles
bearing an additional substituent at C-2 with aliphatic and aromatic α-keto esters was
investigated.
3.8.6.1 Photocycloaddition reactions of 2-ethyl-4-methyl-5-methoxyoxazole with α-keto
esters
Analogous to 2,4-dimethyl-5-methoxyoxazole 36a, irradiation of aliphatic as well as aromatic
α-keto esters in benzene in the presence of 2-ethyl-4-methyl-5-methoxyoxazole 49a afforded
the bicyclic oxetanes 64a-f in high chemical yields.
O
CH3
N
C2H5
+
O
OCH3
O
R
R1
hν
benzene
O
C2H5
R1O2C
O
N
O
R
CH3
OCH 3
exo-R-64a-f
49a
Scheme 3.68: Photoreaction of 49a with α-keto esters.
+
C2H5
N
O
R
O
CO2R1
CH3
OCH 3
endo-R-64a-f
Table 3.43: Simple diastereoselectivity of the Paternò-Büchi reaction of α-keto esters with 2ethyl-4-methyl-5-methoxy oxazole 49a.
Compound
R=
R1 =
d.r.(exo : endo)[a]
Yield (%)[b]
Me
Me
2 : >98
80
64a
t-Bu
Me
>98 : 2
86
64b
Ph
Me
68 : 32
87
64c
Ph
Et
67 : 33
78
64d
Ph
i-Pr
63 : 37
90
64e
Ph
t-Bu
65 : 35
83
64f
products mixture, [b] yield (%) based on the degree of the conversion of the oxazole.
The results in Table 3.43 show that the simple exo/endo diastereoselectivity of the
photoadducts 64a-f were very high with aliphatic α-keto esters in comparison with the
aromatic α-keto esters. From aromatic α-keto esters photoadducts, the simple exo/endo
diastereoselectivity slightly decreased with increasing steric demand of the alkyl
phenylglyoxylate substrates. In all cases, the diastereoisomers were successfully separated by
preparative chromatography.The structural determination of compounds 64a-f was based on
the 1H-NMR and the 13C-NMR analyses. For example, the 1H-NMR spectrum of compound
162
___________________________________________________________________________
64e showed a triplet at a chemical shift δ = 0.68 ppm due to a methyl group attached to
methylene group and established the endo-Ph configuration of the bicyclic oxetane.
Additionally, two singlets at δ 1.53 and 3.66 ppm appeared corresponding to CH3 at C-1 and
13
OCH3 at C-5, respectively. In the
C-NMR spectrum, at δ 78.1, 90.3 and 123.6 ppm, three
signals appeared characteristic for C-1, C-7 and C-5 of the oxetane ring, respectively.
N
O
6.0
5.5
4.5
(ppm)
4.0
3.5
3.0
2.5
1.5
21.9034
21.6909
21.5591
15.7498
9.6987
52.0486
69.8867
78.0842
90.3328
CH3
OCH3
3.0266
2.0
10.299
1.9714
0.6268
0.3026
3.0000
5.0
3.2355
6.5
O
endo-Ph
1.5578
7.0
N
O
C2H5
2.3384
7.5
135.0855
127.8697
127.4302
126.7123
123.5549
CH 3
OCH 3
0.6590
2.0979
5.4898
Integral
8.0
CO2Pri
Ph
O
endo-Ph
8.5
169.5896
168.5640
CO 2Pri
Ph
C2H5
3.6552
2.4185
2.0306
2.0051
2.0012
1.9791
1.9762
1.9507
1.9252
1.8670
1.6745
1.5256
1.2826
1.2621
1.2160
1.1955
1.1176
1.0926
1.0671
1.0603
0.7365
0.7110
0.6861
5.1099
5.0893
5.0683
5.0472
5.0266
7.5226
7.5167
7.4947
7.4903
7.2983
7.2885
7.2635
7.2620
7.2552
7.2400
Moreover, both C-3 and COO group resonate at δ 168.6 and 169.6 ppm, respectively.
1.0
170
0.5
160
150
140
130
120
110
13
100
90
(ppm)
80
70
60
50
40
30
20
10
The 1H-NMR spectrum of compound 64f showed a triplet at 0.67 ppm attributed to the methyl
protons of the ethyl group and confirmed the endo-Ph configuration. Furthermore, there were
three singlets at δ 1.44, 1.54 and 3.66 ppm due to the tert-butyl, CH3 at C-1 and OCH3 at C-5,
respectively. The 13C-NMR spectrum revealed signals at δ 77.9, 90.4, 123.5, 167.9 and 169.5
8.0
7.5
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.0
170
0.5
160
150
140
130
spectrum of endo-64f.
9.6841
15.8303
27.9251
27.8958
21.9034
CH 3
OCH 3
3.3408
3.1130
11.758
1.5
51.9900
77.8791
83.1023
135.4079
127.8844
127.7012
127.2983
126.8368
126.3606
123.5256
90.3841
O
endo-Ph
3.0000
7.0
N
O
C2H5
OCH 3
0.6816
1.6193
5.6243
Integral
8.5
169.4504
167.9047
CH 3
endo-Ph
CO 2But
Ph
O
2.1664
N
O
0.7242
0.6988
0.6738
CO 2But
Ph
C2H5
1.9928
1.9673
1.9624
1.9375
1.5442
1.4496
1.4369
3.6552
7.5055
7.4996
7.4771
7.4727
7.2772
7.2522
7.2503
7.2434
7.2400
ppm indicating C-1, C-7, C-5, C-3, and COO group, respectively.
120
110
13
100
80
70
60
50
40
30
20
10
spectrum of endo-64f.
163
90
(ppm)
___________________________________________________________________________
3.8.6.2 Photocycloaddition reactions of 2-isopropyl-4-methyl-5-methoxyoxazole with αketo esters
Irradiation of α-keto ester substrates in benzene in the presence of 2-isopropyl-4-methyl-5methoxyoxazole resulted in a mixture of diastereoisomers of the bicyclic oxetanes 65a-f in
high chemical yields.
O
CH3
H3C
H3C
N
+
O
OCH3
O
R
R1
hν
benzene
O
H3C
R1O2C
O
N
O
H3C
R
H3C
CH3
OCH3
exo-R-65a-f
49b
+
N
O
R
O
H3C
CO2R1
CH3
OCH3
endo-R-65a-f
Scheme 3.69: Photoreaction of 49b with α-keto esters.
Table 3.44: Simple diastereoselectivity of the Paternò-Büchi reaction of α-keto esters with 2isopropyl-4-methyl-5-methoxy oxazole 49b.
Compound
R=
R1 =
d.r.(exo : endo)[a]
Yield (%)[b]
Me
Me
60 : 40
87
65a
t-Bu
Me
70 : 30
90
65b
Ph
Me
69
:
31
94
65c
Ph
Et
67 : 33
80
65d
Ph
i-Pr
42 : 58
83
65e
Ph
t-Bu
37 : 63
85
65f
1
[a] based on the integration of characteristic signals in the H-NMR spectrum of the crude
products mixture, [b] yield (%) based on the degree of the conversion of the oxazole.
Surprisingly, the simple exo/endo-R diastereoselectivity of methyl pyruvate photoadducts 65a
did not only decrease but inverte, compared to the photoadduct from 49a. For trimethyl
methylpyruvate photoadducts 65b, the exo/endo-tert-butyl diastereoselectivity decreased
when compared with the photoadduct from 49a, but the exo-tert-butyl isomer still dominated.
In case of alkyl phenylglyoxylates photoaddition, by changing the alkyl substituents from Me
to Et, the exo/endo-Ph diastereoselectivity slightly decreased and was complelety inverted
when processing from Et to i-Pr and tert-Bu. The diastereoisomers of the photoadducts 65a-f
in most cases were isolated by preparative chromatography.
The relative configuration of the major diastereoisomer of compound 65b was unambiguously
determined by NOE experiments. Strong NOE enhancements were detected from tert-butyl
protons to CH3 at 1.51 ppm, OCH3 at 3.57 ppm and OCH3 at 3.73 ppm, likewise from the
methyl protons of isopropyl group at 1.16 ppm to OCH3 at 3.73 ppm. Thus, the relative
configuration is all exo- with respect to the tert-butyl group at C-7 of the bicyclic oxetane.
164
___________________________________________________________________________
OCH3
CH3
O
3.73 ppm
H3C
1.16 ppm H3C
O O
N
O
H3C
CH3 1.12
CH3
CH3
CH3
OCH3
ppm
1.51 ppm
3.57 ppm
OCH3
CH3
H3C
CH3
CH3
CH3
Figure 3.184: NOESY (300 MHz, CDCl3) spectrum of compound 65b.
The relative configurations of both the exo-Ph and the endo-Ph diastereoisomers of compound
65f were determined unambiguously from NOESY studies. For exo-Ph isomer, the cross
peaks between the phenyl protons resonances at 7.65 ppm and the methyl protons at 1.06 ppm
and the methoxy protons at 3.61 ppm indicate a strong NOE-effects and hence spatial
proximity (cis relationship between Ph, CH3 and OCH3 groups) which can be assigned to an
exo-Ph configuration. Other NOE-effects between the phenyl protons and the tert-butyl
protons at 1.45 ppm were also detected. For the endo-Ph isomer, no interaction between the
phenyl protons and the methoxy protons is observable while a weak NOE enhancement is
present for the methyl protons at 1.56 ppm and the aromatic protons at 7.27 ppm.
Furthermore, cross peaks between a methyl protons of the isopropyl group at 0.72 and 0.79
ppm and the phenyl protons at 7.27 ppm was observed again indicating their spatial
proximity.
165
___________________________________________________________________________
endo-
CH3 CH3CH3
exo-
CH3
CH3
CH3
H3C
1.45 ppm
H3C
H3C
H3C
H3C
H3C
O
O O
N
O
7.65 ppm
0.72 ppm
H3C
1.06 ppm
CH3
+
OCH3
3.61 ppm
O
N
O
H3C
0.79 ppm
1.44 ppm
CH3
CH3
O
CH3
1.56 ppm
OCH3
endo-Ph
OCH3
OCH 3
exo-Ph
H3C
O
7.27 ppm
Figure 3.185: NOESY (300 MHz, CDCl3) spectrum of compound 65f.
The constitutions of compounds 65a-f were elucidated on the basis of IR, mass spectrometry
and NMR analyses. For example, the IR spectrum of compound 65a showed two strong
absorption bands at 1615 and 1740 cm-1 corresponding to C=N and ester group, respectively.
The 1H-NMR spectrum showed two doublets at δ 0.92 and 1.10 ppm assigned to the isopropyl
group. Additionaly, there appeared four singlets at δ 1.44, 1.91, 3.69 and 3.74 ppm
corresponding to CH3 at C-7, CH3 at C-1, OCH3 at C-5 and OCH3 of the ester group,
respectively. In the
13
C-NMR spectrum, signals at δ 72.4, 87.2, 120.3, 170.4 and 176.2 ppm
were attributed to C-1, C-7, C-5, C-3 and COO group, respectively.
166
H3CO2C
3.8
3.4
3.2
3.0
2.8
2.6
2.4
(ppm)
2.2
2.0
1.8
1.6
1.2
22.5334
18.6068
16.4164
15.6399
37.7562
53.0010
52.4955
72.4068
87.2194
170.3515
176.2267
120.3242
CH 3
OCH 3
2.6985
3.0550
1.4
CH 3
O
N
O
H3C
2.7925
0.8482
3.6
1.1043
1.0818
0.9691
0.9461
CH3
3.0000
2.7134
Integral
4.0
H3C
OCH3
H3C
4.2
H3CO2C
CH3
O
N
O
3.9619
H3C
1.4516
1.4286
1.4212
1.9081
1.8738
1.8513
1.8287
3.7463
3.6978
___________________________________________________________________________
1.0
0.8
170
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of compound 65a.
Prove of the chemical structure of compound 65c was based on NMR analysis. The 1H-NMR
spectrum shows two doublets at δ 1.18 and 1.43 ppm due to the isopropyl group. Furthermore,
three singlets appeared at δ 1.96, 3.11 and 3.29 ppm attributed to CH3 at C-1, OCH3 at C-5
and OCH3 of ester group, respectively, indicating the exo-Ph configuration. In the
13
C-NMR
spectrum, five signals at 81.3, 92.0, 123.3, 169.1 and 173.4 ppm appeared which were
H3CO2C
H3C
N
O
9.5
9.0
8.5
8.0
7.5
CH3
OCH3
6.0
5.5
5.0
(ppm)
4.5
4.0
3.5
3.0
2.0
17.9988
17.2442
16.4091
38.4155
52.6860
52.2025
74.5312
81.3734
Ph
O
CH3
OCH3
exo-Ph
3.2447
3.2040
3.0290
1.0331
2.5
1.5
170
1
160
150
140
130
N
O
H3C
3.0000
2.9977
6.5
92.0397
H3C
exo-Ph
7.0
118.6247
135.2980
135.2614
128.6389
128.1920
128.1334
127.4961
126.4852
125.8258
123.3864
173.3843
169.2600
169.1208
1.4570
1.4344
1.2082
1.1856
H3CO2C
Ph
O
7.4834
4.4723
Integral
H3C
1.9619
3.2962
3.1105
2.8994
2.8397
2.8176
2.7946
7.6362
7.6333
7.6127
7.6093
7.6049
7.5887
7.5784
7.5711
7.3918
7.3669
7.3414
7.3282
7.3242
7.3179
7.3130
7.3051
attributed to C-1, C-7, C-5, C-3 and CO, respectively.
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
Unfortunately, the diastereoisomers of compound 65e could not be separated by preparative
chromatograpy and hence the constitution of both isomers were determined from the NMR
analysis of the diastereoisomer mixture. There are two main differences in the 1H-NMR
spectrum between the exo- and the endo-Ph diastereoisomers as shown in Figure 3.190: (1)
the methyl protons of the isopropyl group at C-3 resonates at higher field compared with the
167
___________________________________________________________________________
exo-Ph isomer. (2) the methyl protons at C-3 resonates at 2.19 ppm in the endo-Ph isomer;
while in the exo-Ph isomer, this absorption is shifted upfield to 1.06 ppm due to ring current
effect of the benzene ring. The 13C-NMR spectrum showed five signals at δ 77.8, 90.2, 123.5,
52.0560
51.8289
28.8408
28.4525
21.8228
21.6909
21.6396
21.5444
21.5078
19.2441
19.0976
18.8998
18.8192
18.6507
15.7717
15.0245
71.0369
69.8501
69.8135
82.4796
78.3040
77.8278
91.2119
90.2229
135.4005
135.0489
127.9942
127.8331
127.3276
126.9393
126.2214
123.5036
122.9981
173.1719
172.6591
168.5274
167.9780
5.0800
5.0594
5.0452
5.0384
5.0242
5.0031
3.6464
3.6204
2.6663
2.6433
2.6197
2.5967
2.5737
2.2852
2.2617
2.2387
2.2157
2.1922
1.5388
1.3899
1.3688
1.3179
1.2968
1.2797
1.2591
1.2385
1.2341
1.2312
1.2086
1.2033
1.1959
1.1822
1.1729
1.0666
0.8051
0.7820
0.7414
0.7184
7.3272
7.3037
7.3012
7.2826
7.2802
7.2552
7.2532
7.2464
7.2400
167.9 and 173.6 ppm related to C-1, C-7, C-5, C-3 and COO group, respectively.
endo
8.0
OCH 3
H3C
N
O
H3C
CH 3
endo
OCH 3
2.8474
endo-Ph
11.337
7.5
7.0
6.5
6.0
5.5
5.0
PriO2C
O
4.5
(ppm)
4.0
3.5
3.0
2.5
H3C
N
O
Ph
CO2Pri
Ph
O
CH3
H3C
+
OCH3
N
O
H3C
exo-Ph
O
CH3
endo-Ph
OCH3
3.2228
0.6397
26.766
2.9739
3.3086
3.4554
+
H3C
1.1784
CH 3
exo-Ph
2.0253
2.5925
Integral
H3C
O
N
O
CO 2Pri
Ph
0.8987
H3C
Ph
3.0000
2.4969
Pr iO2C
2.0
1.5
170
1.0
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of exo-65e & endo-65e.
spectrum of exo-65e & endo-65e.
The diastereoisomers of compound 65f could not be separated by preparative chromatography
and the structure determination was thus based on NMR analysis of the diastereoisomer
mixture. Analogous to compound 65e, there are also two main differences in the 1H-NMR
spectrum between the exo- and endo-isomer: (a) the methyl protons at C-3 in the exo-isomer
resonates at higher field than in the endo-isomer; (b) methyl protons of the isopropyl group at
C-3 in the endo-isomer appear at 0.71 ppm, while it is shifted in the exo-isomer to 1.24 ppm.
In the 13C-NMR spectrum three signals appeared at δ 77.6, 90.3, 122.9 ppm corresponding to
ButO2C
ButO2C
H3C
N
O
H3C
Ph
CO2But
Ph
O
CH 3
OCH 3
exo-Ph
+
H3C
H3C
N
O
H3C
endo
O
H3C
CH3
endo-Ph
N
O
Ph
Ph
O
CH3
+
OCH3
H3C
H3C
exo-Ph
N
O
52.0340
51.7849
28.9580
28.4525
27.9983
27.9104
27.7932
19.2515
19.0537
18.9145
18.8559
15.8743
15.0685
78.1575
77.6447
83.1023
82.8386
91.1093
90.3035
135.7815
135.3859
127.8770
127.6939
127.2251
127.0712
126.3899
123.4596
122.9542
173.1719
172.5639
167.9047
167.1428
3.6532
3.6096
2.6526
2.6291
2.6060
2.4317
2.2793
2.2563
2.2328
2.2098
2.1868
1.5623
1.4511
1.4359
1.2473
1.2444
1.2238
1.2214
1.0642
0.8031
0.7796
0.7345
0.7115
7.5006
7.4785
7.4736
7.3610
7.3360
7.2777
7.2753
7.2508
7.2483
7.2415
7.2400
C-1, C-7 and C-5 of the oxetane ring, respectively.
CO2But
O
CH3
endo-Ph
OCH3
OCH3
endo
endo
endo
8.5
8.0
7.5
7.0
6.5
6.0
1
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
3.1183
15.677
4.1685
1.9525
3.2791
3.2967
1.1157
0.6090
3.0000
1.7346
1.5124
2.2980
7.0901
Integral
endo
2.0
1.5
1.0
0.5
170
160
150
140
130
spectrum of exo-65f & endo-65f.
120
13
110
100
90
(ppm)
80
70
60
40
30
20
168
50
___________________________________________________________________________
3.8.6.3 Photocycloaddition reactions of 2-tert-butyl-4-methyl-5-methoxyoxazole with αketo esters
The [2+2]-photocycloaddition of 2-tert-butyl-4-methyl-5-methoxyoxazole 49c with aliphatic
and aromatic α-keto esters gave two stereoisomers of the bicyclic oxetanes 66a-f in high
chemical yields.
O
CH3
H3C
H3C
H3C
N
+
O
OCH3
R1O2C
O
R
R1
hν
benzene
O
H3C
H3C
H3C
49c
Scheme 3.70: Photoreaction of 49c with α-keto esters.
N
O
R
H3C
O
CH3
OCH3
exo-R-66a-f
N
O
+ H3C
H3C
R
O
CO2R1
CH3
OCH3
endo-R-66a-f
Table 3.45: Simple diastereoselectivity of the Paternò-Büchi reaction of α-keto esters with 2tert-butyl-4-methyl-5-methoxy oxazole 49c.
Compound
R=
R1 =
d.r.(exo : endo)[a]
Yield (%)[b]
Me
Me
54 : 46
86
66a
t-Bu
Me
55 : 45
92
66b
Ph
Me
63 : 37
90
66c
Ph
Et
61 : 39
88
66d
Ph
i-Pr
40 : 60
89
66e
Ph
t-Bu
46 : 54
90
66f
products mixture, [b] yield (%) based on the degree of conversion of the oxazole.
In case of aliphatic α-keto esters (both methyl pyruvate and trimethyl methylpyruvate)
photocycloaddition with 49c, the simple exo/endo-R diastereoselectivity substantially
decreased compared with the photoadducts of these substrates with 49b. Whereas, in the case
of aromatic α-keto esters, the exo/endo-Ph diastereoselectivity was inverted when changing
the substituents from Et to i-Pr and t-Bu similar to 49b.
The difference in the heat of formation (∆Hf) between the exo- and endo-Ph diastereoisomers
of compound 66f from AM1 is approx. 1.00 kcal/mol. The molecular mechanics calculations
revealed, that the observed stereoselectivity corresponds to contrathermodynamic control.
169
___________________________________________________________________________
Figure 3.194: PM1 model of exo-66f.
Figure 3.195: PM1 model of endo-66f.
In most cases, the diastereoisomers of compound 66a-f were successfully separated by
preparative chromatography except compounds 66a and 66f which were separated from the
crude reaction mixtures as pair of stereoisomers.
The relative configuration of the major diastereoisomer of compound 66b was unambiguously
determined by NOE experiment. Irradiation of the tert-butyl protons at 1.12 ppm led to NOE
enhancement of both signals of the methyl protons at 1.50 ppm and the methoxy protons at
3.56 ppm. Furthermore, NOE enhancement was observed for tert-butyl protons signal at 1.18
ppm when methoxy protons signal at 3.73 ppm irradiated.
OCH3
H3C
1.18 ppm H3C
H3C
OCH3
CH3 1.12
CH3
O
3.73 ppm
O O
N
O
H3C
ppm
CH3
CH3
OCH3
1.50 ppm
3.56 ppm
CH3
H3C
CH3
CH3
H3C
CH3
Figure 3.196: NOESY (300 MHz, CDCl3) spectrum of compound 66b.
170
CH3
___________________________________________________________________________
The relative configuration of the exo- and endo-Ph diastereoisomers of compound 66f were
unambiguously determined by NOE measurement. For the endo-Ph isomer, cross peaks
between the phenyl protons at 7.49 ppm and tert-butyl protons at 0.82 ppm indicate a strong
NOE-effect and hence spatial proximity (cis relationship between Ph and tert-butyl group).
Other NOE effects between the phenyl protons and the tert-butyl at 1.58 ppm and the methyl
protons at 1.58 ppm were determined. For the exo-Ph isomer, no interaction between the tertbutyl protons and phenyl protons is observable while a weak one is present for tert-butyl
protons at 1.45 ppm and the phenyl protons at 7.65 ppm. Furthermore, a cross peak between
the methyl protons at 1.07 ppm and phenyl protons at 7.65 ppm was observed again indicating
their spatial proximity.
exo-
endo-
1.45 ppm
H3C
H3C
H3C
CH3
H3C
CH3
H3C
H3C
H3C
O
O O
N
O
7.65 ppm
1.07 ppm
CH3
OCH3
exo-Ph
H3C
CH3
O
7.49 ppm
H3C
CH3
H3C
H3C
H3C
O
N
O
CH3
CH3
O
endo-Ph
0.82 ppm
CH3
1.43 ppm
CH3
1.58 ppm
OCH3
CH3
H3C
CH3
CH3
Figure 3.197: NOESY (300 MHz, CDCl3) spectrum of compound 66f.
The structural assignments of compound 66a-f were made on the basis of the spectroscopic
data. The 1H-NMR spectrum of compound 66a showed five singlets at δ 0.93, 1.35, 1.81, 3.67
and 3.77 ppm attributed to tert-butyl group, CH3 at C-7, CH3 at C-1, OCH3 at C-5 and OCH3
171
___________________________________________________________________________
of ester group respectively. In the
13
C-NMR spectrum, there appeared three signals at 74.0,
H 3CO2C
O
N
O
H3C
H3C
CH3
H3C
OCH3
H3C
H 3C
O
N
O
H3C
+
CH3
H3CO2C
H3C
OCH3
H3C
CH3
3.8
3.4
3.2
3.0
2.8
2.6
2.4
(ppm)
2.2
2.0
1.8
1.6
1.4
H3C
+
CH3
N
O
H3C
OCH3
53.3757
53.3390
52.8262
52.8043
42.4311
40.6216
25.3255
25.0765
23.8531
23.2011
19.1866
18.3808
18.2123
16.8350
CO2CH3
O
CH3
OCH3
H3C
8.9854
4.7945
1.4120
1.5694
1.2496
3.6
H3C
O
N
O
H3C
3.0000
3.0044
Integral
4.0
75.5506
74.0342
CO2CH3
CH3
H3C
4.2
87.2424
86.7370
124.5816
122.6696
179.5684
179.2314
171.3855
171.1658
170.5431
0.9490
0.9304
1.4462
1.4384
1.4320
1.4232
1.4153
1.3590
1.8375
1.8067
3.7669
3.7620
3.6723
86.7 and 124.1 ppm attributed to C-1, C-7 and C-5 of the oxetane ring, respectively.
1.2
1.0
0.8
180
170
160
150
140
130
120
110
100
(ppm)
90
80
70
60
50
40
30
20
13
Figure 3.198:1H-NMR (300 MHz, CDCl3) Figure 3.199: C-NMR (75 MHz, CDCl3) of
compound 66a.
Prove the chemical structure of compound 66c was based on IR, mass spectra and NMR
analyses. The IR spectrum showed two strong absorption bands at 1617 and 1735 cm-1
indicating the presence of an C=N and C=O of ester group, respectively. The mass spectrum
showed a base peak at m/z 292 due to [M+ - CH3CN]. Furthermore, the fragmentation pattern
is summarized in scheme 3.71.
H3C
CO2CH3
O
N
O
-(CO2Me)
CH3
-C
H
m/z = 333
OCH3
H3C
CO2CH3
Ph
O
N
O
-CN
OCH3
O
CH3
m/z = 86
OCH3
O
N
CH3
O
-CH3
O
O
Ph
-CO2
-CO
Ph
O
O
m/z = 164
m/z = 149
m/z = 105
m/z = 77
-OCH3
O
O
-CO
Ph
-CO
Ph
O
m/z = 133
m/z = 105
m/z = 77
Scheme 3.71: Fragmentation pattern of compound 66c.
172
m/z = 169
-(CH3)3CCO)
N
CH3
H3C
OCH3
H3C
CH3
m/z = 110
O
Ph
H3
-(C
H3C
-CH2=CHCO2CH3
CH3
OCH3
CN
) 3C
OCH3
m/z = 276
m/z = 250
H3C
CH3
CO2CH3
N
O
H3C
OCH3
m/z = 274
m/z = 292
H3C
-(PhCO)
CH3
[C16H20O5]
3)
3C
CH3
O
N
O
H3C
m/z = 274
N
Ph
O
H3C
CH3
H3C
3C
-(C
H
-(CH3)3CCN
Ph
O
N
O
H3C
OCH3
H3C
Ph
O
H3C
-(M
eO
CO
)
Ph
H3C
m/z = 84
___________________________________________________________________________
The 1H-NMR spectrum showed four singlets at δ 1.08, 1.25, 3.63 and 3.75 ppm attributed to
CH3 at C-1, tert-butyl group at C-3, OCH3 at C-5 and OCH3 of the ester group, respectively,
and assigned to the exo-Ph configuration. In the
13
C-NMR spectrum, signals appeared at δ
78.6, 91.6, 123.2 ppm due to C-1, C-7 and C-5 of the oxetane ring, respectively. Moreover,
H3CO2C
H3C
N
O
H3C
8.0
7.5
6.5
CH 3
H3C
5.5
5.0
4.5
(ppm)
4.0
3.5
14.9000
27.3537
33.7710
52.4955
51.8875
Ph
O
N
O
H3C
OCH 3
CH 3
OCH 3
exo-Ph
2.5108
10.136
3.2020
exo-Ph
6.0
82.3404
78.6117
91.6001
135.0123
128.4704
128.1554
127.4961
126.1995
126.1482
123.2106
169.0402
H3C
3.0000
2.9568
7.0
175.5967
H3CO2C
Ph
O
2.0985
1.5072
6.7774
Integral
H3C
1.3732
1.2522
1.0896
3.7556
3.6312
7.6700
7.6656
7.3796
7.3747
7.3551
7.3502
7.3443
7.3389
7.3208
7.2934
7.2684
7.2400
both C-3 and COO resonate at lower field at δ 169.0 and 175.6 ppm, respectively.
3.0
2.5
2.0
1.5
170
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
Figure 3.202 shows the 1H-NMR spectrum of the exo-Ph and endo-Ph diastereoisomers of
compound 66f. The tert-butyl protons resonances of the exo-isomer appear at 1.22 ppm while
in the endo-isomer this absorption is shifted upfield to 0.78 ppm due to the ring current effect
of the benzene ring. The
13
C-NMR spectrum revealed signals at δ 77.8, 90.2 and 123.0 ppm
H3C
ButO2C
O
N
O
H3C
Ph
+
CH3
OCH3
H3C
H3C
H3C
exo-Ph
9.0
8.0
7.0
H3C
H3C
CH3
ButO2C
O
N
O
H3C
OCH3
Ph
+
CH 3
OCH 3
H3C
H3C
H3C
exo-Ph
33.8223
33.3535
28.0643
27.9251
27.3024
26.9508
15.9036
15.1711
52.0633
51.7850
CO2But
Ph
O
N
O
83.0804
82.7654
78.2894
77.7106
91.0947
90.2083
135.9427
135.4299
127.8478
127.2544
127.1445
126.4412
123.5915
122.9762
175.1645
174.5565
167.9048
167.1063
1.5415
1.4107
1.3950
1.2211
1.0360
0.7803
CO2But
CH3
OCH3
endo-Ph
3.0000
2.5914
endo-Ph
1.7926
2.2710
7.5928
Integral
Ph
O
N
O
6.0
5.0
4.0
3.0693
17.791
8.3760
2.5987
9.3956
H3C
3.6050
3.5648
7.6276
7.6051
7.6002
7.4729
7.4670
7.4449
7.4405
7.3215
7.2965
7.2858
7.2383
7.2358
7.2108
7.2089
7.2030
corresponding to C-1, C-7 and C-5 of the oxetane ring, respectively.
3.0
2.0
1.0
0.0
170
160
150
140
130
120
(ppm)
13
110
100
90
(ppm)
80
70
60
40
30
20
173
50
___________________________________________________________________________
The regioselectivity of the Paternò-Büchi reaction of aliphatic and aromatic α-keto esters with
5-methoxyoxazoles with additional alkyl substituents either in position C-2 or C-4 is high and
corresponds to the classical 1,4-biradical stablization concept. The stereochemistry of the
triplet 1,4-biradical is attributed to a conformational memory effect during the intersystem
crossing (ISC) process of the triplet 1,4-biradical. According to the Salem-Rowland rules,28
strong spin-oribt coupling (SOC) occurs when the p-orbitals at the spin-bearing atoms are
orthogonal to each other. The possible conformers (A-C) of the triplet 1,4-biradical are
represented by the Newman projections A, B and C, and A` , B` and C` in Scheme 3.72. Bulky
phenyl group prefer to stay away from the former oxazole ring so that conformers A-C are
favored over A`- C`. Among A-C, A and B are expected to be similary populated wheras C is
higher in energy. ISC from A leads to immediate C-C bond formation, whereby the phenyl
group is rotated over the former oxazole ring plane resulting in the endo-Ph product. ISC from
B leads to cleavage of the initially formed C-O bond restoring the starting materials.
Similarly, ISC from C gives the exo-Ph product. The experimental results show that the exoPh product is dominant, thus an interaction between the allylic and exocyclic radical in triplet
1,4-biradical (SOI) as depicted in conformer C must be crucial for the dominance of this
biradical geometry for rapid ISC. The relative stabilities of A and C depend on the the size of
both the substituent R1 in the oxazole moiety and the size of the α-substituent of the phenyl
carbonyl compounds. When the α-substituent is small (such as H) compared to the benzene
ring, C is the conformer responsible for product formation and the exo-Ph is selectively
produced. When the α-substituent is large as in the case of COOR, steric interactions between
COOR and R1 disfavor conformer C, and hence the amount of exo-Ph isomer is expected to
be decreased. If only conformers A-C are responsible for product formation, the exo/endo-Ph
selectivity should not alter significantly with the change of the alkyl group at position C-2 of
the oxazole because the same phenyl substituent is involved in all these compounds, and
therefore the energy differences between A and C are expected to be similar with different
COOR groups. However, I observed significat changes in the product stereochemisty with
variation of the alkyl substituent at position C-2 indicating that the other set of conformers A`C` also plays a role in the product formation process. Analogously to the situation in A-C, A`
leads to the exo-Ph product, C` leads to the endo-Ph product and B` restores the starting
materials after ISC. Conformer C` is highly congested but still populated because secondary
orbital interaction facilitates ISC by means of an increase in spin-orbit coupling and furnishes
the endo-Ph product. Therefore, when the alkyl substituent at position C-2 in oxazole is small
174
___________________________________________________________________________
enough to populate conformer C, exo-Ph products results preferentially. Bulky alkyl groups at
position C-2 of oxazole favor conformer C` and this leads to endo-Ph-isomer.
3O *
OCH3
O
Ph
O
R
2
N
R
H3CO
R
O
O
1
R
2
N
Ph
H3CO
CO2R
O
O
R
1
R2
H3CO
O
N
Ph
O
+
R1 CO2R
R
2
exo-Ph
R2
endo-Ph
R2
O
ISC
O
O
OCH3
N
Ph
R
CO2R
Ph
CO2R
O
ISC
cleavage
R
O
OCH3
ISC
exo-Ph
O
OCH3
O
OCH3
ISC
cleavage
N
R1
B`
B
R2
Ph
RO2C
OCH3
CO2R
Ph
O
R1
exo-Ph
endo-Ph
Ph
CO2R
1
R2
N
ISC
R1 Ph
A`
A
R2
CO2R
O
N
1
N
O
R2
RO2C
O
O
N
OCH3
Ph
O
ISC
endo-Ph
N
R1
R1
C
C`
Scheme 3.72: Mechanistic scenario of the oxazoles-α-keto esters photocycloaddition
reaction.
Comment
The results of the stereochemistry study of the photocycloaddition of 5-methoxyoxazoles with
alkyl phenylglyoxylates are remarkable because the stereochemistry did decrease in contrast
to the results described by Scharf and coworkers,78 and additionally the direction of the
stereocontrol has inverted.
The results of the photocycloaddition of α-keto esters with 5-methoxyoxazoles bearing an
additional substituent either in position C-2 or C-4 suggest, that secondary orbital interactions
(SOI) may play an important role for determining stereoselectivities.
175
___________________________________________________________________________
The important findings from the α-keto esters–oxazole photocycloaddition reactions are as
follows:
(1) Methyl pyruvate adds photochemically to 5-methoxyoxazole with high regio- and
stereoselectivity when the oxazole substrate has small alkyl substituents (Me or Et) in position
C-2 and irrespectively of the nature of alkyl substituent in position C-4. The stereoselectivity
decreased when bulky alkyl substituents (i-Pr and t-Bu) in position C-2 were employed.
(2) The stereoselectivity of the photocycloaddition of methyl trimethylpyruvate with oxazoles
was strongly influenced by the size of alkyl substituent either in position C-2 or C-4.
(3) The exo/endo-Ph diastereoselectivity of the photocycloaddition of alkyl phenylglyoxylates
with 4-substituted oxazoles decreased with increasing steric demand of the alkyl group either
in the oxazole moiety or phenylglyoxylate moiety, albeit the exo-Ph isomer is still favored.
(4) Using bulky alkyl substituents (i-Pr & t-Bu) either in position C-2 of oxazole substrates or
in alkyl phenyl glyoxylates led to an inversion of the exo/endo diastereoselectivity and the
endo-Ph isomer was formed preferentially.
(5) The facial selectivity for both exo and endo photoadducts of the photocycloaddition of
menthyl phenylglyoxylate to oxazole substrates was low, wheras the simple exo/endo-Ph
diastereoselectivity was moderate.
176
___________________________________________________________________________
3.9 Synthesis of erythro (S*,R*) & threo (S*,S*) α-amino-β
derivatives
From a synthetic point of view, the bicyclic oxetanes obtained by the Paternò-Büchi reaction
of aliphatic and aromatic α-keto esters with 5-methoxyoxazoles are not only interesting by
themselves, but also because they might serve as bulding blocks for the stereoselective
construction of α-amino-β-hydroxy succinic acid derivatives. Ring opening of the bicyclic
oxetanes represents the simplest and straight forward strategy for the stereoselective synthesis
of erythro (S*,R*) and threo (S*,S*) α-amino-β-hydroxy succinic acid derivatives depending
on the relative configuration of a substituent at C-7.
3.9.1 Synthesis of erythro (S*,R*) α-acetamido-β
β-hydroxy succinic acid derivatives 67a-f
Acid treatment of the bicyclic oxetanes 54a-f led to the formation of erythro (S*,R*) αacetamido-β-hydroxy succinic acid derivatives 67a-f in high chemical yields.
H3C
H3C
N
O
O
CO2CH3
R1
+
HO
CH3
CO2CH3
AcHN
R1
CO2CH3
H /H2O
OCH3
54a-f
erythro (S*,R*)-67a-f
Scheme 3.73: Synthesis of erythro (S*,R*) α-acetamido-β-hydroxy succinic acid derivatives
67a-f.
The relative configurations of the ring-opened products 67a-f were expected to be erythro
(S*,R*) since the bicyclic oxetane precursors had exo-CO2CH3 configuration as was shown
by NOE measurement. As ultimate proof, the erythro (S*,R*) stereochemistry of compound
67b was confirmed by X-ray analysis, depicted in Figure 3.204.
177
___________________________________________________________________________
Figure 3.204: X-ray analysis of compound 67b.
The structure assignments of the photoaldol products 67a-f were based on IR, mass spectra
and NMR analyses. For example, the IR spectrum of compound 67d showed five strong
absorption bands at 3510, 3340, 1745, 1735 and 1685 cm-1 indicating the presence of OH,
NH, COO, COO and CON groups, respectively. In the 1H-NMR spectrum at δ 0.88 and 1.24
ppm, two doublets appeared assigned to two methyl protons of the isopropyl group. The
acetyl methyl protons appears at δ 2.02 ppm. The
13
C-NMR spectrum showed signals at δ
73.6, 82.4, 171.1, 171.6 and 174.9 ppm corresponding to C-2, C-3, CON, COO and COO
HO
CO 2CH3
AcHN
CO 2CH 3
7.0
6.5
6.0
5.5
5.0
4.5
AcHN
CO 2CH 3
30.7601
25.1267
24.0937
18.8485
18.4749
52.9644
52.2611
3.6088
3.7422
3.8035
3.1791
1.0918
3.1253
170
7.5
CO 2CH3
erythro (S*,R*)
3.0000
Integral
0.8101
1.0497
erythro (S*,R*)
HO
73.5789
82.3990
174.9740
171.6628
171.1134
0.8477
0.8247
1.2493
1.2268
1.6137
1.6098
2.0252
3.0449
3.0219
2.9989
2.9759
2.9533
3.6650
3.8643
7.0901
7.0436
7.0397
groups, respectively.
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
160
150
140
130
spectrum of compound 67d.
120
1.0
13
110
100
(ppm)
90
80
60
50
40
30
20
spectrum of compound 67d.
178
70
___________________________________________________________________________
The 1H-NMR spectrum of compound 67f showed four singlets at δ 1.56, 2.03, 3.56 and 3.65
ppm corresponding to CH3, CH3CO, OCH3 and OCH3 groups, respectively. The amide proton
absorbs at 6.53 ppm. In the 13C-NMR spectrum, there signals at δ 82.4, 89.7, 164.7, 171.3 and
172.5 ppm appeared which were attributed to C-2, C-3, CON, COO and COO groups,
HO
CH3
CO2CH3
AcHN
CO2CH3
HO
CH3
CO2CH3
AcHN
CO2CH3
2 4 .8 4 8 3
2 4 .4 8 9 3
2 3 .4 4 1 8
1 7 .9 7 6 8
1 4 .2 6 2 6
4 3 .3 1 6 4
5 2 .7 2 2 6
5 2 .3 7 8 3
8 2 .4 2 8 4
8 9 .6 6 6 2
1 6 4 .6 7 4 1
1 7 2 .5 1 9 9
1 7 1 .3 0 3 8
0.9530
0.9309
0.8844
0.8624
0.8589
0.8369
2.0388
1.5579
1.4614
1.4477
1.4369
1.4217
1.4173
3.6640
3.6571
5.9920
respectively.
erythro (S*,R*)
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
4.2915
7.5557
3.1909
3.6736
3.0704
3.0000
6.3408
0.3073
Integral
erythro (S*,R*)
1.0
170
0.5
160
150
140
130
120
110
13
100
90
(p p m)
80
70
60
50
40
30
20
spectrum of compound 67f.
spectrum of compound 67f.
3.9.2 Synthesis of threo (S*,S*) α-acetamido-β
β -hydroxy succinic acid derivatives 68a-f
The exo-tert-butyl bicyclic oxetanes 56a-f underwent twofold ring opening when treated with
a mild acid and led to the formation of threo (S*,S*) α-acetamido-β-hydroxy succinic acid
derivatives 68a-f in high chemical yields.
H3CO2C
H3C
N
O
O
CH3
CH3
R1
CH3
H+/H2O
OCH3
56a-f
H3CO2C
HO
CH3
CH3
AcHN
CH3
R1
CO2CH3
threo (S*,S*)-68a-f
Scheme 3.74: Synthesis of threo (S*,S*) α-acetamido-β-hydroxy succinic acid derivatives
68a-f.
The ring-opening reaction is stereospecific; only one stereoisomer is formed. Again, the
relative configurations of the products were expected to be threo (S*,S*), since the oxetanes
precursor had exo-tert-butyl configuration as indicated by NOE measurement.
Proving the chemical structure of compounds 68a-f were based on IR and NMR analyses. For
example, the IR spectrum revealed five strong absorption bands at 3490, 3360, 1740, 1735
and 1685 cm-1 indicating the presence of OH, NH, COO, COO, CON groups, respectively.
179
___________________________________________________________________________
The 1H-NMR spectrum of compound 68a showed five singlets at δ 1.11, 1.49, 1.97, 3.56 and
3.72 ppm attributed to the tert-butyl, CH3, CH3CO, OCH3 and OCH3 groups, respectively. In
the 13C-NMR spectrum, signals at δ 80.7, 82.3, 169.8, 177.5, 180.9 appeared corresponding to
CH3
CH3
H3CO 2C
HO
H3CO 2C
HO
CH3
CO2CH 3
AcHN
threo (S*,S*)
6.0
5.6
5.2
4.8
4.4
4.0
(ppm)
3.6
3.2
2.8
2.4
2.0
1.6
26.4783
26.0644
21.8228
14.6875
14.5264
37.9686
37.0529
10.143
3.0459
3.1766
3.4346
3.0000
6.4
CO2CH 3
threo (S*,S*)
Integral
6.8
CH3
CH3
CH3
AcHN
7.2
51.7739
51.1805
80.6629
169.8387
180.9591
177.5417
1.1117
1.4903
1.9722
3.7228
3.5597
C-2, C-3, CON, COO and COO groups, respectively.
1.2
180
170
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
3.9.3 Synthesis of erythro (S*,R*) and threo (S*,S*) α-acetamido-β
derivatives 69a-f
Acid-treatment of the chromatographically separated exo-Ph and endo-Ph diastereoisomers of
the bicyclic oxetanes 58a-f led to the formation of threo (S*,S*) and erythro (S*,R*) αacetamido-β-hydroxy succinic acid derivatives 69a-f in 80-90 % yields, respectively.
H3CO2C
O
N
H3C
O
Ph
R1
H+/H2O
OCH3
AcHN
exo-Ph-58a-f
H3C
Ph
O
N
O
R
CO2CH3
Ph
R1
CO2CH3
threo (S*,S*)-69a-f
Ph
CO2CH3
1
HO
H+/H2O
OCH3
HO
CO2CH3
AcHN
R1
CO2CH3
endo-Ph-58a-f
Scheme 3.74: Synthesis of threo (S*,S*) and erythro (S*,R*) α-acetamido-β-hydroxy
succinic acid derivatives 69a-f.
The relative configurations of the products 69a-f were determined on the basis of the
characteristic signals in NMR spectra of the diastereoisomeric aldol products. For example, in
180
___________________________________________________________________________
the 1H-NMR spectra of the erythro-isomer, the methoxy group appears around 3.7 ppm, while
in the threo-isomer this absorption is shifted upfield to 3.0 ppm due to ring current effect of
the benzene ring. Also the chemical shift of the α-alkyl group appears at higher field in the
erythro-isomer than in the threo-isomer. As already described for the photoaldol adduct from
aldehydes, both threo and erythro-isomer favor conformations which are stabilized by
hydrogen bonding. This phenomena is displayed in scheme 3.76 and supported by NOE
measurement.
H
O
H
O
H3CO2C
NH
CH3
1.67 ppm
Ph CO2CH3
3.00 ppm
O
H3CO2C
O
NH
CO2CH3
Ph CH3
3.76 ppm
1.53 ppm
erythro (S*,R*)
threo (S*,S*)
Scheme 3.76: Explanation model.
The constitutions of compounds 69a-f were confirmed by IR, mass spectra and NMR
analyses. For example, the IR spectrum of compound 69b showed absorption bands at 3500,
3340, 1745, 1735, 1670, 1600 cm-1 indicating the presence of the OH, NH, COO, COO, CON,
and Ph groups, respectively.
In the 1H-NMR spectrum of compound 69b, there are two striking differences between the
erythro- and the threo-isomers: (a) the methoxy carbonyl group at C-2 in the threo-isomer
appears at higher field (δ = 3.0 ppm) than in the erythro- isomer which resonates at 3.76 ppm;
(b) the diastereotopic protons of the methylene group at C-2 appear down-field shifted in the
threo-isomer at 2.46 ppm, while in the erythro-isomer this resonance is shifted upfield to 2.0
ppm. The 13C-NMR spectra revealed that a significant difference in the chemical shifts of C-2
and C-3 by ca. 10 ppm depending on the configuration; the threo-isomer shows the low-field
shifted signals (see Figure 3.212 and 3.214).
181
AcHN
CO 2CH 3
6.0
5.5
5.0
4.5
(ppm)
4.0
3.0
2.5
2.0
1.5
170
160
150
140
130
120
82.0254
135.1075
127.9869
127.7086
127.0346
127.0053
126.4192
169.8753
165.4579
163.9708
2.1015
2.0952
2.0780
2.0545
2.0295
1.8601
1.8361
1.8121
1.7886
1.7268
0.9579
0.9334
0.9089
3.7717
3.7708
3.6895
3.6885
HO
CO 2CH3
AcHN
CO 2CH 3
AcHN
CO 2CH 3
5.5
5.0
4.5
(ppm)
4.0
3.5
50
9.7720
14.1894
28.8555
40
30
20
10
3.0
2.5
2.0
2.7926
1.3526
1.0345
2.4063
2.0140
4.9312
Integral
60
erythro (S*,R*)
3.9024
3.0000
6.0
70
Ph
CO 2CH3
1.1610
6.5
80
HO
erythro (S*,R*)
7.0
90
(ppm)
Ph
7.5
100
spectrum of threo-69b.
7.4932
7.4707
7.3169
7.2904
7.2415
7.2400
7.1190
7.0661
110
13
8.0
52.8911
51.8142
3.1032
1.3801
1.1207
3.0286
3.0000
3.5
7.9845
7.9625
6.5
14.2919
7.0
22.6066
7.5
3.6712
4.0576
2.9699
Integral
threo (S*,S*)
8.0
CO 2CH 3
threo (S*,S*)
52.7226
51.9388
AcHN
87.0509
92.5745
169.3699
168.7398
165.3627
2.4674
2.4434
2.4233
2.3993
2.2744
1.5848
1.5608
1.5407
1.5167
1.0431
1.0191
0.9946
134.8145
128.4851
127.5987
126.3093
125.3350
CO 2CH3
Ph
HO
CO 2CH3
Ph
77.2418
HO
3.0542
3.7766
7.5471
7.2958
7.2904
7.2875
7.2777
7.2718
7.2400
___________________________________________________________________________
1.5
1.0
170
1
160
150
140
130
spectrum of erythro-69b.
120
110
13
100
90
(ppm)
80
70
60
50
40
30
20
10
The 1H-NMR spectrum of compound 69c showed three singlets at δ 2.23, 3.00 and 3.75 ppm
attributed to CH3CO, OCH3 and OCH3 groups, respectively, and confirmed the threoconfiguration. In the 13C-NMR spectrum, five signals at δ 86.6, 92.6, 165.2, 168.7, 169.5 ppm
appear corresponding to C-2, C-3, CON, COO and COO groups, respectively.
182
CO 2CH3
Ph
HO
AcHN
AcHN
CO2CH 3
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.5
18.7020
14.4311
14.1821
37.8954
52.8618
51.7922
3.6833
3.3586
1.2167
3.0295
3.0000
Integral
2.4463
3.3087
6.5
CO2CH3
threo (S*,S*)
4.3526
7.0
CO2CH3
Ph
HO
threo (S*,S*)
7.5
86.5674
92.6257
134.7779
128.4704
127.5840
126.9906
126.3167
169.5310
168.7398
165.2382
3.0055
2.3467
2.3188
2.3075
2.3046
2.2727
2.2659
2.2252
1.4964
1.4572
1.4543
1.4215
1.4175
1.4082
1.3793
1.3681
0.9072
0.8837
0.8597
3.7450
7.5405
7.5135
7.5076
7.2554
7.2368
7.2309
7.2035
___________________________________________________________________________
170
1.0
160
150
140
130
120
110
13
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of threo-69c.
CDCl3) spectrum of threo-69c.
Figure 3.217 shows the HMQC spectrum which also confirmes the NMR assignments. Figure
3.218 shows the HH-COSY spectrum; the off-diagonal cross peak correctly correlate the
coupled protons.
H6
H5
H7
H11
C6C5
C7&C11
H9
C9
5
O
5
4 O
HO
Ph
3
9
O
Ph
3
10 11
O
1
6
H5
7 8 OO
H5
7 8 OO
9
HN 2
6
H6
O
1
4 O
HO
10 11
H6
HN 2
H10
C10
H7
H9
H7
H9
H10
H10
H11
H11
Figure 3.217: HMQC (300 MHz, CDCl3) Figure 3.218: HH-COSY (300 MHz, CDCl3)
spectrum of compound 69c.
spectrum of compound 69c.
derivatives 70a-f
Analogous to compounds 58a-f, ring opening of the exo- and endo-Ph bicyclic oxetanes 59a-f
procceeded with retention of configuration and gave the threo (S*,S*) and erythro (S*,R*) αacetamido-β-hydroxy succinic acid derivatives 70a-f in high chemical yields, respectively.
183
___________________________________________________________________________
C2H5O2C
O
N
H3C
O
Ph
H+/H2O
R1
OCH3
H3C
CO2C2H5
Ph
R1
CO2CH3
AcHN
exo-Ph-60a-f
Ph
O
N
O
HO
threo (S*,S*)-70a-f
Ph
CO2C2H5
HO
+
CO2C2H5
H /H2O
1
R
R1
CO2CH3
AcHN
OCH3
endo-Ph-60a-f
The constitution of compounds 70a-f was established on the basis of IR and NMR analyses.
For example the IR spectrum of compound 70e exhibits five strong absorption bands at 3490,
3360, 1755, 1729 and 1680 cm-1 indicating the presence of the OH, NH, COO, COO and
CON groups, respectively. Additionally, a band at 1580 cm-1 suggests the presence of phenyl
group. The 1H-NMR spectrum revealed two singlet signals at 2.26 and 3.05 ppm due to
CH3CO and OCH3 groups, respectively, and indicates the threo-configuration. In addition, a
quartet at 4.24 ppm appeared which was attributed to the OCH2 group. In the
13
C-NMR
spectrum five signals at δ 86.4, 92.9, 164.7, 168.1 and 170.1 ppm appear attributed to C-2, C-
HO
AcHN
CO2C2H5
Ph
HO
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.5
25.8006
24.5406
23.3319
14.1894
13.9989
43.9025
51.7483
62.1801
3.6395
3.3861
1.1658
3.2670
1.2090
1.0605
3.0259
3.0000
Integral
1.4922
2.6395
6.5
CO2CH 3
threo (S*,S*)
3.7613
7.0
CO 2C2H5
Ph
AcHN
CO2CH3
threo (S*,S*)
7.5
86.4135
92.9920
134.8291
128.4118
127.5401
126.3973
125.6061
170.0804
168.0585
164.7254
3.0513
2.4062
2.3861
2.3616
2.3415
2.2593
1.8189
1.7969
1.7748
1.4354
1.4158
1.3908
1.3713
1.3286
1.3051
1.2811
0.9696
0.9476
0.8868
0.8643
4.2929
4.2689
4.2454
4.2219
7.5260
7.2836
7.2816
7.2625
7.2571
7.2400
3, CON, COOEt and COOMe groups, respectively.
1.0
170
160
150
140
130
spectrum of threo-70e.
120
13
110
100
90
(ppm)
70
60
50
40
30
20
184
80
___________________________________________________________________________
Figure 3.221 shows the HMQC spectrum which also confirmes the NMR assignments.
C7
C5
C12&C13
C11 C6&C8
C10
6
5
4 O
HO
12
Ph
3 10 11
7
O
H10
O
1
H7
9
13
O
HN 2
8
H5
O
H6 H12&H13
H10
H11
Figure 3.221: HMQC (300 MHz, CDCl3) spectrum of compound 70e.
3.9.5 Synthesis of erythro (S*,R*) and threo (S*,S*) α-amino-β
derivatives 71a-f
Acid hydrolysis of the chromatographically separated exo-Ph and endo-Ph bicyclic oxetanes
61a-f furnished threo (S*,S*) and erythro (S*,R*) α-acetamido-β-hydroxy succinic acid
derivatives 71a-f in high chemical yields, respectively.
185
___________________________________________________________________________
PriO2C
O
N
H3C
O
OCH3
Ph
O
N
O
HO
H+/H2O
R1
AcHN
exo-Ph-61a-f
H3C
CO2Pri
Ph
Ph
R1
CO2CH3
threo (S*,S*)-71a-f
Ph
CO2Pri
HO
H+/H2O
R1
R1
CO2CH3
AcHN
OCH3
CO2Pri
endo-Ph-61a-f
The chemical structures of compounds 71a-f were established on the basis of NMR analyses.
For example, the 1H-NMR spectrum of compound 71c revealed two singlets at δ 2.26 and
3.04 ppm indicating the presence of CH3CO and OCH3 groups, respectively, and assigned the
13
threo-configuration. Additionally, the methine proton appears at 5.03 ppm. In the
C-NMR
spectrum, five signals at 86.3, 92.5, 165.4, 167.6 and 169.7 ppm appeared, corresponding to
C-2, C-3, CON, COO and COO groups, respectively, and reconfirmed the threo assignment
CO 2Pri
HO
Ph
HO
AcHN
AcHN
CO 2CH 3
7.0
6.5
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.5
1.0
170
160
150
140
130
21.6103
21.5810
18.7020
14.4311
14.1894
37.9393
51.7629
70.5094
CO 2CH 3
3.6240
8.0338
2.4516
1.0640
3.0357
3.0000
1.1627
4.0363
Integral
2.2175
7.5
CO 2Pri
Ph
threo (S*,S*)
threo (S*,S*)
8.0
86.3476
92.4792
134.9903
128.3386
127.4741
126.4192
169.6556
167.6044
165.4140
3.0385
2.4067
2.3798
2.3680
2.3651
2.3264
2.2554
1.5643
1.5359
1.5315
1.5221
1.4937
1.3032
1.2821
1.2748
1.2542
0.9427
0.9187
0.8947
5.1212
5.1001
5.0790
5.0585
5.0374
7.5549
7.2870
7.2856
7.2797
7.2762
7.2674
7.2611
7.2400
(see Figure 3.222 & 3.223).
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
10
The IR spectrum of compound 71e showed six strong absorption bands at 3500, 3370, 1745,
1728, 1645 and 1600 cm-1 suggesting the presence of OH, NH, COO, COO, CON and Ph
groups, respectively. In the 1H-NMR spectrum, the methoxy group appears as a singlet at
3.05 ppm assigning the threo- configuration as already described for the compound
186
___________________________________________________________________________
mentioned above. Additionally, four doublets appeared upfield-shifted at δ 0.86, 0.97, 1.27
ppm indicating the presence of two isopropyl groups. The 13C-NMR spectrum showed signals
at δ 86.3, 92.9, 164.9, 167.5 and 170.1 ppm attributed to C-2, C-3, CON, COO and COO
HO
CO 2Pri
Ph
CO2CH3
AcHN
7.5
7.0
6.5
6.0
5.5
5.0
25.8592
24.5479
23.3319
21.6250
14.2187
43.8951
51.7776
70.4215
CO 2CH 3
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
5.3317
3.8122
2.6563
9.2674
2.1605
1.0811
3.0113
1.4334
3.0000
threo (S*,S*)
1.3523
3.7960
2.5336
threo (S*,S*)
86.3036
CO 2Pri
Ph
HO
AcHN
92.9993
134.8951
129.9502
128.8660
128.3752
127.5034
126.4998
170.1390
167.5238
164.9305
3.0571
2.4277
2.4077
2.3832
2.3631
2.2622
2.1515
2.1461
2.1393
2.0917
1.7984
1.4658
1.4462
1.4217
1.4031
1.3825
1.3139
1.2924
1.2782
1.2708
0.9770
0.9549
0.8908
0.8687
5.1246
5.1035
5.0824
7.5373
7.2679
7.2620
7.2400
groups, respectively (see Figure 3.224 and 3.225).
1.0
170
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
derivatives 72a-f
Analogous to the compounds mentioned above, ring-opening of the chromatographically
separated exo-Ph and endo-Ph of the bicyclic oxetanes 62a-f proceeds smoothly and leads to
the formation of threo (S*,S*) and erythro (S*,R*) α-acetamido-β-hydroxy succinic acid
derivatives 72a-f in (80-90 %) yields, respectively.
ButO2C
O
N
H3C
O
Ph
R1
H+/H2O
OCH3
AcHN
exo-Ph-62a-f
H3C
Ph
O
N
O
CO2But
Ph
R1
CO2CH3
threo (S*,S*)-72a-f
Ph
CO2But
+
R1
HO
HO
CO2But
AcHN
R1
CO2CH3
H /H2O
OCH3
endo-Ph-62a-f
187
___________________________________________________________________________
The assignment of the relative configurations of the photoaldol adducts were based on
characteristic signals in NMR analyses. For example, in the 1H-NMR spectra of the threo- and
erythro-isomers of compound 72a, there is a pronouncing difference: the methyl protons
resonance in the threo-isomer appears at 1.71 ppm, while in the erythro-isomer, this
resonance is shifted upfield to 1.50 ppm influencing by a ring current effect of the phenyl
group. The
13
C-NMR spectra showed also a strong chemical shift difference of C-2 and C-3
of about 30 ppm, the threo-isomer absorbs at lower-field chemical shift (see Figure 3.226,
3.227, 3.228 & 3.229). The mass spectrum showed the base peak at m/z 145 due to retro aldol
fragment of N-acetyl alanine methyl ester. Scheme 3.80 summarizes the fragmentation pattern
CO 2But
HO
CO 2But
AcHN
CO2CH 3
AcHN
CO2CH 3
5.0
4.5
(ppm)
4.0
3.0
2.5
2.0
170
160
150
140
130
CO 2But
Ph
HO
6.5
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
170
160
150
140
130
spectrum of threo-72a.
90
80
18.5995
27.7859
23.9106
52.3710
66.5023
70
60
50
40
30
20
CO 2But
Ph
CO 2CH 3
3.0106
12.148
3.7257
Integral
3.0000
7.0
100
(ppm)
threo (S*,S*)
7.2382
7.5
110
AcHN
CO 2CH 3
threo (S*,S*)
8.0
13
136.0818
128.6755
128.5657
128.4777
126.1555
125.5255
170.3222
169.9119
168.4102
1.7117
1.4977
2.1319
3.7855
7.4785
7.4741
7.3786
7.3649
7.3624
7.3433
7.3384
7.3326
AcHN
120
spectrum of erythro-72a.
spectrum of erythro-72a.
HO
79.5713
8.9494
4.9802
3.6309
3.5
16.3724
5.5
27.9031
27.8518
24.2329
6.0
83.4246
6.5
96.9332
7.0
107.9658
7.5
3.0000
erythro (S*,R*)
4.4838
Integral
2.5270
erythro (S*,R*)
8.0
85.3660
128.4631
127.8990
126.9027
137.1660
171.9705
171.2892
169.6702
1.5275
1.5025
Ph
HO
52.7446
Ph
1.9497
3.6713
7.3311
7.3252
7.6867
7.6798
7.6691
7.6632
of compound 72a.
120
13
110
100
90
(ppm)
70
60
50
40
30
20
188
80
___________________________________________________________________________
COOMe
Me
NHCOMe
Ph
- (COOMe)
OH
Me
H
t
t
Bu
O
CO
hC
-P
H
O
Ph
OH
Ph
COOBut
m/z =351
m/z =336
t
- (COOBu )
COOMe
COOMe
NHCOMe
Me
NHCOMe
- Me
OH
COOBu
m/z =292
COOMe
NHCOMe
Me
COOMe
NHCOMe
+
OH
m/z =144
Me
-H
NHCOMe
O
Ph
Ph
m/z =250
O
H
O
COOBut
MeO
MeOCHN
Me
Ph
m/z =249
- PhCOCOOBut
Me
Me
MeOOC
- Me OH
NHCOMe
-(
O
-M
e
CO
Me
NHCOMe
Me
NHCOMe
MeOOC
m/z =130
e)
M
- MeCO
MeOOC
NHCOMe
m/z =113
m/z =145
m/z =351
O
NH
m/z =102
m/z =86
derivatives 73a-f
Despite of the relatively low diastereoselection in the photocycloaddition of menthyl phenyl
glyoxylate with 5-methoxyoxazoles, the ring-opening reaction is a simple and versatile
preparative method to synthesize diastereomerically pure oxetane derivatives, since the four
stereoisomers obtained have quite different physical properties and can be separated by
HPLC. The bicyclic oxetanes are valuable chiral bulding blocks for natural product synthesis
because the degree of chemical yields and conversion allow to produce them in large
amounts. Hydrolysis of the chromatographically separated exo-Ph and endo-Ph oxetanes 63af resulted in the threo (S*,S*) and erythro (S*,R*) α-acetamido-β-hydroxy succinic acid
derivatives 73a-f, respectively, as depicted in scheme 3.81.
189
___________________________________________________________________________
*RO2C
O
N
H3C
O
H+/H2O
R1
OCH3
Ph
O
N
O
HO
R1
CO2CH3
AcHN
exo-Ph-63a-f
H3C
CO2R*
Ph
Ph
threo (S*,S*)-73a-f
Ph
CO2R*
HO
+
CO2R*
H /H2O
1
R
R1
CO2CH3
AcHN
OCH3
endo-Ph-63a-f
R*=
The constitutions of compounds 73a-f were analyzed on grounds of IR, mass spectra and
NMR spectral analyses. For example, the IR spectrum of compound 73a showed strong
absorption bands at 3540, 3370, 1736, 1725, 1670, 1595 cm-1 characteristic for the OH, NH,
COO, COO, CON and Ph groups, respectively. The mass spectrum revealed the base peak at
m/z 374 for the fragment [M+-COOMe]. In the 1H-NMR spectrum, the methoxy protons
resonance which used as guide for assignment of the relative configuration of the photoaldol
adducts appeared at 3.06 ppm indicating the compound has threo-configuration. The
13
C-
NMR spectrum showed signals at δ 82.1, 92.7, 166.2, 167.9 and 170.3 ppm attributed to C-2,
O
Ph
HO
AcHN
CO 2CH 3
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
170
160
150
140
130
Ph
CO2CH 3
2.9986
0.2797
1.5652
0.8919
3.8943
2.4178
3.5096
2.8974
6.9370
1.0148
1.5692
1.5977
2.2412
3.0000
1.3314
Integral
2.6107
4.5064
7.0
O
threo (S*,S*)
threo (S*,S*)
7.5
82.1317
81.7983
77.1941
77.0879
51.9241
51.8985
46.9939
46.9500
40.3898
40.2469
33.9981
31.3682
31.3499
26.0644
25.4527
23.2952
22.8594
21.8997
21.4492
20.6946
20.6726
16.0758
15.5739
14.1198
14.0905
92.6990
135.3859
135.2833
128.1627
128.1371
127.5291
127.4961
127.4522
126.2764
126.0749
125.9907
O
O
HO
AcHN
170.3295
167.9194
167.8864
166.2821
166.1795
3.0635
3.0366
2.2123
2.2039
2.0580
1.6877
1.6823
1.5270
1.4139
1.4075
1.0740
0.8693
0.8653
0.8546
0.8477
0.8438
0.8315
0.7654
0.7184
0.6954
0.6586
0.6351
0.5739
0.5602
0.5372
4.6656
4.6573
4.6514
4.6426
7.2655
7.2616
7.2527
7.2488
7.2400
C-3, CON, COO and COO groups, respectively (see Figure 3.230 and 3.231).
120
13
110
100
90
(ppm)
70
60
50
40
30
20
190
80
Integral
8.0
7.5
7.0
6.5
6.0
HO
O
AcHN
5.5
5.0
4.0
(ppm)
3.5
4.5
4.0
(ppm)
spectrum of erythro-73d.
3.0
3.5
2.5
3.0
2.0
2.5
2.0
1.5
1.5
1.0
1.0
0.5
spectrum of threo-73d.
170
0.5
170
191
160
160
150
150
140
140
130
erythro (S*,R*)
CO2CH3
130
92.8309
92.6624
87.2780
86.6406
76.7729
76.4213
52.4369
52.1732
46.9793
46.8108
40.1004
39.9539
34.2325
34.0347
34.0127
33.6391
31.2729
31.2583
25.6102
25.5589
23.0315
22.9729
21.9620
21.8667
20.7532
20.7386
18.6581
18.5116
15.9036
15.8377
15.6032
15.4274
13.9330
13.8964
4.5
134.0599
128.0968
128.0675
127.7085
127.5108
127.2617
127.0053
5.0
163.3554
5.5
173.3843
172.7104
169.8753
169.2673
6.0
0.6327
3.2713
0.7852
0.6272
0.7126
3.9170
1.4255
1.0779
1.7232
12.094
3.3055
3.0792
6.5
2.8069
2.8171
1.5960
10.032
5.2006
1.8267
0.4193
1.7268
0.4532
1.8088
2.9577
3.0000
0.9444
AcHN
3.0000
7.0
1.0006
0.9653
4.6727
91.2778
89.9079
76.7216
76.2088
51.5725
51.5432
46.8181
46.5617
40.1151
39.7122
34.0787
34.0347
32.4304
32.2546
31.4707
31.3975
25.7200
25.6102
23.2366
22.9876
21.9913
21.9327
20.7825
20.3796
19.0317
18.9071
16.3065
16.0135
15.7937
15.7498
13.9769
13.9110
136.0452
128.6096
127.9723
127.8404
125.6134
125.5914
170.3735
167.1648
167.0989
163.4873
163.4287
3.1522
3.1350
2.2970
2.2891
1.6308
1.6201
1.1592
1.1063
1.1004
1.0691
0.9138
0.9040
0.8913
0.8815
0.8560
0.8496
0.8276
0.7747
0.7708
0.7526
0.7487
0.7316
0.7086
0.6312
0.6086
0.5097
0.4867
0.3623
0.3402
4.8371
4.8229
4.8057
4.8013
4.7910
7.2400
7.2356
13
4.5187
4.5025
4.4859
3.8335
3.8197
3.8119
2.2945
2.2098
2.1863
1.6196
1.6117
1.5995
1.5877
1.5731
1.5662
1.1861
1.1631
0.8668
0.8452
0.8325
0.8227
0.8104
0.8002
0.7889
0.7810
0.7771
0.7575
0.7536
0.6184
0.5954
0.5753
0.5523
0.3657
0.3442
7.7798
7.7656
7.7607
7.3517
7.3473
7.3267
7.3213
7.2400
In the
3.2462
2.0057
___________________________________________________________________________
There are two main differences in the 1H-NMR spectra of compound 73d between the
erythro- and the threo-isomers: (1) the methoxy group in the threo-isomer absorbs at δ 3.15
ppm, while in the erythro-isomer, this absorption is shifted downfield to 3.82 ppm; (2) the
methine proton of the isopropyl group in the erythro-isomer resonates at a much higher field
(δ = 1.53 ppm) than in the threo-isomer which resonates at (δ = 1.79 ppm).
C-NMR spectrum, five signals at δ 89.9, 91.2, 163.4, 167.1 and 170.3 ppm appeared
attributed to C-2, C-3, CON, COO and COO groups, respectively (see Figure 3.232, 3.233,
3.234 and 3.235).
O
O
O
O
HO
Ph
HO
Ph
threo (S*,S*)
CO 2CH 3
AcHN
threo (S*,S*)
120
13
13
110
O
O
O
Ph
HO
Ph
AcHN
120
110
CO2CH 3
100
90
(ppm)
100
90
(ppm)
80
80
70
70
60
60
50
50
40
40
30
30
20
erythro (S*,R*)
CO2CH 3
20
___________________________________________________________________________
3.9.8 Synthesis of erythro (S*,R*) and threo (S*,S*) α-propionylamino-β
β -hydroxy
The chromatographically separated exo-R and endo-R bicyclic oxetanes 64a-f underwent two
fold ring-opening when treated with acid and led to the formation of threo (S*,S*) and
erythro (S*,R*) α-propionylamino-β-hydroxy succinic acid derivatives 74a-f, respectively, in
high chemical yields.
C2H5
R1O2C
O
N
O
CH3
H+/H2O
OCH3
N
O
R
+
CH3
CH3
CO2CH3
threo (S*,S*)-74a-f
CO2R1
R
O
HO
EtOCHN
exo-R-64a-f
C2H5
CO2R1
R
R
HO
H /H2O
EtOCHN
OCH3
CO2R1
CH3
CO2CH3
endo-R-64a-f
Scheme 3.82: Synthesis of threo (S*,S*) and erythro (S*,R*) α-propionylamino-β-hydroxy
Again, the relative configuration of the photoaldol adducts 74a-f was determined on the basis
of NMR anaylses (especially the chemical shift of both methoxy and methyl groups). The
results are summarized in Table 3.46.
Table 3.46: Characterisitic 1H-NMR signals (δppm) of photo-aldol products 74c-f in (CDCl3).
compound
R=
R1 =
erythro
threo
CH3
OCH3
CH3
OCH3
74c
Ph
Me
1.58
3.62
1.87
2.99
74d
Ph
Et
1.67
3.61
1.83
3.00
74e
Ph
i-Pr
1.54
3.65
1.69
3.05
74f
Ph
t-Bu
1.57
3.67
1.72
3.03
The constitutions of compounds 74a-f were determined on the basis of IR and NMR analyses.
For example, the IR spectrum of compound 74d revealed strong bands at 3490, 3365, 1743,
1720 and 1650 cm-1 indicating the presence of OH, NH, COO, COO and CON groups,
respectively. The 1H-NMR spectrum exhibits two singlets at δ 1.67 and 3.61 ppm attributed to
methyl and methoxy groups, respectively, and assigned to the erythro- configuration. In the
192
___________________________________________________________________________
C-NMR spectrum, there signals at δ 66.2, 82.9, 172.1, 172.4 and 174.7 ppm appeared
13
corresponding to C-2, C-3, CON, COO, COO groups, respectively (see Figure 3.236 and
2 9 .9 9 8 3
1 9 .9 1 0 8
1 3 .9 8 7 9
9 .6 2 9 1
5 2 .7 4 0 9
6 6 .7 1 1 0
6 2 .1 8 7 4
8 2 .9 1 9 2
1 2 8 .4 5 5 8
1 2 8 .1 0 0 5
1 2 7 .7 2 3 2
1 2 7 .1 3 3 5
1 3 6 .6 5 6 9
1 7 4 .6 9 2 0
1 7 2 .4 1 3 7
1 7 2 .1 4 2 6
2.2475
2.2431
2.2221
2.2177
2.1961
2.1932
2.1711
2.1682
1.6735
1.3047
1.2807
1.2572
1.2435
1.1352
1.1102
1.0848
3.6116
4.2792
4.2557
4.2469
4.2234
7.3115
7.2400
3.237).
30
20
10
Ph
HO
CO2C2H5
EtOCHN
Ph
HO
CO2CH3
EtOCHN
6.5
6.0
5.5
5.0
CO 2CH 3
4.5
4.0
3.5
3.0
2.5
2.0
4.8654
3.8545
3.0833
2.5096
3.0000
erythro (S*,R*)
2.2303
6.9126
erythro (S*,R*)
7.0
CO2C2H5
1.5
180
(ppm)
170
160
150
140
130
120
13
110
100
90
(p p m)
80
70
60
50
40
3.9.9 Synthesis of erythro (S*,R*) and threo (S*,S*) α-isobutyrylamino-β
β -hydroxy
Analogous to compounds 64a-f, ring opening of the exo- and endo-R bicyclic oxetanes 65a-f
procceeded with retention of configuration and gave the threo (S*,S*) and erythro (S*,R*) αisobutyrylamino-β-hydroxy succinic acid derivatives 75a-f in high chemical yields,
respectively.
H3C
R1O2C
O
N
O
H3C
R
CH3
H+/H2O
H3C
N
O
H3C
CH3
CO2CH3
threo (S*,S*)-75a-f
R
CO2R1
+
CH3
CO2R1
R
PriOCHN
OCH3
exo-R-65a-f
R
O
HO
HO
H /H2O
PriOCHN
OCH3
CO2R1
CH3
CO2CH3
endo-R-65a-f
Scheme 3.83: Synthesis of threo (S*,S*) and erythro (S*,R*) α-isobutyrylamino-β-hydroxy
The structure determination of compounds 75a-f were made on the basis of IR, mass spectra
and NMR analyses. For example, the IR spectrum of compound 75e showed strong
193
___________________________________________________________________________
absorption bands at 3525, 3370, 1756, 1730 and 1645 cm-1 suggesting the presence of OH,
NH, COO, COO and CON groups, respectively. The 1H-NMR spectra revealed that there is a
striking differences between the threo- and erythro isomer: (a) the methoxy group in the
threo- isomer resonates at higher field chemical shift (δ = 3.00 ppm) than in the erythroisomer which appears at 3.68 ppm; (b) the methyl group at C-2 absorbs down-field shifted in
the threo- isomer at 1.68 ppm, while in the erythro-isomer this absorption is shifted upfield to
1.54 ppm.
13
Also, the
C-NMR spectra showed a pronouncing differences in the chemical shifts of C-2
and C-3 by ca. 10 ppm depending on the relative configuration, the threo-isomer has low-field
PriOCHN
CO2CH 3
6.0
5.5
5.0
4.0
3.5
3.0
2.5
2.0
1.5
1.0
170
160
150
140
130
5.5
5.0
4.0
3.5
3.0
2.5
2.0
1.5
170
160
150
140
130
21.5810
21.5078
19.2441
19.2002
18.8266
18.6874
36.0053
66.5755
52.5395
50
40
30
20
CO2CH 3
7.2955
9.6193
3.5766
1.0255
3.0000
4.5
(ppm)
60
threo (S*,S*)
1.3651
6.0
70
CO 2Pri
Ph
PriOCHN
CO2CH 3
7.6768
6.5
80
HO
threo (S*,S*)
7.0
100
90
(ppm)
127.4155
126.1995
135.5471
173.0693
170.3515
167.9706
1.6833
1.3693
1.3595
1.3458
1.3365
1.2684
1.2473
1.2400
1.2184
3.0086
2.8725
2.8495
2.8264
2.8029
2.7804
5.0697
5.0496
5.0286
5.0075
4.9869
CO 2Pri
Ph
PriOCHN
7.5
110
spectrum of erythro-75e.
spectrum of erythro-75e.
7.5358
7.5314
7.2870
7.2630
7.2400
120
13
HO
71.5863
2.9533
8.5398
3.2121
2.0328
2.4242
8.3826
1.4787
3.0000
4.5
(ppm)
1
28.4745
21.7275
21.6543
21.4858
19.4859
19.3174
6.5
51.8215
7.0
CO2CH 3
70.4435
7.5
CO 2Pri
erythro (S*,R*)
1.3211
5.8220
3.2409
Integral
erythro (S*,R*)
8.0
80.0841
137.1807
128.4484
127.8258
126.9540
176.7908
172.4100
171.7873
2.3896
2.3416
2.3186
2.2955
1.5427
1.3257
1.3130
1.3052
1.2919
1.1793
1.1563
1.1039
1.0808
1.0740
1.0505
HO
82.0840
PriOCHN
Ph
CO 2Pri
91.8346
Ph
HO
3.6846
5.1540
5.1329
5.1118
7.6774
7.6710
7.6598
7.6539
7.3384
7.3198
7.3144
shifted signals (see Figure 3.238, 3.239, 3.240 and 3.241).
120
13
110
100
90
(ppm)
70
60
50
40
30
20
194
80
___________________________________________________________________________
In the 1H-NMR spectrum of compound 75f three singlets at δ 1.44, 1.72 and 3.00 ppm
appeared which are characteristic for tert-butyl, methyl and methoxy groups, respectively, and
confirmed the threo- configuration. Additionally, there a doublet at 1.34 ppm appears for the
isopropyl group. In the
C-NMR spectrum, there signals at δ 82.1, 91.9, 167.3, 170.5 and
13
173.0 ppm appeared attributed to C-2, C-3, CON, COO and COO groups, respectively (see
HO
PriOCHN
CO 2But
Ph
HO
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
28.4306
27.9104
21.5957
19.4785
19.3833
51.7922
83.7177
82.0840
9.7778
6.1319
2.9903
1.0202
Integral
2.1688
3.0000
6.5
CO 2CH 3
threo (S*,S*)
3.8562
7.0
CO 2But
Ph
PriOCHN
CO 2CH 3
threo (S*,S*)
7.5
91.9151
136.0159
127.9576
127.3423
126.2141
173.0181
170.5273
167.2527
1.7239
1.4447
1.3600
1.3365
3.0028
2.8597
2.8367
2.8132
2.7902
2.7672
7.5304
7.5094
7.5045
7.2767
7.2527
7.2400
Figure 3.242 and 3.243).
170
1.5
160
150
140
130
120
13
110
100
90
(ppm)
80
70
60
50
40
30
20
spectrum of threo-75f.
3.9.10 Synthesis of erythro (S*,R*) and threo (S*,S*) α-(2,2-dimethyl-propionylamino)-β
βhydroxy succinic acid derivatives 76a-f
Acid hydrolysis of the chromatographically separated exo-R and endo-R bicyclic oxetanes
66a-f furnished threo (S*,S*) and erythro (S*,R*) α-(2,2-dimethyl-propionylamino)-βhydroxy succinic acid derivatives 76a-f in high chemical yields.
H3C
H3C
R1O2C
O
N
O
H3C
R
CH3
H+/H2O
H3C
H3C
H3C
N
O
CH3
CO2CH3
threo (S*,S*)-76a-f
R
CO2R1
+
CH3
CO2R1
R
ButOCHN
OCH3
exo-R-66a-f
R
O
HO
HO
H /H2O
ButOCHN
OCH3
CO2R1
CH3
CO2CH3
endo-R-66a-f
Scheme 3.84: Synthesis of threo (S*,S*) and erythro (S*,R*) α-(2,2-dimethylpropionylamino)-β-hydroxy succinic acid derivatives 76a-f.
195
___________________________________________________________________________
The structure of the compounds 76a-f were established on the basis of IR, mass spectra and
NMR anaylses. For example, the IR spectrum of compound 76d exhibits five strong
absorption bands at 3530, 3420, 1755, 1724, 1675 cm-1 characteristic for OH, NH, COO,
COO and CON groups, respectively. The mass spectrum showed the base peak at m/z 306
due to [M+ - COOMe]. In the 1H-NMR spectra, there are two distinct differences between the
erythro- and threo- isomers: (a) in the threo-isomer, the methoxy resonance appears at 3.00
ppm, while in the erythro-isomer appears down-field shifted to 3.70 ppm; (b) the methyl
protons in the threo-isomer absorbs at 1.67 ppm, whereas in the erythro-isomer this
absorption is shifted upfield to 1.55 ppm. The 13C-NMR spectra also revealed two significant
differences between the threo- and erythro- isomers. Both C-2 and C-3 in the threo-isomer
resonate lower-field shifted than in the erythro- isomer (see Figure 3.244, 3.245, 3.246 and
Ph
ButOCHN
CO2CH 3
5.0
4.5
(ppm)
3.5
3.0
2.5
2.0
1.5
1.0
170
160
150
140
130
135.4884
129.9722
128.8367
128.0895
127.4228
127.3203
127.1078
126.1775
175.0766
170.2636
168.6446
1.6725
1.3757
1.2924
1.2689
1.2498
1.2449
2.9993
4.2175
4.1940
4.1700
4.1464
HO
6.0
5.5
5.0
4.5
(ppm)
3.5
3.0
60
18.5262
13.9989
27.2218
39.0016
50
40
30
20
CO2CH3
2.5
2.0
9.5617
6.2978
3.0685
3.0000
4.0
1.5
170
160
150
140
130
70
threo (S*,S*)
2.7890
Integral
1.6868
5.1044
6.5
80
CO2C2H5
Ph
ButOCHN
CO2CH3
threo (S*,S*)
7.0
100
90
(ppm)
CO2C2H5
HO
Ph
7.5
110
7.5314
7.2890
7.2865
7.2620
7.2400
120
13
ButOCHN
52.6493
2.3360
3.8409
9.0747
3.0000
4.0
13.9769
5.5
1
27.4489
26.9215
21.3979
6.0
33.4633
6.5
1.8638
0.6175
7.0
51.7629
7.5
CO2CH3
erythro (S*,R*)
62.1142
8.0
4.1514
1.7050
Integral
erythro (S*,R*)
82.3111
ButOCHN
Ph
CO2C2H5
HO
CO 2C2H5
91.8932
HO
66.5828
63.1251
80.4577
128.4558
127.8404
126.9687
137.3199
178.5050
172.6884
172.1463
1.5456
1.3487
1.3247
1.3012
1.1087
4.3326
4.3184
4.3086
4.2944
4.2851
4.2709
4.2586
4.2469
3.7037
5.0095
7.6852
7.6769
7.6588
7.6534
7.3424
7.3233
7.3184
7.2400
3.248).
120
13
110
100
90
(ppm)
70
60
50
40
30
20
196
80
___________________________________________________________________________
The 1H-NMR spectrum of compound 76e exhibits three singlets at δ 1.38, 1.69 and 2.99 ppm
characteristic for tert-butyl, methyl and methoxy groups, respectively, and supports the threoconfiguration. Furthermore, two doublets at δ 1.23 ppm appeared attributed to the isoropyl
group. The
13
C-NMR spectrum showed signals at δ 82.3, 91.7, 168.1, 170.3 and 175.1 ppm
corresponding to C-2, C-3, CON, COO and COO groups, respectively, and reconfirmed the
HO
CO2Pri
Ph
ButOCHN
ButOCHN
7.0
6.5
6.0
5.5
5.0
4.0
3.5
3.0
2.5
2.0
27.4929
21.7349
21.6616
21.3466
33.4633
51.7410
70.3043
9.5333
8.2075
3.0062
3.0000
4.5
(ppm)
CO2CH3
threo (S*,S*)
1.3302
4.2318
Integral
1.9486
threo (S*,S*)
7.5
CO2Pri
Ph
HO
CO2CH3
82.2965
91.7466
135.6423
128.0235
127.3569
126.2141
175.0546
170.3368
168.0659
1.6862
1.3766
1.2566
1.2415
1.2356
1.2204
2.9920
5.0918
5.0457
5.0246
5.0036
4.9830
7.5314
7.2821
7.2645
7.2576
7.2522
7.2400
threo- configuration (see Figure 3.248 and 3.249).
170
1.5
1
160
150
140
130
120
13
110
100
(ppm)
90
80
70
60
50
40
30
20
Proving the constitution of compound 76f was made on the basis of IR, mass spectrum and
NMR analyses. The IR spectrum showed absorption bands at 3510, 3450, 1740, 1735, 1670
and 1605 cm-1 indicating the presence of OH, NH, COO, COO, CON and Ph groups,
respectively. The mass spectrum showed the base peak at m/z 187 due to retro aldol cleavage
and formation of 2,2-dimethylpropionylamino alanine methyl ester. As already mentioned
above, there are two striking differences in the 1H-NMR spectra between the threo- and
erythro- isomer: (a) the methoxy group resonates in the threo- isomer at a higher chemical
shift (δ = 2.99 ppm) than in the erythro- isomer which resonates at 3.78 ppm; (b) the methyl
group resonance in the threo- isomer appears at 1.73 ppm, while in the erythro- isomer this
resonance is shifted upfield to 0.96 ppm.
The 13C-NMR spectrum showed signals at δ 82.4, 91.8, 167.4, 170.6 and 174.9 ppm attributed
to C-2, C-3, CON, COO and COO groups, respectively (see Figure 3.250, 3.251, 3.252 and
3.253).
197
ButOCHN
CO 2CH 3
6.5
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.5
170
160
150
140
130
120
13
136.2503
127.8990
127.3056
126.2654
170.5786
167.3919
174.9447
1.4472
1.3762
1.7293
2.9881
7.5304
7.5138
7.5113
7.5064
7.2777
7.2758
7.2576
7.2513
7.2400
HO
CO 2CH 3
6.5
6.0
5.5
5.0
4.5
(ppm)
4.0
3.5
3.0
2.5
2.0
1.5
180
1
170
160
150
140
70
60
50
33.3901
27.9690
27.7273
27.5808
24.4967
40
30
CO2CH3
10.683
9.6740
3.0378
3.0000
7.0
80
threo (S*,S*)
3.9556
Integral
2.3816
7.5
90
CO2But
Ph
ButOCHN
threo (S*,S*)
8.0
100
(ppm)
CO 2But
Ph
ButOCHN
110
spectrum of erythro-76f.
spectrum of erythro-76f.
HO
52.4735
3.0277
1.0
1
27.9690
27.5954
21.5517
7.0
9.3912
9.2874
3.0000
3.6989
7.5
CO 2CH 3
erythro (S*,R*)
33.4267
8.0
CO 2But
91.8199
8.5
1.9261
Integral
erythro (S*,R*)
82.9998
80.8167
92.2521
135.0050
128.1847
127.7598
126.5071
173.3550
172.6151
168.6006
HO
51.7263
ButOCHN
Ph
CO 2But
83.6298
82.4137
Ph
HO
1.4477
1.3923
1.3762
1.3526
0.9613
3.7781
7.5838
7.5775
7.5564
7.5515
7.3492
7.3473
7.3291
7.3223
7.2400
___________________________________________________________________________
130
120
13
110
100
(ppm)
80
70
60
50
40
30
198
90
___________________________________________________________________________
3.10 Magnetic isotope effects on the diastereoselectivity of the triplet photocycloaddition
reactions
Studies of isotope effects are exceedingly important for our understanding of reaction
mechanism. Primary and secondary kinetic isotope effects (KIE) as well as equilibrium
isotope effects (EIE) are frequently discussed as central features. In recent years, spectacular
reinvestigation of numerous basic organic reactions have been performed by Singleton and
coworkers demonstrating the significance of kinetic isotope effects.134 Less often have isotope
effects been used in photochemical reactions,135 partly due to the larger diffculties in
determining reaction rate constants. Furthermore, photochemical reactions present an
additional degree of complexity, the appearance of different spin states which only slowly
interconvert. As already been stated by Turro and Kräuter in a seminal review in 1980,
difference in the nuclear–spin hyperfine coupling constants (HFC) might leads to substantial
differences in process where spin states are interchanging.136 This speculation has created a
new concept, spin chemistry as defined and described in several reviews by Buchachenko.137
In the first part of my dissertation, I have described spin chemistry effects in the
photocycloaddition reactions which were generated by spin-orbit coupling (SOC) phenomena
determining the geometries of triplet biradical intermediates when crossing into singlet
potential hypersurface.51 Spin-orbit coupling is thought to be the dominant factor for triplet
biradicals connected by short hydrocarbon chains as in tetramethylenes or in 2oxatetramethylenes. Additional effects may arise from HFC differences and manifest
themselves in substantial magnetic isotope effects (MIE).
To test the magnetic isotope effect (MIE) on the stereoselectivity of the [2+2] carbonyl-ene
photocycloaddition (Paternò-Büchi reaction), benzaldehyde-1-d, propanal-1d, and 5-d-2,3dihydrofuran were prepared in more than 96 % isomeric purity. These substrates are ideal for
this purpose because they bear a deuterium α- to carbonyl and / or double bond, which allow
estimation of a possible magnetic isotope effect.
3.10.1 Synthesis of starting materials
3.10.1.1 Synthesis of benzaldehyde-1-d
Benzaldehyde-1d was prepared in 60 % yield from benzil when treated with deuterium oxide
and potasium cyanide in p-dioxane following a literature procedure.138
199
___________________________________________________________________________
O
Ph
Ph
O
p-dioxane
+ D2O / KCN
Ph
D
O
77
Scheme 3.85: Synthesis of benzaldehyde-1d.
The structure assignment of compound 77 was based on NMR analyses and also on
129.5839
128.8660
126.5438
136.2283
136.1844
136.1331
134.3456
192.3286
191.9697
191.6180
7.6070
7.5872
7.5858
7.5837
7.5826
7.5814
7.5628
7.5581
7.5532
7.5096
7.5073
7.5050
7.5027
7.4982
7.4867
7.4822
7.4773
7.4723
7.4588
7.4540
7.4502
7.8545
7.8501
7.8484
7.8453
7.8408
7.8295
7.8270
7.8226
7.8177
comparsion with literature data (see Figure 3.254 and 3.255).
O
O
Ph
D
8.10
8.00
7.90
7.80
7.70
(ppm)
D
2.0092
1.0231
2.0000
Integral
Ph
7.60
7.50
7.40
7.30
7.20
190
180
170
160
150
13
140
130
(ppm)
120
110
100
90
80
70
spectrum of compound 77.
3.10.1.2 Synthesis of propanal-1-d
Propanal-1d was synthesized in higher than 96 % isomeric purity by a minor modification of
the Nef reaction139 with nitropropane-1,1-d2 which was prepared by H/D exchange of
nitropropane using deuterium oxide in the presence of sodium hydroxide as depicted in
Scheme 3.86.
NO2
D2O
+
NaOH
∆, 48h
D
D
NO2
78
D
D
(i) 10 % NaOH
NO2
(ii) H2SO4, 0-5°C
78
O
D
79
Scheme 3.86: Synthesis of propanal-1d.
The constitution of propanal-1-d was confirmed by spectroscopic analysis. The 1H-NMR
spectrum showed two signals, one appears as a triplet at 0.87 ppm and the other appears as a
quartet at 2.25 ppm, indicating the presence of ethyl group. In the 13C-NMR spectrum, there
200
___________________________________________________________________________
appeared three signals at 6.0, 37.0, and 202.8 ppm (triplet) attributed to CH3, CH2, and COD
O
O
1.8040
7.0
6.5
6.0
5.5
5.0
4.5
4.0
(ppm)
3.5
3.0
2.5
2.9078
D
Integral
D
7.5
6.0076
37.1712
37.1199
37.0760
203.1278
202.7835
202.4319
0.9089
0.8844
0.8467
2.2857
2.2612
2.2363
2.2118
group, respectively.
2.0
1.5
1.0
200
0.5
180
160
140
13
120
100
(ppm)
80
60
40
20
0
3.10.1.3 Synthesis of 5-deuterio-2,3-dihydrofuran
When 2,3-dihydrofuran 2 was allowed to react with n-butyllithium in n-hexane in the
presence of catalytic amounts of tetramethylethylenediamine (TMEDA) at room temperature,
5-litho-2,3-dihydrofuran was formed immediately, which upon quenching with deuterium
oxide afforded 5-deuterio-2,3-dihydrofuran 80 in good yield.140
+
n-Bu Li
O
TMEDA
n-hexane
D2O
O
Li
2
O
D
80
Scheme 3.85: Synthesis of 5-deuterio-2,3-dihydrofuran 80.
The constitution of compound 80 was established by NMR analyses and also by comparsion
with the literature data. The
13
C-NMR spectrum of compound 80 displays a triplet signal
down-field shifted for C-5 and confirmed the attachment of C-5 to a deuterium atom. In the
1
H-NMR spectrum the disappearance of the H-5 signal proved complete deuteration (see
Figure 3.258 & 3.259).
201
6.0
5.6
5.2
4.8
(ppm)
57.7407
69.4838
99.2555
99.2262
99.1969
D
2.1380
1.0000
6.4
2.0984
O
Integral
6.8
146.0155
145.6272
145.2463
D
O
7.2
2.6266
2.6188
2.5948
2.5864
2.5629
2.5551
4.3198
4.2880
4.2562
4.9340
4.9257
4.9179
___________________________________________________________________________
4.4
4.0
3.6
3.2
2.8
145
140
135
130
125
120
115
110
105
100
(ppm)
95
90
85
80
75
70
65
60
1
1
Figure 3.258: H-NMR (300 MHz, CDCl3) Figure 3.258: H-NMR (300 MHz, CDCl3)
3.10.1.4 Synthesis of 1-trimethylsilyloxy cycloalkenes
Treatment of cyclic ketones (cyclopentanone, cyclohexanone, cycloheptanone) with the
trimethylchlorosilane-sodium iodide-triethylamine reagent in acetonitrile was a convenient
method for the preparation of 1-trimethylsilyloxycycloalkenes in excellent yields as depicted
in Scheme 3.88.141, 142, 143, 144
O
OTMS
Me3SiCl, NaI, Et3N, MeCN
n
n
n = 1,2, 3
81, n = 1
82, n = 2
83, n = 3
Scheme 3.88: Synthesis of 1-trimethylsilyloxy cycloalkenes 81-83.
Table 3.47: Characteristic properties of 1-trimethylsilyloxy cycloalkenes 81-83.
Compound
1
H-NMR[a]
13
C-NMR[b]
B.p10 torr (°C)
Yield (%)
83
4.58
154.9
55-57
75
84
4.98
150.2
78-80
82
85
4.82
155.9
78-81
85
[a] chemical shift of CH= in ppm, [b] chemical shift of C-1 in ppm.
The constitutions of compounds 81-83 were confirmed by NMR analyses. For example, the
1
H-NMR spectrum of compound 82 showed a down-field shifted signal at 4.82 ppm attributed
to the olefinic proton. In addition, there appeared a singlet upfield shifted at 0.14 ppm
characteristic for the trimethylsilyl group. In the
202
13
C-NMR spectrum, the olefinic carbons
___________________________________________________________________________
appear at 104.1 and 150.3 ppm corresponding to C-2 and C-1, respectively (see Figure 3.260
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
(ppm)
3.0
2.5
2.0
1.5
8.9832
2.1078
2.2107
4.2104
OTMS
1.0000
Integral
OTMS
0.2632
0.2412
29.8664
23.7714
23.1414
22.3209
104.1051
150.2571
0.1409
1.6412
1.6216
1.6113
1.6030
1.4923
1.4849
1.4727
1.4648
1.4546
1.9777
1.9713
1.9649
1.9610
1.9576
1.9527
4.8385
4.8341
4.8302
4.8258
4.8214
4.8170
4.8126
and 3.261).
1.0
0.5
140
120
100
13
80
(ppm)
60
40
20
0
3.10.2 Photoreactions of benzaldehyde and benzaldehyde-1-d with cyclic alkenes
In order to evaluate isotope effects on the diastereoselectivity of “pure” triplet
photocycloadditions, benzaldehyde and benzaldehyde-1-d were used as carbonyl substrates.
These carbonyl substrates have high intersystem crossing rates (ISC) (for benzaldehyde, kISC
≅ 1011 sec-1 and ∆EST = 4 kcal/mol) which excludes singlet reactivity.145 As olefinic reaction
partners two sets of cycloalkenes were employed: unsubstituted cycloalkenes (2,3dihydrofuran, 5-deuterio-2,3-dihydrofuran, cyclopentene, cyclohexene) and substituted
cycloalkenes
(5-methyl-2,3-dihydrofuran,
1-methylcyclohexene,
1-trimethylsilyloxy-
cyclopentene, 1-trimethylsilyloxycyclohexene, 1-trimethylsilyloxycycloheptene). Photolysis
of benzaldehyde as well as benzaldehyde-1-d with substituted and unsubstituted cycloalkenes
in benzene gave mixtures of two diastereoisomers as depicted in Scheme 3.89.
H
O
+
X
R
Ph
R1
hν
benzene
1
R = H, D
H
O
O
R1
X
R
Ph
endo-84a-r
+
R1
X
R
Ph
exo-84a-r
Scheme 3.89: Photoreaction of benzaldehyde and benzaldehyde-1-d with cyclic alkenes.
The exo/endo diastereomeric ratios of the photoadducts 84a-r were determined by 1H-NMR
and GC analyses, for reactions with benzaldehyde-1-d additionally by 2H-NMR analysis. The
results are presented in Table 3.48.
203
___________________________________________________________________________
Table 3.48: Simple diastereoselectivity of the photocycloaddition of benzaldehyde and
benzaldehyde-1-d with cyclic alkenes.
Entry
Compound
X=
R=
R1 =
d.r.
(endo : exo)[a]
A
84a
O
H
H
82 : 18
B
84b
O
H
D
93 : 07
C
84c
O
D
H
89 : 11
D
84d
O
D
D
90 : 10
E
84e
O
Me
H
65 : 35
F
84f
O
Me
D
67 : 33
G
84g
CH2
H
H
61 : 39
H
84h
CH2
H
D
87 : 13
I
84i
(CH2)2
H
H
74 : 26
J
84j
(CH2)2
H
D
85 : 15
K
84k
(CH2)2
Me
H
67 : 33
L
84l
(CH2)2
Me
D
75 : 25
M
84m
CH2
OTMS
H
60 : 40
N
84n
CH2
OTMS
D
63 : 37
O
84o
(CH2)2
OTMS
H
80 : 20
P
84p
(CH2)2
OTMS
D
83 : 17
Q
84q
(CH2)3
OTMS
H
60 : 40
R
84r
(CH2)3
OTMS
D
70 : 30
[a] based on integration of the characteristic signals in the 1NMR spectra of the crude reaction
mixture and also on the GC analysis.
In agreement with literature results, the endo-selectivity of the triplet Paternò-Büchi reaction
of benzaldehyde and benzaldehyde-1-d with substituted cycloalkenes was moderate and high
with unsubstituted cycloalkenes (see Table 3.48, entry A, E).
The comparsion between benzaldehyde with benzaldehyde-1-d photoadducts revealed that:
(a) the endo-selectivity increases when the reaction partner contains deuterium;
(b) from the four possible combinations of benzaldehyde/2,3-dihydrofuran (entry A, B, C &
D), the endo-selectivity of benzaldehyde-1-d/2,3-dihydrofuran was the highest one;
204
___________________________________________________________________________
(c) the endo/exo-selectivity of the benzaldehyde-1-d/cyclopentene photoadduct increases by a
factor of 4.2 in comparsion with the benzaldehyde/cyclopentene photoadduct (see entry H &
I);
(d) the same trend appeared in the substituted cycloalkene series; the diastereoselectivity
(favoring the endo-photoadduct) increases with benzaldehyde-1-d compared to benzaldehyde.
The structure determination of the deuterated photoadducts were based on NMR analyses and
mass spectrometry. For example, Figure 3.262A displays 1H-NMR traces of H-7, H-5 and H1 for benzaldehyde/2,3-dihydrofuran photoadduct (top) versus benzaldehyde-1-d/2,3dihydrofuran photoadduct (bottom). In the bottom spectrum, one can clearly see the
disappearance of H-7 signal at 5.72 ppm and the appearance of H-1 at 4.95 ppm as a doublet
which confirmed again the regioselectivity.
H
5 O
7 H
1
O
H
H
5 O
7 H
1
+
O
Ph
H
endo-H1
Ph
endo-H1
endo-H7
endo-H5
exo-H5 exo-H7
exo-H5
endo-H1
H
H
5 O
7 D
1
endo-H5
5.70
5.60
5.50
O
5.40
H
5.30
5 O
7 D
1
+
O
Ph
5.20
H
5.10
endo-H1
Ph
5.00
5.12
5.08
(ppm)
5.04
5.00
4.96
4.92
4.88
4.84
(ppm)
Figure 3.262A: 1H-NMR spectra of 84a & Figure 3.262B: 1H-NMR spectra of H-1 for
84b.
84a & 84b.
There are two main differences in the 1H-NMR spectra of benzaldehyde/2,3-dihydrofuran and
benzaldehyde/5-deuterio-2,3-dihydrofuran photoadducts:
(1) in the bottom spectrum, H-7 appears as singlet and H-5 as doublet whereas in the top
spectrum H-7 appears as doublet and H-5 appears as a doublet of doublet; (2) the
disappearance of the H-1 signal in the bottom spectrum confirmed again the regioselectivity
(see Figures 3.263A & 3.263B).
205
___________________________________________________________________________
H
5 O
7 H
1
O
endo-H7
H
5 O
7 H
1
+
O
Ph
H
endo-H7
Ph
H
endo-H1
endo-H5
exo-H5 exo-H7
exo-H5
exo-H7
H
O
endo-H7
5.70
5.60
5.50
H
5 O
7 H
1
endo-H5
5.40
5.30
O
Ph
D
5 O
1 7 H
+
5.20
5.10
D
Ph
endo-H7
5.00
4.90
5.78
5.76
5.74
(ppm)
5.72
5.70
5.68
5.66
(ppm)
84a & 84c.
84c.
Figures 3.264A & 3.264B display the 1H-NMR spectra of benzaldehyde-1-d/5-deuterio-2,3dihydrofuran photoadducts. As can be seen in the bottom spectrum, the disappearance of both
the H-7 and H-1 signals and the appearance of the H-5 signal as doublet reveal the correct
regiochemistry.
H
5 O
7 H
1
O
H
endo-H5
H
5 O
7 H
1
+
O
Ph
H
Ph
endo-H5
endo-H1
exo-H5
endo-H7
exo-H5 exo-H7
exo-H5
exo-H5
H
H
5 O
1 7 D
O
endo-H5
D
5 O
1 7 D
+
O
Ph
D
Ph
endo-H5
5.70
5.60
5.50
5.40
5.30
5.20
5.10
5.00
5.48
(ppm)
5.46
5.44
5.42
5.40
5.38
5.36
(ppm)
84d.
84a & 84d.
In order to obtain further information on kinetic isotope effects, the reactivity differences
between benzaldehyde and benzaldehyde-1-d competing for the 2,3-dihydrofuran was
determined. The kH/kD values from 1H-NMR analyses for competition reactions with initial
concentrations of 1 : 1 : 1 and 2 : 2 : 1 for benzaldehyde : benzaldehyde-1d : 2,3-dihydrofuran
were 1.05 and 1.1, respectively. Thus, benzaldehyde-1-d is only slightly less reactive with
2,3-dihydrofuran than benzaldehyde, but gives significantly higher diastereomeric ratios. The
effect on kH/kD might also be due to the reduced triplet benzaldehyde lifetimes. An alternative
206
___________________________________________________________________________
explanation is an amplification of the cleavage channel from the intermediate 1,4-biradical.
The quantum yield for the photocycloaddition of benzaldehyde to 2,3-dihydrofuran was
estimated as 0.45.146 Thus, the cleavage channel can compete with product formation with
similar probability in the non-deuterated case.
3.10.3 Photoreactions of propanal and propanal-1-d with 2,3-dihydrofuran and 5deuterio-2,3-dihydrofuran
In order to obtain more evidence for magnetic isotope effects (MIE), the concentration
dependence of the [2+2] photocycloaddition of propanal and propanal-1d with 2,3dihydrofuran as well as 5-deuterio-2,3-dihydrofuran was investigated. This unlabelled
combination (propanal/2,3-dihydrofuran) was used primarily to determine the different in
simple diastereoselectivities of singlet and triplet photocycloadditions.146
The addition of 2,3-dihydrofuran or 5-deuterio-2,3-dihydrofuran to electronically excited
propanal-1-d in hexane at a wide range of substrate concentrations afforded two
diastereoisomers. The endo/exo diastereomeric ratios of the photoadducts were strongly
influenced by the concentration of substrates. The diastereomeric ratios of the photoadducts
were determined by GC and 1H-NMR analyses.
Et
hν
O
Et
H
+
EtCHO
1c
O
H
O
O
O
endo-3c
exo-3c
2
Et
hν
D
O
Et
+
EtCDO
81
O
D
O
O
O
endo-85
exo-85
2
Et
hν
EtCHO
1c
O
H
D
O
O
D
H
+
endo-86
O
Et
O
D
exo-86
82
Et
hν
D
O
Et
+
EtCDO
81
O
D
O
O
82
D
endo-87
D
O
D
exo-87
Scheme 3.90: Photocycloaddition reactions of propanal, propanal-1d with 2,3-dihydrofuran
and 5-deuterio-2,3-dihydrofuran in n-hexane.
207
___________________________________________________________________________
Table 3.49: Concentration dependence of the simple diastereoselectivity of the
photocycloaddition reactions of propanal and propanal-1-d with 2,3-dihydrofuran as well as
5-deuterio-2,3-dihydrofuran in hexane.
Conc. (M)
[a]
d.r.(endo : exo)[a] d.r.(endo : exo)[b] d.r.(endo : exo)[c] d.r.(endo : exo)[d]
1
47.3 : 52.7
46.1 : 53.9
46.9 : 53.1
45.2 : 54.8
0.5
50.2 : 49.8
49.9 : 50.1
50.9 : 49.9
48.3 : 51.7
0.25
54.9 : 45.1
55.1 : 44.9
55.8 : 44.2
53.2 : 46.8
0.125
60.4 : 39.6
60.2 : 39.8
61.4 : 38.6
57.6 : 42.4
0.1
62.8 : 37.2
60.7 : 39.3
62.9 : 37.1
60.3 : 39.7
0.05
64.3 : 35.7
67.8 : 32.2
67.1 : 32.9
66.7 : 33.3
0.025
66.3 : 33.7
70.1 : 29.9
70.3 : 29.7
66.9 : 33.1
0.0125
69.2 : 30.8
73.5 : 26.5
71.4 : 28.6
72.9 : 27.1
simple diastereoselectivity of propanal/2,3-dihydrofuran photocycloaddition reaction determined by 1H-NMR
analysis, [b] simple diastereoselectivity of propanal-1-d/2,3-dihydrofuran photocycloaddition reaction determined
by 1H-NMR analysis,
[c]
simple diastereoselectivity of propanal/5-deuterio-2,3-dihydrofuran photocycloaddition
reaction determined by
1
H-NMR analysis,
[d]
simple diastereoselectivity of propanal-1-d/5-deuterio-2,3-
dihydrofuran photocycloaddition reaction determined by 1H-NMR analysis.
As can be seen from Table 3.49, in all combinations, at higher concentration, the endo/exo
selectivity levels oft around 46 : 54 whereas at lower concentration, the selectivity reached a
maximum value of 74 : 26 with preferential formation of the endo-diastereoisomer.
Comparing the endo/exo selectivity of propanal-1-d/2,3-dihydrofuran, propanal/5-deuterio2,3-dihydrofuran
and
propanal-1-d/5-deuterio-2,3-dihydrofuran
photoadducts
with
propanal/2,3-dihydrofuran photoadducts showed that the selectivity of the singlet reaction is
the same for all combinations whereas the triplet reaction gave higher endo-selectivities when
one or two reaction partners bear a deuterium atom.
In the triplet region (low substrate concentration), a similar isotope effect on the endo/exoratio
was
determined
for
the
5-deuterio-2,3-dihydrofuran/propanal
and
the
2,3-
dihydrofuran/propanal-1-d combinations (Figure 3.265). An average isotope selectivity effect
of 1.2 resulted for both reactions at 0.01M. These results orginate from several factors, all in
connection with intersystem crossing processes: ISC-rates are reduced and thus singlet as well
as triplet lifetimes are increased. This effect seems to be balanced out for the 2,3dihydrofuran/propanal reaction: the inversion regions are nearly identical for all
combinations.
208
___________________________________________________________________________
72
70
endo-selectivity (% )
68
66
64
62
60
58
56
54
52
propanal + 2,3-dihydrofuran
propanal + 5-d-2,3-dihydrofuran
propanal-1-d + 2,3-dihydrofuran
50
48
46
0,01
0,1
1
log [dihydrofuran]
Figure 3.265: Concentration / selectivity profiles for the photocycloaddition of propanal with
2,3-dihydrofuran and deuterated substrate combination.
The stereochemistry of all deuterated photoadducts was confirmed via NOE spectroscopy for
the exo-stereoisomers. A common feature of the NOE measurements was the enhancement of
oxetane ring hydrogen (H-5) resonances following saturation of the methyl group.
D
O
5
O
O
H
5
H
1 H
O
exo-85
O
D
5
H
O
1 D
H
1 D
exo-87
exo-86
Figure 3.266: NOE interactions of the deuterated exo-diastereoisomers.
The structure assignments of the bicyclic oxetanes were based on the NMR analyses. Table
3.50 summerizes the characteristic signals of all possible photoadducts.
Table 3.50: Characteristic 1H-NMR and 13C-NMR signals of compounds 3c, 85, 86, 87.
Compound
H-7
H-5
H-1
C-7
C-5
C-1
exo-3c
4.19
5.17
4.42
88.3
84.2
80.7
endo-3c
4.50
5.22
4.66
86.4
84.1
78.6
exo-85
-
5.15
4.41
87.5
84.0
80.4
endo-85
-
5.22
4.64
85.7
83.8
78.3
exo-86
4.24
5.19
-
88.2
84.2
80.4
endo-86
4.53
5.27
-
86.4
84.0
78.3
exo-87
-
5.14
-
87.6
84.1
80.2
endo-87
-
5.22
-
85.8
83.9
78.1
209
5 6.
5 2.
4 8.
4 4.
4 0.
+
Et
O
H
O
D
3 6.
H
O
3 2.
2 8.
(p p m)
2 4.
spectrum of exo & endo-86.
O
2 0.
1 6.
1 2.
0 8.
0 4.
0 8.
210
90
90
85
85
80
80
70
75
75
65
70
70
60
1
65
65
55
13
Et
13
60
Et
Et
O
60
13
55
55
50
45
(p p m)
Et
O
H
D
50
45
(p p m)
40
O
50
45
(p p m)
40
40
35
H
O
35
30
O
D
35
O
30
25
D
O
30
25
25
20
20
8 .0 5 7 8
7 .6 5 4 9
O
2 1 .9 0 3 4
2 .7 8 3 4
2 .7 8 7 8
+
O
2 6 .5 4 7 9
75
3 3 .0 4 5 8
3 2 .4 7 4 4
80
6 6 .6 8 5 4
85
6 9 .4 2 5 2
90
H
8 .4 9 0 0
8 .0 7 9 8
1 2.
0 8.
8 0 .2 4 5 3
7 8 .1 6 4 8
spectrum of exo- & endo-3c.
8 7 .3 9 5 2
8 7 .0 8 7 5
8 5 .9 0 0 7
8 5 .6 0 0 4
8 5 .3 0 7 4
8 3 .8 7 1 5
8 3 .7 1 7 7
1 2.
O
H
2 2 .3 7 2 2
1 6.
1 .1 0 3 5
Et
2 7 .0 1 6 7
2 0.
6 .0 1 9 4
O
3 3 .4 0 4 7
3 2 .8 4 0 6
2 4.
Et
6 7 .1 4 6 9
3 2.
2 8.
(p p m)
1 6.
6 9 .8 8 6 7
3 6.
O
2 0.
8 0 .7 5 0 8
7 8 .6 7 0 3
4 0.
D
2 4.
8 8 .2 4 5 0
8 6 .4 2 8 2
8 4 .2 0 8 5
8 4 .0 4 7 3
O
2 8.
8 .5 4 7 1
O
D
3 2.
(p p m)
1 2 .0 9 1
3 6.
2 .0 6 9 1
0 .4 0 0 3
O
O
0 .4 1 9 5
4 0.
H
5 .8 0 0 2
1 .8 9 3 4
1 .8 7 6 7
1 .8 4 9 8
1 .8 4 7 8
1 .8 3 1 2
1 .8 1 3 5
1 .8 1 1 1
1 .4 8 1 9
1 .4 6 0 4
1 .4 5 5 0
1 .4 2 2 7
1 .4 0 1 6
1 .3 9 5 7
0 .7 5 4 6
0 .7 3 0 1
0 .7 0 5 1
0 .6 6 9 4
0 .6 4 4 4
0 .6 1 9 4
5 .4 9 3 1
0 .9 9 0 1
0 .9 2 3 8
0 .9 4 4 5
1 .0 0 0 0
0 .9 7 2 2
In teg ra l
O
H
5 .4 5 1 1
4 4.
2 .1 2 8 7
Et
4 .5 4 4 6
5 .1 3 0 0
5 .1 1 6 7
5 .1 0 4 5
5 .0 5 2 1
5 .0 3 8 4
5 .0 2 4 2
4 .5 3 0 9
4 .5 1 8 7
4 .2 9 6 8
4 .2 8 3 1
4 .0 5 0 9
4 .0 4 8 0
4 .0 3 8 7
4 .0 1 1 3
3 .9 9 0 7
3 .9 7 3 5
3 .9 5 3 0
3 .9 3 5 8
Et
1 .3 1 4 4
4 8.
1 .0 9 8 8
0 .9 4 2 9
1 .0 0 0 0
1 .1 2 3 4
In teg ra l
4 4.
2 .0 5 6 5
2 .0 3 9 3
2 .0 2 0 7
2 .0 1 0 9
1 .9 9 3 8
1 .9 7 7 6
1 .9 7 5 2
1 .6 0 7 8
1 .6 0 1 9
1 .5 8 3 3
1 .5 7 5 5
1 .5 7 1 1
1 .5 5 0 5
1 .5 4 7 6
1 .0 6 0 7
1 .0 5 8 8
0 .9 0 5 0
0 .8 8 0 0
0 .8 5 5 5
0 .8 2 2 2
0 .7 9 7 2
0 .7 7 2 2
5 2.
4 8.
0 .6 3 9 4
5 6.
5 2.
5 .1 6 2 0
5 .2 8 2 8
5 .2 6 9 5
5 .2 0 3 4
5 .1 8 9 2
4 .5 6 6 7
4 .5 4 2 2
4 .5 1 7 7
4 .2 4 7 8
4 .2 1 5 5
4 .2 1 2 1
4 .2 0 3 3
4 .1 8 7 1
4 .1 8 4 2
4 .1 7 5 8
4 .1 1 6 1
5 6.
1 .0 1 9 0
In teg ra l
1 .0 0 0 0
0 .7 8 1 7
8 .2 7 7 5
7 .8 7 4 6
2 2 .1 8 9 1
2 6 .8 5 5 5
3 3 .2 1 4 2
3 2 .6 4 2 8
6 6 .9 1 2 5
6 9 .6 5 9 6
8 0 .5 3 8 3
7 8 .4 5 7 8
8 8 .1 3 5 1
8 6 .3 2 5 6
8 4 .1 1 3 3
8 3 .9 5 2 1
2 .1 8 2 4
2 .1 7 3 5
2 .1 5 7 4
2 .1 4 8 6
1 .9 5 7 1
1 .9 1 1 5
1 .5 5 3 0
1 .5 2 7 0
1 .5 2 0 2
1 .4 9 4 7
1 .4 8 9 3
1 .4 6 9 7
1 .4 6 6 3
0 .8 2 6 6
0 .8 0 2 1
0 .7 7 7 1
0 .7 4 2 8
0 .7 1 7 9
0 .6 9 2 9
5 .2 0 0 0
5 .1 8 7 3
5 .1 3 4 4
5 .1 2 0 2
5 .1 0 6 4
4 .6 2 0 6
4 .6 0 8 3
4 .5 9 5 1
4 .4 7 0 7
4 .4 5 7 5
4 .3 8 0 6
4 .3 7 2 2
4 .3 6 6 9
4 .3 5 8 5
4 .1 2 8 3
4 .1 1 8 5
4 .0 9 0 6
4 .0 3 1 8
___________________________________________________________________________
+
Et
O
20
15
15
15
10
spectrum of exo- & endo-3c.
+
Et
+
O
O
10
10
5
+
Et
D
D
5
O
D
Et
O
D
O
D
Et
Et
4 4.
4 0.
3 6.
3 2.
(p p m)
2 8.
2 4.
2 0.
1 6.
O
8 .3 4 3 5
7 .9 3 3 2
D
1 1 .9 1 9
6 .4 0 1 2
4 8.
D
O
D
2 .2 4 3 8
5 2.
O
4 .6 3 6 9
1 .0 0 0 0
1 .0 7 0 2
In teg ra l
5 6.
Et
+
D
O
O
D
+
2 2 .4 0 8 8
2 2 .1 7 4 4
3 3 .3 2 4 1
3 2 .7 6 0 1
6 7 .0 0 0 4
6 9 .7 3 2 9
7 8 .4 5 0 5
7 8 .1 3 5 5
7 7 .8 0 5 8
8 7 .5 9 3 0
8 7 .2 9 2 6
8 6 .2 5 9 7
8 5 .7 9 0 9
8 5 .4 9 7 8
8 4 .0 4 0 0
8 3 .8 8 6 2
2 .0 0 3 1
1 .9 8 7 9
1 .9 8 6 0
1 .9 6 7 3
1 .9 5 9 5
1 .9 5 7 5
1 .9 5 5 1
1 .9 4 0 4
1 .9 2 4 2
1 .9 2 1 8
1 .5 8 9 2
1 .5 8 6 3
1 .5 6 6 7
1 .5 6 2 3
1 .5 4 3 7
1 .5 3 5 3
1 .5 2 9 5
1 .5 0 7 4
0 .8 5 7 9
0 .8 3 3 0
0 .8 0 8 5
0 .7 7 3 7
0 .7 4 8 7
0 .7 2 3 7
5 .2 2 5 0
5 .2 1 1 8
5 .1 4 6 1
5 .1 3 2 9
4 .1 6 1 1
4 .1 5 8 2
4 .1 5 0 4
4 .1 4 9 4
4 .1 4 6 4
4 .1 3 3 2
4 .1 3 0 3
4 .1 2 2 0
4 .1 2 1 0
4 .1 0 2 9
4 .0 8 5 7
4 .0 6 6 1
4 .0 6 4 6
4 .0 4 8 0
___________________________________________________________________________
1 2.
0 8.
90
85
80
75
70
65
60
13
55
50
(p p m)
45
40
35
30
25
20
15
10
The formation of the thermodynamically unfavored endo-products in the triplet
photocycloaddition of a carbonyl to a cyclic alkene was rationalized by assuming spin-orbit
coupling (SOC) controlled intersystem crossing (ISC) geometries at the stage of triplet 1,4biradical.42 Figure 3.275 shows the triplet 1,4-biradical conformer with all possible three spinorbit coupling-active geometries.
RCDO
*
O
H
R
O
3
O
D
O
O
R
D
H
R
D
R
O
O
O
O
H
R
A
D
O
O
H
B
endo
D
cleavage
H
C
exo
Figure 3.275: Conformers of 1,4-biradical intermediates.
The significant increase in endo-selectivity of the deuterated benzaldehyde/2,3-dihydrofuranphotoadducts can be explained as follows: If the radical centers in the triplet biradicals are
separated by distance of several Å or more (like in conformer B), the singlet (S)-triplet (T)
energy gap ∆EST decreases and intersystem crossing (ISC) is more strongly controlled by the
weak hyperfine coupling (HFC) induced by nuclear-electron-spin interactions which are
isotope dependent.
211
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As easily recognized from the gyromagnetic ratios of 1H and 2H, hyperfine coupling is
stronger by a factor of 6 for 1H than for 2H interaction with adjacent carbon radical. Thus,
HFC-induced ISC is more relevant for
1
H-substituted radicals and consequently the
alternative (strong) SOC-mechanism is expected to dominate for 2H-substituted biradicals. As
the endo-selectivity was interpreted (vide supra) as a mechanistic signature for SOCmechanism, it appears logical, that endo-selectivity increases for 2H-substituted 1,4-biradicals.
Basically one has to assume, that the triplet 1,4-biradical lifetime is decreased when going
from deuterated to non-deuterated intermediates, and this expectation has been also
revealed.136
It was reported that the effect of deuterium substitution on the singlet and triplet lifetimes of
carbonyl compounds in the vapor phase is dramatic. For example, the fluorescence quantum
yield of formaldehyde147 increases by a factor of about 20 upon going from CH2=O to
CD2=O. The effect of deutration on acetone lifetime148 is less apparent (τs acetone –h6 is 1.7
ns, acetone-d6 is 2.3 ns) but nonetheless significant. The substitution of D for H decreases the
magnitude of kISC or IC. It is not yet clear whether a spin-orbit or Franck-Condon inhibition is
involved
The lifetime of triplet propanal-1-d 149 is increased in comparsion with undeuterated propanal
in vapor phase by a factor of 4.4. Thus, one should expect the rate of ISC from T1 to S1 will
be decreased on going from propanal to propanal-1-d. However, our experiment did not at all
visualize this effect, i.e. the endo-selectivity of “pure” triplet propanal-1d photoaddition was
higher than for the propanal/2,3-dihydrofuran reaction. The results of propanal1d/dihydrofuran photocycloaddition supported the results of benzaldehyde-1-d/cycloalkene
photocycloaddition and may shed some light on the role of SOC and HFC on ISC.
212
4. Experimental part
___________________________________________________________________________
4.1 General Remarks
Spectroscopic methods:
UV/VIS: Electronic spectra were recorded in acetonitrile unless otherwise stated, using a PerkinElmer Lambda 7 spectrophotometer and are listed as absorbance maxima (nm) followed by the
extinction coefficient ε (cm-1 M-1 ).
IR: Infrared spectra were recorded as KBr or CsI disc for solids or as neat films between sodium
chloride plates for liquids using a Perkin-Elmer 1600 Series FTIR spectrophotometer.
1
H-NMR: The 1 H-NMR spectra were recorded on a Brucker AC 300 (300 MHz) spectrometer.
The
1
H NMR chemical shifts are reported in δ ppm using residual CHCl3 (δ 7.24) in the
perdeuterated solvent as the internal standard. Multiplicities were reported as s (singlet), d
(doublet), t (triplet), q (quartet), and m (multiplet). Coupling constants J are given in Hz.
13
C-NMR: The
13
13
C NMR chemical shifts are reported in δ ppm relative to the internal standard CDCl3 (δ 77).
C-NMR spectra were recorded on Brucker AC 300 (75.5 MHz) spectrometer.
Carbon multiplicities were determined by distortionless enhancement by polarization transfer
(DEPT).
MS: Mass spectra were recorded using Finnigan Incos 500 instrument using positive ion electron
impact (EI) techniques at 20 and 70 eV. Ions are quoted as an m/z value followed by intensity
(%).
HRMS: High resolution mass spectra were recorded on a Finnigan MAT H-SQ 30 (FAB)
spectrometer.
Chromatographic methods:
CC: Column chromatography was performed using SiO 2 60 (0.063 – 0.200 mm) as stationary
phase. As a mobile phase, a mixture of n-hexane and ethyl acetate were used.
213
___________________________________________________________________________
TLC: Thin layer chromatography was conducted on commercially precoated polygram SIL –
G/UV 254 plates (Macherey – Nagel) and also on precoated silica gel foils 60 F254 supplied by
Merck and the chromatograms were visulized under a 254 nm UV lamp and / or with 5 % I2
solution.
PLC: Preparative thick layer chromatography was carried out on 20 x 20 cm glass plates coated
with silica gel (Merck Kieselgel G F254 ) and eluted with the solvent system indicated. The
separated compounds were located under 254 nm UV light and extracted using methylene
chloride.
GC: Gas chromatography was performed on a Hewlett-Packard 5890 Series II instrument
equipped with a capillary HP-5 cross-linked phenylmethylpolysiloxane (30 m x 0.32 mm)
column, connected to FI- Detector and a HP 3395 calculating integrator, temperature program,
60-250°C in 20°C/min steps (1 min initial time), N2 was used as flow gas.
Analytical methods:
X-ray analysis: The X – ray anaylsis was performed on an Enraf-Nonius CAD4 diffractometer
at the Institute of Organic Chemistry-University of Cologne.
Elemental analysis: Combustion analyses were conducted at a Elementar Vario El. Instrument.
Melting points (M.p °C): All melting points were determined with a Büchi melting point
apparatus (type Nr. 535) and are uncorrected.
Photolyses:
Glas apparatus: Quartz and pyrex vessel were used for irradiation.
Reactors: Rayonet chamber photoreactors PRR- 208 (8 x 3000 Å lamps, ca. 800 W, λ = 300 ±
10 nm), RPR – 100 (16 x 3500 Å lamps, ca. 400 W, λ = 350 ± 20 nm) were used for irradiation
and high pressure mercury lamp(λ > 290 nm).
214
___________________________________________________________________________
Solvent and Reagents: Benzene was purchased from Fluka and used without purification. All
reagents were purchased from standard chemical supplies and purified to match the reported
physical and spectral data.
Solvent and Reagents:
Solvents were dried by distillation over drying agents as follows: acetonitrile (P2 O5 ),
dichloromethane, chloroform, dimethyl formamide and pentane (CaH2 ), diethylether, THF (Na /
benzophenone), methanol, ethanol, propanol (Mg), pyridine and triethyl amine (KOH).
Conversion and Yield (%):
The conversion and yield % were determined by integration of characteristic signals in the crude
1
NMR spectra with an approx. error ± 5%.
Nomenclature:
All new compounds were named according to the Autonom program. 150
4.2 General procedure for the photolyses of aldehydes and alkenes on the analytical scale:
(Concentration study):
The mechanistic studies of carbonyl-ene photoreaction including concentration effect were
carried out on a merry-go-round apparatus. This equipment consists of a rotating turntable
having nine holes in an inner ring surrounding a quartz immersion well. The light source was a
high pressure mercury lamp. Use of the merry-go-round apparatus ensured that all the samples
recieve the same light quantity. The quartz tubes that were used were of a uniform quality, the
samples to be irradiated always contained the same concentration of both aldehydes and alkenes
so that equal light quantity were absorbed by all samples in any given run. Samples were made
up in 10 mL volumetric flasks, then transfered to the tubes which were deoxygenated using N2 ,
corked and placed in the merry-go-round for irradiation at 10°C for 10 h. After photolysis the
samples were analysed by GC and spectroscopic data. There are several common features in the
spectral data of these bicyclic oxetane products. In the IR spectra, the two asymmetric C-O-C
stretching bands of the oxetane ring are at ≅ 980 and 1030 cm-1 .151 In the mass spectrum, retrocycloaddition leads to the cation-radical peak for the carbonyl compound.
215
___________________________________________________________________________
4.2.1 General procedure for the photolyses of aldehydes and alkenes on the preparative
scale:
Alkenes (5 mmol) and aldehydes (5 mmol) were dissolved in 100 mL benzene, the solution
transfered to a vacum – jacket pyrex tube and deoxygenated with a steady stream of N2 gas. The
reaction mixture was cooled to 10°C by means of a cold finger and irradiated in a Rayonet
photoreactor (RPR 300 nm). The solvent was evaporated (40 °C, 20 torr) and the residue was
purified by bulb-to-bulb distillation.
4.2.1.1 Photolyses of 2,3-dihydrofuran with aldehydes 1a-f:
Irradiation of 2,3-dihydrofuran with benzaldehyde (sbo-157)
A solution of 2,3-dihydrofuran (0.35 g, 5 mmol) and benzaldehyde (0.53 g, 5 mmol) in 100 mL
benzene was irradiated for 24 h according to the above general procedure. Distillation of the
residue after evaporation of the solvent afforded 0.76 g (86 %) of inseparable mixture of
oxetanes as a pale yellow viscous oil.
endo-7-Phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-3a)152
H
5 O
1 7
4
3
O
Ph
H
IR: (Nujol, mixture of endo & exo)
ν~ (cm-1 ) = 3020, 2920, 1605, 1505, 1470, 1400, 1050, 835, 778.
1
H-NMR: (300 MHz, CDCl3 )
δ ppm = 1.64 (ddd, J = 8.4, 11.2, 13.4 Hz, 1H, 4-H), 2.12 (dd, J = 5.4, 13.7 Hz, 1H, 4-H),
3.73 (ddd, J = 5.4, 8.6, 11.2 Hz, 1H, 3-H), 3.97 (dd, J = 8.4, 8.6 Hz, 1H, 3-H), 5.05 (dd,
J = 4.5, 4.5 Hz, 1H, 1-H), 5.51 (dd, J = 4.5, 4.5 Hz, 1H, 5-H), 5.80 (d, J = 4.5 Hz, 1H,
7-H), 7.15-7.35 (m, 5H, Harom.).
13
C-NMR: (75.5 MHz, CDCl3 )
δ ppm = 32.9 (t, C-4), 69.0 (t, C-3), 79.7 (d, C-1), 85.2 (d, C-5), 85.3 (d, C-7), 124.6 (d,
CHarom.), 127.0 (d, CHarom.), 127.8 (d, CHarom.), 137.6 (s, Cqarom.).
MS: (EI, 20 eV)
m/z (%) = 176 (M+, 27), 120 (40), 105 (20), 104 (25), 91 (100), 77 (20), 70 (20).
216
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exo-7-Phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-3a)152
H
O
Ph
O
1
H
δ ppm = 1.77 (dddd, J = 4.2, 8.8, 10.8, 13.7 Hz, 1H, 4-H), 2.24 (dd, J = 4.5, 13.7 Hz, 1H,
4-H), 4.37 (m, 2H, 3-H & 3-H), 4.64 (dd, J = 2.4, 4.0 Hz, 1H, 1-H), 5.41 (d, J = 2.4 Hz,
1H, 1-H), 5.50 (dd, J = 4.2, 4.2 Hz, 1H, 5-H), 7.20-7.50 (m, 5H, Harom.).
13
δ ppm = 32.9 (t, C-4), 69.0 (t, C-3), 79.7 (d, C-1), 85.2 (d, C-5), 85.3 (d, C-7), 124.6 (d,
Irradiation of 2,3-dihydrofuran with acetaldehyde (sbo-167)
A solution of 2,3-dihydrofuran (0.35 g, 5 mmol) and acetaldehyde (0.22 g, 5 mmol) in 100 mL
oxetanes as a colorless viscous oil.
endo-7-Methyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-3b)153
H
O
O
H
GC: Rt = 3.5 min.
1
δ ppm = 1.10 -1.85 (m, 2H, 4-H), 1.25 (d, J = 6.5 Hz, 3H, CH3 ), 3.65 – 4.40 (m, 2H, 3H), 4.58 (dq, J = 2.8, 6.5 Hz, 1H, 7-H), 4.73 (dd, J = 3.8, 3.8 Hz, 1H, 5-H), 5.36 (dd, J
= 2.8, 3.8 Hz, 1H, 1-H).
13
δ ppm = 20.1 (q, CH3 ), 33.3 (t, C-4), 67.2 (t, C-3), 79.2 (d, C-1), 82.2 (d, C-5), 83.9 (d,
C-7).
217
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exo-7-Methyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-3b)153
H
O
O
H
GC: Rt = 3.4 min.
1
δ ppm = 1.10 -1.85 (m, 2H, 4-H), 1.41 (d, J = 6.4 Hz, 3H, CH3 ), 3.65–4.40 (m, 2H, 3-H),
4.49 (dd, J = 2.6, 4.0 Hz, 1H, 5-H), 4.93 (dq, J = 4.2, 6.4 Hz, 1H, 7-H), 5.32 (dd, J =
4.0, 4.2 Hz, 1H, 1-H).
13
δ ppm = 20.5 (q, CH3 ), 32.8 (t, C-4), 69.8 (t, C-3), 81.6 (d, C-1), 83.8 (d, C-5), 84.4 (d,
C-7).
Irradiation of 2,3-dihydrofuran with propionaldehyde (sbo-P2)
A solution of 2,3-dihydrofuran (0.35 g, 5 mmol) and propionaldehyde (0.29 g, 5 mmol) in 100
mL benzene was irradiated for 24 h according to the above general procedure. Distillation of the
endo-7 -Ethyl-2,6-dioxa-bicyclo[[ 3.2.0]] heptane (endo-3c)154
H
O
O
H
GC: Rt = 6.5 min.
1
δ ppm = 0.85 (t, J = 7.4 Hz, 3H, CH3 ), 1.59 - 1.65 (m, 2H, CH2 CH3 ), 1.66 - 2.06 (m, 2H,
4-H), 4.17-4.27 (m, 2H, 3-H), 4.60 (ddd, J = 4.1, 4.0, 4.1 Hz, 1H, 7-H), 4.75 (dd, J =
3.8, 4.0 Hz, 1H, 1-H), 5.34 (dd, J = 3.8, 3.8 Hz, 1H, 5-H).
13
δ ppm = 8.6 (q, CH3 ), 22.5 (t, CH2 ), 32.9 (t, C-4), 70.0 (t, C-3), 78.8 (d, C-1), 84.3 (d, C5), 86.6 (d, C-7).
MS: (EI, 20 eV)
m/z (%) = 128 (M+, 20), 99 (100), 86 (43), 71 (50), 70 (68), 58 (60), 57 (78).
218
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exo-7- Ethyl-2,6-dioxa-bicyclo[[ 3.2.0]] heptane (exo-3c)154
H
O
O
H
GC: Rt = 6.4 min.
1
δ ppm = 0.94 (t, J = 7.4 Hz, 3H, CH3 ), 1.67-1.76 (m, 2H, CH2 CH3 ), 1.77 - 2.08 (m, 2H,
4-H), 4.17 - 4.26 (m, 2H, 3-H), 4.31 (dd, J = 2.5, 2.9 Hz, 1H, 7-H), 4.51 (dd, J = 4.1,
4.3 Hz, 1H, 1-H), 5.25 (dd, J = 3.8, 3.8 Hz, 1H, 5-H).
13
δ ppm = 8.2 (q, CH3 ), 27.2 (t, CH2 ), 33.5 (t, C-4), 67.3 (t, C-3), 80.9 (d, C-1), 84.4 (d, C5), 88.5 (d, C-7).
Irradiation of 2,3-dihydrofuran with 3-methylbutyraldehyde (sbo-P4)
A solution of 2,3-dihydrofuran (0.35 g, 5 mmol) and 3-methylbutyraldehyde (0.43 g, 5 mmol) in
100 mL benzene was irradiated for 24 h according to the above general procedure. Distillation of
the residue after evaporation of the solvent afforded 0.68 g (87 %) of inseparable mixture of
endo-7-Isobutyl-2,6-dioxa-bicyclo[[ 3.2.0]] heptane (endo-3d)
H
O
O
H
GC: Rt = 9.2 min.
1
δ ppm = 0.85 (d, J = 6.6 Hz, 6H, 2CH3 ), 1.43 (m, 1H, CH), 1.54 - 1.61 (m, 2H, CH2 ),
1.96 - 2.16 (m, 2H, 4-H), 4.18 (m, 2H, 3-H), 4.73 (dd , J = 3.8, 4.0 Hz, 1H, 1-H), 4.78
(ddd, J = 4.0, 4.0, 3.5 Hz, 1H, 7-H), 5.33 (dd, J = 3.7, 3.8 Hz, 1H, 5-H).
13
δ ppm = 22.7 (q, CH3 ), 22.8 (q, CH3 ), 22.9 (d, CH), 33.3 (t, C-4) , 38.4 (t, CH2 ), 70.2 (t,
C-3), 79.9 (d, C-1), 84.8 (d, C-5) , 84.9 (d, C-7).
219
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exo-7-Isobutyl-2,6-dioxa-bicyclo[[ 3.2.0]] heptane (exo-3d)
H
O
O
H
GC: Rt = 9.1 min.
1
δ ppm = 0.92 (d, J = 6.7 Hz, 6H, 2CH3 ), 1 .43 - 1.48 (m, 2H, CH2 ), 1.96 - 2.10 (m, 2H,
4-H), 2.11-2.13 (m, 1H, CH) , 4.12(m , 2H , 3-H), 4.30 (dd, J = 4.1, 2.6 Hz, 1H, 1-H),
4.5 (ddd, J = 2.8, 1.3, 2.2 Hz, 1H, 7-H), 5.27 (dd, J = 4.1, 4.1 Hz, 1H, 5-H).
13
δ ppm = 22.8 (q, CH3 ), 22.9 (q, CH3 ), 23.0 (d, CH), 33.9 (t, C-4) , 43.3 (t, CH2 ), 68.6 (t,
C-3), 82.2 (d, C-1), 84.8 (d, C-5), 86.6 (d, C-7).
Irradiation of 2,3-dihydrofuran with pivalaldehyde (sbo-P16)
A solution of 2,3-dihydrofuran (0.35 g, 5 mmol) and pivalaldehyde (0.43 g, 5 mmol) in 100 mL
endo-7-tert-Butyl-2,6-dioxa-bicyclo[[ 3.2.0]] heptane (endo-3e)
H
O
O
1
H
δ ppm = 0.98 (s, 9H, 3CH3 ), 1.99 (m, 2H, 4-H) , 3.50-3.66 (m, 2H, 3-H), 3.82 (d, J =
3.5Hz, 1H, 7-H), 4.60 (dd, J = 3.7, 3.5 Hz, 1H, 1-H), 5.10 (dd, J = 3.7, 4.0 Hz, 1H, 5H).
13
δ ppm = 23.4 (q, CH3 ), 24.8 (q, CH3 ), 26.7 (q, CH3 ), 31.3 (s, Cq), 37.8 (t, C-4) , 69.3 (t,
C-3), 81.1 (d, C-1), 86.5 (d, C-5), 90.6 (d, C-7).
220
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exo-7-tert-Butyl-2,6-dioxa-bicyclo[[ 3.2.0]] heptane (exo-3e)
H
O
O
1
H
δ ppm = 0.67 (s, 9H , 3CH3 ), 1.88 (m, 2H, 4-H), 3.50 - 3.66 (m, 2H, 3-H), 4.05 (d, J =
3.67 Hz, 1H, 7-H), 4.45 (dd, J = 3.7, 4.1 Hz, 1H, 1-H), 5.0 (dd, J = 4.1, 4.1 Hz, 1H, 5H).
13
δ ppm = 23.4 (q, CH3 ), 24.8 (q, CH3 ), 26.7 (q, CH3 ), 32.7 (s, Cq), 33.3 (t, C-4), 66.6 (t,
C-3), 83.0 (d, C-1) , 83.8 (d, C-5), 83.9 (d, C-7).
Irradiation of 2,3-dihydrofuran with 3-phenylpropionaldehyde (sbo-P6)
A solution of 2,3-dihydrofuran (0.35 g, 5 mmol) and 3-phenylpropionaldehyde (0.67 g, 5 mmol)
in 100 mL benzene was irradiated for 24 h according to the above general procedure. Distillation
of the residue after evaporation of the solvent afforded 0.76 g (75 %) of inseparable mixture of
endo-7-Phenethyl-2,6-dioxa-bicyclo[[ 3.2.0]] heptane (endo-3f)
H
O
Ph
O
1
H
δ ppm = 1.15 (t, J = 7.7 Hz, 2H, CH2 ), 1.45 (m, 2H, CH2 ), 1.98 (m, 2H, 4-H), 4.05 (m,
2H, 3-H), 4.60 (dd, J = 4.0, 4.0 Hz, 1H, 1-H), 4.70 (dt, J = 4.1, 4.0, 4.0 Hz, 1H, 7-H),
5.30 (dd, J = 3.7, 3.7 Hz, 1H, 5-H), 7.21 - 7.77 (m, 5H, Harom.).
13
δ ppm = 29.9 (t, CH2 ), 30.3 (t, CH2 ), 35.4 (t, C-4), 69.4 (t, C-3), 78.3 (d, C-1), 83.8 (d,
C-5), 84.0 (d, C-7), 125.4 (d, CHarom.), 127.8 (d, CHarom), 129.3 (d, CHarom.), 140.7 (s,
Cqarom.).
221
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exo-7-Phenethyl-2,6-dioxa-bicyclo[[ 3.2.0]] heptane (exo-3f)
H
O
Ph
O
1
H
2H, 4-H), 4.38 (dddd, J = 2.5, 2.5, 2.4, 2.2 Hz, 1H, 7-H), 4.49 (dd, J = 2.5, 2.5 Hz, 1H,
1-H), 5.27 (dd, J = 4.1, 4.0 Hz, 1H, 5-H), 7.20 - 7.45 (m, 5H, Harom.).
13
δ ppm = 29.9 (t, CH2 ), 32.4 (t, CH2 ), 32.9 (t, C-4), 66.7 (t, C-3), 80.5 (d, C-1), 83.9 (d,
C-5), 85.9 (d, C-7), 126.4 (d, CHarom.), 127.4 (d, CHarom.), 128.4 (d, CHarom.), 140.8 (s,
Cqarom.).
4.2.1.2 Photolyses of 2,3-dihydropyran with aldehydes 1a-d:
Irradiation of 2,3-dihydropyran with benzaldehyde (sbo-68)
A solution of 2,3-dihydropyran (0.42 g, 5 mmol) and benzaldehyde (0.53 g, 5 mmol) in 100 mL
endo-8-Phenyl-2,7-dioxa-bicyclo[[ 4.2.0]] octane (endo-5a)152
H
O
O
1
H
Ph
δ ppm = 1.50 – 2.20 (m, 4H, 4-H & 5-H), 3.25 (dt, J = 2.2, 11.2 Hz, 2H, 3-H), 4.66 (dd, J
= 4.0, 4.0 Hz, 1H, 1-H), 4.91 (m, 1H, 6-H), 5.70 (d, J = 4.0 Hz, 1H, 8-H), 7.20 – 7.50
(m, 5H, Harom.).
13
20.9 (t, C-4), 26.0 (t, C-5), 63.5 (t, C-3), 73.5 (d, C-1), 74.8 (d, C-6), 82.9 (d, C-8),
126.7 (d, CHarom.), 127.7 (d, CHarom.), 128.9 (d, CHarom.), 136.9 (s, Cqarom.).
222
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exo-8-Phenyl-2,7-dioxa-bicyclo[[ 4.2.0]] octane (exo-5a)152
H
O
O
Ph
H
1
δ ppm = 1.52 – 2.20 (m, 4H, 4-H & 5-H), 3.25 (dt, J = 2.2, 11.2 Hz, 2H, 3-H), 4.36 (dd, J
= 4.0, 4.0 Hz, 1H, 1-H), 4.91 (m, 1H, 6-H), 5.62 (d, J = 4.1 Hz, 1H, 8-H), 7.20 – 7.50
(m, 5H, Harom.).
13
20.5 (t, C-4), 26.2 (t, C-5), 64.5 (t, C-3), 73.6 (d, C-1), 74.5 (d, C-6), 82.8 (d, C-8),
126.7 (d, CHarom), 127.3 (d, CHarom), 128.2 (d, CHarom.), 136.9 (s, Cqarom.).
Irradiation of 2,3-dihydropyran with acetaldehyde (sbo-67)
A solution of 2,3-dihydropyran (0.42 g, 5 mmol) and acetaldehyde (0.22 g, 5 mmol) in 100 mL
endo-8-Methyl-2,7-dioxa-bicyclo[[ 4.2.0]] octane (endo-5b)153
H
O
O
H
GC: Rt = 4.5 min.
1
δ ppm = 1.21 (d, J = 5.2 Hz, 3H, CH3 ), 1.52 – 2.20 (m, 4H, 4-H & 5-H), 3.25 (dt, J = 2.2,
11.2 Hz, 2H, 3-H), 4.36 (dd, J = 4.0, 4.0 Hz, 1H, 1-H), 4.69 (d, J = 5.2 Hz, 1H, 6-H),
5.41 (dq, J = 4.1, 5.2 Hz, 1H, 8-H).
13
19.9 (q, CH3 ), 21.5 (t, C-4), 28.2 (t, C-5), 67.5 (t, C-3), 79.6 (d, C-1), 84.5 (d, C-6),
89.8 (d, C-8).
223
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exo-8-Methyl-2,7-dioxa-bicyclo[[ 4.2.0]] octane (exo-5b)153
H
O
O
H
GC: Rt = 4.6 min.
1
δ ppm = 1.35 (d, J = 6.5 Hz, 3H, CH3 ), 2.34 (m, 2H, 5-H), 2.37 (m, 2H, 4-H), 3.58 –
3.73 (m, 2H, 3-H), 4.36 (dd, J = 4.0, 4.0 Hz, 1H, 1-H), 4.64 (dq, J = 3.4, 6.5 Hz, 1H, 8H), 5.54 (d, J = 4.3 Hz, 1H, 6-H).
13
20.8 (q, CH3 ), 26.2 (t, C-5), 33.7 (t, C-4), 62.5 (t, C-3), 72.6 (d, C-1), 78.5 (d, C-6),
83.8 (d, C-8).
Irradiation of 2,3-dihydropyran with propionaldehyde (sbo-66)
A solution of 2,3-dihydropyran (0.42 g, 5 mmol) and propionaldehyde (0.29 g, 5 mmol) in 100
endo-8-Ethyl-2,7-dioxa-bicyclo[[ 4.2.0]] octane (endo-5c)153
H
O
O
H
GC: Rt = 5.3 min.
1
δ ppm = 0.85 (t, J = 7.4 Hz, 3H, CH3 ), 1.74 (dq, J = 2.0, 7.4 Hz, 2H, CH2 ), 1.82 – 2.20
(m, 4H, 4-H & 5-H), 3.25 (dt, J = 2.2, 11.2 Hz, 2H, 3-H), 4.41 (dd, J = 4.0, 4.0 Hz, 1H,
1-H), 4.98 (m, 1H, 6-H), 5.35 (d, J = 4.1 Hz, 1H, 8-H).
13
8.5 (q, CH3 ), 22.4 (t, CH2 ), 23.5 (t, C-4), 26.2 (t, C-5), 64.5 (t, C-3), 73.6 (d, C-1), 78.5
(d, C-6), 92.8 (d, C-8).
224
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exo-8-Ethyl-2,7-dioxa-bicyclo[[ 4.2.0]] octane (exo-5c)153
H
O
O
H
GC: Rt = 5.4 min.
1
δ ppm = 0.92 (t, J = 7.3 Hz, 3H, CH3 ), 1.67 (dq, J = 2.6, 7.3 Hz, 2H, CH2 ), 1.82 – 2.25
(m, 4H, 4-H & 5-H), 3.25 (dt, J = 2.2, 11.2 Hz, 2H, 3-H), 4.44 (dd, J = 4.2, 4.2 Hz, 1H,
1-H), 4.87 (m, 1H, 6-H), 5.45 (dd, J = 4.2, 4.1 Hz, 1H, 8-H).
13
8.6 (q, CH3 ), 23.2 (t, CH2 ), 25.8 (t, C-4), 26.9 (t, C-5), 69.5 (t, C-3), 78.6 (d, C-1), 79.5
(d, C-6), 86.8 (d, C-8).
Irradiation of 2,3-dihydropyran with 3-methylbutyraldehyde (sbo-74)
A solution of 2,3-dihydropyran (0.42 g, 5 mmol) and 3-methylbutyraldehyde (0.43 g, 5 mmol) in
endo-8-Isobutyl-2,7-dioxa-bicyclo[[ 4.2.0]] octane (endo-5d)
H
O
O
H
GC: Rt = 6.6 min.
1
δ ppm = 0.87 (d, J = 6.8 Hz, 6H, 2CH3 ), 1.12 (m, 1H, CH), 1.34 - 1.43 (m, 2H, CH2 ),
1.52 – 2.20 (m, 4H, 4-H & 5-H), 3.25 (dt, J = 2.2, 11.2 Hz, 2H, 3-H), 4.41 (dd, J = 4.1,
4.0 Hz, 1H, 1-H), 4.96 (m, 1H, 6-H), 5.52 (d, J = 4.1 Hz, 1H, 8-H).
13
16.3 (q, CH3 ), 17.4 (q, CH3 ), 20.9 (t, C-4), 25.3 (d, CH), 26.8 (t, C-5), 37.5 (t, CH2 ),
67.5 (t, C-3), 78.6 (d, C-1), 79.5 (d, C-6), 87.8 (d, C-8).
225
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exo-8-Isobutyl-2,7-dioxa-bicyclo[[ 4.2.0]] octane (exo-5d)
H
O
O
H
GC: Rt = 6.7 min.
1
δ ppm = 0.93 (d, J = 6.6 Hz, 6H, 2CH3 ), 1.18 (m, 1H, CH), 1.38-1.48 (m, 2H, CH2 ), 1.52
– 2.20 (m, 4H, 4-H & 5-H), 3.25 (dt, J = 2.2, 11.2 Hz, 2H, 3-H), 4.36 (dd, J = 4.0, 4.0
Hz, 1H, 1-H), 4.91 (m, 1H, 6-H), 5.62 (d, J = 4.1 Hz, 1H, 8-H).
13
18.6 (q, CH3 ), 18.9 (q, CH3 ), 20.5 (t, C-4), 24.7 (d, CH), 26.2 (t, C-5), 64.5 (t, C-3),
73.6 (d, C-1), 74.5 (d, C-6), 82.8 (d, C-8).
4.1.2.3 Photolysis of cyclopentene with propionaldehyde (sbo-P1)
A solution of propionaldehyde (0.29 g, 5 mmol) and cyclopentene (0.34 g, 5 mmol) in 100 mL
benzene was irradiated following the general procedure for 24 h. Distillation of the residue after
evapouation of the solvent afforded 0.52 g (83 %) of inseparable mixture of oxetanes as a
colorless viscous oil.
endo-7-Ethyl-6-oxa-bicyclo[[ 3.2.0]] heptane (endo-7c)
H
O
H
1
δ ppm = 0.72 (t, 3H, CH3 ), 1.59 - 1.65 (m, 2H, CH2 ), 1.70-2.38 (m, 6H, 3CH2 ), 3.93
(ddd, J = 4.2, 4.1, 4.0 Hz, 1H, 1-H), 4.55 (dd, J = 7.2, 7.1 Hz, 1H, 7-H), 5.10 (dd, J =
4.2, 4.3 Hz, 1H, 5-H).
13
δ ppm = 8.6 (q, CH3 ), 25.4 (t, CH2 ), 29.8 (t, C-2), 30.1 (t, C-3), 33.85 (t, C-4), 40.3 (d,
C-5), 82.1 (d, C-1), 84.4 (d, C-7).
226
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exo-7-Ethyl-6-oxa-bicyclo[[ 3.2.0]] heptane (exo-7c)
H
O
H
1
δ ppm = 0.94 (t, 3H, CH3 ), 1.67 - 1.76 (m, 2H, CH2 ), 1.77 - 2.38 (m, 6H, 3CH2 ), 3.50
(m, 1H, 1-H), 4.05 (dd, J = 4.1, 4.3 Hz, 1H, 7-H), 4.99 (dd, J = 5.0, 4.3 Hz, 1H, 5-H).
13
δ ppm = 7.9 (q, CH3 ), 25.8 (t, CH2 ), 26.6(t, C-2), 30.8 (t, C-3), 34.4 (t, C-4), 42.9 (d, C5), 84.5 (d, C-1), 86.4 (d, C-7).
4.2.1.4 Photolyses of 5-methyl-2,3-dihydrofuran with aldehydes 1a-d:
Irradiation of 5-methyl-2,3-dihydrofuran with benzaldehyde (sbo-268)
A solution of 5-methyl-2,3-dihydrofuran (0.42 g, 5 mmol) and benzaldehyde (0.53 g, 5 mmol) in
endo-7-Phenyl-1-methyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-9a)152
H
O
Ph
O
1
δ ppm = 1.52 (s, 3H, CH3 ), 1.68 (dddd, J = 4.2, 8.2, 11.2, 13.8 Hz, 1H, 4-H), 2.04 (dd, J
= 5.3, 13.8 Hz, 1H, 4-H), 3.71 (ddd, J = 5.3, 8.8, 11.2 Hz, 1H, 3-H), 3.88 (dd, J = 8.2,
8.8 Hz, 1H, 3-H), 5.10 (d, J = 4.5 Hz, 1H, 5-H), 5.58 (s, 1H, 7-H), 7.17 - 7.32 (m, 5H,
Harom.).
13
δ ppm = 21.4 (q, CH3 ), 33.0 (t, C-4), 69.1 (t, C-3), 77.2 (s, C-1), 89.1 (d, C-5), 89.6 (d,
C-7), 124.3 (d, CHarom.), 127.0 (d, CHarom.), 128.1 (d, CHarom.), 137.8 (s, Cqarom.).
exo-7-Phenyl-1-methyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-9a)152
227
___________________________________________________________________________
H
O
Ph
O
1
δ ppm = 0.88 (s, 3H, CH3 ), 1.80 (m, 1H, 4-H), 2.14 (m, 1H, 4-H), 4.29-4.36 (m, 2H, 3H), 4.99 (d, J = 4.0 Hz, 1H, 5-H), 5.44 (s, 1H, 7-H), 7.19 - 7.33 (m, 5H, Harom.).
13
δ ppm = 17.8 (q, CH3 ), 34.1 (t, C-4), 67.7 (t, C-3), 89.3 (d, C-5), 89.5 (s, C-1), 90.9 (d,
C-7), 125.3 (d, Carom.), 127.6 (d, Carom.), 128.4 (d, Carom.), 138.8 (s, Cqaroms. ).
Irradiation of 5-methyl-2,3-dihydrofuran with acetaldehyde (sbo-203)
A solution of 5-methyl-2,3-dihydrofuran (0.42 g, 5 mmol) and acetaldehyde (0.22 g, 5 mmol) in
endo-1,7-Dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-9b)
H
O
O
1
δ ppm = 1.10 (d, J = 6.5 Hz, 3H, CH3 ), 1.21 (s, 3H, CH3 ), 2.35 (dd, J = 6.9, 6.9 Hz, 2H,
4-H), 4.15 - 4.21 (m, 2H, 3-H ), 4.62 ( q, J = 6.5 Hz, 1H, 7-H ), 4.87 (d, J = 3.8 Hz, 1H,
5-H ).
13
δ ppm = 15.9 (q, CH3 ), 19.8 (q, CH3 ), 32.6 (t, C-4), 69.5 (t, C-3), 85.2 (s, C-1), 85.5 (d,
C-5), 88.0 (d, C-7).
exo-1,7-Dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-9b)
H
O
O
1
228
___________________________________________________________________________
δ ppm = 1.22 (s, 3H, CH3 ), 1.28 (d, J = 6.5 Hz, 3H, CH3 ), 2.43 (dd, J = 7.2, 7.2 Hz, 2H,
4-H), 4.15 - 4.21 (m, 2H, 3-H), 4.54 (q, J = 6.5 Hz, 1H, 7-H), 4.77 (d, J = 4.1 Hz, 1H,
5-H).
13
δ ppm = 14.4 (q, CH3 ), 18.2 (q, CH3 ), 33.8 (t, C-4), 67.0 (t, C-3), 85.3 (s, C-1), 85.6 (d,
C-5), 87.9 (d, C-7).
Irradiation of 5-methyl-2,3-dihydrofuran with propionaldehyde (sbo-251)
A solution of 5-methyl-2,3-dihydrofuran (0.42 g, 5 mmol) and propionaldehyde (0.29 g, 5 mmol)
in 100 mL benzene was irradiated for 24 h according to the above general procedure. Distillation
of the residue after evaporation of the solvent afforded 0.72 g (88 %) of inseparable mixture of
endo-7-Ethyl-1-methyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-9c)
H
O
O
1
δ ppm = 0.85 (t, J = 7.5 Hz, 3 H, CH3 ), 1.34 (s, 3H, CH3 ), 1.63 - 1.78 (m, 2H, CH2 ), 1.85
- 2.00 (m, 2H, CH2 ), 4.05 - 4.15 (m, 2H, 3-H), 4.45 (dd, J = 7.2, 7.35 Hz, 1H, 7-H ),
4.93 (d , J = 3.8 Hz, 1H, 5-H).
13
δ ppm = 8.4 (q, CH3 ), 19.8 (q, CH3 ), 21.8 (t, CH2 ), 33.1 (t, C-4), 66.2 (t, C-3), 84.4 (s,
C-1), 86.9 (d, C-5), 89.8 (d, C-7).
exo-7-Ethyl-1-methyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-9c)
H
O
O
1
δ ppm = 0.92 (t, J = 7.5 Hz, 3H, CH3 ), 1.32 (s, 3H, CH3 ), 1.63 - 1.78 (m, 2H, CH2 ), 1.85
- 2.00 (m, 2H, 4-H), 4.05 (m, 2H, 3-H ), 4.30 (dd, J =5.6, 5.4 Hz, 1H, 7-H), 4.82 (d, 4.0
Hz, 1H, 5-H).
229
___________________________________________________________________________
13
δ ppm = 7.8 (q, CH3 ), 15.2 (q, CH3 ), 25.3 (t, CH2 ), 32.0 (t, C-4), 68.9 (t, C-3), 84.8 (s, C1), 87.2 (d, C-5), 89.9 (d, C-7).
Irradiation of 5-methyl-2,3-dihydrofuran with 3-methylbutyraldehyde (sbo-260)
A solution of 5-methyl-2,3-dihydrofuran (0.42 g, 5 mmol) and 3-methylbutyraldehyde (0.43 g, 5
mmol) in 100 mL benzene was irradiated for 24 h according to the above general procedure.
Distillation of the residue after evaporation of the solvent afforded 0.69 g (81 %) of inseparable
mixture of oxetanes as a colorless viscous oil.
endo-7-Isobutyl-1-methyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-9d)
H
O
O
1
δ ppm = 0.83 (d, J = 6.6 Hz, 2CH3 ), 0.85 - 0.93 (m, 1H, CH), 1.25 (s, 3H, CH3 ), 1.55 1.65 (m, 2H, CH2 ), 1.92 (m, 2H, 4-H), 4.10 - 4.19 (m, 2H, 3-H), 4.56 (dd, J = 6.8, 6.6
Hz, 1H, 7-H), 4.85 (d, J = 3.8 Hz, 1H, 5-H).
13
δ ppm = 19.9 (q, CH3 ), 21.8 (q, CH3 ), 22.3 (q, CH3 ), 24.0 (d, CH), 32.4 (t, C-4), 37.6 (t,
CH2 ), 69.1 (t, C-3), 85.0 (s, C-1), 87.4 (d, C-5), 87.4 (d, C-7).
exo-7-Isobutyl-1-methyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-9d)
H
O
O
1
δ ppm = 0.83 (d, J = 6.7 Hz, 6 H, 2CH3 ), 1.25 (s, 3H, CH3 ), 1.55 - 1.65 (m, 2H, CH2 ),
2.12 (m, 2H, 4-H), 4.10 - 4.20 (m, 2H, 3-H), 4.44 (dd, J = 3.7, 9.7 Hz, 1H, 7-H), 4.74
(d, J = 4.0 Hz,1H, 5-H).
13
δ ppm = 15.7 (q, CH3 ), 21.5 (q, CH3 ), 22.5 (q, CH3 ), 24.2 (d, CH), 33.4 (t, C-4), 41.4 (t,
CH2 ), 66.6 (t, C-3), 85.4 (s, C-1), 87.4 (d, C-5), 87.6 (d, C-7).
230
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4.3 Synthesis of 2,2-dimethyl-2,3-dihydrofuran
Preparation of 2-methyl-pent-4-en-2-ol (10) (sbo-211)
OH
Method A:87
A 250 mL three neck round-bottomed flask, containing a magnetic stirring bar, was equipped
with a dropping funnel, and a reflux condenser. Finely powdered magnesium of
good quality
(18.3 g, 0.75 mol) was covered with dry ether (50 mL), and allyl bromide (30.3 g, 0.25 mol)
dissolved in ether (150 mL), was added with vigrous stirring during 4 h, the solvent continued in
gentle boiling through the reaction, and stirred for further 3h, then heated to reflux for 30 min.
After cooling to room temperature, acetone (14.5 g, 0.25 mol) in ether (25 mL) was added
dropwise and the stirring is continued further for 1h. Then the mixture was added dropwise into a
cold saturated solution of ammonium chloride, extracted with ether, washed with brine solution
and dry over anhydrous Mg SO4 . Then evaporated the solvent under reduced pressure and the
remainder solution was subjected to long column distillation to give the pure product in 40 %
yield, (B.p = 117 – 118 °C, Lit,87 115-118°C).
Method B:88
Into a stirred solution of acetone (7.34 g, 0.127 mol) and allyl bromide (19.88 g, 0.127 mol) in a
125 mL dimethylformamide, zinc dust (12.5 g) was added at room temperature under the
atmosphere. An exothermic reaction started within 10 min. and it ceased in 30 min, Then the
reaction mixture was poured into a saturated aqueous solution of ammonium chloride (100 mL),
extracted with ether (30 mL x 3), and the combined organic phase was dried over anhydrous Mg
SO4 . Rotoevaporation of the solvent (20 °C, 15 torr) yielded 8.3 g (70%) of a yellow liquid,
which on distillation (B.p = 117-118 °C) afforded 7.5 g (68 %) of the allylic alcohol as a
colorless liquid.
1
δ ppm = 1.13 (s, 6H, 2CH3 ), 2.00 (s, 1H, OH ), 2.15 (d, J = 7.5 Hz, 2H, CH2 ), 5.04 (m,
2H, 5-H), 5.83 (m, 1H, 4-H).
13
δ ppm = 28.9 (q, 2CH3 ), 48.1 (t, CH2 ), 70.18 (s, Cq), 118.2 (t, C-5), 134.2 (d, C-4).
231
___________________________________________________________________________
Preparation of 4-bromo-2,2-dimethyl-tetrahydrofuran (11)86 (sbo-215)
Br
O
A 250- mL two-necked round-bottomed flask, containing stirring bar, is equipped with a
dropping funnel, reflux condenser. The dropping funnel is charged with Br2 (8.8 g, 55 mmol).
The flask is charged with dimethyl allyl carbinol (5.5 g, 55 mmol) with 100 mL of dry ether and
cooled with an ice-water bath (0-5°C). Bromine is added dropwise over a period of 8 min. The
solution is stirred for a further 2h, then quinoline (7.8 g) is added in one portion and the solution
is slowly heated to reflux. The reflux is continued for 2h, (notice the separation of a white ppt
from quinoline hydrobromide salt during the heating). Then the solution is allowed to cool to
room temperature and the precipitate was filtered, washed with dry ether and the solvent was
evaporated under vacum. Fractional distillation of the residue (B.p 62 °C, 10 torr) yielded 3.5 g
(70 %) of 4-bromo-2,2-dimethyl-tetrahydrofuran 11 as a colorless liquid.
1
δ ppm = 1.20 (s, 3H, CH3 ), 1.37 (s, 3H, CH3 ), 2.12 (dd, J = 13.8, 5.6 Hz, 1H, 3-H), 2.33
(dd, J = 13.8, 7.7 Hz, 3-H), 4.0 (dd, J = 10.0, 5.6 Hz, 1H, 5-H), 4.16 (dd, J = 10.1, 5.7
Hz, 1H, 5-H), 4.36 (dddd, J = 13.2, 11.2, 7.7, 5.6 Hz, 4-H).
13
δ ppm = 28.4 (q, CH3 ), 28.5 (q, CH3 ), 45.2 (t, C-3), 48.9 (d, C-4) , 74.6 (t, C-5) , 81.2 (s,
C-2).
Preparation of 2,2-dimethyl-2,3-dihydrofuran (13)86 (sbo-216)
O
Distillation of 2,2-dimethyl-4-bromotetrahydrofuran (3.58 g, 20 mmol) with 2 g of potassium
hydroxide pellets gave a mixture of two regioisomers of dihydrofuran at B.p 78 –82 °C which
separated by column chromatography using a mixture of ethyl acetate and n-hexane as eluent,
the less polar being the major product, 2,2-dimethyl-2,3-dihydrofuran (13).
Yield: 0.9 g (46 %)
TLC: Rf = 0.23 (EA/n-HE 1 : 4)
232
___________________________________________________________________________
1
δ ppm = 1.31 (s, 6H, 2CH3 ), 2.37 (m, 2H, 3-H), 4.73 (m, 1H, 4-H), 6.61 (m, 1H, 5-H).
13
δ ppm = 28.1 (q, CH3 ), 28.1 (q, CH3 ), 42.2 (t, C-3), 73.9 (s, C-2), 98.2 (d, C-4), 144.0 (d,
C-5).
2,2-Dimethyl-2,5-dihydrofuran (12)86
O
Yield: 0.23 g (12 %)
TLC: Rf = 0.43 (EA/n-HE 1 : 4)
1
δ ppm = 1.31 (s, 6H, 2CH3 ), 4.59 (m, 2H, 5-H), 5.71 (m, 2H, 3-H & 4-H).
13
δ ppm = 27.6 (q, CH3 ), 29.0 (q, CH3 ), 84.3 (t, C-5), 87.4 (s, C-2), 124.6 (d, C-3), 135.2
(d, C-4).
4.3.1 Photolyses of 2,2-dimethyl-2,3-dihydrofuran with aldehydes; General procedure:
Under a nitrogen atmosphere, a solution of 2,2-dimethyl-2,3-dihydrofuran (3 mmol) and
aldehyde (3 mmol) in 30 mL benzene in a quartz tube was irradiated in a Rayonet Photoreactor
(300 nm) at room temperature. The solvent was removed in vacuo, and the residue was purified
by bulb to bulb distillation.
Irradiation of 2,2-dimethyl-2,3-dihydrofuran with benzaldehyde (sbo-220)
A solution of 2,2-dimethyl-2,3-dihydrofuran (0.29 g, 3 mmol) and benzaldehyde (0.31 g, 3
mmol) in 30 mL benzene was irradiated for 24 h following the above general procedure.
Distillation of the residue after evaporation of the solvent yielded 0.45 g (74 %) of inseparable
endo-3,3-Dimethyl-7-phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-14a)
H
O
Ph
O
H
233
___________________________________________________________________________
1
δ ppm = 1.15 (s, 3H, CH3 ), 1.47 (s, 3H, CH3 ), 1.74 - 1.94 (m, 2H, 4-H), 4.38 (dd, J = 3.7,
3.8 Hz, 1H, 1-H), 5.30 (dd, J = 3.8, 3.8 Hz, 1H,5-H), 5.73 (d, J = 3.8 Hz, 1H, 7-H),
7.25 - 7.32 (m, 5H, Harom.).
13
C-5), 89.4 (d, C-7), 126.4 (d, CHarom.), 128.4 (d, CHarom.), 129.2 (d, CHarom.), 134.3 (s,
Cqarom.).
HRMS: (C 13 H16 O2 , M = 204.12)
Calcd: 204.1178
Found: 204.1176
exo-3,3-Dimethyl-7-phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-14a)
H
O
Ph
O
1
H
δ ppm = 1.21 (s, 3H, CH3 ), 1.51 (s, 3H, CH3 ), 1.79 - 1.98 (m, 2H, 4-H), 4.64 (dd, J = 3.8,
3.8 Hz, 1H, 1-H), 4.97 (d, J = 3.8 Hz, 1H,7-H), 5.23 (dd, J = 3.8, 3.8 Hz, 1H, 5-H),
7.26 – 7.33 (m, 5H, Harom.).
13
C-5), 90.4 (s, C-7), 126.8 (d, CHarom.), 128.9 (d, CHarom.), 129.6 (d, CHarom.), 135.3 (s,
Cqarom.).
Irradiation of 2,2-dimethyl-2,3-dihydrofuran with o-tolualdehyde (sbo-224g)
A solution of 2,2-dimethyl-2,3-dihydrofuran (0.29 g, 3 mmol) and o-tolualdehyde (0.36 g, 3
mixture of oxetanes as a pale yellow viscous oil.
endo-3,3-Dimethyl-7-o-tolyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-14b)
234
___________________________________________________________________________
H
O
O
1
H
δ ppm = 1.17 (s, 3H, CH3 ), 1.45 (s, 3H, CH3 ), 1.76 - 1.96 (m, 2H, 4-H), 2.12 (s, 3H,
CH3 ), 4.41 (dd, J = 3.9, 3.9 Hz, 1H, 1-H), 5.35 (dd, J = 3.8, 3.8 Hz, 1H, 5-H), 5.65 (d, J
= 3.8 Hz, 1H, 7-H), 7.25 - 7.32 (m, 4H, Harom.).
13
δ ppm = 20.9 (q, CH3 ), 29.6 (q, CH3 ), 30.9 (q, CH3 ), 49.8 (t, C-4), 76.3 (s, C-3), 87.4 (d,
C-1), 89.6 (d, C-5), 91.4 (s, C-7), 126.5 (d, CHarom.), 128.2 (d, CHarom.), 129.9 (d,
CHarom.), 135.1 (s, Cqarom.).
exo-3,3-Dimethyl-7-o-tolyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-14b)
H
O
O
1
H
δ ppm = 1.27 (s, 3H, CH3 ), 1.53 (s, 3H, CH3 ), 1.78 – 2.05 (m, 2H, 4-H), 2.15 (s, 3H,
CH3 ), 4.67 (dd, J = 4.0, 3.9 Hz, 1H, 1-H), 5.15 (d, J = 3.9 Hz, 1H, 7-H), 5.35 (dd, J =
3.8, 3.9 Hz, 1H, 5-H), 7.28 - 7.35 (m, 4H, Harom.).
13
δ ppm = 23.1 (q, CH3 ), 29.4 (q, CH3 ), 33.5 (q, CH3 ), 50.8 (t, C-4), 79.3 (s, C-3), 88.3 (d,
C-1), 89.8 (d, C-5), 91.6 (s, C-7), 126.8 (d, CHarom.), 128.4 (d, CHarom.), 129.3 (d,
Irradiation of 2,2-dimethyl-2,3-dihydrofuran with propionaldehyde (sbo-235)
A solution of 2,2-dimethyl-2,3-dihydrofuran (0.29 g, 3 mmol) and propionaldehyde (0.17 g, 3
endo-7-Ethyl-3,3-dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-14c)
235
___________________________________________________________________________
H
O
O
1
H
δ ppm = 0.73 (t, J = 7.5 Hz, 3H, CH3 ), 1.14 (s, 3H, CH3 ), 1.45 (s, 3H, CH3 ), 1.58 - 1.67
(m, 2H, CH2 ), 1.74 - 1.94 (m, 2H, 4-H), 4.38 (dd, J = 3.7, 3.8 Hz, 1H, 7-H), 4.70 (dd, J
= 3.8, 3.8 Hz, 1H,1-H), 5.18 (ddd, J = 8.4, 5.7, 3.8 Hz, 1H, 5-H).
13
δ ppm = 8.2 (q, CH3 ), 22.4 (t, CH2 ), 29.0 (q, CH3 ), 29.7 (q, CH3 ), 46.4 (t, C-4), 79.3 (s,
C-3), 84.4 (d, C-1), 85.0 (d, C-5), 86.4 (d, C-7).
HRMS: (C 9 H16 O2 , M = 156.12)
Calcd: 156.1264
Found: 156.1256
exo-7-Ethyl-3,3-dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-14c)
H
O
O
1
H
δ ppm = 0.83 (t, J = 7.5 Hz, 3H, CH3 ), 1.22 (s, 3H, CH3 ), 1.51 (s, 3H, CH3 ), 1.55 - 1.63
(m, 2H, CH2 ), 1.60 - 2.07 (m, 2H, 4-H), 4.16 (dd, J = 3.7, 3.8 Hz, 1H, 7-H), 4.4 (dd, J
= 6.5, 6.8 Hz, 1H, 1-H), 5.23 (dd, J = 5.0, 4.9 Hz, 1H, 5-H).
13
δ ppm = 8.1 (q, CH3 ), 26.9 (t, CH2 ), 29.1 (q, CH3 ), 29.9 (q, CH3 ), 45.5 (t, C-4), 82.0 (s,
C-3), 85.7 (d, C-1), 86.8 (d, C-5), 89.8 (d, C-7).
Irradiation of 2,2-dimethyl-2,3-dihydrofuran with isobutyraldehyde (sbo-224c)
A solution of 2,2-dimethyl-2,3-dihydrofuran (0.29 g, 3 mmol) and isobutyraldehyde (0.22 g, 3
endo-7-Isopropyl-3,3-dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-14d)
236
___________________________________________________________________________
H
O
O
1
H
δ ppm = 0.83 (d, J = 6.8 Hz, 6H, 2CH3 ), 1.24 (s, 3H, CH3 ), 1.51 (s, 3H, CH3 ), 1.55 - 1.63
(m, 1H, CH), 1.78 - 2.07 (m, 2H, 4-H), 4.21 (dd, J = 3.8, 3.8 Hz, 1H, 7-H), 4.41 (dd, J
= 5.0, 6.8 Hz, 1H,1-H), 5.25 (dd, J = 5.0, 4.9 Hz, 1H, 5-H).
13
δ ppm = 18.3 (q, CH3 ), 18.9 (q, CH3 ), 25.4 (d, CH), 29.1 (q, CH3 ), 29.7 (q, CH3 ), 46.5 (t,
C-4), 82.6 (s, C-3), 86.7 (d, C-1), 88.8 (d, C-5), 89.9 (d, C-7).
exo-7-Isopropyl-3,3-dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-14d)
H
O
O
1
H
δ ppm = 0.93 (d, J = 6.8 Hz, 6H, 2CH3 ), 1.17 (m, 1H, CH), 1.21 (s, 3H, CH3 ), 1.50 (s,
3H, CH3 ), 1.64 - 2.06 (m, 2H, 4-H), 4.18 (dd, J = 4.0, 6.8 Hz, 1H, 7-H), 4.46 (dd, J =
4.0, 5.0 Hz, 1H,1-H), 5.29 (dd, J = 5.0, 4.8 Hz, 1H, 5-H).
13
C-4), 84.7 (s, C-3), 85.9 (d, C-1), 87.8 (d, C-5), 90.8 (d, C-7).
HRMS: (C 10 H18 O2 , M = 170.13)
Calcd: 170.1264
Found: 170.1269
Irradiation of 2,2-dimethyl-2,3-dihydrofuran with 3-methylbutyraldehyde (sbo-224e)
A solution of 2,2-dimethyl-2,3-dihydrofuran (0.29 g, 3 mmol) and 3-methylbutyraldehyde (0.26
g, 3 mmol) in 30 mL benzene was irradiated for 24 h following the above general procedure.
237
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endo-7-Isobutyl-3,3-dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-14e)
H
O
O
1
H
δ ppm = 0.83 (d, J = 6.2 Hz, 6H, 2CH3 ), 0.88 (m, 2H, CH2 ), 1.14 (s, 3H, CH3 ), 1.29 (m,
1H, CH), 1.45 (s, 3H, CH3 ), 1.74 - 1.94 (dd, J = 13.9, 4.7 Hz, 2H, 4-H), 4.57 (dd, J =
3.7, 3.8 Hz, 1H, 7-H), 4.68 (dd, J = 4.3, 3.8 Hz, 1H,1-H), 5.15 (dd, J = 4.3 , 4.3 Hz,
1H, 5-H).
13
CH2 ), 45.6 (t, C-4), 80.30 (s, C-3), 82.9 (d, C-1), 85.7 (d, C-5), 86.3 (d, C-7).
exo-7-Isobutyl-3,3-dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-14e)
H
O
O
1
H
δ ppm = 0.83 (d, J = 6.18 Hz, 6H, 2CH3 ), 0.88 (m, 2H, CH2 ), 1.14 (s, 3H, CH3 ), 1.29 (m,
1H, CH ), 1.45 (s, 3H, CH3 ), 1.74 - 1.94 (dd, J = 13.9, 4.7 Hz, 2H, 4-H), 4.30 (ddd, J =
2.1, 4.1, 6.0 Hz, 1H, 7-H), 4.38 (dd, J = 4.9, 4.6 Hz, 1H,1-H), 5.23 (dd, J = 4.9, 4.9 Hz,
1H, 5-H).
13
CH2 ), 46.4 (t, C-4), 79.3 (s, C-3), 80.0 (d, C-), 85.0 (d, C-5), 87.5 (d, C-7).
Irradiation of 2,2-dimethyl-2,3-dihydrofuran with pivalaldehyde (sbo-224f)
A solution of 2,2-dimethyl-2,3-dihydrofuran (0.29 g, 3 mmol) and pivalaldehyde (0.26 g, 3
238
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endo-7-tert-Butyl-3,3-dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-14f)
H
O
O
1
H
δ ppm = 0.90 (s, 9H, 3CH3 ), 1.45 (s, 3H, CH3 ), 1.51 (s, 3H, CH3 ), 1.79 - 2.04 (dd, J =
13.9, 4.7 Hz, 2H, 4-H), 4.27 (d, J = 4.0 Hz, 1H, 7-H), 4.54 (dd, J = 4.0, 4.3 Hz, 1H,1H), 5.33 (dd, J = 4.0, 5.0 Hz, 1H, 5-H).
13
δ ppm = 22.2 (q, CH3 ), 22.4 (q, CH3 ), 23.8 (q, 3CH3 ), 33.7 (s, Cq), 48.9 (t, C-4), 80.6 (s,
C-3), 83.4 (d, C-1), 85.0 (d, C-5), 87.5 (d, C-7).
exo-7-tert-Butyl-3,3-dimethyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-14f)
H
O
O
1
H
δ ppm = 0.83 (s, 9H, 3CH3 ), 1.21 (s, 3H, CH3 ), 1.41 (s, 3H, CH3 ), 1.83 - 2.34 (dd, J =
13.9, 4.7 Hz, 2H, 4-H), 4.17 (d, J = 4.0 Hz, 1H, 7-H), 4.34 (dd, J = 4.0, 4.3 Hz, 1H,1H), 5.30 (dd, J = 4.0, 4.9 Hz, 1H, 5-H).
13
δ ppm = 22.4 (q, CH3 ), 22.8 (q, CH3 ), 24.8 (q, 3CH3 ), 33.9 (s, Cq), 49.7 (t, C-4), 81.6 (s,
C-3), 85.4 (d, C-1), 86.2 (d, C-5), 88.5 (d, C-7).
4.4 Photolysis of 2,3-dihydrofuran with 2-methylbutyraldehyde (sbo-237)
Under a nitrogen atmosphere, a solution of 2,3-dihydrofuran (0.7 g, 10 mmol) and 2methylbutyraldehyde (0.82 g, 10 mmol) in 100 mL benzene was irradiated in Rayonet
Photoreactor (300 nm) for 24 h. Distillation of the solvent under vacum, followed by Büchi
distillation of the residue afforded 0.9 g (90 %) of inseparable mixture of oxetanes as a colorless
oil.
endo-7-sec-Butyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-3g)153
239
___________________________________________________________________________
H
O
O
1
H
δ ppm = 0.84 - 0.97 (m, 6H, 2CH3 ), 1.28 - 1.83 (m, 4H), 2.02 (dd, J = 4.7, 5.0 Hz, 1H, 4H), 4.03 - 4.29 (m , 3H, 3-H & 5-H), 4.71 (dd, J = 3.4, 6.6 Hz, 1H, 7-H), 5.26 (dd, J =
3.2, 3.4 Hz, 1H, 1-H).
exo-7-sec-Butyl-2,6-dioxa-bicyclo[3,2,0]heptane (exo-9g)153
H
O
O
1
H
δ ppm = 0.84 - 0.97 (m, 6H, 2 CH3 ), 1.28 - 1.83 (m, 4H), 2.08 (dd, J = 4.7, 5.0 Hz, 1H,
4-H), 4.03 - 4.29 ( m, 3H, 3-H & 5-H), 4.55 (m, 1H, 7-H), 5.18 (dd, J = 4.2, 6.7 Hz,
1H, 1-H).
13
C-NMR: (75.5 MHz, CDCl3 ) (endo & exo mixture)
δ ppm = 10.6, 10.9, 11.0, 11.3 (each q), 12.5, 13.2, 13.4, 13.6 (each q), 23.7, 23.8, 23.9,
24.3 (each t), 32.9, 33.4, 33.9, 34.0 (each t), 38.0 (d, 2C), 67. 1, 67.5, 69.7, 69.9 (each
t), 78.7 (d , 2C), 79.9 (d), 80.0 (d), 83.4 (d), 83.5 (d), 84.1 (d), 84.2 (d), 89.0 (d), 89.6
(d), 90.9 (d), 91.0 (d).
4.4.1 Photolysis of 5-methyl-2,3-dihydrofuran with 2-methylbutyraldehyde (sbo-261)
Under a nitrogen atmosphere, a solution of 5-methyl-2,3-dihydrofuran (0.84 g, 10 mmol) and 2methylbutyraldehyde (0.82 g, 10 mmol) in 100 mL benzene was irradiated in Rayonet
Photoreactor (300 nm) for 24 h. Distillation of the solvent under vacum, followed by Büchi
distillation of the residue afforded 0.94 g (87 %) of inseparable mixture of oxetanes as a
colorless oil.
endo-7-sec-Butyl-1-methyl-2,6-dioxabicyclo[3.2.0]heptane (endo-9g)
H
O
O
1
240
___________________________________________________________________________
δ ppm = 0.73 (s, 3H, CH3 ), 0.81 - 0.91 (m, 6H, 2 CH3 ), 1.26 - 1.33 (m, 4H), 2.31 (dd, J =
7.4, 7.2 Hz, 2H, 4-H), 4.15 (dd, J = 7.7, 7.9 Hz, 1H, 3-H), 4.19 (m, 1H, 5-H), 4.81 (dd,
J = 4.0, 4.0 Hz, 1H, 7-H).
exo-7-sec-Butyl-1-methyl-2,6-dioxabicyclo[3.2.0]heptane (exo-9g)
H
O
O
1
δ ppm = 0.71 (s, 3H, CH3 ), 0.81-0.91 (m, 6H, 2CH3 ), 1.26 - 1.33 (m, 4H), 2.42 (dd, J =
6.9, 7.1 Hz, 2H, 4-H), 4.00 (dd, 3.5, 3.0 Hz, 1H, 3-H), 4.19 (m, 1H, 5-H), 4.65 (d, 1H,
J = 3.97 Hz, 1H, 7-H).
13
C-NMR: (75.5 MHz, CDCl3 ) (endo & exo mixture)
δ ppm = 9.7, 9.8, 9.9, 10.2 (each q), 12.6, 12.7, 13.1, 13.4 (each q), 16.0 (q), 23.2, 23.5,
23.6, 24.1 (each t), 32.1, 33.2, 33.2, 33.8 (each t), 37.2 (d, 2C), 38.1 (d, 2C), 66.3, 66.5,
69.1, 69.2 (each t), 84.3 (d, 2C), 84.5 (d), 85.1 (d), 86.3 (d), 86.7 (d), 86.8 (d), 91.8 (d),
86.7 (d).
4.5 Photolysis of furan with acetaldehyde (sbo-192)
A solution of furan (0.34 g, 5 mmol) and acetaldehyde (0.22 g, 5 mmol) in 25 mL benzene was
degassed by N2 bubbling. The test-tube shaped reaction apparatus was equipped parallel to
Rayonet lamp (300 nm) and irradiated for 24 h. The solvent was removed using a rotary
evaporator to give the products. The photolysate was analysed by 1 H-NMR in order to determine
the product ratios. Distillation of the residue yielded 0.5 g (89 %) of oxetane as a colorless
liquid.
exo-6 Methyl-2,7-dioxa-bicyclo[3.2.0]hept-3-ene (exo-16b)155
H
O
O
1
H
241
___________________________________________________________________________
δ ppm = 1.52 (d, J = 6.3 Hz, 3H, CH3 ), 3.42 (dddd, J = 1.2, 2.9, 3.1, 4.3 Hz, 1H, 5-H),
4.71 (ddq, J = 0.6, 3.1, 6.3 Hz, 1H, 6-H), 5.33 (dd, J = 2.9, 2.9 Hz, 1H, 4-H), 6.31 (d, J
= 4.3 Hz, 1H, 1-H), 6.61 (dd, J = 1.0, 2.9 Hz, 1H, 3-H).
13
δ ppm = 23.3 (q, CH3 ), 50.2 (d, C-5), 88.8 (d, C-6), 104.1 (d, C-4), 107.5 (d, C-1), 147.9
(d, C-3).
endo-6 Methyl-2,7-dioxa-bicyclo[3.2.0]hept-3-ene (endo-16b)155
H
O
O
1
H
δ ppm = 1.52 (d, J = 6.3 Hz, 3H, CH3 ), 3.42 (dddd, J = 1.2, 2.9, 3.1, 4.3 Hz, 1H, 5-H),
4.71 (ddq, J = 0.6, 3.1, 6.3 Hz, 1H, 6-H), 5.13 (dd, J = 2.9, 2.9 Hz, 1H, 4-H), 6.21 (d, J
= 4.3 Hz, 1H, 1-H), 6.61 (dd, J = 1.0, 2.9 Hz, 1H, 3-H).
13
δ ppm = 23.1 (q, CH3 ), 50.7 (d, C-5), 88.9 (d, C-6), 104.4 (d, C-4), 107.9 (d, C-1), 147.3
(d, C-3).
4.6 Determination of solvent polarity effects on the stereoselectivity of the Paternò-Büchi
reaction of 2,3-dihydrofuran with aldehydes 1b & 1c: (sbo-90, sbo-93, sbo-94, sbo-95, sbo96, sbo-97, sbo-98)
A solution of an equimolar ratio of
aldehydes and 2,3-dihydrofuran in different solvents
(acetonitrile, THF, methanol, n-hexane, benzene) was irradiated in Rayonet Photoreactor (300
nm) until complete conversion of the aldehydes. The product composition was determined
directly from crude mixture by both GC and 1 H-NMR analyses.
4.7 Determination of solvent viscosity effects on the stereoselectivity of the Paternò-Büchi
reaction of 2,3-dihydrofuran with aldehydes 1a-d: (sbo-127, sbo-141, sbo-156, sbo-158, sbo159, sbo-162)
A solution of 1M of aldehydes 1a-d and 1M of 2,3-dihydrofuran in 10 mL solvent (benzene, nhexane, acetonitrile, methanol, ethanol, propanol, octanol, glycol, 1,2-propandiol, 1,4-butanediol,
glycerol) was irradiated in quartz tube using Rayonet Photoreactor (300 nm) for 8 h. The product
composition was determined from crude mixture by GC anaylsis.
242
___________________________________________________________________________
4.8 Determination of temperature effects on the stereoselectivity of the Paternò-Büchi
reaction of 2,3-dihydrofuran with aldehydes 1a-d: (sbo-114, sbo-116, sbo-120, sbo-166, sbo167, sbo-168, sbo-198, sbo-204)
A quartz tube was charged with equimolar ratio of aldehydes and 2,3-dihydrofuran in 10 mL nhexane (both substrates 1M). The samples were put in a dewar had a window and irradiated at >
290 nm using using high pressure mercury lamp at a wide range of temperature ( from 30 °C to –
78 °C) for 8 h. The product distribution was determined directly by both GC and 1 H-NMR
analyses.
4.9 Fluorescence quenching study: (sbo-272)
Solutions of propionaldehyde (0.2 M) with various concentrations of 2,3-dihydrofuran as
quencher (0.02 – 1.00 M) were measured in benzene; both benzene and quencher showing
negligible fluorescence. Solutions were placed in 3 cm2 quartz cells after deoxygenated by N2
bubbling for 30 sec and the fluorescence spectra were recorded. The exciation wavelength was
310 nm, the intensity of the emmision (F) at the maximum (∼ 400 nm) for propionaldehyde was
compared to the intensity (F0 ) in the abscence of quencher. A stern – Volmer plot was drawn of
F0 / F versus molarity of quencher, and the slope determined at least from four points using
linear portion of the curve.
4.10 Quantum yield determination: (sbo-201)
A benzene solution of valerophenone (0.1 M) as chemical actiometer (Φ acetophenone = 0.33)90 was
irradiated parallel to the sample solution (1M of 2,3-dihydrofuran & 0.1 M of benzaldehyde) on
a merry – go – round apparatus. The reactions were monitored by GC. The intergration of the
peaks from GC were callibrated with n-undecane as internal standard. Quantum yield reported
are average of three measurement.
4.11 Preparation of trans-cyclooctene (E-17) (sbo-122)
Method (A):100
A pentane solution (150 mL) of 6.6 g (0.06 mol, 7.8 mL) of cyclooctene and 1.0 g (3.65 mmol)
of dimethylisophthalate placed in quartz photoreactor and then irradiated at 254 nm under N2
with cooling to 10°C. The irradiation was occured with RPR (254 nm) for 72 h. The irradiated
243
___________________________________________________________________________
solution was extracted with three 25 mL portions of 20% aq. Ag NO3 solution at < 5°C. The
aqueous extracts were combined, washed with two 10 mL portions of pentane at < 5°C, and then
added dropwise into a stirred conc. aq. NH3 solution (100 mL) at 0°C. The resulting mixture
was extracted with three 25 mL portions of pentane. The combined pentane extracts were
washed with water, dried over Mg SO4 , and concentrated at a reduced presure (50-100 torr) to
give an almost pure product, which was finally trap to trap distilled in vacuo to afford transcyclooctene in 13 % yield (Lit.100 , 18 %).
Method (B):101 (sbo-152)
A 150 mL quartz irradiation vessel was charged with 25 mL of cis-cyclooctene, (0.18mol) and
7.0 g of freshly cuprous chloride (0.07 mol). The vessel was fitted with a condenser and nitrogen
bubbler was purged, the mixture was irradiated at 253 nm for 24 h. The solution was then
evaporated at 1.0 mmHg to a thick oil. To this oil was added concentrated ammonia and pentane,
and it was shaken, decolorized with sodium cyanide and separted. The aqueous layer was then
extracted twice with pentane, and all pentane solutions were combined, dried over Mg SO4 , and
concentrated by distillation to ca. 50 mL. The solution was then extracted with 20% aqueous Ag
NO3 and the aqueous layer was washed once with pentane. Treatment of the aqueous layer with
concentrated ammonia followed by extractions three time with pentane. Evapouation of the
solvent and distillation of the residue under vacum yielded trans-cyclooctene 1.4 g (19 % ).101
1
δ ppm = 0.75 - 0.84 (m, 2H), 1.38 - 1.56 (m, 2H), 1.79 - 1.84 (m, 2H), 1.91 - 2.00 (m,
4H), 2.35 - 2.39 (m, 2H), 5.48-5.52 (m, 2H, CH=).
13
δ ppm = 29.3 (t), 35.7 (t), 35.8 (t), 133.9 (d, CH=).
4.11.1 General procedure for the photolyses of aldehydes (1b & 1c) with cyclooctene (Z-17
& E-17) on the analytical scale:
An equimolar ratio of cyclooctene (Z-17 or E-17) and aldehydes (1b or 1c) were dissolved in 10
mL benzene, and transfered to quartz tube. The samples were degassed for 2 min with a steady
stream of N2 gas, the quartz tubes were sealed and placed into a Rayonet Photoreactor (λ = 300
nm), and irradiated for 24 h. The solvent was evaporated (40°C, 20 torr) and the residue were
analyzed by 1 H-NMR spectroscopy to determine the diastereomeric ratios from the relative areas
of the relevant 1 H-NMR peaks.
244
___________________________________________________________________________
4.11.2 General procedure for the photolyses of aldehydes (1b & 1c) with cyclooctene (Z-17
& E-17) on the preparative scale:
The cyclooctene (1.1 g, 0.01 mol) and aldehydes (0.01 mol) were dissolved in 50 mL benzene,
the solution transfered to a vacum-jacket pyrex tube and degassed with a steady stream of
nitrogen gas. The reaction mixture was cooled to 10°C by means of a cold finger and irradiated
in a Rayonet Photoreactor (RPR λ = 300 nm) for 48 h. The solvent was evaporated (40°c, 20
torr) and the residue was purified by bulb to bulb distillation.
Irradiation of cyclooctene with propionaldehyde (sbo-107)
A solution of cyclooctene (1.1 g, 10 mmol) and propionaldehyde (0.58 g, 10 mmol) in 50 mL
residue after evaporation of the solvent yielded 1.2 g (71 %) of inseparable mixture of oxetanes
as a colorless viscous oil.
cis, cis-10-Ethyl-9-oxa-bicyclo[6.2.0]decane (cc-18)
H
O
H
1
δ ppm = 0.90 (t, J = 7.5 Hz, 3H, CH3 ), 1.64 (m, 2H, CH2 ), 0.82 - 1.92 (m, 12H, 2-H to 7H), 2.78 (ddd, J = 11.8, 7.5, 3.4 Hz, 1H, 1-H), 4.63 (dt, J = 7.5, 6.5 Hz, 1H, 10-H), 4.76
(ddd, J = 11.8, 7.5, 2.8 Hz, 1H, 8-H).
13
δ ppm = 9.2 (q), 24.8, 25.5, 25.8, 25.9, 26.6, 28.9, 30.7 (7 t), 40.7 (d, C-1), 82.5 (d, C10), 82.9 (d, C-8).
trans, cis-10-Ethyl-9-oxa-bicyclo[6.2.0]decane (tc-18)
H
O
H
1
245
___________________________________________________________________________
δ ppm = 0.93 (t, J=7.5 Hz, 3H, CH3 ), 1.73 (m, 2H, CH2 ), 0.54 - 1.77 (m, 12H, 2-H to 7H), 2.44 (ddd, J = 11.8, 7.5, 3.4 Hz, 1H, 1-H), 4.13 (dt, J = 6.5, 6.5 Hz, 1H, 10-H), 4.64
(ddd, J = 11.8, 7.9, 2.7 Hz, 1H, 8-H).
13
δ ppm = 8.23 (q), 22.7, 25.6, 25.6, 26.7, 28.3, 29.6, 32.2 (7 t ), 43.0 (d, C-1), 82.3 (d, C8), 85.9 (d, C-10).
trans, trans-10-Ethyl-9-oxa-bicyclo[6.2.0]decane (tt-18)
H
O
H
1
δ ppm = 0.91 (t, J = 6.5 Hz, 3H, CH3 ), 1.68 (m, 2H, CH2 ), 0.82 - 1.95 (m, 12H, 2-H to 7H), 2.33 (ddd, J = 10.9, 7.5, 3.2 Hz, 1H, 1-H), 4.25 (dt, J = 7.5, 6.6 Hz, 1H, 10-H), 4.53
(ddd, J = 10.9, 7.5, 3.3 Hz, 1H, 8-H).
13
δ ppm = 8.07 (q), 26.9, 28.3, 28.4, 29.0, 29.2, 30.0, 38.5 (7 t), 48.7 (d, C-1), 84.9 (d, C8), 85.6 (d, C-10).
Irradiation of cyclooctene with acetaldehyde (sbo-113)
A solution of cyclooctene (1.1 g, 10 mmol) and acetaldehyde (0.44 g, 10 mmol) in 50 mL
residue after evaporation of the solvent yielded 0.98 g (68 %) of inseparable mixture of oxetanes
as a colorless viscous oil.
cis, cis-10-Methyl-9-oxa-bicyclo[6.2.0]decane (cc-19)
H
O
H
1
δ ppm = 0.82 - 1.92 (m, 12H, 2-H to 7-H), 1.24 (d, J = 6.03 Hz, 3H, CH3 ), 2.76 (ddd, J =
11.8, 7.4, 2.8 Hz, 1H, 1-H), 4.77 (ddd, J = 11.8, 7.5, 2.8 Hz, 1H, 8-H), 4.94 (dq, J =
7.5, 6.0 Hz, 1H, 10-H).
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13
δ ppm = 18.28 (q), 22.0, 24.9, 25.8, 25.9, 26.9, 28.8 (6 t), 40.8 (d, C-1), 77.3 (d, C-10),
83.7 (d, C-8).
trans, cis-10-Methyl-9-oxa-bicyclo[6.2.0]decane (tc-19)
H
O
H
1
δ ppm = 1.06 (m, 1H), 1.15 - 1.33 (m, 6H ), 1.37 (m, 1H ), 1.40 (d, J = 6.2 Hz, 3H, CH3 ),
1.86 (m, 1H), 4.36 (dq, J = 7.9, 6.2 Hz, 1H, 10-H), 4.66 (ddd, J = 11.8, 7.9, 2.7 Hz, 1H,
8-H).
13
δ ppm = 22.6 (q), 24.8, 25.8, 25.9, 26.6, 28.9, 30.7 (6 t), 45.2 (d, C-1), 81.3 (d, C-10),
82.5 (d, C-8).
trans, trans-10-Methyl-9-oxa-bicyclo[6.2.0]decane (tt-19)
H
O
H
1
δ ppm = 1.34 (d, J = 6.5 Hz, 3H, CH3 ), 0.82 - 1.96 (m, 12H, 2-H to 7-H), 2.76 (ddd, J =
10.9, 7.5, 3.4 Hz, 1H, 1-H), 4.44 (dq, J = 7.5, 6.5 Hz, 1H, 10-H), 4.52 (ddd, J = 10.9,
7.5, 3.2 Hz, 1H, 8-H).
13
δ ppm = 22.8 (q), 26.9, 28.3, 28.4, 29.0, 29.2, 38.5 (6 t ), 51.1 (d, C-1), 80.9 (d, C-10),
85.2 (d, C-8).
Fluorescence Quenching: (sbo-273)
A propanal solution 0.2 M was prepared in benzene. A known volume of the propanal solution
was pipetted into a quartz fluorescence cell and the fluorescence was obseved using excitation
wavelength of 310 nm. Aliquots of cyclooctene was added to the solution by means of a micro
syringe while monitoring the decrease in fluoresence intensity at 420 nm.
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4.12 Synthesis of allylic alcohols and acetates
Preparation of mesitylol (22)102 (sbo-85)
OH
Under a N2 atmosphere, a solution of (50.0 g, 0.51 mol) of mesityl oxide in 100 mL of dry ether
was added dropwise to a suspention of (9.8 g, 0.26 mol) of LiAlH 4 in dry ether. After stirring for
1h at room temperature (ca. 20°C), the reaction was stopped by adding carefully 15 mL of ice
water, 15 mL of a 15% NaOH solution and 50 mL of water. The phases were separated, the
aqueous phase was extracted with ether (3 x 50 mL), the combined organic phases were dried
over MgSO4 , and the solvent was rotoevaporated (20°C, 30 torr). Fractional distillation of the
residue (B.p 52°C, 22 torr) yielded 35.0 g (70%) of 4-methyl-pent-3-en-2-ol (22) as a colorless
liquid.
1
δ = 1.15 (d, J = 6.3 Hz, 3H, CH3 ), 1.62 (d, J = 1.2 Hz, 3H, CH3 ), 1.65 (d, J = 1.2 Hz,
3H, CH3 ), 2.41 (brs, 1H, OH), 4.48 (dq, J = 8.5, 6.3 Hz, 1H, CHOH) , 5.13 (d , J=
8.5Hz ,1H, CH=)
13
δ = 17.9 (q, CH3 ), 23.5 (q, CH3 ), 25.5 (q, CH3 ), 64.5 (d, CHO), 129.3 (d, CH), 133.7
(s, Cq)
Preparation of prenyl acetate (23)103 (sbo-535)
OAc
To prenol (4.3 g, 0.05 mol), in 20 mL of dry pyridine, acetic anhydride (10 g, 0.09 mol) was
added at room temperature with stirring. After stirring overnight, the reaction mixture was
poured into water from which the product was recovered by ether extraction. Washing of the
combined extracts with 10% HCl, saturated NaHCO3 , and saturated NaCl, drying (MgSO4 ), and
248
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evaporation left the product as a yellow oil. Distillation gave a colorless oil: B.p 74°C (55
mmHg); yield 85% .
1
δ = 1.59 (s, 3H, CH3 ), 1.64 (s, 3H, CH3 ), 1.92 (s, 3H, CH3 CO), 4.46 (d, J = 7.4 Hz, 2H,
CH2 ), 5.24 (m, 1H, CH=).
13
δ = 17.6 (q, CH3 ), 20.6 (q, CH3 ), 25.4 (q, CH3 ), 61.1 (t, CH2 ), 118.6 (d, CH), 138.6 (s,
Cq), 170.8 (s, CO).
Preparation of mesityl acetate (24)104 (sbo-536)
OAc
To 4-methyl-3-penten-2-ol (5.0 g, 0.05 mol), in 20 mL of dry pyridine, acetic anhydride (10.0 g,
0.09 mol) was added at room temperature with stirring. After stirring overnight, the reaction
mixture was poured into water from which the product was recovered by
ether extraction.
Washing of the combined extracts with 10% HCl, saturated NaHCO3 , and saturated NaCl, drying
(MgSO4 ), and evaporation left the product as a yellow oil. Distillation gave a colorless oil: B.p
50-52°C (15 mmHg); yield 87% .
1
δ = 1.25 (d, J = 6.0 Hz, 3H, CH3 ), 1.70 (d, J = 1.5 Hz, 6H, 2CH3 ), 1.95 (s, 3H,
CH3 CO), 4.40 (dq, J = 9.0, 6.0 Hz, 1H, CHO), 4.85 (d, J = 9.0 Hz, 1H, CH=).
13
δ =18.2 (q, CH3 ), 20.9 (q, CH3 ), 21.4 (q, CH3 ), 25.6 (q, CH3 ), 68.1 (d, CHO), 124.9 (d,
CH), 136.2 (s, Cq), 170.4 (s, CO).
4.12.1 General procedure for the photolyses of propionaldehyde and allylic substrates
(21&23) on the analytical scale: (sbo-83, sbo-89, sbo-105)
An equimolar ratio of both allylic substrates (21 or 23) and propionaldehyde were dissolved in
10 mL benzene, and transfered to a quartz tube. The samples were degassed for 2 min with a
steady stream of N2 gas, the quartz tubes were sealed and placed into a merry-go-round system
equiped with a 125 W high pressure mercury lamp (λ > 290 nm), cooled to 13°C, and irradiated
249
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for 24h. The solvent was evaporated (40 °C, 20 torr) and the residue were analyzed by 1 H-NMR
spectroscopy to determine the diastereomeric ratios from the relative areas of the relevant 1 HNMR peaks .
4.12.2 General procedure for the photolyses of aldehydes and the allylic substrates on the
preparative scale:
The allylic substrates (2.9 mmol) and aldehydes (2.9 mmol) were dissolved in 50 mL benzene,
the solution transfered to a vacuum-jacket pyrex vessel and degassed with a steady stream of
nitrogen gas. The reaction mixture was cooled to 10 °C by means of a cold finger and irradiated
in a Rayonet photoreactor (RPR, λ = 300 nm). The solvent was evaporated (40°C, 20 torr) and
the residue was purified by Kugelrohr distillation or by silica gel preparative chromatography
using a mixture of ethyl acetate and n-hexane as eluent.
Irradiation of prenol with benzaldehyde (sbo-534a)
A solution of (0.25 g, 2.9 mmol) of prenol and (0.31 g, 2.9 mmol) of benzaldehyde in 50 mL
benzene was irradiated for 24 h according to the above general procedure. Preparative
chromatography of the residue yielded 0.32 g (65 %) of oxetane as colorless oil.
cis- (3,3-Dimethyl-4-phenyl-oxetan-2-yl)-methanol (cis-25a)
OH
O
Ph
TLC: Rf = 0.36 (ethyl acetate/n-hexane 1: 3)
IR: (Nujol)
ν~ (cm-1 ) = 3500, 3055, 1559, 1445, 1035, 975, 835, 770.
1
δ ppm = 0.54 (s, 3H, CH3 ), 1.25 (s, 3H, CH3 ), 1.55 (bs, 1H, OH), 3.51 (dd, J = 12.0, 4.3
Hz, 1H, CHOH), 3.72 (dd, J = 12.0, 7.4 Hz, 1H, CHOH), 4.52 (dd, J = 4.3, 7.4 Hz, 1H,
2-H) , 5.31 (s, 1H, 4-H), 7.12 - 7.14 (m, 5H, Harom.).
13
δ ppm = 16.9 (q, CH3 ), 27.5 (q, CH3 ), 42.0 (s, C-3), 62.9 (t, CH2 O) , 87.8 (d, C-2), 89.3
(d, C-4), 124.9 (d, CHarom.), 125.4 (d, CHarom.), 127.3 (d, CHarom.), 128.0 (d, CHarom.),
139.4 (s, Cqarom).
250
___________________________________________________________________________
MS: (EI, 70 eV)
m/z (%) = 191 (M+-1, 38), 161 (25), 105 (75), 91 (24), 85 (42), 77 (45), 71 (100).
HRMS: (C 12 H16 O2 , M = 192.11 g/mol)
Calcd:
192.1072
Found:
192.1070
Irradiation of prenol with acetaldehyde (sbo-548)
A solution of (0.25 g, 2.9 mmol) of prenol and (0.13 g, 2.9 mmol) of acetaldehyde in 50 mL
residue ( B.p = 65-68 °C, 10 torr) yielded 0.28 g (75 %) of oxetane as a colorless oil.
cis- (3,3,4-Trimethyl-oxetan-2-yl)-methanol (cis-25b)
OH
O
IR: (Nujol)
ν~ (cm-1 ) = 3515, 30330, 1538, 1425, 1055, 972, 885, 770.
1
δ ppm = 1.01 (s, 3H, CH3 ), 1.17 (s, 3H, CH3 ), 1.19 (d, J = 6.5 Hz, 3H, CH3 ), 1.25 (bs,
1H, OH), 3.60 (dd, J =12.1, 4.8 Hz, 1H, CHOH), 3.70 (dd, J =12.1, 6.5 Hz, 1H,
CHOH), 4.37 (dd, J = 4.3, 6.5 Hz, 1H, 2-H), 4.52 (q, J = 6.5 Hz, 1H, 2-H).
13
δ ppm = 15.5 (q, CH3 ), 17.6 (q, CH3 ), 27.7 (q, CH3 ), 39.4 (s, C-3), 63.1 (t, CH2 O), 85.2
(d, C-2), 87.7 (d, C-4).
Anal: (C 7 H14 O2 , M = 140.1 g/mol)
Calcd:
C 64.58 H 10.84
Found:
C 63.98 H 10.37
trans- (3,3,4-Trimethyl-oxetan-2-yl)-methanol (trans-25b)
OH
O
251
___________________________________________________________________________
1
δ ppm = 1.02 (s, 3H, CH3 ), 1.09 (s, 3H, CH3 ), 1.26 (d, J = 4.4Hz, 3H, CH3 ), 3.73 (dd, J =
12.0, 6.9 Hz, 1H, CHOH), 3.77 (dd, J = 12.0, 4.3Hz, 1H, CHOH), 4.12 (dd, J = 4.3, 6.9
Hz, 1H, 4-H), 4.75 (q, J = 4.4 Hz, 1H, 2-H).
13
δ ppm = 20.5 (q, CH3 ), 24.6 (q, CH3 ), 30.3 (q, CH3 ), 40.1 (s, C-3), 67.2 (t, CH2 O), 90.2
(d, C-2), 95.7 (d, C-4).
Irradiation of prenol with propionaldehyde (sbo-529)
A solution of (0.25 g, 2.9 mmol) of prenol and (0.17 g, 2.9 mmol) of propionaldehyde in 50 mL
cis- 4-Ethyl-(3,3-dimethyl-oxetan-2-yl)-methanol (cis-25c)
OH
O
IR: (Nujol)
ν~ (cm-1 ) = 3508, 3058, 1534, 1445, 1035, 970, 865, 778.
1
δ ppm = 0.62 (t, J = 7.4 Hz, 3H, CH3 ), 0.81 (s, 3H, CH3 ), 0.96 (s, 3H, CH3 ), 1.25 (s, 1H,
OH), 1.35 (m, 2H, CH2 ), 3.33 (dd, J = 12.0, 4.9 Hz, 1H, CHOH), 3.44 (dd, J = 12.0,
6.6Hz, 1H, CHOH), 4.15 (dd, J = 4.9, 6.6 Hz, 1H, 2-H), 4.23 (dd, J = 6.3, 7.8 Hz, 1H,
4-H).
13
δ ppm = 8.2 (q, CH3 ), 14.3 (q, CH3 ), 24.3 (t, CH2 ), 38.6 (s, C-3), 61.9 (t, CH2 O), 86.6 (d,
C-2), 89.4 (d, C-4).
MS: (EI, 70 eV)
m/z (%) = 127 (M+-OH, 30), 111 (25), 109 (30), 97 (27), 85 (87), 71 (50), 69 (82), 59
(23), 57 (100).
Anal: (C 8 H16 O2 , M = 144.2 g/mol)
Calcd:
C 66.63 H 11.18
Found:
C 66.61 H 11.20
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trans- 4-Ethyl-(3,3-dimethyl-oxetan-2-yl)-methanol (trans-25c)
OH
O
1
δ ppm = 0.62 (t, J = 7.5 Hz, 3H, CH3 ), 0.87 (s, 3H, CH3 ), 0.92 (s, 3H, CH3 ), 1.30 (m, 2H,
CH2 ), 3.53 (dd, J = 12.0, 3.8, 1H, CHOH), 3.62 (dd, J = 12.0, 6.8, 1H, CHOH), 3.83
(dd, J = 7.4, 9.0 Hz, 1H, 4-H), 3.93 (dd, J = 3.8, 6.8 Hz, 1H, 2-H).
13
δ ppm = 9.0 (q, CH3 ), 20.0 (q, CH3 ), 23.5 (t, CH2 ), 29.0 (q, CH3 ), 37.3 (s, C-3), 56.4 (t,
CH2 O), 87.0 (d, C-2), 90 (d, C-4).
Irradiation of prenol with 3-methylbutyraldehyde (sbo-530)
A solution of (0.25 g, 2.9 mmol) of prenol and (0.25 g, 2.9 mmol) of 3-methylbutyraldehyde in
the residue ( B.p = 84 °C, 10 torr) yielded 0.37 g (80 %) of oxetane as a pale yellow oil.
cis- (4-Isobutyl-3,3-dimethyl-oxetan-2-yl)-methanol (cis-25d)
OH
O
IR: (Film)
ν~ (cm-1 ) = 3406, 2956, 2871, 1467, 1385, 1169, 1042, 997.
1
δ ppm = 0.85 (d, J = 6.5 Hz, 3H, CH3 ), 0.88 (d, J = 6.5Hz, 3H, CH3 ), 0.89 (m, 1H, CH),
1.02 (s, 3H, CH3 ), 1.19 (s, 3H, CH3 ), 1.25 (bs, 1H, OH), 1.35 (m, 2H, CH2 ), 3.55 (dd, J
= 12.0, 4.4 Hz, 1H, CHOH), 3.65 (dd, J =12.0, 6.5 Hz, 1H, CHOH), 4.31 (dd, J = 4.4,
6.5 Hz, 1H, 2-H), 4.5 (dd, J = 4., 8.5 Hz, 1H, 4-H).
13
δ ppm = 15.67 (q, CH3 ), 22.4 (q, CH3 ), 23.2 (q, CH3 ), 24.6 (d, CH), 27.7 (q, CH3 ), 39.7
(t, CH2 ), 41.1 (s, C-3), 63.0 (t, CH2 O), 87.3 (d, C-2), 87.5 (d, C-4).
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Anal: (C 10 H20 O2 , M = 172.2 g/mol)
Calcd:
C 69.72 H 11.70
Found:
C 69.45 H 12.00
trans- (4-Isobutyl-3,3-dimethyl-oxetan-2-yl)-methanol (trans-25d)
OH
O
1
δ ppm = 0.86 (d, J = 6.5 Hz, 6H, 2CH3 ), 0.91 (m, 1H), 1.13 (s, 3H, CH3 ), 1.32 (s, 3H,
CH3 ), 1.35 (bs, 1H, OH), 1.42 (m, 2H, CH2 ), 3.70 (dd, J = 12.0, 4.0 Hz, 1H, CHOH),
3.75 (dd, J = 12.0, 6.5 Hz, 1H, CHOH), 3.82 (dd, J = 4.0, 6.5 Hz, 1H, 2-H), 4.2 (dd, J =
4.5, 8.0 Hz, 1H, 4-H).
13
δ ppm = 15.7 (q, CH3 ), 22.4 (q, CH3 ), 23.2 (q, CH3 ), 24.6 (d, CH), 27.7 (q, CH3 ), 39.7 (t,
CH2 ), 41.1 (s, C-3), 63.0 (t, CH2 O), 87.3 (d, C-2), 87.5 (d, C-4).
Irradiation of prenyl acetate with benzaldehyde (sbo-537a)
A solution of (0.35 g, 3.0 mmol) of prenyl acetate and (0.32 g, 3.0 mmol) of benzaldehyde in 50
mL benzene was irradiated for 24 h according to the above general procedure. Preparative
chromatography of the residue yielded 0.37 g (75 %) of oxetane as a colorless oil.
cis-3,3-Dimethyl-4-phenyl-oxetan-2-ylmethylacetate (cis-26a)
OAc
O
Ph
IR: (Film)
ν~ (cm-1 ) = 3100, 2989, 1742, 1559, 1445, 1035, 975, 835, 770.
1
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δ ppm = 0.68 (s, 3H, CH3 ), 1.40 (s, 3H, CH3 ), 2.08 (s, 3H, CH3 CO), 4.18 (dd, J = 12.0,
6.9 Hz, 1H, CHOAc), 4.23 (dd, J =12.0, 4.9 Hz, 1H, CHOAc), 4.70 (dd, J = 6.9, 4.9
Hz, 1H, 2-H), 5.47 (s, 1H, 4-H), 7.12 - 7.28 (m, 5H, Harom.).
13
δ ppm = 17.1 (q, CH3 ), 20.9 (q, CH3 ), 27.4 (q, CH3 ), 42.5 (s, C-3), 64.8 (t, CH2 OAc),
84.5 (d, C-2) , 89.4 (d, C-4), 125.7 (d, CHarom.), 127.3 (d, CHarom.), 136.4 (s, Cqarom.),
170.7 (s, CO).
Anal: (C 14 H18 O3 , M = 234.2 g/mol)
Calcd:
C 71.77 H 7.74
Found:
C 71.64 H 7.70
Irradiation of prenyl acetate with acetaldehyde (sbo-549b)
A solution of (0.35 g, 3.0 mmol) of prenyl acetate and (0.32 g, 3.0 mmol) of acetaldehyde in 50
mL benzene was irradiated for 24 h according to the above general procedure. Preparative
cis-3,3,4-Trimethyl-oxetan-2-ylmethylacetate (cis-26b)
OAc
O
IR: (Film)
ν~ (cm-1 ) = 2965, 1737, 1547, 1462, 1380, 1020, 970, 855, 770.
1
δ ppm = 1.03 (s, 3H, CH3 ), 1.18 (d, J = 6.5 Hz, 3H, CH3 ), 1.20 (s, 3H, CH3 ), 2.04 (s, 3H,
CH3 CO), 4.10 (dd, J = 12.0, 7.6 Hz, 1H, CHOAc), 4.17 (dd, J = 12.0, 4.3 Hz, 1H,
CHOAc), 4.64 (dd, J = 7.6, 4.3 Hz, 1H, 2-H), 4.53 (q, J = 6.5 Hz, 1H, 4-H).
13
δ ppm = 15.6 (q, CH3 ), 17.5 (q, CH3 ), 20.8 (q, CH3 ), 27.1 (q, CH3 ), 39.8 (s, C-3), 65.2 (t,
CH2 OAc), 84.4 (d, C-2), 85.1 (d, C-4), 170.9 (s, CO).
Anal: (C 10 H18 O3 , M = 186.3 g/mol)
Calcd:
C 64.49 H 9.74
Found:
C 64.87 H 9.68
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trans-3,3,4-Trimethyl-oxetan-2-ylmethylacetate (trans-26b)
OAc
O
1
δ ppm = 1.00 (s, 3H, CH3 ), 1.05 (s, 3H, CH3 ), 1.26 (d, J = 6.4Hz, 3H, CH3 ), 1.97 (s, 3H,
CH3 CO), 3.98 (dd, J = 12.0, 6.9 Hz, 1H, CHOH), 4.17 (dd, J = 12.0, 4.4 Hz, 1H,
CHOH), 4.12 (dd, J = 4.4, 6.9 Hz, 1H, 4-H), 4.65 (q, J = 6.4 Hz, 1H, 2-H).
13
δ ppm = 18.4 (q, CH3 ), 20.8 (q, CH3 ), 24.8 (q, CH3 ), 32.3 (q, CH3 ), 40.0 (s, C-3), 67.7 (t,
CH2 O), 86.6 (d, C-2), 87.7 (d, C-4), 171.3 (s, CO).
Irradiation of prenyl acetate with propionaldehyde (sbo-543)
A solution of (0.35 g, 3.0 mmol) of prenyl acetate and (0.20 g, 3.0 mmol) of propionaldehyde in
50 mL benzene was irradiated for 24 h according to the above general procedure. Preparative
cis-4-Ethyl-3,3-dimethyl-oxetan-2-ylmethylacetate (cis-26c)
OAc
O
IR: (Nujol)
ν~ (cm-1 ) = 3085, 2980, 1740, 1490, 1475, 1380, 1245, 1035, 970, 865, 710.
1
δ ppm = 0.77 (t, J = 7.5 Hz, 3H, CH3 ), 0.84 (m, 2H, CH2 ), 1.00 (s, 3H, CH3 ), 1.15 (s, 3H,
CH3 ), 1.95 (s, 3H, CH3 CO), 4.12 (dd, J = 12.0, 7.6 Hz, 1H, CHOAc), 4.16 (dd, J
=12.0, 4.4 Hz, 1H, CHOAc), 4.22 (dd, J = 6.2, 7.8Hz, 1H, 2-H), 4.43 (dd, J = 4.4, 7.6
Hz, 1H, 4-H).
13
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δ ppm = 9.1 (q, CH3 ), 15.3 (q, CH3 ), 20.7 (q, CH3 ), 27.4 (q, CH3 ), 32.0 (t, CH2 ), 39.9 (s,
C-3), 64.9 (t, CH2 OAc), 83.9 (d, C-2), 90.3 (d, C-4), 170.1 (s, CO ).
Anal: (C 10 H18 O3 , M = 186.13 g/mol)
Calcd:
C 64.49 H 9.74
Found:
C 64.38 H 9.48
trans-4-Ethyl-3,3-dimethyl-oxetan-2-ylmethylacetate (trans-26c)
OAc
O
1
δ ppm = 0.62 (t, J = 7.5 Hz, 3H, CH3 ), 0.87 (s, 3H, CH3 ), 0.92 (s, 3H, CH3 ), 1.30 (m, 2H,
CH2 ), 2.12 (s, 3H, CH3 CO), 3.59 (dd, J = 12.0, 3.8 Hz, 1H, CHOAc), 3.64 (dd, J =
12.0, 7.8, 1H, CHOAc), 3.89 (dd, J = 7.8, 9.0 Hz, 1H, 4-H), 3.99 (dd, J = 3.8, 7.8 Hz,
1H, 2-H).
13
δ ppm = 9.4 (q, CH3 ), 20.4 (q, CH3 ), 22.8 (q, CH3 ), 23.8 (t, CH2 ), 29.3 (q, CH3 ), 39.3 (s,
C-3), 59.4 (t, CH2 O), 84.8 (d, C-2), 90.6 (d, C-4), 171.2 (s, CO).
Irradiation of prenyl acetate with 3-methylbutyraldehyde (sbo-546d)
A solution of (0.35 g, 3.0 mmol) of prenyl acetate and (0.26 g, 3.0 mmol) of 3methylbutyraldehyde in 50 mL benzene was irradiated for 24 h according to the above general
procedure. Preparative chromatography of the residue yielded 0.39 g (80 %) of oxetane as a
colorless oil.
cis-4-Isobutyl-3,3-dimethyl-oxetan-2-ylmethylacetate (cis-26d)
OAc
O
1
δ ppm = 0.88 (d, J = 6.5 Hz, 6H, 2CH3 ), 0.99 (s, 3H, CH3 ), 1.13 (s, 3H, CH3 ), 1.30 (m,
1H, CH), 1.55 (m, 2H, CH2 ), 2.04 (s, 3H, CH3 CO), 4.05 (dd, J = 12.0, 7.6 Hz, 1H,
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CHOAc), 4.17 (dd, J = 12.0, 4.4 Hz, 1H, CHOAc) , 4.43 (dd, J = 4.4, 7.6 Hz, 1H, 2-H),
4.46 (dd, J = 4.7, 7.9 Hz, 1H, 4-H).
13
δ ppm = 15.7 (q, CH3 ), 22.3 (q, CH3 ), 20.9 (q, CH3 ), 22.4 (q, CH3 ), 24.4 (d, CH), 27.1 (q,
CH3 ), 40.2 (s, C-3), 41.0 (t, C-2), 65.1 (t, CH2 OAc), 84.1 (d, C-2), 87.4 (d, C-4), 170.9
(s, CO).
Anal: (C 12 H22 O3 , M = 214.16 g/mol)
Calcd:
C 67.26 H 10.35
Found:
C 67.17 H 10.32
trans-4-Isobutyl-3,3-dimethyl-oxetan-2-ylmethylacetate (trans-26d)
OAc
O
1
δ ppm = 0.86 (d, J = 6.5 Hz, 6H, 2CH3 ), 0.91 (m, 1H), 1.13 (s, 3H, CH3 ), 1.32 (s, 3H,
CH3 ), 1.42 (m, 2H, CH2 ), 2.00 (s, 3H, CH3 CO), 4.05 (dd, J = 12.0, 4.0 Hz, 1H,
CHOAc), 4.17 (dd, J = 12.0, 6.5 Hz, 1H, CHOAc), 4.28 (dd, J = 4.0, 6.5 Hz, 1H, 2-H),
4.44 (dd, J = 4.5, 8.0 Hz, 1H, 4-H).
13
CH3 ), 39.8 (s, C-3), 41.1 (t, CH2 ), 63.9 (t, CH2 O), 85.3 (d, C-2), 87.5 (d, C-4), 171.3 (s,
CO).
Irradiation of mesitylol with acetaldehyde (sbo-554)
A solution of (0.3 g, 3.0 mmol) of mesitylol and (0.25 g, 3.5 mmol) of acetaldehyde in 50 mL
threo-1-(3,3,4-Trimethyl-oxetan-2-yl)-ethanol (threo-27b)
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___________________________________________________________________________
OH
O
IR: (Nujol)
ν~ (cm-1 ) = 3514, 3068, 1536, 1453, 1031, 975, 868, 777.
1
δ ppm = 0.91 (s, 3H, CH3 ), 0.93 (d, J = 6.5 Hz, 3H, CH3 ), 1.05 (s, 3H, CH3 ), 1.09 (d, J =
6.5Hz, 3H, CH3 ), 3.75 (dq, J = 8.4, 6.2 Hz, 1H, CHOH), 3.92 (d, J = 8.4Hz, 1H, 2-H),
4.42 (q, J = 6.5 Hz, 1H, 2-H).
13
δ ppm = 14.7 (q, CH3 ), 16.8 (q, CH3 ), 17.1 (q, CH3 ), 26.2 (q, CH3 ), 38.5 (s, C-3), 66.5 (d,
CHOH), 83.1 (d, C-2), 90.5 (d, C-4).
Anal: (C 8 H16 O2 , M = 144.12 g/mol)
Calcd:
C 66.63 H 11.18
Found:
C 66.60 H 11.12
Irradiation of mesitylol with propionaldehyde (sbo-104)
A solution of (0.3 g, 3.0 mmol) of mesitylol and (0.20 g, 3.0 mmol) of propionaldehyde in 50
threo-1-(4-Ethyl-3,3-dimethyl-oxetan-2-yl)-ethanol (threo-27c)
OH
O
IR: (Nujol)
ν~ (cm-1 ) = 3510, 3050, 1544, 1435, 1039, 978, 885, 773.
1
δ ppm = 0.77 (t, J = 7.5 Hz, 3H, CH3 ), 0.91 (d , J = 6.2 Hz, 3H, CH3 ), 0.95 (s, 3H, CH3 ),
1.07 (s, 3H, CH3 ), 1.45 (m, 2H, CH2 ), 3.73 (dq, J = 8.4, 6.2 Hz, 1H, CHOH), 3.92 (d, J
= 8.4 Hz, 1H, 2-H), 4.12 (dd, J = 6.4, 7.7 Hz, 1H, 4-H).
13
259
___________________________________________________________________________
δ ppm = 8.4 (q, CH3 ), 14.7 (q, CH3 ), 17.3 (q, CH3 ), 24.2 (t, CH2 ), 26.7 (q, CH3 ), 38.8 (s,
C-3), 66.6 (d, CHO), 88.6 (d, C-2), 90.0 (d, C-4).
Anal: (C 9 H18 O2 , M = 158.2 g/mol)
Calcd:
C 68.31 H 11.47
Found:
C 68.57 H 11.32
Irradiation of mesitylol with 3-methylbutyraldehyde (sbo-559a)
A solution of (0.3 g, 3.0 mmol) of mesitylol and (0.25 g, 3.0 mmol) of 3-methylbutyraldehyde in
the residue ( B.p = 80-82 °C, 10 torr) yielded 0.43 g (84 %) of oxetane as a colorless oil.
threo-1-(4-Isobutyl-3,3-dimethyl-oxetan-2-yl)-ethanol (threo-27d)
OH
O
1
δ ppm = 0.86 (d, J = 6.6 Hz, 3H, CH3 ), 0.92 (d, J = 6.6 Hz, 3H, CH3 ), 1.02 (d, J = 6.2 Hz,
3H, CH3 ), 1.03 (s, 3H, CH3 ), 1.18 (s, 3H, CH3 ), 1.30 (m, 1H, CH), 1.53 (m, 2H, CH2 ),
3.83 (dq, J = 8.1, 6.2 Hz, 1H, CHOH), 3.92 (d, J = 8.1 Hz, 1H, 2-H), 4.42 (dd, J = 4.7,
8.7 Hz, 1H, 2-H).
13
CH3 ), 39.5 (s, C-3), 41.0 (t, CH2 ), 67.6 (d, CHO), 86.47 (d, C-2), 90.6 (d, C-4).
Anal: (C 11 H12 O2 , M = 186.2 g/mol)
Calcd:
C 70.92 H 11.90
Found:
C 70.43 H 11.64
Irradiation of mesityl acetate with acetaldehyde (sbo-134)
A solution of (0.47 g, 3.0 mmol) of mesityl acetate and (0.32 g, 3.8 mmol) of acetaldehyde in 50
residue afforded 0.42 g (75 %) of the product as a pale yellow oil.
threo-1-(3,3,4-Trimethyl-oxetan-2-yl)-ethylacetate (threo-28b)
260
___________________________________________________________________________
OAc
O
1
δ ppm = 1.02 (d, J = 6.5 Hz, 3H, CH3 ),1.13 (s, 3H, CH3 ), 1.20 (d, J = 6.5 Hz, 3H, CH3 ),
1.25 (s, 3H, CH3 ), 4.12 (dq, J = 9.2, 6.5 Hz, 1H, CHOAc), 4.46 (d, J = 9.2 Hz, 1H, 2H), 4.55 (q, J = 6.5 Hz, 1H, 2-H).
13
CHOAc), 86.4 (d, C-2), 98.2 (d, C-4), 171.4 (s, CO).
erythro-1-(3,3,4-Trimethyl-oxetan-2-yl)-ethylacetate (erythro-28b)
OAc
O
1
δ ppm = 1.05 (d, J = 6.5 Hz, 3H, CH3 ),1.17 (s, 3H, CH3 ), 1.26 (d, J = 6.5 Hz, 3H, CH3 ),
1.29 (s, 3H, CH3 ), 4.32 (dq, J = 6.2, 6.5 Hz, 1H, CHOAc), 4.47 (d, J = 6.2 Hz, 1H, 2H), 4.62 (q, J = 6.5 Hz, 1H, 2-H).
13
CHOAc), 88.4 (d, C-2), 97.6 (d, C-4), 171.7 (s, CO).
261
___________________________________________________________________________
4.13 Synthesis of oxazole substrates
Preparation of glycine methyl ester hydrochloride (30)156 (sbo-370)
-
+
ClH3N
CO2CH3
A 250 mL two necked round bottomed flask containing a magnetic stirring bar, is equipped
with a dropping funnel, reflux condenser protected from moisture by a CaCl2 tube and a
rubber septum. The dropping funnel is charged with (4.2 mL, 60 mmol) of thionyl chloride.
The flask is charged with 50 mL of absolute methanol and cooled with ice-salt bath to -10°C.
Thionyl chloride is added dropwise over a period of 5 min. The solution is stirred for a further
5 min, then glycine (2.25 g, 30 mmol) is added in one portion and the solution is slowly
heated to reflux. The reflux is continued for 3 h, then the solution is allowed to cool to room
temperature and the solvent is removed under reduced pressure to give glycine methyl ester
hydrochloride as a white crystalline material.
Yield: 92 %
M.p: 175-176 °C (Lit.156 , 180°C).
1
δ ppm = 3.54 (s, 3H, OCH3 ), 3.97 (s, 2H, CH2 ), 8.64 (s, 3H, NH3 ).
13
δ ppm = 42.5 (t, CH2 ), 52.1 (q, OCH3 ), 170.1 (s, CO).
Preparation of N-acetyl glycine methyl ester (31)157 (sbo-370a)
AcHN
CO2CH3
To a stirred suspension of glycine methyl ester hydrochloride (3.0 g, 24 mmol) in chloroform
(50 mL) was added triethyl amine (6.7 mL, 53 mmol) at 0°C and the mixture was stirred for 5
min at room temperature. The acetyl chloride (2.1 g, 26 mmol) was added dropwise and
stirring was continued for 30 min, the solvent was removed under reduced pressure; ethyl
acetate (300 mL) was added and the mixture was filtered through a pad of silica gel.
Evaporation of the solvent under reduced pressure afforded 3.0 g of N-acetyl glycine methyl
ester as white solid.
Yield: 96 %
M.p: 53-55 °C (Lit.157 , 58-59°C).
1
δ ppm = 1.90 (s, 3H, CH3 CO), 3.52 (s, 3H, OCH3 ), 3.75 (d, J = 5.7 Hz, 2H, CH2 ).
262
___________________________________________________________________________
13
δ ppm = 22.0 (q, CH3 ), 40.7 (t, CH2 ), 51.7 (q, OCH3 ), 170.2 (s, CON), 170.9 (s, CO).
Synthesis of 2-methyl-5-methoxyoxazole (32)111 (sbo-417)
H
N
H3C
O
OCH3
Method (A):112
A mixture of (13.1 g, 0.1 mol) N-acetyl glycine methyl ester and (40.0 g, 0.15 mol) of
phosphorous pentoxide in (100 mL) chloroform was heated to reflux with mechanical stirring
for a period of 24 h. After cooling to room temperature, the residual phosphorous pentoxide
was carefully crushed, and the resulting thick suspension was slowly added, in small portions,
to ice-cold saturated sodium bicarbonate maintaining the pH of 6-7. The organic layer was
separated and the aqueous layer was extracted with 4 x 75 mL of methylene chloride. The
combined extracts were then washed with brine, dried over anhydrous magnesium sulphate,
concentrated and distilled to afford 10.0 g (80 %) as a colorless oil.
Method (B):111
N-Acetyl glycine methyl ester (655 mg, 5 mmol) was added to phosphorous oxychloride (2.3
mL, 25 mmol) and heated at reflux temperature for 4 h. After cooling to room temperature,
the reaction mixture was poured onto crushed ice with stirring and neutralized with 20% aq.
KOH solution. It was extracted with chloroform (3 x 15 mL), washed with water (2 x 15 mL),
and brine solution (20 mL). The organic phase was dried over anhydrous Na2 SO4 , the solvent
was removed in vacuo and the residual oil was distilled over Kugelrohr apparatus to give the
product (32) as a colorless liquid.
Yield: 70 %
B.p: 64-66°C, 10 torr (Lit.,113 60°C, 0.2 mmHg).
UV/Vis: (CH3 CN, c = 1.6 x 10-4 mol/l, d = 1 cm)
λmax (nm, log ε) = 220 (4.18).
IR: (Nujol)
ν~ (cm-1 ) = 2984, 1623, 1580, 1283, 1084, 980, 770.
1
δ ppm = 2.27 (s, 3H, CH3 ), 3.79 (s, 3H, OCH3 ), 5.87 (s, 1H, CH).
13
δ ppm = 13.9 (q, CH3 ), 58.4 (q, OCH3 ), 97.8 (d, C-4), 152.0 (s, C-5), 160.5 (s, C-2).
263
___________________________________________________________________________
Synthesis of amino acid methyl ester hydrochloride 34a-f ; General procedure:
A 250 mL, two-necked, round-bottomed flask, contanining a magnetic stirring bar, is
equipped with a dropping funnel, reflux condenser protected from moisture by a calcium
chloride-filled drying tube and a rubber septum. The dropping funnel is charged with (4.2 mL,
60 mmol) of thionyl chloride. The flask is charged with 50 mL of absolute methanol and
cooled with ice-salt bath to (-10°C). Thionyl chloride is added dropwise over a period of 5
min. The solution is stirred for a further 5 min, then solid (L)-amino acid (30 mmol) is added
in one portion and the solution is slowly heated to reflux. The reflux is continued for 3 h, then
the solution is allowed to cool to room temperature and the solvent is removed under reduced
pressure to give aminoacid methyl ester hydrochloride as a white crystalline solid that is used
without further purification.
L-Alanine methyl ester hydrochloride (34a)158 (sbo-289)
-
+
ClH3N
CO2 CH3
The reaction was carried out according to the above general procedure using L-alanine (2.67
g, 30 mmol) and thionyl chloride (4.2 mL, 60 mmol) to give 3.85 g of the product as a white
powder.
Yield: 92 %
M.p: 151-153°C (Lit.158 , 154-155°C).
1
δ ppm = 1.72 (d, J = 7.2 Hz, 3H, CH3 ), 3.79 (s, 3H, OCH3 ), 4.26 (m, 1H, CHN), 8.67
(bs, 3H, NH3 ).
13
δ ppm = 16.0 (q, CH3 ), 49.3 (d, CHN), 53.2 (q, OCH3 ), 170.5 (s, CO).
2-Amino butyric acid methyl ester hydrochloride (34b) 159 (sbo-363)
-
+
ClH3N
CO2 CH3
The reaction was carried out according to the above general procedure using 2-amino butyric
acid (3.1 g, 30 mmol) and thionyl chloride (4.2 mL, 60 mmol) to give 4.4 g of the product as a
white powder.
264
___________________________________________________________________________
Yield: 96 %
M.p: 1444-146 °C (Lit.159 , 145-146°C).
1
δ ppm = 1.06 (t, J = 6.8 Hz, 3H, CH3 ), 2.06 (quintet, J = 6.8 Hz, 2H, CH2 ), 3.77 (s,
3H, OCH3 ), 4.12 (d, J = 6.8 Hz, 1H, CHN), 8.69 (bs, 3H, NH3 ).
13
δ ppm = 9.6 (q, CH3 ), 23.7 (t, CH2 ), 52.9 (q, OCH3 ), 54.4 (d, CHN), 169.8 (s, CO).
L-Norvaline methyl ester hydrochloride (34c)160 (sbo-330)
-
+
ClH3N
CO2 CH3
The reaction was carried out according to the above general procedure using norvaline (3.51
powder.
Yield: 95 %
M.p: 86-88°C (Lit.160 , 85°C).
1
δ ppm = 0.71 (t, J = 7.5 Hz, 3H, CH3 ), 1.14 (sextet, J = 7.5 Hz, 2H, CH2 ), 1.43 (m,
2H, CH2 ), 3.56 (s, 3H, OCH3 ), 4.41 (m, 1H, CHN), 8.61 (bs, 3H, NH3 ).
13
δ ppm = 13.0 (q, CH3 ), 22.1 (t, CH2 ), 33.7 (t, CH2 ), 51.6 (q, OCH3 ), 51.7 (d, CHN),
173.0 (s, CO).
L-Valine methyl ester hydrochloride (34d) 161 (sbo-315)
-
+
ClH3N
CO2 CH3
The reaction was carried out according to the above general procedure using L-valine (3.51 g,
30 mmol) and thionyl chloride (4.2 mL, 60 mmol) to give 4.5 g of the product as a white
powder.
Yield: 90 %
M.p: 178-179°C (Lit.161 , 180°C).
265
___________________________________________________________________________
1
δ ppm = 0.85 (d, J = 7.5 Hz, 6H, 2CH3 ), 2.0 (m, 1H, CH), 3.70 (s, 3H, OCH3 ), 4.51
(m, 1H, CHN), 8.50 (bs, 3H, NH3 ).
13
δ ppm = 17.7 (q, CH3 ), 18.7 (q, CH3 ), 30.0 (d, CH), 51.9 (q, OCH3 ), 56.0 (d, CHN),
173.0 (s, CO).
L-Leucine methyl ester hydrochloride (34e)162 (sbo-329a)
-
+
ClH3N
CO2CH3
The reaction was carried out according to the above general procedure using L-leucine (3.93
powder.
Yield: 93 %
M.p: 151-153°C (Lit.162 , 153-154°C).
1
δ ppm = 0.80 (d, J = 6.0 Hz, 6H, 2CH3 ), 1.47 (m, 1H, CH), 1.57 (m, 2H, CH2 ), 3.71
(s, 3H, OCH3 ), 4.41 (m, 1H, CH), 8.64 (bs, 3H, NH3 ).
13
δ ppm = 21.8 (q, CH3 ), 22.6 (q, CH3 ), 24.7 (d, CH), 41.9 (t, CH2 ), 51.0 (q, OCH3 ),
52.3 (d, CHN), 173.7 (s, CO).
L-Isoleucine methyl ester hydrochloride (34f)163 (sbo-327)
-
+
ClH3N
CO2 CH3
The reaction was carried out according to the above general procedure using L-isoleucine
(3.93 g, 30 mmol) and thionyl chloride (4.2 mL, 60 mmol) to give 5.1 g of the product as a
white powder.
Yield: 94 %
M.p: 118-120°C (Lit.163 , 117-119°C).
1
266
___________________________________________________________________________
δ ppm = 0.87 (d, J = 7.0 Hz, 6H, 2CH3 ), 1.17 (m, 2H, CH2 ), 1.90 (m, 1H, CH), 3.67
(s, 3H, OCH3 ), 4.51 (m, 1H, CHN), 8.70 (bs, 3H, NH3 ).
13
δ ppm = 11.0 (q, CH3 ), 15.3 (q, CH3 ), 25.2 (t, CH2 ), 37.0 (d, CH), 51.0 (q, OCH3 ),
56.0 (d, CHN), 173.0 (s, CO).
Synthesis of N-acetylamino acid methy ester 35a-f; General procedure:
To a stirred suspension of amino acid methyl ester hydrochloride (100 mmol) in absolute
chloroform (150 mL) was added triethyl amine (28 mL , 200 mmol) at 0°C and the mixture
was stirred for 15 min at room temperature. The acetyl chloride (7.2 mL, 100 mmol) was
added dropwise and stirring was continued for 45 min. The solvent was removed under
reduced pressure; ethyl acetate (750 mL) was added and the mixture was filtered through a
pad of silica gel. Evaporation of the solvent under reduced pressure afforded the amide in
high purity.
Methyl 2-acetylaminopropionate (35a)164 (sbo-292)
AcHN
CO2 CH3
Alanine methyl ester hydrochloride (13.96 g, 0.1 mol) and acetyl chloride (7.2 mL, 0.1 mol)
were allowed to react according to the above general procedure to give 13.1 g of methyl 2acetylaminopropionate as a white powder.
Yield: 90 %
M.p: 45-47 °C (Lit.164 , 47-48°C).
1
δ ppm = 1.34 (d, J = 7.2 Hz, 3H, CH3 ), 1.98 (s, 3H, CH3 CO), 3.70 (s, 3H, OCH3 ),
4.51 (m, 1H, CHN).
13
δ ppm = 17.3 (q, CH3 ), 22.2 (q, CH3 ), 47.6 (d, CHN), 51.8 (q, OCH3 ), 170.0 (s,
CON), 173.2 (s, CO).
Methyl 2-acetylaminobutyrate (35b) 165 (sbo-364)
AcHN
CO2 CH3
267
___________________________________________________________________________
2-Acetylamino butyric acid methyl ester hydrochloride (15.4 g, 0.1 mol) and acetyl chloride
(7.2 mL, 0.1 mol) were allowed to react according to the above general procedure to give 14.9
g of methyl 2-acetylaminopentanoate as a white powder.
Yield: 94 %
M.p: 43-45 °C (Lit.165 , 44-45°C).
1
δ ppm = 0.72 (t, J = 7.5 Hz, 3H, CH3 ), 1.45 (septet, J = 7.4 Hz, 1H, CH), 1.66 (d, J =
7.5 Hz, 1H, CH), 1.82 (s, 3H, CH3 CO), 3.52 (s, 3H, OCH3 ), 4.29 (m, 1H, CHN),
6.94 (d, J = 7.7 Hz, 1H, NH).
13
δ ppm = 9.4 (q, CH3 ), 22.4 (q, CH3 ), 24.8 (t, CH2 ), 51.7 (q, OCH3 ), 53.1 (d, CHN),
170.3 (s, CON), 172.7 (s, CO).
Methyl 2-acetylaminopentanoate (35c)166 (sbo-342)
AcHN
CO2 CH3
Norvaline methyl ester hydrochloride (16.8 g, 0.1 mol) and acetyl chloride (7.2 mL, 0.1 mol)
were allowed to react according to the above general procedure to give 15.6 g of methyl 2acetylaminopentanoate as a white powder.
Yield: 90 %
M.p: 78-79 °C (Lit.166 , 78°C).
1
δ ppm = 0.72 (t, J = 7.5 Hz, 3H, CH3 ), 1.16 (sextet, J = 7.5 Hz, 2H, CH2 ), 1.50 (m,
2H, CH2 ), 1.83 (s, 3H, CH3 CO), 3.53 (s, 3H, OCH3 ), 4.38 (m, 1H, CHN), 6.94 (d, J
= 7.2 Hz, 1H, NH).
13
δ ppm = 13.2 (q, CH3 ), 18.3 (q, CH3 ), 22.3 (t, CH2 ), 33.7 (t, CH2 ), 51.7 (d, CHN),
51.8 (q, OCH3 ), 170.3 (s, CON), 173.0 (s, CO).
Methyl 2-acetylamino-3-methylbutyrate (35d) 167 (sbo-315a)
Ac HN
CO2 CH3
268
___________________________________________________________________________
Valine methyl ester hydrochloride (16.8 g, 0.1 mol) and acetyl chloride (7.2 mL, 0.1 mol)
were allowed to react according to the above general procedure to give 15.9 g of methyl 2acetylamino-3-methylbutyrate as a white powder.
Yield: 92 %
M.p: 67-68 °C (Lit.167 , 68-69°C).
1
δ ppm = 0.83 (d, J = 9.4 Hz, 3H, CH3 ), 0.86 (d, J = 9.4 Hz, 3H, CH3 ), 1.97 (s, 3H,
CH3 CO), 2.06 (m, 1H, CH), 3.67 (s, 3H, OCH3 ), 4.49 (dd, 1H, J = 5.1, 2.5 Hz, 1H,
CHN), 6.13 (d, J = 5.1Hz, 1H, NH).
13
δ ppm = 17.7 (q, CH3 ), 18.7 (q, CH3 ), 23.0 (q, CH3 ), 31.1 (d, CH), 51.9 (q, OCH3 ),
56.9 (d, CHN), 169.9 (s, CON), 172.6 (s, CO).
Methyl 2-acetylamino-4-methylpentanoate (35e)168 (sbo-329)
AcHN
CO2CH3
Leucine methyl ester hydrochloride (18.2 g, 0.1 mol) and acetyl chloride (7.2 mL, 0.1 mol)
were allowed to react according to the above general procedure to give 17.6 g of methyl 2acetylamino-4-methylpentanoate as a white powder.
Yield: 94 %
M.p: 75-77 °C (Lit.168 , 77°C).
1
(s, 3H, CH3 CO), 3.66 (s, 3H, OCH3 ), 4.56 (ddd, J = 7.8, 5.2, 4.9 Hz, 1H, CHN),
6.30 (d, 1H, J = 7.8 Hz, 1H, NH).
13
δ ppm = 21.8 (q, CH3 ), 22.6 (q, CH3 ), 22.9 (q, CH3 ), 24.7 (d, CH), 41.4 (t, CH2 ), 50.6
(q, OCH3 ), 52.1 (d, CHN), 170.0 (s, CON), 173.7 (s, CO).
Methyl 2-acetylamino-3-methylpentanoate (35f)169 (sbo-332)
269
___________________________________________________________________________
AcHN
CO2 CH3
Isoleucine methyl ester hydrochloride (18.2 g, 0.1 mol) and acetyl chloride (7.2 mL, 0.1 mol)
were allowed to react according to the above general procedure to give 17.77 g of methyl 2acetylamino-3-methylpentanoate as a white powder.
Yield: 95 %
M.p: 54-56 °C (Lit.169 , 54-55°C).
1
δ ppm = 0.84 (d, J = 7.1 Hz, 6H, 2CH3 ), 1.13 (m, 1H, CH), 1.98 (s, 3H, CH3 CO), 3.70
(s, 3H, OCH3 ), 4.57 (m, 1H, CH), 6.14 (bs, 1H, NH).
13
δ ppm = 11.5 (q, CH3 ), 15.3 (q, CH3 ), 23.1 (q, CH3 ), 25.2 (t, CH2 ), 37.9 (d, CH), 52.0
(q, OCH3 ), 56.4 (d, CHN), 169.9 (s, CON), 172.6 (s, CO).
Synthesis of 4-substituted 2-methyl-5-methoxyoxazoles (36a-f); General procedure:
N-Acetyl-L-amino acid methyl ester (0.1 mol) was dissolved in 20 ml of chloroform in a 250
ml flask, 20.8 g (0.1 mol) of phosphorous pentachloride was added and the flask was fitted
with a calcium chloride tube. The solution was gently warmed by means of a water bath (ca.
60 °C) with stirring until the HCl gas evolution ceased and the solution became intensively
yellow. Then, the flask was cooled by an ice-salt bath and 50 ml of absolute ether was added.
To the cooled mixture, 20 % aqueous KOH was added dropwise until neutralization with
vigorous stirring. The mixture was stirred at room temperature for 30 min. The organic layer
was subsequently separated and the aqueous layer was extracted with 2 x 200 mL of ether.
The combined organic extracts were washed with water and brine and dried over anhydrous
MgSO4. After removal of the solvents under vacum, the remaining oil was distilled by a Büchi
Kugelrohr apparatus to give the product 36a-f.
2,4-Dimethyl-5-methoxyoxazole (36a)170 (sbo-295)
CH3
N
H3C
O
270
OCH3
___________________________________________________________________________
Reaction of methyl N-acetylamino alaninate (14.5 g, 0.1 mol) and PCl5 (20.8 g, 0.1 mol)
according to the above general procedure afforded 7.6 g of 2,4-dimethyl-5-methoxyoxazole as
a colorless liquid.
Yield: 60 %
B.p: 61-63 °C, 10 torr.
IR: (Film)
ν~ (cm-1 ) = 2943, 1625, 1598, 1440, 1341, 1052, 967.
1
δ ppm = 1.96 (s, 3H, CH3 ), 2.27 (s, 3H, CH3 ), 3.83 (s, 3H, OCH3 ).
13
δ ppm = 9.8 (q, CH3 ), 14.1 (q, CH3 ), 61.2 (q, OCH3 ), 111.2 (s, C-4), 151.9 (s, C-5),
154.6 (s, C-2).
4-Ethyl-2-methyl-5-methoxyoxazole (36b) 115 (sbo-365)
N
H3C
O
OCH3
Reaction of methyl 2-acetylamino butyrate (15.9 g, 0.1 mol) and PCl5 (20.8 g, 0.1 mol)
according to the above general procedure afforded 10.4 g of 4-ethyl-2-methyl-5methoxyoxazole as a colorless liquid.
Yield: 74 %
B.p: 64-67 °C, 10 torr (Lit.115 , 65 °C, 10 torr).
1
δ ppm = 1.07 (t, J = 7.5 Hz, 3H, CH3 ), 2.22 (s, 3H, CH3 ), 2.28 (q, J=7.5 Hz, 2H, CH2 ),
3.77 (s, 3H, OCH3 ).
13
δ ppm = 13.0 (q, CH3 ), 14.1 (q, CH3 ), 17.9 (t, CH2 ), 61.2 (q, OCH3 ), 117.1 (s, C-4),
151.8 (s, C-5), 154.0 (s, C-2).
2-Methyl-4-propyl-5-methoxyoxazole (36c) (sbo-343)
N
H3 C
O
271
OCH3
___________________________________________________________________________
Reaction of methyl N-acetylamino norvalinate (17.3 g, 0.1 mol) and PCl5 (20.8 g, 0.1 mol)
according to the above general procedure afforded 10.5 g of 2-methyl-4-propyl-5methoxyoxazole as a colorless liquid.
Yield: 68 %
B.p: 75-78 °C, 10 torr.
1
δ ppm = 0.83 (t, J = 7.5 Hz, 3H, CH3 ), 1.52 (sextet, J = 7.5 Hz, 2H, CH2 ), 2.21 (t, J =
7.5 Hz, 2H, CH2 ), 2.22 (s, 3H, CH3 ), 3.77 (s, 3H, OCH3 ).
13
δ ppm = 13.6 (q, CH3 ), 14.1 (q, CH3 ), 21.7 (t, CH2 ), 26.5 (t, CH2 ), 115.6 (s, C-4),
151.9 (s, C-5), 154.6 (s, C-2).
4-Isopropyl-2-methyl-5-methoxyoxazole (36d) 115 (sbo-322)
N
H3C
O
OCH3
Reaction of methyl N-acetylamino valinate (17.3 g, 0.1 mol) and PCl5 (20.8 g, 0.1 mol)
according to the above general procedure afforded 10.0 g of 4-isopropyl-2-methyl-5methoxyoxazole as a colorless liquid.
Yield: 65 %
B.p: 71-73 °C, 10 torr (Lit.,115 72°C, 10 torr).
1
δ ppm = 1.09 (d, J=7.1 Hz, 6H,2CH3 ), 2.20 (s, 3H, CH3 ), 2.65 (septet, J=7.1 Hz, 1H,
CH), 3.75 (s, 3H, OCH3 ).
13
δ ppm = 14.1 (q, CH3 ), 21.5 (q, CH3 ), 24.7 (d, CH), 61.2 (q, OCH3 ), 121.1 (s, C-4),
151.8 (s, C-5), 153.2 (s, C-2).
4-Isobutyl-2-methyl-5-methoxyoxazole (36e)115 (sbo-331)
N
H3C
O
272
OCH3
___________________________________________________________________________
Reaction of methyl N-acetylamino leucinate (18.7 g, 0.1 mol) and PCl5 (20.8 g, 0.1 mol)
according to the above general procedure afforded 11.8 g of 4-isobutyl-2-methyl-5methoxyoxazole as a colorless liquid.
Yield: 70 %
B.p: 86-88 °C, 10 torr (Lit.115 , 88°C, 10 torr).
1
δ ppm = 0.80 (d, J = 6.8 Hz, 6H, 2CH3 ), 1.79 (sextet, J = 6.6 Hz, 1H, CH), 2.08 (d, J =
6.8 Hz, 2H, CH2 ), 2.19 (s, 3H, CH3 ), 3.74 (s, 3H, OCH3 ).
13
(q, OCH3 ), 114.8 (s, C-4), 151.7 (s, C-5), 154.9 (s, C-2).
4-sec-Butyl-2-methyl-5-methoxyoxazole (36f) (sbo-333)
N
H3C
O
OCH3
Reaction of methyl N-acetylamino isoleucinate (18.7 g, 0.1 mol) and PCl5 (20.8 g, 0.1 mol)
according to the above general procedure afforded 12.7 g of 4-sec-butyl-2-methyl-5methoxyoxazole as a colorless liquid.
Yield: 75 %
B.p: 89-93 °C, 10 torr.
1
δ ppm = 0.77 (t, J = 7.4 Hz, 3H, CH3 ), 1.12 (d, J = 7.1 Hz, 3H, CH3 ), 1.50 (m, 2H,
CH2 ), 2.26 (s, 3H, CH3 ), 2.42 (m, 1H, CH), 3.79 (s, 3H, OCH3 ).
13
(q, OCH3 ), 119.9 (s, C-4), 152.1 (s, C-5), 154.1 (s, C-2).
4.14 Photolyses of 2-methyl-5-methoxyoxazole (32) with aldehydes (37a-f); General
procedure:
2-Methyl-5-methoxyoxazole 32, (0.56 g, 0.005 mol) and aldehydes (0.005 mol) were
dissolved in 50 mL benzene, the solution transfered to a vacuum-jacket quartz tube and
degassed with a steady stream of N2 gas. The reaction mixture was irradiated at 10°C in a
273
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Rayonet photoreactor (RPR 300 nm) for 24 h. The solvent was evaporated (40°C, 20 torr) and
the residue was submitted to 1 H-NMR analysis to determine the diastereomeric ratio of the
photoadducts. Purification was carried out by bulb to bulb distillation. The thermally and
hydrolytically unstable primary products could in most cases not be characterized by
combustion analysis and were hydrolyzed subsequently to the more stable α-amino-βhydroxy esters.
exo-5-Methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-38a)
(sbo-419)
H3C
N
O
H
O
Ph
H
OCH3
A solution of benzaldehyde (0.53 g, 5 mmol) and 2-methyl-5-methoxyoxazole (0.57 g, 5
mmol) in benzene (50 mL) was irradiated for 24h according to the above general procedure.
Distillation of the solvent under vaccum afforded 0.82 g of the oxetane as a pale yellow oil.
The product was thermally unstable and was subsequently hydrolyzed to give the
corresponding α-amino-β-hydroxy ester (see later).
Yield: 75 %
IR: (Film)
ν~ (cm-1 ) = 2987, 1635, 1600, 1558, 1440, 1341, 1012, 967.
1
δ ppm = 2.11 (s, 3H, CH3 ), 3.79 (s, 3H, OCH3 ), 4.58 (d, J = 7.7 Hz, 1H, 1-H), 5.68 (d,
J = 7.7 Hz, 1H, 7-H), 7.26-7.31 (m, 5H, Harom).
13
δ ppm = 15.9 (q, CH3 ), 52.8 (q, OCH3 ), 76.2 (d, C-1), 83.0 (d, C-7), 122.9 (s, C-5),
125.4 (d, CHarom), 126.2 (d, CHarom), 128.1 (d, CHarom), 134.3 (s, Cqarom), 167.7 (s,
C-3).
HRMS: (C 12 H13 NO3 , M = 219.09 g/mol)
Calcd: 219.0892
Found: 219.0886
exo-5-Methoxy-3-methyl-7-naphthalen-2-yl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-38b) (sbo-428)
274
___________________________________________________________________________
H
H3C
N
O
O
H
OCH3
A solution of 2-naphthaldehyde (0.78 g, 5 mmol) and 2-methyl-5-methoxyoxazole (0.57 g, 5
Yield: 82 %
1
δ ppm = 2.00 (s, 3H, CH3 ), 3.76 (s, 3H, OCH3 ), 4.62 (d, J = 7.8 Hz, 1H, 1-H), 5.91 (d,
J = 7.8 Hz, 1H, 7-H), 7.25-8.00 (m, 7H, Harom).
13
δ ppm = 15.5 (q, CH3 ), 51.9 (q, OCH3 ), 78.0 (d, C-1), 84.1 (d, C-7), 123.1 (s, C-5),
Cqarom), 139.1 (s, Cqarom), 168.0 (s, C-3).
exo-5-Methoxy-3-methyl-7-phenethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-38c)
(sbo-439)
H3C
N
O
H
O
H
OCH3
A solution of 3-phenylpropionaldehyde (0.67 g, 5 mmol) and 2-methyl-5-methoxyoxazole
(0.57 g, 5 mmol) in benzene (50 mL) was irradiated for 24h according to the above general
procedure. Distillation of the solvent under vaccum afforded 0.98 g of the oxetane as a pale
yellow oil. The product was thermally unstable and was subsequently hydrolyzed to give the
Yield: 79 %
1
275
___________________________________________________________________________
δ ppm = 1.99 (s, 3H, CH3 ), 2.08 (m, 2H, CH2 ), 2.82 (m,2H, CH2 ), 3.69 (s, 3H, OCH3 ),
4.87 (d, J = 5.2 Hz, 1H, 1-H), 4.91 (dd, J = 5.2, 3.4 Hz, 1H, 7-H), 7.20-7.28 (m, 5H,
Harom).
13
δ ppm = 15.9 ( q, CH3 ), 27.9 (t, CH2 ), 35.1 (t, CH2 ), 52.2 (q, OCH3 ), 73.3 (d, C-1),
73.6 (d, C-7), 124.5 (s, C-5), 125.7 (d, Carom), 127.6 (d, Carom), 135.5 (s, Cqarom),
169.6 (s, C-3).
exo-7-Ethyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene (exo-38d)
(sbo-422)
H3C
N
O
H
O
H
OCH3
A solution of propionaldehyde (0.29 g, 5 mmol) and 2-methyl-5-methoxyoxazole (0.57 g, 5
Yield: 89 %
1
δ ppm = 0.98 (t, J = 7.5 Hz, 3H, CH3 ), 1.25 (m, 2H, CH2 ), 2.07 (s, 3H, CH3 ), 3.83 (s,
3H, OCH3 ), 5.04 (d, J = 7.4 Hz, 1H, 1-H), 5.24 (ddd, J = 11.6, 7.4, 4.7 Hz, 1H, 7H).
13
δ ppm = 8.7 (q, CH3 ), 14.7 (q, CH3 ), 24.7 (t, CH2 ), 52.2 (q, OCH3 ), 73.3 (d, C-1), 75.5
(d, C-7), 124.6 (s, C-5), 167.5 (s, C-3).
exo-7-Isopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(sbo-435)
H
H3C
N
O
O
276
H
OCH3
(exo-38e)
___________________________________________________________________________
A solution of isobutyraldehyde (0.36 g, 5 mmol) and 2-methyl-5-methoxyoxazole (0.57 g, 5
Yield: 84 %
1
δ ppm = 1.05 (d, J = 6.2 Hz, 6H, 2CH3 ), 1.54 (m, 1H, CH), 1.95 (s, 3H, CH3 ), 3.65 (s,
3H, OCH3 ), 4.52 (d, J = 3.5 Hz, 1H, 1-H), 4.64 (dd, J=3.5, 7.9 Hz, 1H, 7-H).
13
78.4 (d, C-1), 87.3 (d, C-7), 124.6 (s, C-5), 170.3 (s, C-3).
exo-7-Isobutyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-38f)
(sbo-427)
H3C
N
O
H
O
H
OCH3
A solution of 3-methylbutyraldehyde (0.43 g, 5 mmol) and 2-methyl-5-methoxyoxazole (0.57
g, 5 mmol) in benzene (50 mL) was irradiated for 24h according to the above general
Yield: 85 %
1
(s, 3H, CH3 ), 3.65 (s, 3H, OCH3 ), 4.32 (d, J = 4.2 Hz, 1H, 1-H), 4.44 (dd, J = 4.2,
6.8 Hz, 1H, 7-H).
13
(q, OCH3 ), 80.8 (d, C-1), 84.5 (d, C-7), 144.7 (s, C-5), 167.4 (s, C-3).
HRMS: (C 10 H17 NO3 , M = 199.12 g/mol)
Calcd: 199.1275
277
___________________________________________________________________________
Found: 199.1271
4.14.1 Ring opening of the bicyclic oxetanes (exo-38a-f); General procedure:
A (0.002 mol) of bicyclic oxetanes 38a-f was dissolved in 20 mL of methylene chloride and
0.5 ml of conc. HCl was added. The mixture is stirred in an open flask at room temperature
for 2 h and the reaction was controled by TLC. When the reaction is finished, the reaction
mixture was poured into water and extract with methylene chloride. The organic layer was
washed with 5 % NaHCO3 , brine, dried over anhydrous MgSO4 . The solvent was removed in
vacuo and the residual oil was purified by preparative chromatography using a mixture of
ethyl acetate and n-hexane as eluent.
Synthesis of erythro (S*,S*) α -acetamido-β
β -hydroxy esters 39a-f:
erythro-Methyl (2S* ,3S*) 2-acetylamino-3-hydroxy-3-phenylpropionate (erythro-39a)117
(sbo-419a)
HO
AcHN
CO2 CH3
According to the the above general procedure, the bicyclic oxetane 38a (0.44 g, 2 mmol) was
cleaved hydrolytically in 3h. Preparative chromatography yielded 0.33 g of the product as a
colorless oil.
Yield: 70 %
TLC: Rf = 0.34 (ethylacetate/n-hexane 1: 4)
1
δ ppm = 2.07 (s, 3H, CH3 CO), 3.97 (s, 3H, OCH3 ), 4.45 (d, J = 9.7 Hz, 1H, CHN),
5.85 (d, J = 9.7 Hz, 1H, CHOH), 6.37 (bs, 1H, NH), 7.28-7.35 (m, 5H, Harom).
13
δ ppm = 23.7 (q, CH3 ), 52.4 (q, OCH3 ), 75.4 (d, C-2), 81.6 (d, C-3), 126.2 (d, CHarom),
128.9 (d, CHarom), 129.6 (d, CHarom), 134.3 (s, Cqarom), 169.3 (s, CON), 170.3 (s,
COO).
Anal: (C 12 H15 NO4 , M = 237.10 g/mol)
Calcd:
C 60.75 H 6.37 N 5.90
Found:
C 60.86 H 6.52 N 6.00
278
___________________________________________________________________________
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-3-naphthalen-2-yl-propionate
(erythro-39b) (sbo-428a)
HO
AcHN
CO2CH3
According to the the above general procedure, the bicyclic oxetane 38b (0.54 g, 2 mmol) was
colorless oil.
Yield: 75 %
1
δ ppm = 2.12 (s, 3H, CH3 CO), 3.85 (s, 3H, OCH3 ), 4.47 (d, J = 9.6 Hz, 1H, CHN),
5.91 (d, J = 9.6 Hz, 1H, CHOH), 6.24 (bs, 1H, NH), 7.25-8.04 (m, 7H, Harom).
13
δ ppm = 23.0 (q, CH3 ), 51.9 (q, OCH3 ), 76.1 (d, C-2), 83.1 (d, C-3), 126.7 (d, CHarom),
128.5 (d, CHarom), 129.1 (d, CHarom), 134.5 (s, Cqarom), 135.7 (s, Cqarom), 139.1 (s,
Cqarom), 169.3 (s, CON), 172.0 (s, COO).
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-5-phenylpentanoate
(erythro-39c)
(sbo-439a)
HO
AcHN
CO2CH3
According to the the above general procedure, the bicyclic oxetane 38c (0.49 g, 2 mmol) was
colorless oil.
Yield: 65 %
1
δ ppm = 1.97 (s, 3H, CH3 CO), 2.43 (m, 2H, CH2 ), 2.89 (m,2H, CH2 ), 3.74 (s, 3H,
OCH3 ), 4.84 (dd, J=3.2, 8.2 Hz, 1H, CHN), 5.06 (dd, J = 3.2, 7.4 Hz, 1H, CHOH),
6.24 (bs, 1H, NH), 7.12-7.28 (m, 5H, Harom).
279
___________________________________________________________________________
13
δ ppm = 23.1 (q, CH3 ), 30.6 (t, CH2 ), 36.4 (t, CH2 ), 52.6 (q, OCH3 ), 55.0 (d, C-2),
73.8 (d, C-3), 126.2 (d, CHarom), 128.5 (d, CHarom), 129.3 (d, CHarom), 140.6 (s,
Cqarom), 169.8 (s, CON), 172.8 (s, COO).
HRMS: (C 15 H21 NO4 , M = 279.15 g/mol)
Calcd: 279.1465
Found: 279.1458
erythro-Methyl (2S*, 3S*) 2-acetylamino-3-hydroxy pentanoate (erythro-39d)171
(sbo-422b)
HO
AcHN
CO2CH3
According to the the above general procedure, the bicyclic oxetane 38d (0.34 g, 2 mmol) was
colorless oil.
Yield: 72 %
IR: (Film)
ν~ (cm-1 ) = 3320, 3300, 2989, 1725, 1648, 1440, 1341, 1052, 967.
1
δ ppm = 1.06 (t, J = 7.5 Hz, 3H, CH3 ), 1.67 (m, 2H, CH2 ), 2.03 (s, 3H, CH3 CO), 3.77
(s, 3H, OCH3 ), 4.01 (dd, J = 8.2, 4.7 Hz, 1H, CHN), 4.88 (dd, J = 8.2, 3.4 Hz, 1H,
CHOH).
13
δ ppm = 11.5 (q, CH3 ), 23.1 (q, CH3 ), 28.6 (t, CH2 ), 52.6 (q, OCH3 ), 56.5 (d, C-2),
65.3 (d, C-3), 169.1 (s, CON), 169.6 (s, COO).
erythro-Methyl (2S*,3S*) 2-acetylamino-3-hydroxy-4-methylpentanoate (erythro-39e)118
(sbo-435a)
HO
AcHN
CO2CH3
280
___________________________________________________________________________
According to the the above general procedure, the bicyclic oxetane 38e (0.37 g, 2 mmol) was
colorless oil.
Yield: 78 %
1
δ ppm = 0.93 (d, J = 6.6 Hz, 3H, CH3 ), 0.98 (d, J = 6.8 Hz, 3H, CH3 ), 1.67 (m, 1H,
CH), 2.04 (s, 3H, CH3 CO), 3.76 (s, 3H, OCH3 ), 4.45 (dd, J = 8.6, 3.3 Hz, 1H,
CHN), 4.75 (dd, J = 7.4, 3.3 Hz, 1H, CHOH).
13
54.3 (d, C-2), 69.8 (d, C-3), 169.3 (s, CON), 171.1 (s, COO).
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-5-methylhexanoate
(erythro-39f)
(sbo-427b)
HO
AcHN
CO2CH3
According to the the above general procedure, the bicyclic oxetane 38f (0.4 g, 2 mmol) was
colorless oil.
Yield: 74 %
1
(s, 3H, CH3 CO), 3.75 (s, 3H, OCH3 ), 4.18 (ddd, J = 7.6, 3.2, 4.7 Hz, 1H, CHN),
4.87 (dd, J = 8.2, 3.2 Hz, 1H, CHOH).
13
(q, OCH3 ), 56.8 (d, C-2), 61.8 (d, C-3), 169.3 (s, CON), 171.3 (s, COO)
HRMS: (C 10 H19 NO4 , M = 217.13 g/mol)
Calcd:
217.1287
Found:
217.1281
281
___________________________________________________________________________
Independent synthesis of methyl (2S*,3R*) 2-acetylamino-3-hydroxy butanoate (threo39g)116
(sbo-425a)
HO
AcHN
CO2CH3
A 100 mL, three-necked, round bottomed flask, containing a magnetic stirring bar, is
equipped with a dropping funnel and reflux condenser. The dropping funnel is charged with
7.8 mL of acetyl chloride. The flask is charged with 50 mL of methanol and cooled with an
ice-bath to 0°C. Acetyl chloride is added dropwise over a period of 10 min. The solution is
stirred for a further 5 min, then L-threonine (4.5 g, 38 mmol) is added in one portion and the
solution is slowly heated to reflux. Reflux is continued for 3h, then the solution is allowed to
cool to room temperature and the solvent is reomved under reduced pressure to give 4.8 g (94
%) of methyl threoniate hydrochloride.
A 250 mL two necked flask, is equipped with a magnetic stirring bar, reflux condenser and a
pressure-equalizing dropping funnel that is charged with acetyl chloride (2.1 mL, 30 mmol).
Methyl threoniate hydrochloride (4.6 g, 30 mmol) is placed in the flask and suspended in 100
mL of chloroform and triethyl amine (7.6 mL, 60 mmol). The resulting white suspension is
cooled with an ice-bath and the solution of acetyl chloride is added dropwise over a period of
30 min. After 15 min of additional stirring, the ice-bath is removed and the suspension is
stirred for a further 2h. The solvent was removed under vacuo, ethylacetate (150 mL) was
added and the mixture was filtered through a pad of silica gel, evapouation of the solvent
under reduced pressure afforded 4.9 g (89 %) of N-acetyl methyl threoniate as white crystal.
M.p: 106-108°C (Lit.116 , 105-106°C).
1
δ ppm = 0.92 (d, J = 6.4 Hz, 3H, CH3 ), 1.97 (s, 3H, CH3 CO), 3.59 (s, 3H, OCH3 ),
4.16 (ddq, J = 2.6, 6.0, 6.4 Hz, 1H, CHOH), 4.35 (dd, J = 8.8, 2.6 Hz, 1H, CHN).
13
δ ppm = 13.4 (q, CH3 ), 20.2 (q, CH3 ), 52.1 (q, OCH3 ), 57.6 (d, C-2), 67.3 (d, C-3),
171.3 (s, CON), 171.4 (s, COO).
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4.14.2
Synthesis
of
(Z)-α
α ,β
β -didehydroamino
acid
derivatives
(40a-d); General
procedure:
The aldol product (1 mmol) was added to methylene chloride (15 mL) previously saturated
with conc. HCl for 5 min and the solution stirred at room temperature until TLC indicated
completion of the reaction. The reaction mixture was then washed with saturated NaHCO3 ,
saturated NaCl, dried over anhydrous Na2 SO4 and then evaporated. The residue was purified
by preparative thick-layer chromatography.
Methyl 2-acetylamino-3-phenylacrylate (Z-40a)172 (sbo-419b)
According
to
the
the
above
H
CO2CH3
Ph
NHAc
general
procedure,
methyl
2-acetylamino-3-hydroxy-3-
phenylpropionate 39a (0.24 g, 1 mmol) was dehydrated in 20h. Preparative chromatography
yielded 0.17 g of the product as a colorless oil which was solidified from a mixture of
chloroform and petroleum ether as a white powder.
Yield: 80 %
M.p: 122-124°C (Lit.172 , 125°C).
TLC: Rf = 0.52 (ethylacetate/n-hexane 1:4)
1
δ ppm = 2.05 (s, 3H, CH3 CO), 3.82 (s, 3H, OCH3 ), 6.73 (s, 1H, CH=), 7.23-7.35 (m,
5H, Harom).
13
δ ppm = 22.5 (q, CH3 ), 52.1 (q, OCH3 ), 123.6 (d, CHolefin ), 125.2 (d, CHarom), 126.2
(d, Carom), 127.3 (d, CHarom), 135.5 (s, Cqolefin ), 135.9 (s, Cqarom), 165.1 (s, CON),
168.3 (s, COO).
Methyl 2-acetylamino-pent-2-enoate (Z-40b)173 (sbo-422c)
H
CO2CH3
NHAc
According to the the above general procedure, methyl 2-acetylamino-3-hydroxypentanoate
39d (0.19 g, 1 mmol) was dehydrated in 24h. Preparative chromatography yielded 0.13 g of
283
___________________________________________________________________________
the product as a colorless oil which was solidified by treatment with petroleum ether as a
white powder.
Yield: 75 %
M.p: 55-56°C (Lit.173 , 58-60°C).
1
(s, 3H, OCH3 ), 6.84 (t, J=7.5 Hz, 1H, CH=).
13
δ ppm = 9.5 (q, CH3 ), 21.7 (q, CH3 ), 24.5 (t, CH2 ), 52.1 (q, OCH3 ), 125.1 (d, CHolefin ),
138.1 (s, Cqolefin ), 165.1 (s, CON), 167.1 (s, COO).
Methyl 2-acetylamino-4-methyl-pent-2-enoate (Z-40c)174 (sbo-435b)
H
CO2CH3
NHAc
According
to
the
the
above
general
procedure,
methyl
methylpentanoate 39e (0.2 g, 1 mmol) was dehydrated in 24h. Preparative chromatography
yielded 0.14 g of the product as a colorless oil which was solidified by treatment with
petroleum ether as a white powder.
Yield: 78 %
M.p: 71-72°C (Lit.174 , 73-75°C).
1
δ ppm = 0.98 (d, J = 6.8 Hz, 6H, 2 CH3 ), 1.35 (m, 1H, CH), 2.06 (s, 3H, CH3 CO),
3.82 (s, 3H, OCH3 ), 6.54 (d, J = 6.6 Hz, 1H, CH=).
13
124.1 (d, CHolefin ), 139.1 (s, Cqolefin ), 165.1 (s, CON), 167.5 (s, COO).
Methyl 2-acetylamino-5-methyl-hex-2-enoate (Z-40d)175 (sbo-427c)
CO2CH3
H
NHAc
284
___________________________________________________________________________
According
to
the
the
above
general procedure,
methyl
methylhexanoate 39f (0.22 g, 1 mmol) was dehydrated in 24h. Preparative chromatography
yielded 0.17 g of the product as a colorless oil which was solidified by treatment with
petroleum ether as a white powder.
Yield: 83 %
M.p: 66-68°C (Lit.175 , 70-71°C).
IR: (Film)
ν~ (cm-1 ) = 3305, 2978, 1698, 1627, 1580, 1440, 1340, 1062, 987.
1
(s, 3H, OCH3 ), 6.70 (t, J = 7.2 Hz, 1H, CH=), 6.84 (s, 1H, NH).
13
(q, OCH3 ), 125.3 (s, Cqolefin ), 138.2 (d, CHolefin ), 165.1 (s, CON), 168.3 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 199 (M+, 5), 168 (M+-OMe, 8), 167 (M+-MeOH, 13), 156 (M+-COMe,
22), 125 (10), 114 (100), 97 (12), 55 (17), 54 (65).
HRMS: (C 10 H17 NO3 , M = 199.12 g/mol)
Calcd:
199.1208
Found:
199.1203
4.14.3 Synthesis of methyl 1-methyl isoquinoline-3-carboxylate (41)121 (sbo-419c)
CO2 CH3
N
CH3
To a solution of (Z)-2-acetylamino-3-phenylacrylate (0.21 g, 0.001 mol) in methylene
chloride (20 mL), phosphorous oxychloride (0.2 g, 0.0015 mol) was added, and the mixture
was warmed at 60 °C for 2 h. After the reaction was quenched with saturated sodium
bicarbonate (25 mL), the mixture was extracted with methylene chloride (3 x 10 mL) and
dried over MgSO4 . After removal of the solvent, the residue was purified by preparative
chromatography to give 0.29 g of the product as a white powder.
Yield: 78 %
285
___________________________________________________________________________
M.p: 105-107°C (Lit.,121 104-105°C).
IR: (CsI)
ν~ (cm-1 ) = 2985, 1685, 1620, 1600, 1550, 1013, 970.
1
δ ppm = 3.03 (s, 3H, CH3 ), 4.03 (s, 3H, OCH3 ), 7.72 (t, J = 1.7 Hz, 1H, 7-Harom), 7.74
(t, J = 1.7 Hz, 1H, 6-Harom), 7.93 (dd, J = 1.7, 2.2 Hz, 1H, 5-Harom), 8.17 (m, 1H, 8Harom), 8.44 (s, 1H, 4-H).
13
δ ppm = 22.7 (q, CH3 ), 52.9 (q, OCH3 ), 125.8 (d, CHarom), 128.7 (d, CHarom), 128.9 (s,
Cqarom),129.4 (d, CHarom), 130.7 (d, CHarom), 135.5 (s, Cqarom), 140.4 (s, C-3), 159.4
(s, C-1), 166.5 (s, CO).
4.15 Photolyses of 4-substituted 2-methyl-5-methoxyoxazoles 36a-f with aldehydes 37a-f;
General procedure:
5-Methoxyoxazoles (0.005 mol) and aldehydes (0.005 mol) were dissolved in 50 mL of
benzene, the solution transfered to a vacuum-jacket quratz vessel and degassed with a steady
stream of N2 gas. The reaction mixture was irradiated at 10°C in a Rayonet photoreactor (RPR
300 nm) for 24 h. The solvent was evaporated (40°C , 20 torr) and the residue was analyzed
by 1 H-NMR analysis. Purification was carried out by bulb to bulb distillation. The thermally
and hydrolytically unstable primary products could in most cases not be characterized by
combustion analysis and were hydrolyzed subsequently to the more stable α-amino-βhydroxy esters.
Photolyses of benzaldehyde with 5-methoxyoxazoles 36a-f:
exo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-
42aa) (sbo-573)
H3C
N
O
H
O
Ph
CH3
OCH3
A solution of benzaldehyde (0.53 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole (0.64 g, 5
286
___________________________________________________________________________
Yield: 82 %
1
δ ppm = 0.79 (s, 3H, CH3 ), 1.99 (s, 3H, CH3 ), 3.52 (s, 3H, OCH3 ), 5.19 (s, 1H, 7-H),
7.21-7.25 (m, 5H, Harom).
13
δ ppm = 13.4 (q, CH3 ), 14.8 (q, CH3 ), 51.2 (q, OCH3 ), 75.8 (s, C-1), 89.3 (d, C-7),
124.5 (s, C-5), 125.7 (d, CHarom), 128.6 (d, CHarom), 129.3 (d, CHarom), 136.9 (s,
Cqarom), 164.9 (s, C-3).
HRMS: (C 13 H15 NO3 , M = 233.1 g/mol)
Calcd: 233.0762
Found: 233.0758
exo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-
42ab) (sbo-400)
H
H3C
N
O
Ph
O
OCH3
A solution of benzaldehyde (0.53 g, 5 mmol) and 4-ethyl-2-methyl-5-methoxyoxazole (0.71
Yield: 87 %
1
δ ppm = 0.84 (t, J = 7.2 Hz, 3H, CH3 ), 1.06 (q, J = 7.2 Hz, 2H, CH2 ), 2.00 (s, 3H,
CH3 ), 3.89 (s, 3H, OCH3 ), 5.79 (s, 1H, 7-H), 7.26-7.35 (m, 5H, Harom).
13
δ ppm = 8.5 (q, CH3 ), 23.7 (q, CH3 ), 24.9 (t, CH2 ), 51.7 (q, OCH3 ), 79.2 (s, C-1), 82.0
(d, C-7), 124.5 (s, C-5), 125.6 (d, CHarom), 127..3 (d, CHarom), 129.2 (d, CHarom),
136.5 (s, Cqarom), 164.9 (s, C-3).
HRMS: (C 14 H17 NO3 , M = 247.12 g/mol)
Calcd: 247.1204
287
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Found: 247.1197
exo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42ac) (sbo-348)
H3C
N
O
H
O
Ph
OCH3
A solution of benzaldehyde (0.53g, 5 mmol) and 2-methyl-4-propyl-5-methoxyoxazole (0.75
Yield: 87 %
IR: (Film)
ν~ (cm-1 ) = 2992, 1628, 1598, 1440, 1348, 1042, 960.
1
δ ppm = 0.55 (t, J = 7.1 Hz, 3H, CH3 ), 0.78 (sextet, J = 7.1 Hz, 2H, CH2 ), 1.12 (t, J =
7.1 Hz, 2H, CH2 ), 2.00 (s, 3H, CH3 ), 3.55 (s, 3H, OCH3 ), 5.17 (s, 1H, 7-H), 7.257.32 (m, 5H, Harom).
13
δ ppm = 14.1 (q, CH3 ), 15.1 (q, CH3 ), 16.4 (t, CH2 ), 29.6 (t, CH2 ), 51.3 (q, OCH3 ),
78.9 (s, C-1), 89.9 (d, C-7), 124.6 (s, C-5), 126.4 (d, CHarom), 128.2 (d, CHarom),
137.1 (s, Cqarom), 165.1 (s, C-3).
HRMS: (C 15 H19 NO3 , M = 261.14 g/mol)
Calcd: 261.1360
Found: 261.1356
exo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42ad) (sbo-326)
H3C
N
O
H
O
Ph
OCH3
A solution of benzaldehyde (0.53g, 5 mmol) and 4-isopropyl-2-methyl-5-methoxyoxazole
288
___________________________________________________________________________
yellow oil. The products were thermally unstable and were subsequently hydrolyzed to give
the corresponding α-amino-β-hydroxy esters (see later).
Yield: 85 %
1
CH), 2.02 (s, 3H, CH3 ), 3.61 (s, 3H, OCH3 ), 5.26 (s, 1H, 7-H), 7.28-7.35 (m, 5H,
Harom).
13
128.2 (d, Carom), 135.9 (s, Cqarom), 164.8 (s, C-3).
endo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(endo-42ad) (sbo-326)
H3C
1
Ph
O
N
O
H
OCH3
CH), 1.67 (s, 3H, CH3 ), 3.71 (s, 3H, OCH3 ), 5.28 (s, 1H, 7-H), 7.30-7.35 (m, 5H,
Harom).
13
128.2 (d, CHarom), 135.5 (s, Cqarom), 165.1 (s, C-3).
exo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42ae) (sbo-338)
H3C
N
O
H
O
Ph
OCH3
A solution of benzaldehyde (0.53 g, 5 mmol) and 4-isobutyl-2-methyl-5-methoxyoxazole
289
___________________________________________________________________________
Yield: 84 %
1
CH), 1.20 (dd, J = 5.3, 7.8 Hz, 2H, CH2 ), 2.21 (s, 3H, CH3 ), 3.67 (s, 3H, OCH3 ),
5.26 (s, 1H, 7-H), 7.30-7.49 (m, 5H, Harom).
13
(q, OCH3 ), 78.7 (s, C-1), 90.4 (d, 7-H), 124.8 (s, C-5), 126.8 (d, Carom), 127.9 (d,
Carom), 128.8 (d, Carom), 164.7 (s, C-3).
exo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42af) (sbo-344)
H3C
N
O
H
O
Ph
OCH3
A solution of benzaldehyde (0.53 g, 5 mmol) and 4-sec-butyl-2-methyl-5-methoxyoxazole
Yield: 90 %
IR: (Film)
ν~ (cm-1 ) = 2985, 1620, 1600, 1550, 1108, 1042, 980.
1
CH2 ), 0.91 (m, 1H, CH), 2.13 (s, 3H, CH3 ), 3.68 (s, 3H, OCH3 ), 5.27 (s, 1H, 7-H),
7.30-7.53 (m, 5H, Harom).
13
δ ppm = 11.3 (q, CH3 ), 11.5 (q, CH3 ), 11.7 (t, CH2 ), 20.9 (d, CH), 32.0 (t, CH2 ), 51.1
(q, OCH3 ), 82.9 (s, C-1), 90.8 (d, CH), 124.7 (s, C-5), 126.4 (d, Carom), 127.9 (d,
Carom), 128.5 (d, Carom), 137.3 (s, Cqarom), 165.2 (s, C-3).
290
___________________________________________________________________________
MS: (EI, 70 eV)
m/z (%) = 234 (M+-CH3 CN, 15), 218 (M+-Busec, 10), 198 (28), 169 (100), 168 (52),
155 (32), 144 (75), 126 (63), 112 (43), 99 (20), 95 (15), 84 (55), 70 (18), 57 (60).
Photolysis of 2-naphthaldehyde with 2,4-dimethyl-5-methoxyoxazole 36a:
exo-5-Methoxy-1,3-dimethyl-7-naphth-2-yl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42ba) (sbo-304)
H3C
N
O
H
O
CH3
OCH3
A solution of 2-naphthalaldehyde (0.64 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole (0.64
Yield: 92 %
1
δ ppm = 0.82 (s, 3H, CH3 ), 2.00 (s, 3H , CH3 ), 3.54 (s, 3H, OCH3 ), 5.21 (s, 1H, 7-H),
7.42-7.81 (m, 7H, Harom).
13
δ ppm = 13.6 (q, CH3 ), 14.9 (q, CH3 ), 51.4 (q, OCH3 ), 75.9 (s, C-1), 89.5 (d, C-7),
Cqarom), 136.2 (s, Cqarom), 137.0 (s, Cqarom), 165.3 (s, C-3).
Photolyses of 3-phenylpropionaldehyde with 5-methoxyoxazoles 36a & 36d:
exo-5-Methoxy-1,3-dimethyl-7-phenethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
42ca) (sbo-313)
H3C
N
O
H
O
CH3
OCH3
291
(exo-
___________________________________________________________________________
A solution of 3-phenylpropionaldehyde (0.67 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole
Yield: 87 %
1
δ ppm = 1.18 (s, 3H, CH3 ), 1.95 (s, 3H, CH3 ) , 2.70 (m, 2H, CH2 ), 2.92 (m, 2H, CH2 ),
3.43 (s, 3H, OCH3 ), 4.15 (dd, J = 4.3, 9.5 Hz, 1H, 7-H), 7.26 (m, 5H, Harom).
13
129.5 (d, CHarom), 140.7 (s, Cqarom), 164.8 (s, C-3).
HRMS: (C 15 H19 NO3 , M = 261.14 g/mol)
Calcd: 261.1360
Found: 261.1358
exo-1-Isopropyl-5-methoxy-3-methyl-7-phenethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene (exo-42cd) (sbo-313)
H3C
N
O
H
O
OCH3
A solution of 3-phenylpropionaldehyde (0.67 g, 5 mmol) and 4-isopropyl-2-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24h according to the
above general procedure. Distillation of the solvent under vaccum afforded 1.27 g of the
oxetane as a pale yellow oil. The product was thermally unstable and was subsequently
hydrolyzed to give the corresponding α-amino-β-hydroxy ester (see later).
Yield: 87 %
1
CH2 ), 1.95 (s, 3H, CH3 ), 2.44 (m, 2H, CH2 ), 2.75 (m, 1H, CH), 3.46 (s, 3H, OCH3 ),
4.18 (dd, J = 11.2, 2.7 Hz, 1H, 7-H), 7.21-7.34 (m, 5H, Harom).
292
___________________________________________________________________________
13
(t, CH2 ), 50.8 (q, OCH3 ), 79.9 (s, C-1), 88.3 (d, C-7), 124.5 (s, C-5), 125.6 (d,
CHarom), 126.1 (d, CHarom), 128.9 (d, CHarom), 140.2 (s, Cqarom), 165.2 (s, C-3).
Photolyses of propionaldehyde with 5-methoxyoxazoles 36a-f:
exo-1-Ethyl-5-methoxy-1,3-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42da)
(sbo-300)
H3C
N
O
H
O
CH3
OCH3
A solution of propionaldehyde (0.29 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole (0.64 g,
5 mmol) in benzene (50 mL) was irradiated for 24h according to the above general procedure.
Yield: 84 %
1
δ ppm = 0.84 (t, J = 7.2 Hz, 3H, CH3 ), 1.80 (s, 3H, CH3 ), 1.55 (dt, J = 7.8, 7.2 Hz, 2H,
CH2 ), 1.95 (s, 3H, CH3 ), 3.41 (s, 3H, OCH3 ), 4.05 (dd, J = 7.8, 6.3 Hz, 1H, 7-H).
13
δ ppm = 8.7 (q, CH3 ), 11.8 (q, CH3 ), 14.7 (q, CH3 ), 25.1 (t, CH2 ), 51.0 (q, OCH3 ),
73.2 (s, C-1), 90.1 (d, C-7), 124.3 (s, C), 164.7 (s, C-3).
HRMS: (C 9 H15 NO3 , M = 185.11 g/mol)
Calcd: 185.1048
Found: 185.1039
exo-1-Diethyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42db)
(sbo-410)
H
H3C
N
O
O
OCH3
A solution of propionaldehyde (0.29 g, 5 mmol) and 4-ethyl-2-methyl-5-methoxyoxazole
293
___________________________________________________________________________
Yield: 90 %
1
δ ppm = 0.76 (t, J = 7.5 Hz, 3H, CH3 ), 0.82 (t, J = 7.4 Hz, 3H, CH3 ), 1.55 (q, J = 7.5
Hz, 2H, CH2 ), 1.58 (m, 2H, CH2 ), 1.93 (s, 3H, CH3 ), 3.58 (s, 3H, OCH3 ), 4.03 (dd,
J = 5.7, 8.3 Hz, 1H, 7-H).
13
δ ppm = 7.8 (q, CH3 ), 8.9 (q, CH3 ), 14.7 (q, CH3 ), 19.0 (t, CH2 ), 24.9 (t, CH2 ), 50.8
(q, OCH3 ), 76.7 (s, C-1), 90.4 (d, C-7), 124.3 (s, C-5), 164.8 (s, C-3).
exo-7-Ethyl-5-methoxy-3-methyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-
42dc) (sbo-349)
H
H3C
N
O
O
OCH3
A solution of propionaldehyde (0.29 g, 5 mmol) and 2-methyl-4-propyl-5-methoxyoxazole
Yield: 86 %
IR: (Film)
ν~ (cm-1 ) = 2998, 1615, 1440, 1110, 967.
1
δ ppm = 0.81 (t, J = 7.1 Hz, 3H, CH3 ), 0.84 (t, J = 7.5 Hz, 3H, CH3 ), 0.85 (t, J = 7.1
Hz, 2H, CH2 ), 1.21 (m, 2H, CH2 ), 1.65 (m, 2H, CH2 ), 1.96 (s, 3H, CH3 ), 3.41 (s,
3H, OCH3 ), 4.07 (dd, J = 6.0, 8.0 Hz, 1H, 7-H).
13
δ ppm = 8.9 (q, CH3 ), 14.2 (q, CH3 ), 16.9 (t, CH2 ), 24.9 (t, CH2 ), 28.3 (t, CH2 ), 50.8
(q, OCH3 ), 76.4 (s, C-1), 90.5 (d, C-7), 124.3 (s, C-5), 164.5 (s, C-3).
MS: (EI, 70 eV)
294
___________________________________________________________________________
m/z (%) = 184 (M+-Et, 12), 172 (M+-CH3 CN, 16), 155 (80), 144 (75), 126 (34), 112
(43), 99 (20), 95 (15), 86 (55), 68 (88), 57 (100).
exo-7-Ethyl-1-isopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42dd) (sbo-324)
H
H3C
O
N
O
OCH3
A solution of propionaldehyde (0.29 g, 5 mmol) and 4-isopropyl-2-methyl-5-methoxyoxazole
Yield: 83 %
1
δ ppm = 0.71 (d, J = 6.8 Hz, 3H, CH3 ), 0.87 (t, J = 7.5 Hz, 3H, CH3 ), 1.65 (m, 2H,
CH2 ), 1.97 (s, 3H, CH3 ), 2.15 (s, 3H, CH3 ), 3.42 (s, 3H, OCH3 ), 4.10 (dd, J = 9.4,
4.4 Hz, 1H, 7-H).
13
δ ppm = 9.0 (q, CH3 ), 14.9 (q, CH3 ), 16.6 (q, CH3 ), 17.7 (q, CH3 ), 21.5 (d, CH), 24.7
(t, CH2 ), 50.7 (q, OCH3 ), 80.0 (s, C-1), 90.8 (d, C-7), 124.5 (s, C-5), 164.9 (s, C-3).
exo-7-Ethyl-1-isobutyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42de) (sbo-337)
H
H3C
N
O
O
OCH3
A solution of propionaldehyde (0.29 g, 5 mmol) and 4-isobutyl-2-methyl-5-methoxyoxazole
Yield: 87 %
1
295
___________________________________________________________________________
CH), 1.54 (t, J = 7.5 Hz, 3H, CH3 ), 1.67 (m, 2H, CH2 ), 1.88 (m, 2H, CH2 ), 1.95 (s,
3H, CH3 ), 3.42 (s, 3H, OCH3 ), 4.05 (dd, J = 7.6, 6.2 Hz, 1H, 7-H).
13
(t, CH2 ), 34.1 (t, CH2 ), 50.8 (q, OCH3 ), 76.9 (s, C-1), 90.9 (d, C-7), 124.4 (s, C-5),
164.0 (s, C-3).
HRMS: (C 12 H21 NO3 , M = 227.15 g/mol)
Calcd: 227.1516
Found: 227.1512
exo-1-sec-Butyl-7-ethyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42df) (sbo-341)
H
H3C
N
O
O
OCH3
A solution of propionaldehyde (0.29 g, 5 mmol) and 4-sec-butyl-2-methyl-5-methoxyoxazole
Yield: 88 %
1
δ ppm = 0.76 (d, J = 6.6 Hz, 3H, CH3 ), 0.83 (m, 3H, CH3 ), 0.92 (t, J = 7.4 Hz, 3H,
CH3 ), 1.43 (m, 1H, CH), 1.83 (m, 2H, CH2 ), 2.10 (s, 3H, CH3 ), 3.47 (s, 3H, OCH3 ),
4.16 (dd, J = 3.7, 7.5 Hz, 1H, 7-H).
13
164.9 (s, C-3).
MS: (EI, 70 eV)
m/z (%) = 216 (M+-Et, 10), 196 (5), 186 (18), 170 (20), 169 (35), 168 (52), 155
(32), 144 (75), 126 (100), 112 (43), 99 (20), 95 (15), 84 (55), 70 (18), 57 (60).
296
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Photolyses of isobutyraldehyde with 5-methoxyoxazoles 36a-f:
exo-7-Isopropyl-5-methoxy-1,3-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-
42ea) (sbo-320)
H
H3C
N
O
O
CH3
OCH3
A solution of isobutyraldehyde (0.36 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole (0.64 g,
5 mmol) in benzene (50 mL) was irradiated for 24h according to the above general procedure.
Yield: 93 %
1
δ ppm = 0.82 (d, J = 7.5 Hz, 3H, CH3 ), 0.85 (d, J = 7.2 Hz, 3H, CH3 ), 0.87 (m,1H,
CH), 1.31 (s, 3H, CH3 ), 2.10 (s, 3H, CH3 ), 3.48 (s, 3H, OCH3 ), 4.28 (d, J = 3.4 Hz,
1H, 7-H).
13
(q, OCH3 ), 73.0 (s, C-1), 93.9 (d, C-7), 124.6 (s, C-5), 165.0 (s, C-3).
exo-1-Ethyl-7-isopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42eb) (sbo-415)
H
H3C
N
O
O
OCH3
A solution of isobutyraldehyde (0.36 g, 5 mmol) and 4-ethyl-2-methyl-5-methoxyoxazole
Yield: 87 %
1
297
___________________________________________________________________________
δ ppm = 0.75 (d, J = 7.2 Hz, 6H, 2CH3 ), 0.85 (m, 1H, CH), 1.00 (t, J = 7.5 Hz, 3H,
CH3 ), 1.58 (m, 2H, CH2 ), 2.15 (s, 3H, CH3 ), 3.60 (s, 3H, OCH3 ), 4.04 (d, J = 8.4
Hz, 1H, CH).
13
δ ppm = 8.7 (q, CH3 ), 15.0 (q, CH3 ), 18.3 (q, CH3 ), 18.9 (q, CH3 ), 21.2 (t, CH2 ), 27.8
(d, CH), 50.8 (q, OCH3 ), 78.3 (s, C-1), 85.1 (d, C-7), 124.1 (s, C-5), 164.1 (s, C-3).
exo-7-Isopropyl-5-methoxy-3-methyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42ec) (sbo-353)
H
H3C
N
O
O
OCH3
A solution of isobutyraldehyde (0.36 g, 5 mmol) and 2-methyl-4-propyl-5-methoxyoxazole
Yield: 86 %
1
δ ppm = 0.79 (d, J = 6.8 Hz, 6H, 2CH3 ), 0.82 (t, J = 7.2 Hz, 3H, CH3 ), 1.12 (m, 2H,
CH2 ), 1.23 (m, 2H, CH2 ), 1.75 (m, 2H, CH2 ), 1.78 (m, 1H, CH), 2.21 (s, 3H, CH3 ),
3.44 (s, 3H, OCH3 ), 3.66 (d, J = 12.2 Hz, 1H, 7-H).
13
164.8 (s, C-3).
HRMS: (C 12 H21 NO3 , M = 227.15 g/mol)
Calcd: 227.1516
Found: 227.1509
exo-1,7-Diisopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
42ed) (sbo-p38)
298
(exo-
___________________________________________________________________________
H
H3C
N
O
O
OCH3
A solution of isobutyraldehyde (0.36 g, 5 mmol) and 4-isopropyl-2-methyl-5-methoxyoxazole
Yield: 81 %
1
δ ppm = 0.78 (d, J = 6.6 Hz, 6H, 2CH3 ), 0.82 (m, 1H, CH), 0.85 (d, J = 7.2 Hz, 3H,
CH3 ), 0.92 (t, J = 7.4 Hz, 3H, CH3 ), 1.43 (m, 1H, CH), 1.85 (m, 2H, CH2 ), 2.00 (s,
3H, CH3 ), 3.62 (s, 3H, OCH3 ), 4.18 (d, J = 8.4 Hz, 1H, 7-H).
13
δ ppm = 8.7 (q, CH3 ), 11.3 (q, CH3 ), 11.9 (t, CH2 ), 14.5 (q, CH3 ), 19.3 (q, CH3 ), 19.5
(q, CH3 ), 22.3 (d, CH), 27.2 (d, CH), 52.0 (q, OCH3 ), 82.3 (s, C-1), 88.1 (d, C-7),
124.3 (s, C-5), 165.7 (s, C-3).
exo-1-Isobutyl-7-isopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42ee) (sbo-340)
H
H3C
N
O
O
OCH3
A solution of isobutyraldehyde (0.36 g, 5 mmol) and 4-isobutyl-2-methyl-5-methoxyoxazole
Yield: 91 %
1
δ ppm = 0.82 (d, J = 6.8 Hz, 6H, 2CH3 ), 0.85 (d, J = 7.2 Hz, 6H, 2CH3 ), 1.12 (m, 2H,
2CH), 1.78 (m, 2H, CH2 ), 1.98 (s, 3H, CH3 ), 3.46 (s, 3H, OCH3 ), 3.79 (d, J = 12.1
Hz, 1H, 7-H).
299
___________________________________________________________________________
13
δ ppm = 14.1 (q, CH3 ), 14.9 (q, CH3 ), 17.7 (q, CH3 ), 18.6 (q, CH3 ), 18.9 (q, CH3 ),
29.7 (d, CH), 34.4 (d, CH), 40.6 (t, CH2 ), 50.8 (q, OCH3 ), 91.5 (s, C-1), 94.1 (d, C7), 124.3 (s, C-5), 164.5 (s, C-3).
exo-1-sec-Butyl-7-isopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene (exo-42ef) (sbo-346)
H
H3C
N
O
O
OCH3
A solution of isobutyraldehyde (0.36 g, 5 mmol) and 4-sec-butyl-2-methyl-5-methoxyoxazole
Yield: 83 %
1
δ ppm = 0.82 (d, J = 6.6 Hz, 3H, CH3 ), 0.84 (d, J = 6.8 Hz, 3H, CH3 ), 0.89 (d, J = 7.2
Hz, 3H, CH3 ), 0.91 (t, J = 7.1 Hz, 3H, CH3 ), 1.10 (m, 2H, CH2 ), 1.43 (m, 1H, CH),
2.00 (s, 3H, CH3 ), 3.53 (s, 3H, OCH3 ), 4.17 (d, J = 4.2 Hz, 1H, 7-H).
13
δ ppm = 9.3 (q, CH3 ), 11.8 (q, CH3 ), 12.7 (q, CH3 ), 19.3 (q, CH3 ), 19.4 (q, CH3 ), 23.3
(d, CH), 24.2 (t, CH2 ), 27.3 (d, CH), 52.3 (q, OCH3 ), 80.0 (s, C-1), 81.3 (d, C-7),
124.3 (s, C-5), 164.7 (s, C-3).
HRMS: (C 13 H23 NO3 , M = 241.17 g/mol)
Calcd: 241.1672
Found: 241.1667
Photolyses of 3-methylbutyraldehyde with 5-methoxyoxazoles 36a-f:
exo-7-Isobutyl-5-methoxy-1,3-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
42fa) (sbo-312)
300
(exo-
___________________________________________________________________________
H
H3C
N
O
O
CH3
OCH3
A solution of 3-methylbutyraldehyde (0.43 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole
Yield: 84 %
1
CH), 1.23 (s, 3H, CH3 ), 1.43 (m, 2H, CH2 ), 2.02 (s, 3H, CH3 ), 3.47 (s, 3H, OCH3 ),
4.32 (dd, J = 4.0, 8.5 Hz, 1H, 7-H).
13
(t, CH2 ), 51.3 (q, OCH3 ), 73.6 (s, C-1), 82.8 (d, C-7), 124.6 (s, C-5), 165.0 (s, C-3).
HRMS: (C 11 H19 NO3 , M = 213.14 g/mol)
Calcd: 213.1360
Found: 213.1353
exo-1-Ethyl-7-isobutyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42fb) (sbo-412)
H
H3C
A
solution
of
N
O
O
(0.43
OCH3
g,
5
mmol)
and
4-ethyl-2-methyl-5-
methoxyoxazole (0.64 g, 5 mmol) in benzene (50 mL) was irradiated for 24h according to the
Yield: 86 %
1
301
___________________________________________________________________________
δ ppm = 0.88 (d, J = 6.8 Hz, 3H, CH3 ), 0.92 (d, J = 6.6 Hz, 3H, CH3 ), 1.02 (t, J = 7.5
Hz, 3H, CH3 ), 1.23 (m, 1H, CH), 1.43 (m, 2H, CH2 ), 1.54 (m, 2H, CH2 ), 1.54 (m,
2H, CH2 ), 2.03 (s, 3H, CH3 ), 3.78 (s, 3H, OCH3 ), 4.12 (dd, J = 9.2, 2.1 Hz, 1H, 7H).
13
(d, CH), 34.1 (t, CH2 ), 50.2 (q, OCH3 ), 79.2 (s, C-1), 88.3 (d, C-7), 124.2 (s, C-5),
164.7 (s, C-3).
exo-7-Isobutyl-5-methoxy-3-methyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42fc) (sbo-350)
H
H3C
A
solution
of
O
N
O
OCH3
(0.43
g,
5
mmol)
and
2-methyl-4-propyl-5-
Yield: 83 %
1
δ ppm = 0.80 (d, J = 7.1 Hz, 6H, 2CH3 ), 0.83 (t, J = 7.2 Hz, 3H, CH3 ), 1.23 (m, 2H,
CH2 ), 1.65 (m, 2H, CH2 ), 1.73 (m, 1H, CH), 1.98 (s, 3H, CH3 ), 3.41 (s, 3H, OCH3 ),
4.27 (dd, J = 10.2, 4.9 Hz, 1H, 7-H).
13
δ ppm = 14.3 (q, CH3 ), 14.9 (q, CH3 ), 16.9 (t, CH2 ), 21.7 (d, CH), 23.2 (q, CH3 ), 24.2
(q, CH3 ), 28.4 (t, CH2 ), 40.4 (t, CH2 ), 50.9 (q, OCH3 ), 76.5 (s, C-1), 87.8 (d, C-7),
124.4 (s, C-5), 164.7 (s, C-3).
HRMS: (C 13 H23 NO3 , M = 241.17 g/mol)
Calcd: 241.1764
Found: 241.1762
302
___________________________________________________________________________
exo-7-Isobutyl-1-isopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42fd) (sbo-325)
H
H3C
N
O
O
OCH3
A solution of 3-methylbutyraldehyde (0.43 g, 5 mmol) and 4-isopropyl-2-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24h according to the
Yield: 87 %
1
Hz, 6H, 2CH3 ), 1.35 (m, 2H, 2CH), 1.76 (m, 2H, CH2 ), 1.98 (s, 3H, CH3 ), 3.42 (s,
3H, OCH3 ), 4.29 (dd, J = 11.2, 2.3 Hz, 1H, 7-H).
13
23.9 (d, CH), 24.7 (d, CH), 40.1 (t, CH2 ), 50.7 (q, OCH3 ), 80.0 (s, C-1), 87.9 (d, C7), 124.4 (s, C-5), 164.9 (s, C-3).
exo-1,7-Diisobutyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-
42fe) (sbo-339)
H
H3C
A
solution
of
N
O
O
OCH3
3-methylbutyraldehyde (0.43 g, 5 mmol) and 4-isobutyl-2-methyl-5-
Yield: 88 %
1
303
___________________________________________________________________________
Hz, 3H, CH3 ), 0.89 (d, J = 7.5 Hz, 3H, CH3 ), 1.53 (m, 2H, CH2 ), 1.54 (m, 2H, CH2 ),
1.56 (m, 2H, CH2 ), 2.00 (s, 3H, CH3 ), 3.46 (s, 3H, OCH3 ), 4.27 (dd, J = 1.3, 7.7 Hz,
1H, 7-H).
13
24.2 (d, CH), 24.4 (d, CH), 34.3 (t, CH2 ), 40.7 (t, CH2 ), 51.0 (q, OCH3 ), 76.3 (s, C1), 88.3 (d, C-7), 124.6 (s, C-5), 164.2 (s, C-3).
HRMS: (C 14 H25 NO3 , M = 255.18 g/mol)
Calcd: 255.1828
Found: 255.1822
exo-1-sec-Butyl-7-isobutyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-42ff) (sbo-345)
H
H3C
N
O
O
OCH3
A solution of 3-methylbutyraldehyde (0.43 g, 5 mmol) and 4-sec-butyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24h according to the
Yield: 88 %
IR: (Film)
ν~ (cm-1 ) = 2984, 1605, 1445, 1009, 980.
1
δ ppm = 0.81 (t, J = 7.4 Hz, 3H, CH3 ), 0.83 (d, J = 6.8 Hz, 3H, CH3 ), 0.89 (d, J = 7.2
Hz, 3H, CH3 ), 0.91 (d, J = 7.1 Hz, 3H, CH3 ), 1.10 (m, 2H, CH2 ), 1.43 (m, 1H, CH),
1.65 (m, 2H, CH2 ), 2.0 (s, 3H, CH3 ), 2.35 (m, 1H, CH), 3.47 (s, 3H, OCH3 ), 4.25
(dd, 1H, J = 5.3, 6.0 Hz, 1H, 7-H).
13
304
___________________________________________________________________________
δ ppm = 9.0 (q, CH3 ),11.5 (q, CH3 ), 11.9 (q, CH3 ), 12.9 (q, CH3 ), 13.9 (q, CH3 ), 14.9
(q, CH3 ), 23.5 (d, CH), 24.7 (d, CH), 24.8 (t, CH2 ), 32.1 (t, CH2 ), 50.8 (q, OCH3 ),
80.5 (s, C-1), 80.9 (d, C-7), 124.6 (s, C-5), 165.2 (s, C-3).
MS: (EI, 70 eV)
m/z (%) = 214 (M+-CH3 CN, 5), 198 (M+-Bui, 23), 169 (55), 168 (32), 155 (52), 144
(75), 126 (100), 112 (43), 99 (20), 95 (15), 86 (55), 68 (18), 57 (40).
4.15.1 Synthesis of erythro (2S*,3S*)-α
α -acetamido-α
α -alkylated-β
β -hydroxy esters 43aa-ff;
General procedure:
To a solution of the bicyclic oxetane 42aa-ff (0.002 mol) in 20 mL of methylene chloride, 0.5
ml of conc. HCl was added. The mixture is stirred in an open flask at room temperature for 2
h and the reaction was controled by TLC. The reaction mixture was quenched with water and
extracted with methylene chloride (3 x 20 mL). The organic layer was washed with 5 %
NaHCO3 , brine, and dried over anhydrous MgSO4 . The solvent was removed in vacuo and the
residual oil was purified by preparative chromatography.
erythro-Methyl
(2S*,3S*)
2-(N-acetylamino)-3-hydroxy-2-methyl-3-phenylpropanoate
(erythro-43aa) (sbo-305b)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42aa (0.47 g, 2 mmol) was
hydrolytically cleaved in 3h. Preparative chromatography yielded 0.33 g of the product as a
colorless oil.
Yield: 65 %
IR: (Film)
ν~ (cm-1 ) = 3350, 3320, 2988, 1720, 1680, 1580, 1440, 1340, 1062, 987.
1
δ ppm = 1.23 (s, 3H, CH3 ), 2.12 (s, 3H, CH3 CO), 3.79 (s, 3H, OCH3 ), 4.06 (s, 1H,
CHOH), 7.32 (m, 5H, Harom).
13
305
___________________________________________________________________________
δ ppm = 13.5 (q, CH3 ), 21.4 (q, CH3 ), 23.4 (q, CH3 ), 47.7 (s, C-2), 49.1 (d, C-3), 52.9
(q, OCH3 ), 127.6 (d, CHarom), 128.4 (d, CHarom), 133.5 (s, Cqarom), 169.9 (s, CON),
179.4 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 249 (M+-H2 , 4), 236 (M+-Me, 8), 202 (8), 192 (M+-CO2 Me, 15), 191
(78), 160 (10), 132 (12), 131 (100), 105 (50), 91 (20), 77 (30), 51 (10).
HRMS: (C 13 H17 NO4 , M = 251.12 g/mol)
Calcd: 251.1254
Found: 251.1249
erythro-Methyl
(2S*,3S*)
2-(N-acetylamino)-2-ethyl-3-hydroxy-3-phenylpropanoate
(erythro-43ab) (sbo-400a)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42ab (0.49 g, 2 mmol) was
colorless oil.
Yield: 73 %
1
δ ppm = 1.08 (t, J = 7.5 Hz, 3H, CH3 ), 1.35 (q, J = 7.5 Hz, 2H, CH2 ), 1.99 (s, 3H,
CH3 CO), 3.89 (s, 3H, OCH3 ), 4.35 (s, 1H, CHOH), 7.26-7.34 (m, 5H, Harom).
13
δ ppm = 8.8 (q, CH3 ), 24.1 (q, CH3 ), 25.4 (t, CH2 ), 53.0 (q, OCH3 ), 63.2 (s, C-2), 70.2
(d, C-3), 126.1 (d, CHarom), 128.1 (d, CHarom), 129.3 (d, CHarom), 134.5 (s, Cqarom),
170.3 (s, CON), 171.5 (s, COO).
erythro-Methyl
(2S*,3S*)
2-(N-acetylamino)-2-(hydroxy-phenyl-methyl)pentanoate
(erythro-43ac) (sbo-348a)
HO
AcHN
CO2CH3
306
___________________________________________________________________________
Following the above general procedure, the bicyclic oxetane 42ac (0.52 g, 2 mmol) was
colorless oil.
Yield: 58 %
1
δ ppm = 0.88 (t, J = 7.4 Hz, 3H, CH3 ), 1.27 (m, 2H, CH2 ), 1.51-1.81(m, 2H, CH2 ),
1.98 (s, 3H, CH3 CO), 3.78 (s, 3H, OCH3 ), 4.02 (s, 1H, CHOH), 6.21 (bs, 1H, NH),
7.22-7.26 (m, 5H, Harom).
13
70.1 (s, C-2), 78.0 (d, C-3), 125.7 (d, CHarom), 126.9 (d, CHarom), 128.1 (d, CHarom),
136.4 (s, Cqarom), 169.8 (s, CON), 173.3 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 278 (M+-1, 5), 262 (M+-OH, 7), 202 (8), 220 (M+-CO2 Me, 10), 219 (55),
155 (78), 127 (100), 105 (43), 91 (15), 77 (30), 59 (13).
Anal: (C 15 H21 NO4 , M = 279.33 g/mol)
Calcd:
C 64.50 H 7.58 N 5.01
Found:
C 64.72 H 7.42 N 5.16
erythro-Methyl
(2S*,3S*)
2-(N-acetylamino)-2-(hydroxy-phenyl-methyl)-3-
methylbutanoate (erythro-43ad) (sbo-336c)
HO
AcHN
Ph
CO2 CH3
Following the above general procedure, the bicyclic oxetane 42ad (0.52 g, 2 mmol) was
hydrolytically cleaved in 4h. Preparative chromatography yielded 0.27 g of the erythro-isomer
and 0.12 g of the threo-isomer, both as a colorless oil.
Yield: 48 %
1
δ ppm = 0.76 (d, J = 6.9 Hz, 3H, CH3 ), 1.23 (d, J = 6.8 Hz, 3H, CH3 ), 1.43 (sextet, J =
6.8 Hz, 1H, CH), 2.13 (s, 3H, CH3 CO), 3.78 (s, 3H, OCH3 ), 4.14 (s, 1H, CHOH),
7.32-7.34 (m, 5H, Harom).
307
___________________________________________________________________________
13
Anal: (C 15 H21 NO4 , M = 279.33 g/mol)
Calcd:
C 64.50 H 7.58 N 5.01
Found:
C 64.65 H 7.38 N 4.98
threo-Methyl
(2S*,3R*)
2-(N-acetylamino)-2-(hydroxy-phenyl-methyl)-3-methyl
butanoate (threo-43ad) (sbo-326a)
HO
Ph
AcHN
CO2 CH3
Yield: 25 %
1
CH3 CO), 2.33 (sextet, J = 6.8 Hz, 1H, CH), 3.09 (s, 3H, OCH3 ), 3.83 (s, 1H,
CHOH), 7.14-7.26 (m, 5H, Harom).
13
HRMS: (C 15 H21 NO4 , M = 279.15 g/mol)
Calcd:
279.1465
Found:
279.1460
erythro-Methyl
(2S*,3S*)
methylpentanoate (erythro-43ae) (sbo-338a)
HO
AcHN
Ph
CO2CH3
308
___________________________________________________________________________
Following the above general procedure, the bicyclic oxetane 42ae (0.55 g, 2 mmol) was
Yield: 58 %
1
CH), 1.89 (dd, J = 13.4, 6.7 Hz, 1H, CH), 1.92 (s, 3H, CH3 CO), 2.72 (dd, J = 13.4
Hz, 4.5 Hz, 1H, CH), 3.80 (s, 3H, OCH3 ), 3.82 (s, 1H, CHOH), 7.25-7.38 (m, 5H,
Harom).
13
(q, OCH3 ), 68.3 (s, C-2), 71.0 (d, C-3), 126.1 (d, CHarom), 129.8 (d, CHarom), 137.2
(s, Cqarom), 169.6 (s, CON), 172.9 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 278 (M+-1, 5), 261 (M+-H2 O, 8), 218 (10), 202 (12), 156 (15), 155 (100),
140 (38), 127 (80), 112 (45), 105 (65), 84 (27), 77 (30), 55 (8).
threo-Methyl
(2S*,3R*)
2-(N-acetylamino)-2-(hydroxy-phenyl-methyl)-4-methyl
pentanoate (threo-43ae) (sbo-338b)
HO
AcHN
Ph
CO2CH3
Yield: 24 %
1
CH), 1.70 (dd, J = 13.5, 5.6 Hz, 1H, CH), 2.17 (s, 3H, CH3 CO), 2.80 (dd, J = 13.5,
5.6 Hz, 1H, CH), 3.09 (s, 3H, OCH3 ), 3.77 (s, 1H, CHOH), 7.23-7.36 (m, 5H,
Harom).
13
(d, CHarom), 140.6 (s, Cqarom), 165.7 (s, CON), 171.5 (s, COO).
309
___________________________________________________________________________
erythro-Methyl
(2S*,3S*)
methylpentanoate (erythro-43af) (sbo-344c)
HO
Ph
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42af (0.55 g, 2 mmol) was
Yield: 40 %
1
CH2 ), 1.94 (s, 3H, CH3 CO), 2.67 (m, 1H, CH), 3.82 (s, 3H, OCH3 ), 4.13 (s, 1H,
CHOH), 6.65 (bs, 1H, NH), 7.05-7.16 (m, 5H, Harom).
13
Anal: (C 16 H23 NO4 , M = 293.3 g/mol)
Calcd:
C 65.51 H 7.90 N 4.77
Found:
C 65.66
threo-Methyl
H 7.53
N 4.74
(2S*,3R*)
methylpentanoate (threo-43af) (sbo-344b)
HO
AcHN
Ph
CO2CH3
Yield: 19 %
1
CH), 1.47 (m, 2H, CH2 ), 2.20 (s, 3H, CH3 CO), 3.08 (s, 3H, OCH3 ), 3.84 (s, 1H,
CHOH), 7.21-7.53 (m, 5H, Harom).
310
___________________________________________________________________________
13
erythro-Methyl
(2S*,3S*)
2-(N-acetylamino)-3-hydroxy-2-methyl-3-naphthen-2-
ylpropanoate (erythro-43ba) (sbo-304c)
HO
AcHN
CO2 CH3
Following the above general procedure, the bicyclic oxetane 42ba (0.57 g, 2 mmol) was
colorless oil.
Yield: 48 %
1
CHOH), 7.46-7.92 (m, 7H, Harom).
13
δ ppm = 13.5 (q, CH3 ), 23.5 (q, CH3 ), 47.9 (s, C-2), 49.3 (d, C-3), 53.0 (q, OCH3 ),
126.3 (d, CHarom), 127.8 (d, CHarom), 128.3 (d, CHarom), 129.3 (d, CHarom), 133.2 (s,
Carom), 136.9 (s, Cqarom), 166.9 (s, CON), 180.0 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 299 (M+-H2 , 5), 242 (4), 241 (50), 207 (28), 206 (30), 182 (19), 181
(100), 140 (30), 139 (48), 102 (10), 89 (5), 63 (4).
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-2-methyl-5-phenylpentanoate
(erythro-43ca) (sbo-313a)
HO
AcHN
CO2CH3
311
___________________________________________________________________________
Following the above general procedure, the bicyclic oxetane 42ca (0.52 g, 2 mmol) was
colorless oil.
Yield: 55 %
IR: (Film)
ν~ (cm-1 ) = 3420, 3270, 2986, 1735, 1690, 1600, 1550, 1340, 1062, 957.
1
δ ppm = 1.35 (s, 3H, CH3 ), 1.94 (dd, J = 6.3, 14.0 Hz, 2H, CH2 ), 2.03 (s, 3H,
CH3 CO), 2.68-2.92 (dd, J = 7.4, 14.0 Hz, 2H, CH2 ), 3.76 (s, 3H, OCH3 ), 4.66 (dd, J
= 7.4, 6.3 Hz, 1H, CHOH), 5.30 (s, 1H, NH), 7.21-7.31 (m, 5H, Harom).
13
75.0 (s, C-2), 83.9 (d, C-3), 126.1 (d, Carom), 128.3 (d, Carom), 129.3 (d, C arom), 141.0
(s, Cqarom), 165.2 (s, CON), 174.3 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 279 (M+, 5), 261 (M+-H2 O, 6), 220 (M+-CO2 Me, 5), 178 (8), 145 (45),
119 (8), 113 (40), 102 (100), 92 (10), 91 (78), 77 (15), 51 (7).
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-2-isopropyl-5-phenylpentanoate
(erythro-43cd) (sbo-328b)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42cd (0.58 g, 2 mmol) was
colorless oil.
Yield: 55 %
1
δ ppm = 0.85 (d, J = 6.8 Hz, 3H, CH3 ), 1.23 (m, 1H, CH), 2.02 (s, 3H, CH3 CO), 2.13
(dd, J = 7.4, 14.0 Hz, 2H, CH2 ), 2.63-2.92 (dd, J = 6.4, 14.0 Hz, 2H, CH2 ), 3.68 (s,
3H, OCH3 ), 4.32 (dd, J = 10.4, 3.3 Hz, 1H, CHOH), 7.21-7.33 (m, 5H, Harom).
312
___________________________________________________________________________
13
(t, CH2 ), 52.1 (q, OCH3 ), 67.5 (s, C-2), 75.1 (d, C-3), 126.1 (d, CHarom), 128.3 (d,
CHarom), 129.3 (d, CHarom), 141.0 (s, Cqarom), 169.5 (s, CON), 171.3 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 307 (M+, 5), 290 (M+-OH, 4), 289 (M+-H2 O, 10), 246 (M+-CO2 Me, 8),
231 (15), 230 (100), 214 (20), 188 (13), 141 (10), 133 (28), 130 (40), 105 (60), 91
(78), 79 (7), 70 (10), 55 (8).
erythro-Methyl (2S*,3S*) 2-acetylamino-3-hydroxy-2-methylpentanoate (erythro-43da)
(sbo-300a)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42da (0.37 g, 2 mmol) was
colorless oil.
Yield: 70 %
IR: (Film)
ν~ (cm-1 ) = 3330, 3260, 2983, 1720, 1685, 1448, 1345, 1042, 987.
1
δ ppm = 1.03 (t, J = 7.2 Hz, 3H, CH3 ), 1.55 (s, 3H, CH3 ), 1.76 (dq, J = 2.1, 7.2 Hz,
2H, CH2 ), 1.96 (s, 3H, CH3 CO), 3.71 (s, 3H, OCH3 ), 4.15 (dd, J = 11.1, 2.1 Hz, 1H,
CHOH), 6.22 (bs, 1H, NH).
13
63.5 (s, C-2), 69.9 (d, C-3), 169.4 (s, CON), 171.7 (s, COO).
HRMS: (C 9 H17 NO4 , M = 203.12 g/mol)
Calcd:
203.1248
Found:
203.1247
erythro-Methyl
(2S*,3S*)
2-acetylamino-2-ethyl-3-hydroxypentanoate
(sbo-410b)
313
(erythro-43db)
___________________________________________________________________________
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42db (0.4 g, 2 mmol) was
colorless oil.
Yield: 65 %
1
δ ppm = 0.75 (t, J = 7.4 Hz, 3H, CH3 ), 1.03 (t, J = 7.4 Hz, 3H, CH3 ), 1.50 (m, 2H,
CH2 ), 2.07 (s, 3H, CH3 CO), 2.13 (sextet, J = 7.4 Hz, 1H, CH), 3.78 (s, 3H, OCH3 ),
4.23 (dd, J = 11.6, 2.1 Hz, 1H, CHOH), 6.40 (bs, 1H, NH).
13
δ ppm = 9.0 (q, CH3 ), 12.0 (q, CH3 ), 24.5 (t, CH2 ), 26.7 (t, CH2 ), 53.2 (q, OCH3 ), 69.9
(s, C-2), 70.2 (d, C-3), 169.5 (s, CON), 172.2 (s, COO).
Anal: (C 10 H19 NO4 , M = 217.3 g/mol)
Calcd:
C 55.28 H 8.81 N 6.46
Found:
C 55.85 H 8.22
N 6.41
erythro-Methyl (2S*,3S*) 2-acetylamino-3-hydroxy-2-propylpentanoate (erythro-43dc)
(sbo-349b)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42dc (0.43 g, 2 mmol) was
Yield: 75 %
1
CH2 ), 1.64 (dd, J = 7.2, 2.1 Hz, 1H, CH), 1.76 (ddd, J = 7.2, 4.6, 3.2 Hz, 1H, CH),
2.00 (s, 3H, CH3 CO), 2.15 (m, 1H, CH), 2.85 (m, 1H, CH), 3.77 (s, 3H, OCH3 ),
314
___________________________________________________________________________
13
(t, CH2 ), 53.2 (q, OCH3 ), 69.2 (s, C-2), 70.3 (d, C-3), 169.5 (s, CON), 172.3 (s,
COO).
HRMS: (C 11 H21 NO4 , M = 231.15 g/mol)
Calcd:
231.1465
Found:
231.1461
threo-Methyl (2S*,3R*) 2-acetylamino-3-hydroxy-2-propylpentanoate (threo-43dc) (sbo349a)
HO
AcHN
CO2CH3
Yield: 12 %
1
CH2 ), 1.48 (m, 2H, CH2 ), 1.67 (m, 2H, CH2 ), 1.95 (s, 3H, CH3 CO), 3.69 (s, 3H,
OCH3 ), 4.33 (dd, J = 10.1, 3.5 Hz, 1H, CHOH), 6.41 (bs, 1H, NH).
13
COO).
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-2-isopropylpentanoate
(erythro-
43dd) (sbo-324b)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42dd (0.43 g, 2 mmol) was
colorless oil.
Yield: 67 %
315
___________________________________________________________________________
IR: (Film)
ν~ (cm-1 ) = 3339, 3220, 2998, 1740, 1665, 1450, 1355, 1042, 980.
1
Hz, 3H, CH3 ), 1.56 (ddq, J = 7.2, 7.1, 4.4 Hz, 1H, CH), 2.01 (s, 3H, CH3 CO), 2.14
(dd, J = 7.2, 1.6 Hz, 1H, CH), 2.71 (sextet, J = 6.9 Hz, 1H, CH), 3.79 (s, 3H,
OCH3 ), 4.51 (dd, J = 11.7, 1.7 Hz, 1H, CHOH), 6.45 (bs, 1H, NH).
13
(q, OCH3 ), 69.9 (s, C-2), 73.5 (d, C-3), 169.7 (s, CON), 171.8 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 215 (M+-H2 O, 27), 214 (M+-OH, 21), 172 (29), 164 (42), 154 (50), 130
(100), 112 (48), 98 (25), 95 (30), 70 (87), 60 (67), 57 (50).
HRMS: (C 11 H21 NO4 , M = 231.15 g/mol)
Calcd:
231.1465
Found:
231.1463
threo-Methyl
(2S*,3R*)
2-acetylamino-3-hydroxy-2-isobutylpentanoate
(threo-43de)
(sbo-337a)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42de (0.45 g, 2 mmol) was
colorless oil.
Yield: 70 %
IR: (Film)
ν~ (cm-1 ) = 3335, 3210, 2978, 1745, 1675, 1453, 1355, 1042, 980.
1
δ ppm = 0.80 (d, J = 6.6 Hz, 3H, CH3 ), 0.88 (d, J = 6.6 Hz, 3H , CH3 ), 1.02 (t, J = 7.4
Hz, 3H, CH3 ), 1.41 (dd, J = 13.4, 5.0 Hz, 1H, CH), 1.62 (m, 2H, CH2 ), 1.87 (m, 1H,
CH), 1.96 (s, 3H, CH3 CO), 2.03 (dd, J = 13.9, 3.5Hz, 1H, CH), 3.64 (s, 3H, OCH3 ),
4.20 (dd, J = 10.1, 3.5 Hz, 1H, CHOH).
316
___________________________________________________________________________
13
(t, CH2 ), 42.0 (t, CH2 ), 52.3 (q, OCH3 ), 77.9 (s, C-2), 87.8 (d, C-3), 164.9 (s, CON),
174.9 (s, COO).
Anal: (C 12 H23 NO4 , M = 245.16 g/mol)
Calcd:
C 58.75 H 9.45 N 5.71
Found:
C 58.52 H 9.27 N 5.49
erythro-Methyl
(2S*,3S*)
2-acetylamino-2-(1-hydroxy-propyl)-3-methylpentanoate
(erythro-43df) (sbo-341d)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42df (0.45 g, 2 mmol) was
colorless oil. A crystalline sample for X-ray crystal structure analysis could be obtained by
crystallization of the product from chloroform.
Yield: 75 %
M.p: 43-45 °C
1
δ ppm = 0.76 (d, J = 6.9, Hz, 3H, CH3 ), 0.85 (t, J = 7.2, Hz, 3H, CH3 ), 0.96 (t, J = 7.1
Hz, 3H, CH3 ), 1.21 (m, 1H, CH), 2.08 (s, 3H, CH3 CO), 2.42 (m,1H, CH), 3.77 (s,
3H, OCH3 ), 4.62 (dd, J = 11.7, 1.7 Hz, 1H, CHOH), 6.90 (bs, 1H, NH).
13
172.8 (s, COO).
Anal: (C 12 H23 NO4 , M = 245.32 g/mol)
Calcd:
C 58.75 H 9.45 N 5.71
Found:
C 59.03 H 9.38 N 5.62
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-2,4-dimethylpentanoate
43ea) (sbo-320a)
317
(erythro-
___________________________________________________________________________
HO
Ac HN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42ea (0.4 g, 2 mmol) was
colorless oil.
Yield: 70 %
1
CH), 1.43 (s, 3H, CH3 ), 2.10 (s, 3H, CH3 CO), 3.78 (s, 3H, OCH3 ), 4.43 (d, J = 9.2
Hz, 1H, CHOH).
13
(q, OCH3 ), 68.1 (s, C-2), 78.1 (d, C-3), 169.1 (s, CON), 170.3 (s, COO).
erythro-Methyl (2S*,3S*) 2-acetylamino-2-ethyl-3-hydroxy-4-methylpentanoate (erythro43eb) (sbo-415a)
HO
Ac HN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42eb (0.43 g, 2 mmol) was
colorless oil.
Yield: 71 %
1
δ ppm = 0.90 (t, J = 7.4 Hz, 3H, CH3 ), 0.95 (d, J = 6.9 Hz, 6H, 2CH3 ), 1.31 (m, 1H,
CH), 1.59 (m, 2H, CH2 ), 1.99 (s, 3H, CH3 CO), 3.74 (s, 3H, OCH3 ), 4.16 (d, J = 8.4
Hz, 1H, CHOH).
13
(d, CH), 52.4 (q, OCH3 ), 78.6 (s, C-2), 90.8 (d, C-3), 165.2 (s, CON), 174.5 (s,
COO).
318
___________________________________________________________________________
Anal: (C 11 H21 NO4 , M = 231.29 g/mol)
Calcd:
C 57.12 H 9.12 N 6.06
Found:
C 56.92 H 8.96 N 5.87
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-4-methyl-2-propylpentanoate
(erythro-43ec) (sbo-353a)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42ec (0.45 g, 2 mmol) was
colorless oil.
Yield: 73 %
1
Hz, 3H, CH3 ), 1.21 (m, 1H, CH), 1.24 (m, 2H, CH2 ), 1.54 (m, 2H, CH2 ), 2.05 (s,
3H, CH3 CO), 3.74 (s, 3H, OCH3 ), 4.34 (d, J = 8.9 Hz, 1H, CHOH).
13
(d, CH), 39.2 (t, CH2 ), 52.0 (q, OCH3 ), 68.2 (s, C-2), 74.1 (d, C-3), 169.1 (s, CON),
172.1 (s, COO).
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-2-isopropyl-4-methylpentanoate
(erythro-43ed) (sbo-p39a)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42ed (0.45 g, 2 mmol) was
colorless oil.
Yield: 59 %
1
319
___________________________________________________________________________
δ ppm = 0.85 (d, J = 6.8 Hz, 6H, 2CH3 ), 0.89 (d, J = 6.5 Hz, 3H, CH3 ), 0.93 (d, J = 6.6
Hz, 3H, CH3 ), 1.03 (m, 2H, 2CH), 2.04 (s, 3H, CH3 CO), 3.79 (s, 3H, OCH3 ), 4.44
(d, J = 8.4 Hz, 1H, CHOH).
13
23.8 (d, CH), 27.2 (d, CH), 52.7 (q, OCH3 ), 66.3 (s, C-2), 73.5 (d, C-3), 170.1 (s,
CON), 171.8 (s, COO).
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-2-isobutyl-4-methylpentanoate
(erythro-43ee) (sbo-340a)
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42ee (0.48 g, 2 mmol) was
colorless oil.
Yield: 65 %
1
δ ppm = 0.65 (dd, J = 6.6, 6.6 Hz, 6H, 2CH3 ), 0.75 (dd, J = 7.5, 7.5 Hz, 6H , 2CH3 ),
1.30 (m, 1H, CH), 1.65 (dd, J = 1.6, 3.4 Hz, 1H, CH), 1.94 (s, 3H, CH3 CO), 2.42
(dd, J = 7.5, 1.5 Hz, 1H, CH), 3.50 (m, 1H, CH), 3.72 (s, 3H, OCH3 ), 3.92 (dd, J =
4.5, 1.6 Hz, 1H, CHOH), 6.97 (bs, 1H, NH).
13
174.5 (s, COO).
HRMS: (C 13 H25 NO4 , M = 259.18 g/mol)
Calcd:
259.1777
Found:
259.1773
erythro-Methyl
(2S*,3S*)
2-acetylamino-2-sec-butyl-3-hydroxy-4-methylpentanoate
(erythro-43ef) (sbo-346b)
320
___________________________________________________________________________
HO
AcHN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42ef (0.48 g, 2 mmol) was
colorless oil.
Yield: 68 %
1
Hz, 3H, CH3 ), 0.99 (t, J = 7.5 Hz, 3H, CH3 ), 1.43 (m, 1H, CH), 1.55 (m, 2H, 2CH),
1.98 (s, 3H, CH3 CO), 3.72 (s, 3H, OCH3 ), 4.19 (dd, J = 8.4 Hz, 1H, CHOH).
13
25.2 (t, CH2 ), 27.1 (d, CH), 29.3 (d, CH), 52.9 (q, OCH3 ), 74.3 (s, C-2), 79.3 (d, C3), 169.5 (s, CON), 172.0 (s, COO).
erythro-Methyl (2S*,3S*) 2-acetylamino-3-hydroxy-2,5-dimethylhexanoate (erythro-43fa)
(sbo-312a)
HO
Ac HN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42fa (0.43 g, 2 mmol) was
colorless oil.
Yield: 55 %
1
CH), 1.24 (dd, J = 1.9, 1.8 Hz, 1H, CH), 1.54 (s, 3H, CH3 ), 1.87 (m, 1H, CH), 1.96
(s, 3H, CH3 CO), 3.71 (s, 3H, OCH3 ), 4.25 (dd, J = 11.4, 1.8 Hz, 1H, CHOH), 6.20
(bs, 1H, NH).
13
321
___________________________________________________________________________
COO).
MS: (EI, 70 eV)
m/z (%) = 299 (M+-H2 , 5), 214 (M+-OH, 4), 190 (15), 172 (8), 154 (18), 148 (52),
112 (22), 102 (100), 85 (20), 70 (18), 57 (18).
erythro-Methyl (2S*,3S*) 2-acetylamino-2-ethyl-3-hydroxy-5-methylhexanoate (erythro43fb) (sbo-412c)
HO
Ac HN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42fb (0.45 g, 2 mmol) was
colorless oil.
Yield: 66 %
1
Hz, 3H, CH3 ), 1.23 (m, 1H, CH), 1.63 (ddd, J = 10.1, 2.1, 2.1 Hz, 2H, CH2 ), 1.85
(m, 1H, CH), 2.12 (s, 3H, CH3 CO), 2.80 (sextet, J = 7.5 Hz, 1H, CH), 3.76 (s, 3H,
OCH3 ), 4.40 (dd, J = 11.5 , 2.1 Hz, 1H, CHOH), 6.39 (bs, 1H, NH).
13
172.2 (s, COO).
HRMS: (C 12 H23 NO4 , M = 245.16 g/mol)
Calcd:
245.1621
Found:
245.1618
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-5-methyl-2-propylhexanoate
(erythro-43fc) (sbo-350b)
322
___________________________________________________________________________
HO
Ac HN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42fc (0.48 g, 2 mmol) was
colorless oil.
Yield: 68 %
1
δ ppm = 0.83 (d, J = 6.5 Hz, 3H, CH3 ), 0.86 (t, J = 4.3 Hz, 3H, CH3 ), 0.91 (d, J = 6.6
Hz, 3H, CH3 ), 1.52 (dddd, J = 3.1, 3.2, 3.1, 3.2 Hz, 2H, CH2 ), 1.65 (ddd, J = 6.5,
2.1, 1.9 Hz, 1H, CH), 1.81 (m, 2H, CH2 ), 2.00 (s, 3H, CH3 CO), 3.77 (s, 3H, OCH3 ),
13
172.3 (s, COO).
Anal: (C 13 H25 NO4 , M = 259.18 g/mol)
Calcd:
C 60.21 H 9.72 N 5.40
Found:
C 59.98 H 9.61 N 5.32
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-2-isopropyl-5-methylhexanoate
(erythro-43fd) (sbo-325c)
HO
Ac HN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42fd (0.48 g, 2 mmol) was
colorless oil.
Yield: 62 %
IR: (Film)
323
___________________________________________________________________________
ν~ (cm-1 ) = 3396, 2919, 1738, 1668, 1471, 1056, 1031, 978, 680.
1
2.04 (s, 3H, CH3 CO), 3.57 (sextet, J = 6.9 Hz, 1H, CH), 3.79 (s, 3H, OCH3 ), 4.69
(dd, J = 11.2, 2.4 Hz, 1H, CHOH), 6.43 (bs, 1H, NH).
13
171.8 (s, COO).
Anal: (C 13 H25 NO4 , M = 259.3 g/mol)
Calcd:
C 60.21 H 9.72 N 5.40
Found:
C 59.89 H 9.64 N 5.27
erythro-Methyl
(2S*,3S*)
2-acetylamino-3-hydroxy-2-isobutyl-5-methylhexanoate
(erythro-43fe) (sbo-339c)
HO
Ac HN
CO2CH3
Following the above general procedure, the bicyclic oxetane 42fe (0.51 g, 2 mmol) was
Yield: 45 %
1
δ ppm = 0.74 (d, J = 6.5 Hz, 3H, CH3 ), 0.81 (d, J = 6.6 Hz, 3H , CH3 ), 0.86 (d, J = 6.6,
1.94 (s, 3H, CH3 CO), 2.21 (m, 1H, CH), 2.26 (dd, J = 13.5, 3.5 Hz, 1H, CH), 2.81
(dd, J = 13.5, 1.8 Hz, 1H, CH), 3.78 (s, 3H, OCH3 ), 4.43 (dd, J = 11.6, 1.8 Hz, 1H,
CHOH), 6.50 (bs, 1H, NH).
13
324
___________________________________________________________________________
172.9 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 271 (M+-H2 , 5), 256 (M+-H2 O, 7), 214 (M+-CO2 Me, 12), 196 (22), 187
(60), 170 (20), 154 (30), 112 (26), 102 (100), 85 (70), 57 (52).
threo-Methyl (2S*,3R*) 2-acetylamino-3-hydroxy-2-isobutyl-5-methylhexanoate (threo43fe) (sbo-339a)
HO
Ac HN
CO2CH3
Yield: 13 %
1
δ ppm = 0.81 (d, J = 6.8 Hz, 3H, CH3 ), 0.88 (d, J = 6.6 Hz, 3H , CH3 ), 0.93 (dd, J =
7.5, 7.4 Hz, 6H, 2CH3 ), 1.00 (dd, J = 6.9 Hz, 1H, CH), 1.12 (dd, J = 7.0, 1.8 Hz, 1H,
CH), 1.53 (m, 1H, CH), 2.00 (s, 3H, CH3 CO), 2.43 (dd, J = 7.5, 1.5 Hz,1H, CH),
3.67 (s, 3H, OCH3 ), 4.00 (dd, J = 8.5, 1.4 Hz, 1H, CHOH), 6.97 (bs, 1H, NH).
13
174.9 (s, COO).
Anal: (C 14 H27 NO4 , M = 273.2 g/mol)
Calcd:
C 61.51 H 9.96 N 5.12
Found:
C 61.62 H 9.86 N 4.97
erythro-Methyl
(2S*,3S*)
2-acetylamino-2-sec-butyl-3-hydroxy-5-methylhexanoate
(erythro-43ff) (sbo-345a)
HO
Ac HN
CO2CH3
325
___________________________________________________________________________
Following the above general procedure, the bicyclic oxetane 42ff (0.51 g, 2 mmol) was
and 0.11 g of the threo-isomer, all as a colorless oil.
Yield: 73 %
IR: (Film)
ν~ (cm-1 ) = 3305, 2874, 1732, 1673, 1455, 1051, 1031, 960, 670.
1
δ ppm = 0.81 (d, J = 6.9, Hz, 3H, CH3 ), 0.88 (d, J = 6.5, Hz, 3H , CH3 ), 0.94 (d, J =
6.6 Hz, 3H, CH3 ), 0.99 (t, J = 7.5 Hz, 3H, CH3 ), 1.43 (m, 1H, CH), 1.53 (m, 2H,
2CH), 1.97 (s, 3H, CH3 CO), 3.71 (s, 3H, OCH3 ), 4.15 (dd, J = 11.2, 1.6 Hz, 1H,
CHOH), 6.33 (bs, 1H, NH).
13
24.7 (d, CH), 25.5 (d, CH), 34.3 (t, CH2 ), 39.7 (t, CH2 ), 52.6 (q, OCH3 ), 71.9 (s, C2), 74.2 (d, C-3), 169.4 (s, CON), 173.0 (s, COO).
Anal: (C 14 H27 NO4 , M = 273.2 g/mol)
Calcd:
C 61.51 H 9.96 N 5.12
Found:
C 61.67 H 9.66 N 5.12
threo-Methyl (2S*,3R*) 2-acetylamino-2-sec-butyl-3-hydroxy-5-methylhexanoate (threo43ff) (sbo-345c)
HO
Ac HN
CO2CH3
Yield: 15 %
IR: (Film)
ν~ (cm-1 ) = 3340, 2956, 1738, 1682, 1471, 1056, 1031, 978, 680.
1
δ ppm = 0.81 (d, J = 7.5, Hz, 3H, CH3 ), 0.84 (d, J = 7.5, Hz, 3H , CH3 ), 0.88 (t, J = 6.5
326
___________________________________________________________________________
1.75 (m, 2H, CH2 ), 2.00 (s, 3H, CH3 CO), 3.69 (s, 3H, OCH3 ), 4.38 (dd, J = 10.5, 2.5
Hz, 1H, CHOH), 6.33 (bs, 1H, NH).
13
24.8 (d, CH), 26.5 (d, CH), 37.4 (t, CH2 ), 37.9 (t, CH2 ), 51.9 (q, OCH3 ), 82.3 (s, C2), 83.9 (d, C-3), 165.4 (s, CON), 174.3 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 255 (M+-H2 O, 15), 218 (M+-CO2 Me, 18), 196 (20), 187 (68), 170 (20),
154 (30), 112 (26), 102 (100), 86 (70), 68 (52).
4.15.2 Transacylation; General procedure:
To a solution of α-acetamido-β-hydroxy ester (0.3 g, 15 mmol) in chloroform (15 mL), 1N
aq. HCl (0.2 mL) was added at room temperature, the mixture was left to stirr overnight. After
the reaction was quenched with water, (15 mL), the mixture was extracted with methylene
chloride (3 x 15 mL) and the organic extract was washed with 5% sodium bicarbonate
solution, dried (Mg SO4 ) and the solvent was removed under vacum. The residue was purified
by preparative chromatography.
Methyl (2S*,3S*) 3-acetoxy-2-amino-2-methylpentanoate (erythro-44da) (sbo-300b)
AcO
H2N
CO2CH3
Preparative chromatography yielded 0.21 g of the product as a colorless oil.
Yield: 82 %
IR: (Film)
ν~ (cm-1 ) = 3336, 2919, 1760, 1738, 1471, 1056, 1031, 978, 680.
1
δ = 0.81 (t, J = 7.2, Hz, 3H, CH3 ), 1.62 (m, 2H, CH2 ), 1.70 (s, 3H, CH3 ), 2.21 (s,
3H, CH3 CO), 3.85 (s, 3H, OCH3 ), 5.24 (dd, J = 10.9, 2.9 Hz, 1H, CHOAc), 6.20
(bs, 2H, NH2 ).
13
δ = 11.0 (q, CH3 ), 20.8 (q, CH3 ), 21.9 (q, CH3 ), 23.2 (t, CH2 ), 53.9 (q, OCH3 ), 63.7
(s, Cq), 76.0 (d, CHOAc), 171.9 (COOCH3 ), 173.0 (s, OCOCH3 ).
327
___________________________________________________________________________
Methyl (2S*,3S*) 3-acetoxy-2-amino-2-propyl pentanoate (erythro-44dc) (sbo-349d)
AcO
H2N
CO2CH3
Yield: 79 %
TLC: Rf = 0.57 (ethylacetate/ n-hexane 1: 3)
1
δ = 0.78 (t, J = 7.4, Hz, 3H, CH3 ), 0.84 (t, J = 6.0 Hz, 2H, CH2 ), 1.10 (t, J = 7.6 Hz,
3H, CH3 ), 1.42 (m, 2H, CH2 ), 1.75 (m, 2H, CH2 ), 1.98 (s, 3H, CH3 CO), 3.69 (s, 3H,
OCH3 ), 5.30 (dd, J = 10.9, 2.6 Hz, 1H, CHOAc), 6.38 (bs, 2H, NH2 ).
13
δ = 9.2 (q, CH3 ), 11.3 (q, CH3 ), 13.3 (t, CH2 ), 17.6 (q, CH3 ), 23.7 (t, CH2 ), 36.0 (t,
CH2 ), 52.8 (q, OCH3 ), 67.8 (s, Cq), 77.6 (d, CHOAc), 172.9 (COOCH3 ), 173.6 (s,
OCOCH3 ).
HRMS: (C 11 H21 NO4 , M = 231.15 g/mol)
Calcd:
231.1473
Found:
231.1471
Methyl (2S*,3S*) 3-acetoxy-2-amino-5-methyl-2-propylhexanoate (erythro-44fc)
(sbo-350c)
AcO
H2N
CO2CH3
Yield: 72 %
1
δ = 0.84 (t, J = 6.5, Hz, 3H, CH3 ), 0.85 (m, 2H, CH2 ), 0.91 (dd, J = 6.5, 6.5 Hz, 6H,
2CH3 ), 1.23 (m, 1H, CH), 1.54 (m, 2H, CH2 ), 1.99 (s, 3H, CH3 CO), 3.70 (s, 3H,
OCH3 ), 5.49 (dd, J = 7.7, 3.9 Hz, 1H, CHOAc), 6.36 (bs, 2H, NH2 ).
13
328
___________________________________________________________________________
δ = 13.9 (q, CH3 ), 17.6 (q, CH3 ), 21.3 (q, CH3 ), 23.6 (q, CH3 ), 24.3 (t, CH2 ), 32.1
(d, CH), 39.1 (t, CH2 ), 43.3 (t, CH2 ), 52.8 (q, OCH3 ), 67.7 (s, Cq), 74.3 (d,
CHOAc), 172.3 (COOCH3 ), 172.9 (s, OCOCH3 ).
Synthesis of methyl 2-acetylamino-2-hydroxypentanoate (45) (sbo-392)
OH
CO2CH3
AcHN
To a solution of methyl 2-acetylamino-3-hydroxy-2-propylpentanoate 43dc (0.22 g, 1 mmol)
in methanol (20 mL), 10 % sodium hydroxide (20 mL) was added, and the mixture was
heated under reflux for 6h. After the reaction mixture was neutralized with 1N HCl, the
solvent was evaporated in vacuo and the residue was purified by preparative chromatography
to give 0.15 g of 45 as a white needle crystal.
Yield: 85 %
M.p: 123-124 °C.
IR: (CsI)
ν~ (cm-1 ) = 3329, 2971, 2878, 1738, 1660, 1445, 1097, 1031, 968, 684.
1
δ = 0.91 (t, J = 7.4, Hz, 3H, CH3 ), 1.27 (m, 1H, CH), 1.46 (m, 1H, CH), 1.78 (m,
2H, CH2 ), 1.97 (s, 3H, CH3 CO), 3.78 (s, 3H, OCH3 ), 4.82 (bs, 1H, OH), 6.35 (bs,
1H, NH).
13
δ = 13.8 (q, CH3 ), 16.3 (t, CH2 ), 22.9 (q, CH3 ), 40.0 (t, CH2 ), 53.2 (q, OCH3 ), 82.5
(s, Cq), 171.2 (CON), 172.2 (s, COO).
Anal: (C 8 H15 NO4 , M = 189.2 g/mol)
Calcd:
C 50.78 H 7.99 N 7.40
Found:
C 50.76 H 7.94 N 7.42
4.16 Photolyses of 5-methoxyoxazoles 36a-f with 2-methylbutyraldehyde; Genernal
procedure:
A mixture of 5-methoxyoxazoles 36a-f (5 mmol) and 2-methylbutyraldehyde (5 mmol) in 50
mL benzene was irradiated (λ = 300 nm) in a pyrex vessel for 24 h while purging with a slow
stream of nitrogen and cooling to ca. 15 °C. After irradiation, the solvent was evaporated at
329
___________________________________________________________________________
40°C/200 torr and the residue was submitted to
1
H-NMR analysis to determine the
diastereomeric ratio of the product. Purification was carried out by Büchi distillation. The
thermally and hydrolytically unstable primary products could in most cases not be
characterized by combustion analysis and were hydrolyzed subsequently to the more stable αamino-β-hydroxy esters.
exo-7-sec-Butyl-5-methoxy-1,3-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-
46a) (sbo-372)
H3C
N
O
H
O
CH3
OCH3
A solution of 2-methylbutyraldehyde (0.43 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole
Yield: 90 %
1
δ ppm = 0.76 (d, J = 6.8, Hz, 3H, CH3 ), 0.78 (t, J = 7.4, Hz, 3H , CH3 ), 0.92 (m, 2H,
CH2 ), 1.43 (s, 3H, CH3 ), 1.58 (m, 1H, CH), 2.05 (s, 3H, CH3 ), 3.56 (s, 3H, OCH3 ),
3.68 (d, J = 4.6 Hz, 1H, 7-H).
13
(t, CH2 ), 51.1 (q, OCH3 ), 73.5 (s, C-1), 92.5 (s, C-7), 124.1 (s, C-5), 165.1 (s, C-3).
HRMS: (C 11 H19 NO3 , M = 213.14 g/mol)
Calcd: 213.1360
Found: 213.1352
exo-7-sec-Butyl-1-ethyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo- 46b) (sbo-369)
330
___________________________________________________________________________
H3C
A
solution
of
N
O
H
O
OCH3
(0.43
g,
5
mmol)
and
4-ethyl-2-methyl-5-
Yield: 87 %
1
δ ppm = 0.75 (t, J = 7.5, Hz, 3H, CH3 ), 0.78 (d, J = 6.8, Hz, 3H , CH3 ), 0.81 (m, 2H,
CH2 ), 1.13 (m, 2H, CH2 ), 1.17 (m, 1H, CH), 2.12 (s, 3H, CH3 ), 3.57 (s, 3H, OCH3 ),
3.72 (d, J = 4.2 Hz, 1H, 7-H).
13
(t, CH2 ), 35.8 (t, CH2 ), 52.1 (q, OCH3 ), 77.1 (s, C-1), 92.7 (s, C-7), 124.2 (s, C-5),
165.1 (s, C-3).
exo-7-sec-Butyl-5-methoxy-3-methyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo- 46c) (sbo-393)
H3C
A
solution
of
N
O
H
O
OCH3
(0.43
g,
5
mmol)
and
2-methyl-4-propyl-5-
Yield: 90 %
1
331
___________________________________________________________________________
δ ppm = 0.77 (t, J = 7.4, Hz, 3H, CH3 ), 0.79 (d, J = 6.9, Hz, 3H , CH3 ), 0.83 (t, J = 6.5
Hz, 3H, CH3 ), 0.87 (m, 2H, CH2 ), 1.49 (m, 1H, CH), 1.53 (m, 2H, CH2 ), 1.67 (m,
2H, CH2 ), 2.00 (s, 3H, CH3 ), 3.53 (s, 3H, OCH3 ), 3.67 (d, J = 4.4 Hz, 1H, 7-H).
13
(t, CH2 ), 35.8 (t, CH2 ), 36.4 (t, CH2 ), 50.8 (q, OCH3 ), 77.8 (s, C-1), 92.8 (s, C-7),
124.2 (s, C-5), 164.7 (s, C-3).
exo-7-sec-Butyl-1-isopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene (exo-46d ) (sbo-396)
H3C
N
O
H
O
OCH3
A solution of 2-methylbutyraldehyde (0.43 g, 5 mmol) and 4-isopropyl-2-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24h according to the
Yield: 87 %
1
δ ppm = 0.74 (d, J = 6.6 Hz, 3H, CH3 ), 0.78 (d, J = 6.8, Hz, 3H , CH3 ), 0.80 (t, J = 7.4
Hz, 3H, CH3 ), 0.83 (d, J = 7.2 Hz, 3H, CH3 ), 1.12 (m, 1H, CH), 1.23 (m, 2H, CH2 ),
2.10 (s, 3H, CH3 ), 3.64 (s, 3H, OCH3 ), 4.12 (d, J = 4.7 Hz, 1H, 7-H).
13
21.4 (d, CH), 25.4 (d, CH), 27.5 (t, CH2 ), 50.4 (q, OCH3 ), 80.4 (s, C-1), 93.1 (s, C7), 124.4 (s, C-5), 164.7 (s, C-3).
exo-7-sec-Butyl-1-isobutyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-46e ) (sbo-398)
332
___________________________________________________________________________
H3C
A
solution
of
N
O
H
O
OCH3
2-methylbutyraldehyde (0.43 g, 5 mmol) and 4-isobutyl-2-methyl-5-
Yield: 78 %
1
δ ppm = 0.86 (d, J = 6.6 Hz, 6H, 2CH3 ), 0.88 (t, J = 7.4, Hz, 3H , CH3 ), 0.93 (t, J = 6.5
Hz, 3H, CH3 ), 1.12 (m, 1H, CH), 1.23 (m, 2H, CH2 ), 1.43 (m, 2H, CH2 ), 1.65 (m,
2H, CH2 ), 2.12 (s, 3H, CH3 ), 3.67 (s, 3H, OCH3 ), 4.12 (d, J = 4.8 Hz, 1H, 7-H).
13
24.7 (d, CH), 24.9 (t, CH2 ), 31.0 (d, CH), 40.7 (t, CH2 ), 50.9 (q, OCH3 ), 78.0 (s, C1), 90.3 (s, C-7), 124.5 (s, C-5), 164.9 (s, C-3).
HRMS: (C 14 H25 NO3 , M = 255.18 g/mol)
Calcd: 255.1825
Found: 255.1822
exo-1,7-Di-sec-butyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene
(exo-
46f) (sbo-397)
H
H3C
N
O
O
OCH3
A solution of 2-methylbutyraldehyde (0.43 g, 5 mmol) and 4-sec-butyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24h according to the
Yield: 85 %
333
___________________________________________________________________________
1
δ ppm = 0.85 (d, J = 6.6 Hz, 6H, 2CH3 ), 0.87 (t, J = 6.5, Hz, 6H , 2CH3 ), 0.97 (m, 2H,
CH2 ), 1.23 (m, 2H, 2CH), 2.12 (s, 3H, CH3 ), 3.66 (s, 3H, OCH3 ), 4.27 (d, J = 6.2
Hz, 1H, 7-H).
13
(d, CH), 25.1 (d, CH), 27.1 (t, CH2 ), 29.1 (t, CH2 ), 51.2 (q, OCH3 ), 79.4 (s, C-1),
89.1 (s, C-7), 124.3 (s, C-5), 164.1 (s, C-3).
4.16.1 Synthesis of lyxo- & ribo- α -acetamido-β
β -hydroxy esters (47a-f); General
procedure:
To a solution of bicyclic oxetanes 46a-f (1 mmol) in 20 mL of methylene chloride, 0.3 mL of
1N HCl was added, and the mixture was stirred at room temperature for 6 h. The reaction was
quenched by the addition of water (20 mL), the mixture was extracted with methylene
chloride (3 x 15 mL) and the organic extract was washed with saturated NaHCO3 , brine, dried
(MgSO4 ). After removal of the solvent, the residue was purified by preparative thick-layer
chromatography.
lyxo-Methyl (2R*,3R*,4S*) 2-acetylamino-3-hydroxy-2,4-dimethylhexanoate (lyxo-47a)
(sbo-372a)
CO2CH3
H3C
NHAc
H
OH
H3C
H
Et
Following the above general procedure, bicyclic oxetane 46a (0.43 g, 2 mmol) was
hydrolytically cleaved in 6h. Preparative chromatography yielded 0.35 g of the two
inseparable diastermeric lyxo-& ribo-isomers as a colorless oil.
Yield: 75 % (lyxo- & ribo-isomer)
1
CH), 1.48 (m, 2H, CH2 ), 1.68 (m, 2H, CH2 ), 2.12 (s, 3H, CH3 CO), 3.73 (s, 3H,
OCH3 ), 4.40 (d, J = 9.9 Hz, 1H, CHOH).
13
334
___________________________________________________________________________
(d, CH), 52.8 (q, OCH3 ), 74.5 (s, C-2), 88.9 (s, C-3), 165.5 (s, CON), 174.4 (s,
COO).
Anal: (C 11 H21 NO4 , M = 231.15 g/mol)
Calcd:
C 57.12 H 9.15 N 6.06
Found:
C 57.08 H 8.98 N 5.97
ribo-Methyl (2S*,3S*,4S*) 2-acetylamino-2-ethyl-3-hydroxy-4-methylhexanoate (ribo47a) (sbo-372a)
CO2CH3
AcHN
CH3
HO
H
H3C
H
Et
1
CH), 1.48 (m, 2H, CH2 ), 1.68 (m, 2H, CH2 ), 2.12 (s, 3H, CH3 CO), 3.73 (s, 3H,
OCH3 ), 4.44 (d, J = 8.5 Hz, 1H, CHOH).
13
(d, CH), 52.8 (q, OCH3 ), 74.5 (s, C-2), 88.9 (s, C-3), 165.4 (s, CON), 174.5 (s,
COO).
HRMS: (C 11 H21 NO4 , M = 231.15 g/mol)
Calcd: 231.1519
Found: 231.1513
lyxo-Methyl (2R*,3R*,4S*) 2-acetylamino-2-ethyl-3-hydroxy-4-methylhexanoate (lyxo47b) (sbo-369a)
CO2CH3
Et
NHAc
H
OH
H3C
H
Et
335
___________________________________________________________________________
Following the above general procedure, bicyclic oxetane 46b (0.45 g, 2 mmol) was
1
CH2 ), 1.54 (m, 4H, 2CH2 ), 1.68 (m, 1H, CH), 2.12 (s, 3H, CH3 CO), 3.72 (s, 3H,
OCH3 ), 4.22 (d, J = 9.3 Hz, 1H, CHOH).
13
(d, CH), 33.9 (t, CH2 ), 52.4 (q, OCH3 ), 78.5 (s, C-2), 88.9 (s, C-3), 165.4 (s, CON),
174.6 (s, COO).
HRMS: (C 12 H23 NO4 , M = 245.16 g/mol)
Calcd: 245.1621
Found: 245.1613
ribo-Methyl (2S*,3S*,4S*) 2-acetylamino-3-hydroxy-4-methyl-2-propylhexanoate (ribo47b) (sbo-369a)
CO2CH3
Ac HN
Et
HO
H
H3C
H
Et
1
CH2 ), 1.54 (m, 4H, 2CH2 ), 1.68 (m, 1H, CH), 2.12 (s, 3H, CH3 CO), 3.72 (s, 3H,
OCH3 ), 4.33 (d, J = 7.1 Hz, 1H, CHOH).
13
(d, CH), 34.5 (t, CH2 ), 52.4 (q, OCH3 ), 78.9 (s, C-2), 88.8 (s, C-3), 165.2 (s, CON),
174.5 (s, COO).
336
___________________________________________________________________________
lyxo-Methyl (2R*,3R*,4S*) 2-acetylamino-3-hydroxy-4-methyl-2-propylhexanoate (lyxo47c) (sbo-393a)
CO2CH3
Pr
NHAc
H
OH
H3C
H
Et
Following the above general procedure, bicyclic oxetane 46c (0.48 g, 2 mmol) was
1
δ ppm = 0.86 (t, J = 7.5 Hz, 3H, CH3 ), 0.90 (t, J = 7.5 Hz, 3H, CH3 ), 0.92 (d, J = 6.6
Hz, 3H, CH3 ), 1.23 (m, 2H, CH2 ), 1.54 (m, 2H, CH2 ), 1.68 (m, 1H, CH), 1.98 (s,
13
(d, CH), 33.9 (t, CH2 ), 34.9 (t, CH2 ), 52.4 (q, OCH3 ), 78.2 (s, C-2), 88.9 (s, C-3),
165.1 (s, CON), 174.7 (s, COO).
ribo-Methyl (2S*,3S*,4S*) 2-acetylamino-3-hydroxy-4-methyl-2-propylhexanoate (ribo47c) (sbo-393a)
CO2CH3
AcHN
Pr
HO
H
H3C
H
Et
1
δ ppm = 0.86 (t, J = 7.5 Hz, 3H, CH3 ), 0.90 (t, J = 7.5 Hz, 3H, CH3 ), 0.92 (d, J = 6.6
Hz, 3H, CH3 ), 1.23 (m, 2H, CH2 ), 1.54 (m, 2H, CH2 ), 1.68 (m, 1H, CH), 1.98 (s,
13
337
___________________________________________________________________________
(d, CH), 34.5 (t, CH2 ), 35.1 (t, CH2 ), 52.5 (q, OCH3 ), 78.6 (s, C-2), 89.8 (s, C-3),
165.1 (s, CON), 174.8 (s, COO).
lyxo-Methyl
(2R*,3R*,4S*)
(lyxo-47d) (sbo-396b)
CO2CH3
Pr i
NHAc
H
OH
H3C
H
Et
Following the above general procedure, bicyclic oxetane 46d (0.48 g, 2 mmol) was
1
Hz, 3H, CH3 ), 1.16 (d, J = 6.9 Hz, 3H, CH3 ), 1.72 (m, 2H, CH2 ), 1.99 (s, 3H,
CH3 CO), 3.72 (s, 3H, OCH3 ), 4.06 (d, J = 10.0 Hz, 1H, CHOH).
13
26.3 (d, CH), 30.4 (d, CH), 33.7 (t, CH2 ), 52.1 (q, OCH3 ), 81.9 (s, C-2), 89.1 (s, C3), 167.2 (s, CON), 173.9 (s, COO).
HRMS: (C 13 H25 NO4 , M = 259.18 g/mol)
Calcd: 259.1777
Found: 259.1770
ribo-Methyl
(2S*,3S*,4S*)
(ribo-47d) (sbo-396b)
CO2CH3
Pri
Ac HN
HO
H
H3C
H
Et
338
___________________________________________________________________________
1
Hz, 3H, CH3 ), 1.16 (d, J = 6.9 Hz, 3H, CH3 ), 1.72 (m, 2H, CH2 ), 1.99 (s, 3H,
CH3 CO), 3.72 (s, 3H, OCH3 ), 4.28 (d, J = 8.1 Hz, 1H, CHOH).
13
26.7 (d, CH), 30.3 (d, CH), 34.3 (t, CH2 ), 52.1 (q, OCH3 ), 81.9 (s, C-2), 89.1 (s, C3), 167.2 (s, CON), 173.9 (s, COO).
lyxo-Methyl
(2R*,3R*,4S*)
2-acetylamino-3-hydroxy-2-isobutyl-4-methylhexanoate
(lyxo-47e) (sbo-398b)
CO2CH3
Bui
NHAc
H
OH
H3C
H
Et
Following the above general procedure, bicyclic oxetane 46e (0.51 g, 2 mmol) was
inseparable diastermeric lyxo-& ribo-isomer as a colorless oil.
1
δ ppm = 0.82 (d, J = 6.6 Hz, 6H, 2CH3 ), 0.88 (t, J = 7.4 Hz, 3H, CH3 ), 0.92 (d, J = 6.6
Hz, 3H, CH3 ), 1.12 (m, 2H, 2CH), 1.54 (m, 2H, CH2 ), 1.67 (m, 2H, CH2 ), 1.96 (s,
13
24.6 (d, CH), 26.2 (d, CH), 33.8 (d, CH), 40.7 (t, CH2 ), 52.3 (q, OCH3 ), 78.1 (s, C2), 89.6 (s, C-3), 164.8 (s, CON), 175.2 (s, COO).
ribo-Methyl (2S*,3S*,4S*) 2-acetylamino-3-hydroxy-2-isobutyl-4-methylhexanoate (ribo47e) (sbo-398b)
339
___________________________________________________________________________
CO2CH3
Bui
Ac HN
HO
H
H3C
H
Et
1
δ ppm = 0.82 (d, J = 6.6 Hz, 6H, 2CH3 ), 0.88 (t, J = 7.4 Hz, 3H, CH3 ), 0.92 (d, J = 6.6
Hz, 3H, CH3 ), 1.12 (m, 2H, 2CH), 1.54 (m, 2H, CH2 ), 1.67 (m, 2H, CH2 ), 1.96 (s,
13
24.8 (d, CH), 26.7 (d, CH), 34.2 (d, CH), 40.7 (t, CH2 ), 52.4 (q, OCH3 ), 78.1 (s, C2), 89.6 (s, C-3), 164.8 (s, CON), 175.2 (s, COO).
lyxo-Methyl
(2R*,3R*,4S*)
(lyxo-47f) (sbo-397b)
CO2CH3
se c
Bu
NHAc
H
OH
H3C
H
Et
Following the above general procedure, bicyclic oxetane 46f (0.51 g, 2 mmol) was
1
δ ppm = 0.80 (t, J = 6.6 Hz, 3H, CH3 ), 0.85 (d, J = 6.8 Hz, 3H, CH3 ), 0.87 (t, J = 7.5
1.54 (m, 1H, CH), 1.98 (s, 3H, CH3 CO), 3.72 (s, 3H, OCH3 ), 4.15 (d, J = 9.2 Hz,
1H, CHOH).
13
340
___________________________________________________________________________
25.9 (d, CH), 26.2 (d, CH), 33.7 (t, CH2 ), 37.9 (t, CH2 ), 52.1 (q, OCH3 ), 82.5 (s, C2), 88.9 (s, C-3), 174.4 (s, CON), 179.8 (s, COO).
ribo-Methyl
(2S*,3S*,4S*)
(ribo-47f) (sbo-397b)
CO2CH3
Busec
AcHN
HO
H
H3C
H
Et
1
1.54 (m, 1H, CH), 1.98 (s, 3H, CH3 CO), 3.72 (s, 3H, OCH3 ), 4.28 (d, J = 8.1 Hz,
1H, CHOH).
13
25.4 (d, CH), 26.7 (d, CH), 33.1 (t, CH2 ), 37.4 (t, CH2 ), 52.4 (q, OCH3 ), 81.9 (s, C2), 88.5 (s, C-3), 174.2 (s, CON), 179.1 (s, COO).
Anal: (C 14 H27 NO4 , M = 273.17 g/mol)
Calcd:
C 61.51
H 9.96
N 5.12
Found:
C 61.42 H 9.64 N 5.04
341
___________________________________________________________________________
4.17 Synthesis of 2-substituted 4-methyl-5-methoxyoxazoles
Synthesis of N-acylalanine methyl ester 48a-c; General procedure:
To a stirred suspension of alanine methyl ester hydrochloride (13.96 g, 100 mmol) in absolute
chloroform (150 mL) was added triethylamine (28 mL, 200 mmol) at 0°C and the mixture
was stirred for 15 min at room temperature. The appropriate acid chloride (100 mmol) was
added dropwise and stirring was continued for 45 min. The solvent was removed under
reduced pressure; ethyl acetate (750 mL) was added and the mixture was filtered through a
pad of silica gel. Evaporation of the solvent under reduced pressure afforded the amide in
high purity.
Methyl 2-propionylaminopropionate (48a)129 (sbo-420)
EtOCHN
CO2CH3
Alanine methyl ester hydrochloride (13.96 g, 0.1 mol) and propionyl chloride (8.74 mL, 0.1
mol) were allowed to react according to the above general procedure to give 14.3 g of methyl
2-propionylaminopropionate as a colorless viscous oil.
Yield: 90 %
B.p: 130-132 °C, 10 torr (Lit.129 , 129-129.5°C, 10 torr).
1
δ ppm = 1.03 (t, J = 7.5 Hz, 3H, CH3 ), 1.26 (d, J = 7.2 Hz, 3H, CH3 ), 2.12 (q, J = 7.5
Hz, 2H, CH2 ), 3.62 (s, 3H, OCH3 ), 4.46 (quintet, J = 7.2 Hz, 1H, CHN), 6.39 (d, J =
5.3 Hz, 1H, NH).
13
δ ppm = 9.4 (q, CH3 ), 17.9 (t, CH2 ), 29.1 (q, CH3 ), 47.7 (d, CHN), 52.1 (q, OCH3 ),
173.4 (s, CON), 173.5 (s, CO).
Methyl 2-isobutyrylaminopropionate (48b) 176 (sbo-448)
Pri OCHN
CO2CH3
Alanine methyl ester hydrochloride (13.96 g, 0.1 mol) and isobutyryl chloride (10.55 mL, 0.1
mol) were allowed to react according to the above general procedure to give 16.6 g of methyl
2-isobutyrylaminopropionate as a colorless white solid.
342
___________________________________________________________________________
Yield: 96 %
M.p: 55-57 °C (Lit.176 , 55.5-57°C).
1
δ ppm = 1.05 (d, J = 6.9 Hz, 6H, 2CH3 ), 1.28 (d, J = 7.2 Hz, 3H, CH3 ), 2.32 (septet, J
= 6.9 Hz, 1H, CH), 3.64 (s, 3H, OCH3 ), 4.48 (quintet, J = 7.2 Hz, 1H, CHN), 6.26
(d, J = 5.6 Hz, 1H, NH).
13
δ ppm = 18.1 (q, CH3 ), 19.1 (q, CH3 ), 19.2 (q, CH3 ), 35.1 (d, CH), 47.6 (d, CHN),
52.2 (q, OCH3 ), 173.6 (s, CON), 176.5 (s, CO).
Methyl 2-(2,2-dimethyl-propionylamino)propionate (48c) (sbo-413)
But OCHN
CO2CH3
Alanine methyl ester hydrochloride (13.96 g, 0.1 mol) and pivaloyl chloride (12.3 mL, 0.1
mol) were allowed to react according to the above general procedure to give 16.84 g of
methyl 2-(2,2-dimethyl-propionylamino)propionate as a colorless white solid.
Yield: 90 %
M.p: 61-63 °C
1
δ ppm = 1.03 (s, 9H, 3CH3 ), 1.22 (d, J = 7.2 Hz, 3H, CH3 ), 3.56 (s, 3H, OCH3 ), 4.34
(quintet, J = 7.2 Hz, 1H, CHN), 6.23 (bs, 1H, NH).
13
δ ppm = 17.8 (q, CH3 ), 27.0 (q, 3CH3 ), 38.2 (s, Cq), 47.6 (d, CHN), 51.9 (q, OCH3 ),
173.4 (s, CON), 177.8 (s, CO).
Synthesis of 2-substituted 4-methyl-5-methoxyoxazoles (49a-c); General procedure:
N-Acyl-L-alanine methyl ester (0.1 mol) was dissolved in 20 ml of chloroform in a 250 ml
flask, 20.8 g (0.1 mol) of phosphorous pentachloride was added and the flask was fitted with a
calcium chloride tube. The solution was gently warmed by means of a water bath (ca. 60 °C)
with stirring until the HCl gas evolution ceased and the solution became intensively yellow.
Then, the flask was cooled by an ice-salt bath and 50 ml of absolute ether was added. To the
cooled mixture, 20 % aqueous KOH was added until neutralization dropwise with vigorous
stirring. The mixture was stirred at room temperature for 30 min. The organic layer was
subsequently separated and the aqueous layer was extracted with 2 x 200 mL of ether. The
343
___________________________________________________________________________
combined organic extracts were washed with water, brine and dried over anhydrous MgSO4.
After removal of the solvents under vacuum, the remaining oil was distilled by a Büchi
Kugelrohr apparatus to give the product 49a-f.
2-Ethyl-4-methyl-5-methoxyoxazole (49a)129 (sbo-421)
CH3
N
OCH3
O
Reaction of methyl 2-propionylaminopropionate (15.9 g, 0.1 mol) and PCl5 (20.8 g, 0.1 mol)
according to the above general procedure afforded 10.6 g of 2-ethyl-4-methyl-5methoxyoxazole as a colorless liquid.
Yield: 75 %
B.p: 80-83 °C, 10 torr (Lit.,129 81°C, 31 torr).
λmax (nm, log ε) = 228 (4.18), 236 (4.28).
IR: (Film)
ν~ (cm-1 ) = 2987, 1625, 1598, 1448, 1348, 1052, 963.
1
δ ppm = 1.18 (t, J = 7.5 Hz, 3H, CH3 ), 1.92 (s, 3H, CH3 ), 2.54 (q, J = 7.5 Hz, 2H,
CH2 ), 3.78 (s, 3H, OCH3 ).
13
δ ppm = 9.8 (q, CH3 ), 10.8 (q, CH3 ), 21.7 (t, CH2 ), 61.0 (q, OCH3 ), 111.0 (s, C-4),
154.4 (s, C-5), 156.1 (s, C-2).
2-Isopropyl-4-methyl-5-methoxyoxazole (49b) (sbo-449)
CH3
N
O
OCH3
Reaction of methyl 2-isobutyrylaminopropionate (17.3 g, 0.1 mol) and PCl5 (20.8 g, 0.1 mol)
according to the above general procedure afforded 12.4 g of 2-isopropyl-4-methyl-5methoxyoxazole as a pale yellow liquid.
Yield: 80 %
B.p: 94-97 °C, 10 torr.
1
344
___________________________________________________________________________
δ ppm = 1.19 (d, J = 6.9 Hz, 6H, 2CH3 ), 1.92 (s, 3H, CH3 ), 2.82 (septet, J = 7.1 Hz,
1H, CH), 3.78 (s, 3H, OCH3 ).
13
δ ppm = 9.7 (q, CH3 ), 19.9 (q, 2CH3 ), 28.3 (d, CH), 60.8 (q, OCH3 ), 110.7 (s, C-4),
154.1 (s, C-5), 159.2 (s, C-2).
2-tert-Butyl-4-methyl-5-methoxyoxazole (49c) (sbo-414)
CH3
N
OCH3
O
Reaction of methyl 2-(2,2-dimethyl-propionylamino)propionate (18.7 g, 0.1 mol) and PCl5
(20.8 g, 0.1 mol) according to the above general procedure afforded 13.2 g of 2-tert-butyl-4methyl-5-methoxyoxazole as a pale yellow liquid.
Yield: 78 %
B.p: 100-102 °C, 10 torr.
λmax (nm, log ε) = 234 (4.15), 245 (3.94).
IR: (Film)
ν~ (cm-1 ) = 2972, 1672, 1567, 1480, 1395, 1332, 995.
1
δ ppm = 1.24 (s, 9H, 3CH3 ), 1.94 (s, 3H, CH3 ), 3.79 (s, 3H, OCH3 ).
13
δ ppm = 9.8 (q, CH3 ), 28.2 (q, 3CH3 ), 33.5 (s, Cq), 60.9 (q, OCH3 ), 110.6 (s, C-4),
154.2 (s, C-5), 161.4 (s, C-2).
4.18 Synthesis of α -keto ester substrates
Synthesis of methyl trimethyl pyruvate (50)130 (sbo-466)
O
O
O
3,3-Dimethyl-2-butanone (10 g, 0.1 mol) was rapidly added to KMnO 4 (31.6 g, 0.2 mol) in
750 mL of water containing 10g of sodium hydroxide at room temperature. The mixture was
345
___________________________________________________________________________
stirred for 5h, then filtered on a Büchner funnel (eliminating MnO2 ) and concentrated until
one-fifth of the initial volume remained. Concentrated HCl (38 mL) was slowly added in
small amounts. The supernatant oily liquid was decanted and the aqueous layer was salted out
with sodium chloride and concentrated. The obtained ketoacid was stirred with 15 g of
methanol and 7.5 g of conc. H2 SO4 . The mixture was heated under reflux for 2h. After
cooling, the mixture was decanted, extracted three times with pentane, and the organic layer
was neturalized with 5% sodium bicarbonate solution and dried over sodium sulfate. The
solvents were evapourated under reduced pressure and the ketoester was distilled to give 7.5 g
of pure methyl trimethylpyruvate.
Yield: 70 %
B.p: 65-67 °C, 10 torr (Lit.,130 68-70 °C, 1o torr).
λmax (nm, log ε) = 352 (2.18), 296 (3.34).
IR: (Film)
ν~ (cm-1 ) = 2974, 2875, 1742, 1716, 1480, 1463, 1435, 1368, 833.
1
δ ppm = 1.20 (s, 9H, 3CH3 ), 3.79 (s, 3H, OCH3 ).
13
δ ppm = 25.6 (q, 3CH3 ), 42.5 (s, Cq), 52.1 (q, OCH3 ), 163.9 (s, COO), 201.6 (s, CO).
Anal: (C 7 H12 O3 , M = 144.2 g/mol)
Calcd:
C 58.32 H 8.39
Found:
C 58.15 H 8.17
Synthesis of isopropyl phenyl glyoxylate (51)131b (sbo-452)
O
O
O
To a stirring solution of benzoyl formic acid (2.60 g, 17.3 mmol) in 40 mL of dry benzene
were added 4-(dimethylamino)pyridine (DMAP) (213 mg, 1.7 mmol) and 2.21 g, 35 mmol of
isopropyl alcohol and N,N-dicyclohexylcarbodiimide (DCC) (3.57 g, 17.3 mmol) was added
to the reaction mixture kept in ice-bath. The mixture was stirred in the ice bath for 10 min and
then stirred at room temperature for another 10 h. Precipitated urea was filtered by vacuum
filteration. The resulting solution was washed with water, 0.5N HCl, and saturated sodium
346
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bicarbonate solution three times and chromatographed with eluent (ethylacetate/hexane, 1/5)
to yield 2.74 g of pure isopropyl phenylglyoxylate as a colorless viscous oil.
Yield: 90 %
1
δ ppm = 1.37 (d, J = 6.3Hz, 6H, 2CH3 ), 5.30 (septet, J = 6.3 Hz, 1H, CH), 7.43 (m,
2H, Harom), 7.59 (m, 1H, Harom), 7.99 (d, J = 6.0 Hz, 2H, Harom).
13
δ ppm = 21.6 (q, 2CH3 ), 70.6 (d, OCH), 128.8 (d, CHarom), 129.8 (d, CHarom), 132.4
(d, CHarom), 134.7 (s, Cqarom), 163.6 (s, COO), 186.6 (s, CO).
Synthesis of tert-butyl phenylglyoxylate (52)131a (sbo-440)
O
O
O
To a stirring solution of benzoyl formic acid (2.60 g, 17.3 mmol) in 40 mL of dry benzene
were added 4-(dimethylamino)pyridine (DMAP) (213 mg, 1.7 mmol) and 2.22 g, 30 mmol of
tert-butyl alcohol and N,N-dicyclohexylcarbodiimide (DCC) (3.57 g, 17.3 mmol) was added
to the reaction mixture kept in ice-bath. The mixture was stirred in the ice bath for 10 min and
then stirred at room temperature for another 10 h. Precipitated urea was filtered by vacuum
filteration. The resulting solution was washed with water, 0.5N HCl, and saturated sodium
bicarbonate solution, dried (MgSO4 ). After removal of the solvent under vacum, the residue
was purified by columm chromatography using a mixture of ethyl acetate and n-hexane as
eluent to give 3.54 g of tert-butyl phenylglyoxylate as a colorless viscous oil.
Yield: 92 %
1
δ ppm = 1.63 (s, 9H, 3CH3 ), 7.50 (t, J = 6.0 Hz, 2H, Harom), 7.64 (t, J = 6.0 Hz, 1H,
Harom), 7.79 (d, J = 6.0 Hz, 2H, Harom).
13
δ ppm = 27.9 (q, 3CH3 ), 84.6 (s, Cq), 128.7 (d, CHarom), 129.7 (d, CHarom), 132.4 (d,
CHarom), 134.5 (s, Cqarom), 163.6 (s, COO), 186.7 (s, CO).
347
___________________________________________________________________________
Synthesis of (-)-menthyl phenylglyoxylate (53)132 (sbo-360)
O
O
O
Oxalyl chloride (9.45 mL, 0.11 mol) in acetonitrile (10 mL) is added dropwise to a solution of
dimethylformamide (25 mL) in acetonitrile (120 mL) at –15°C under nitrogen. After 15min,
phenyl glyoxylic acid (15.0 g, 0.1 mol) is added with stirring and stirring is continued until
the precipitate dissolves (∼30 min). Menthol (15.6 g, 0.1 mol) dissolved in acetonitrile (15
mL) is added and the mixture is stirred at room temperature for 6h. The mixture is then cooled
to 0°C, pyridine (15 mL) in acetonitrile (30 mL) is added dropwise, and the mixture is stirred
for 1h. Dichloromethane (300 mL) is added, the solution is washed with sodium carbonate
solution (300 mL), extracted with dichloromethane (300mL). The extract is dried with
magnesium sulfate and the solvent is evaporated. The residue is cooled to – 25°C and mixed
with an equal volume of 1/1 ether/pentane. After 5-10 h, the crystals are filtered, washed with
pentane and the mother liquor is again evaporated and collected to give 24.5 g of menthyl
phenylglyoxylate as a colorless needles.
Yield: 85 %
M.p: 64-67°C.
λmax (nm, log ε) = 348 (2.34), 310 (3.49).
IR: (Film)
ν~ (cm-1 ) = 2957, 2937, 2900, 2876, 1733, 1685, 1594, 1450, 1387, 1296, 1177,
980.
1
Hz, 3H, CH3 ), 1.10 (m, 1H, CH), 1.20 (m, 1H, CH), 1.53 (m, 2H, CH2 ), 1.73 (m,
2H, CH2 ), 2.19 (m, 1H, CH), 4.98 (ddd, J = 11.0, 4.6, 4.4 Hz, 1H, OCH), 7.49 (m,
2H, Harom), 7.65 (m, 1H, Harom), 7.97 (m, 2H, Harom).
13
(d, CH), 40.6 (t, CH2 ), 46.8 (d, CH), 77.0 (d, OCH), 128.9 (d, CHarom), 129.9 (d,
CHarom), 132.6 (s, Cqarom), 163.9 (s, COO), 186.8 (s, CO).
Anal: (C 18 H24 O3 , M = 288.38 g/mol)
348
___________________________________________________________________________
Calcd:
C 74.97 H 8.39
Found:
C 74.89 H 8.31
4.19 Photolyses of α -keto esters with 5-methoxyoxazoles; General procedure:
Under a nitrogen atmosphere, a solution of α-keto ester substrates (5 mmol) and 5methoxyoxazole substrates (5 mmol) in 50 mL of benzene was irradiated in a Rayonet
photoreactor (350 nm) at 10°C for 24. The solvent was evaporated in vacuo, and the residue
was analyzed by 1 H-NMR spectroscopy to determine the diastereoselectivity. Purification was
carried out by preparative chromatography using silica gel which was firstly neutralized by
elution with 1% TEA/CH2 Cl2 . The thermally and hydrolytically unstable primary products
could in most cases not be characterized by combustion analysis and were hydrolyzed
subsequently to the more stable α-amino-β-hydroxy esters.
Photolyses of methyl pyruvate with 5-methoxyoxazoles 36a-f:
5-Methoxy-1,3,7-trimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7-carboxylic
acid
methyl ester (55a) (sbo-494c)
H3 C
H3 C
O
N
O
CO2 CH3
CH3
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole (0.62 g,
5 mmol) in benzene (50 mL) was irradiated for 24 h according to the above general procedure
to give 0.98 g of a yellow oil. Preparative chromatography on silica gel yielded 0.85 g of the
oxetane as a colorless oil. The product was thermally unstable and was subsequently
Yield: 74 %
TLC: Rf = 0.37 (ethylacetate/n-hexane 1: 4).
IR: (Film)
ν~ (cm-1 ) = 2989, 2895, 1725, 1610, 1600, 1445, 1095, 980, 770.
1
δ ppm = 1.22 (s, 3H, CH3 ), 1.44 (s, 3H, CH3 ), 2.08 (s, 3H, CH3 ), 3.56 (s, 3H, OCH3 ),
3.78 (s, 3H, OCH3 ).
13
349
___________________________________________________________________________
δ ppm = 14.6 (q, CH3 ), 14.9 (q, CH3 ), 18.0 (q, CH3 ), 51.8 (q, OCH3 ), 52.4 (q, OCH3 ),
76.0 (s, C-7), 88.7 (s, C-1), 123.9 (s, C-5), 166.2 (s, C-3), 171.5 (s, COO).
HRMS: (C10 H15 NO5 , M = 229.10 g/mol)
Calcd:
229.0946
Found:
229.0941
1-Ethyl-5-methoxy-3,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7-carboxylic
acid methyl ester (55b) (sbo-399e)
H3C
H3C
N
O
CO2CH3
O
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 4-ethyl-2-methyl-5-methoxyoxazole
(0.71 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the above general
procedure to give 0.96 g of a yellow oil. Preparative chromatography on silica gel yielded
0.80 g of the oxetane as a colorless oil. The product was thermally unstable and was
subsequently hydrolyzed to give the corresponding α-amino-β-hydroxy ester (see later).
Yield: 66 %
TLC: Rf = 0.36 (ethyl acetate/n-hexane 1:4).
1
δ ppm = 0.84 (t, J = 7.5 Hz, 3H, CH3 ), 1.47 (s, 3H, CH3 ), 1.58 (m, 1H, CH), 1.68 (m,
1H, CH), 2.13 (s, 3H, CH3 ), 3.59 (s, 3H, OCH3 ), 3.79 (s, 3H, OCH3 ).
13
52.4 (q, OCH3 ), 79.5 (s, C-7), 89.0 (s, C-1), 124.0 (s, C-5), 166.3 (s, C-3), 171.7 (s,
COO).
5-Methoxy-3,7-dimethyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7-carboxylic
acid methyl ester (55c) (sbo-405b)
H3 C
H3 C
O
N
O
CO2 CH3
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 2-methyl-4-propyl-5-methoxyoxazole
350
___________________________________________________________________________
procedure to give 1.1 g of a yellow oil. Preparative chromatography on silica gel yielded 0.92
g of the oxetane as a colorless oil. The product was thermally unstable and was subsequently
Yield: 73 %
1
δ ppm = 1.05 (t, J = 7.5 Hz, 3H, CH3 ), 1.33 (t, J = 7.1 Hz, 2H, CH2 ), 1.47 (s, 3H,
CH3 ), 2.08 (s, 3H, CH3 ), 2.14 (sextet, J = 7.5 Hz, 2H, CH2 ), 3.74 (s, 3H, OCH3 ),
3.77 (s, 3H, OCH3 ).
13
(q, OCH3 ), 52.4 (q, OCH3 ), 63.6 (s, C-7), 73.3 (s, C-1), 124.2 (s, C-5), 165.2 (s, C3), 168.4 (s, COO).
1-Isopropyl-5-methoxy-3,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (55d) (sbo-406)
H3C
H3C
N
O
CO2CH3
O
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 4-isopropyl-2-methyl-5-methoxyoxazole
Yield: 60 %
1
δ ppm = 0.84 (d, J = 6.6 Hz, 3H, CH3 ), 1.01 (d, J = 6.6 Hz, 3H, CH3 ), 1.23 (septet, J =
6.6 Hz, 1H, CH), 1.55 (s, 3H, CH3 ), 2.14 (s, 3H, CH3 ), 3.64 (s, 3H, OCH3 ), 3.79 (s,
3H, OCH3 ).
13
(q, OCH3 ), 52.3 (q, OCH3 ), 82.8 (s, C-7), 90.2 (s, C-1), 124.1 (s, C-5), 166.4 (s, C3), 171.8 (s, COO).
351
___________________________________________________________________________
HRMS: (C 12 H19 NO5 , M = 257.13 g/mol)
Calcd:
257.1374
Found:
257.1371
1-Isobutyl-5-methoxy-3,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (55e) (sbo-407d)
H3C
H3C
N
O
CO2CH3
O
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 4-isobutyl-2-methyl-5-methoxyoxazole
Yield: 72 %
1
CH), 1.18 (m, 2H, CH2 ), 1.46 (s, 3H, CH3 ), 1.93 (s, 3H, CH3 ), 3.54 (s, 3H, OCH3 ),
3.63 (s, 3H, OCH3 ).
13
27.8 (d, CH), 36.1 (t, CH2 ), 51.7 (q, OCH3 ), 52.4 (q, OCH3 ), 78.9 (s, C-7), 89.3 (s,
C-1), 124.1 (s, C-5), 165.6 (s, C-3), 171.7 (s, COO).
1-sec-Butyl-5-methoxy-3,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (55f) (sbo-408b)
H3C
H3C
O
N
O
CO2CH3
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 4-sec-butyl-2-methyl-5-methoxyoxazole
352
___________________________________________________________________________
Yield: 68 %
1
CH2 ), 1.48 (s, 3H, CH3 ), 2.08 (s, 3H, CH3 ), 3.57 (s, 3H, OCH3 ), 3.67 (m, 1H, CH),
3.77 (s, 3H, OCH3 ).
13
(d, CH), 51.5 (q, OCH3 ), 52.4 (q, OCH3 ), 83.5 (s, C-7), 90.4 (s, C-1), 124.2 (s, C-5),
165.8 (s, C-3), 171.9 (s, COO).
Photolyses of methyl trimethylpyruvate with 5-methoxyoxazoles 36a-f:
7-tert-Butyl-5-methoxy-1,3-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (56a) (sbo-480a)
H3CO2C
H3C
A
solution
of
methyl
N
O
trimethylpyruvate
O
CH3
OCH3
(0.36
g,
2.5
mmol)
and
2,4-dimethyl-5-
methoxyoxazole (0.32 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
the above general procedure to give 0.58 g of a yellow oil. Preparative chromatography on
silica gel yielded 0.5 g of the oxetane as a colorless oil. The product was thermally unstable
and was subsequently hydrolyzed to give the corresponding α-amino-β-hydroxy ester (see
later).
Yield: 74 %
1
δ ppm = 1.03 (s, 3H, CH3 ), 1.11 (s, 9H, 3CH3 ), 1.49 (s, 3H, CH3 ), 1.97 (s, 3H, CH3 ),
3.56 (s, 3H, OCH3 ), 3.72 (s, 3H, OCH3 ).
13
353
___________________________________________________________________________
δ ppm = 14.7 (q, CH3 ), 15.6 (q, CH3 ), 25.7 (q, 3CH3 ), 36.6 (s, Cq), 51.3 (q, OCH3 ),
51.7 (q, OCH3 ), 86.8 (s, C-1), 87.1 (s, C-7), 122.2 (s, C-5), 168.1 (s, C-3), 176.0 (s,
COO).
HRMS: (C 13 H21 NO5 , M = 271.14 g/mol)
Calcd:
271.1381
Found:
271.1386
7-tert-Butyl-1-ethyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (56b) (sbo-390)
H3CO2C
H3C
O
N
O
OCH3
A solution of methyl trimethylpyruvate (0.36 g, 2.5 mmol) and 4-ethyl-2-methyl-5methoxyoxazole (0.35 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
later).
Yield: 84 %
1
δ ppm = 0.77 (t, J = 7.5 Hz, 3H, CH3 ), 0.94 (m, 2H, CH2 ), 1.04 (s, 9H, 3CH3 ), 1.99 (s,
3H, CH3 ), 3.54 (s, 3H, OCH3 ), 3.70 (s, 3H, OCH3 ).
13
δ ppm = 8.0 (q, CH3 ), 14.6 (q, CH3 ), 21.8 (q, 3CH3 ), 27.0 (s, Cq), 33.7 (t, CH2 ), 34.6
(s, Cq), 51.6 (q, OCH3 ), 53.1 (q, OCH3 ), 80.6 (s, C-1), 81.2 (s, C-7), 122.9 (s, C-5),
166.2 (s, C-3), 171.8 (s, COO).
7-tert-Butyl-5-methoxy-3-methyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (56c) (sbo-389)
H3CO2C
H3C
N
O
O
OCH3
354
___________________________________________________________________________
A solution of methyl trimethylpyruvate (0.36 g, 2.5 mmol) and 2-methyl-4-propyl-5methoxyoxazole (0.38 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
later).
Yield: 70 %
1
3CH3 ), 1.55 (m, 1H, CH), 1.78 (m, 1H, CH), 2.11 (s, 3H, CH3 ), 3.54 (s, 3H, OCH3 ),
3.68 (s, 3H, OCH3 ).
13
δ ppm = 13.3 (q, CH3 ), 14.6 (q, CH3 ), 21.4 (q, CH3 ), 25.8 (q, 3CH3 ), 27.3 (t, CH2 ),
36.7 (t, CH2 ), 38.2 (s, Cq), 50.8 (q, OCH3 ), 51.3 (q, OCH3 ), 92.3 (s, C-1), 97.3 (s,
C-7), 123.9 (s, C-5), 165.6 (s, C-3), 172.1 (s, COO).
7-tert-Butyl-1-isopropyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (56e) (sbo-574)
H3CO2C
H3C
N
O
O
OCH3
A solution of methyl trimethylpyruvate (0.36 g, 2.5 mmol) and 2-isopropyl-4-methyl-5methoxyoxazole (0.38 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
silica gel yielded 0.51 g of oxetane as a colorless oil.
Yield: 69 %
1
3CH3 ), 1.45 (m, 1H, CH), 2.12 (s, 3H, CH3 ), 3.58 (s, 3H, OCH3 ), 3.64 (s, 3H,
OCH3 ).
13
355
___________________________________________________________________________
δ ppm = 13.7 (q, CH3 ), 16.6 (q, CH3 ), 16.7 (q, CH3 ), 26.1 (q, 3CH3 ), 27.2 (d, C), 36.7
(s, Cq), 50.5 (q, OCH3 ), 51.8 (q, OCH3 ), 90.7 (s, C-1), 94.2 (s, C-7), 124.1 (s, C-5),
168.2 (s, C-3), 173.4 (s, COO).
7-tert-Butyl-1-isobutyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (56e) (sbo-575)
H3CO2C
H3C
N
O
O
OCH3
A solution of methyl trimethylpyruvate (0.36 g, 2.5 mmol) and 2-isobutyl-4-methyl-5methoxyoxazole (0.42 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
later).
Yield: 70 %
1
3CH3 ), 1.52 (m, 1H, CH), 1.78 (m, 2H, CH2 ), 2.07 (s, 3H, CH3 ), 3.59 (s, 3H,
OCH3 ), 3.73 (s, 3H, OCH3 ).
13
δ ppm = 13.4 (q, CH3 ), 18.9 (q, CH3 ), 19.4 (q, CH3 ), 25.8 (q, 3CH3 ), 27.3 (d, CH),
39.7 (s, Cq), 40.2 (t, Cq), 51.2 (q, OCH3 ), 51.8 (q, OCH3 ), 92.4 (s, C-1), 96.2 (s, C7), 124.4 (s, C-5), 169.2 (s, C-3), 173.4 (s, COO).
HRMS: (C 16 H27 NO5 , M = 313.19 g/mol)
Calcd:
313.1927
Found:
313.1924
7-tert-Butyl-1-sec-butyl-5-methoxy-3-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (56f) (sbo-576)
356
___________________________________________________________________________
H3CO2C
H3C
N
O
O
OCH3
A solution of methyl trimethylpyruvate (0.36 g, 2.5 mmol) and 4-sec-butyl-2-methyl-5methoxyoxazole (0.42 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
silica gel yielded 0.54 g of oxetane as a colorless oil.
Yield: 69 %
1
δ ppm = 0.88 (t, J = 7.5 Hz, 3H, CH3 ), 1.00 (d, J = 7.4 Hz, 3H, CH3 ), 1.05 (s, 9H,
3CH3 ), 1.23 (m, 2H, CH2 ), 1.56 (m, 1H, CH), 2.06 (s, 3H, CH3 ), 3.64 (s, 3H,
OCH3 ), 3.73 (s, 3H, OCH3 ).
13
δ ppm = 13.3 (q, CH3 ), 14.6 (q, CH3 ), 21.4 (q, CH3 ), 25.8 (q, 3CH3 ), 26.2 (t, CH2 ),
28.7 (d, CH), 38.2 (s, Cq), 50.2 (q, OCH3 ), 51.9 (q, OCH3 ), 90.6 (s, C-1), 95.8 (s, C7), 124.0 (s, C-5), 167.6 (s, C-3), 173.4 (s, COO).
Photolyses of methyl phenylglyoxylate with 5-methoxyoxazoles 36a-f:
exo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-58a) (sbo-35a)
H3CO 2C
O
N
H3C
O
Ph
CH3
OCH3
A solution of methyl phenylglyoxylate (0.82 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole
0.75 g of the exo-isomer (and 0.4 g of the endo-isomer) as a colorless oil.The products were
thermally unstable and were subsequently hydrolyzed to give the corresponding α-amino-βhydroxy esters (see later).
Yield: 51 %
IR: (Film)
357
___________________________________________________________________________
ν~ (cm-1 ) = 2994, 2898, 1728, 1615, 1605, 1550, 1440, 1065, 980, 775.
1
δ ppm = 1.09 (s, 3H, CH3 ), 2.09 (s, 3H, CH3 ), 3.66 (s, 3H, OCH3 ), 3.76 (s, 3H,
OCH3 ), 7.23-7.35 (m, 5H, Harom).
13
δ ppm = 14.7 (q, CH3 ), 28.1 (q, CH3 ), 51.8 (q, OCH3 ), 52.6 (q, OCH3 ), 82.3 (s, C-1),
91.5 (s, C-7), 123.3 (s, C-5), 125.6 (d, CHarom), 126.2 (d, CHarom), 134.8 (s, Cqarom),
165.5 (s, C-3), 169.6 (s, COO).
endo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (endo-58a) (sbo-359)
Ph
N
O
H3C
CO2CH3
O
CH3
OCH3
Yield: 28 %
1
δ ppm = 1.53 (s, 3H, CH3 ), 1.71 (s, 3H, CH3 ), 3.68 (s, 3H, OCH3 ), 3.78 (s, 3H,
OCH3 ), 7.23-7.38 (m, 5H, Harom).
13
166.6 (s, C-3), 172.4 (s, COO).
HRMS: (C 15 H17 NO5 , M = 291.11 g/mol)
Calcd:
291.1123
Found:
291.1118
exo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-58b) (sbo-368)
H3CO2C
H3C
N
O
Ph
O
OCH3
358
___________________________________________________________________________
A
solution
of
methyl
phenylglyoxylate (0.82 g, 5 mmol) and 4-ethyl-2-methyl-5-
methoxyoxazole (0.71 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
above general procedure to give 1.35 g of a yellow oil. Preparative chromatography on silica
gel yielded 0.8 g of the exo-isomer (and 0.35 g of the endo-isomer) as a colorless oil. The
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
corresponding α-amino-β-hydroxy esters (see later).
Yield: 52 %
1
δ ppm = 0.71 (t, J = 7.5 Hz, 3H, CH3 ), 1.00 (m, 1H, CH), 1.26 (m, 1H, CH), 2.08 (s,
3H, CH3 ), 3.66 (s, 3H, OCH3 ), 3.77 (s, 3H, OCH3 ), 7.26-7.35 (m, 5H, Harom).
13
δ ppm = 7.3 (q, CH3 ), 14.3 (q, CH3 ), 21.2 (t, CH2 ), 51.7 (q, OCH3 ), 52.6 (q, OCH3 ),
82.1 (s, C-1), 91.8 (s, C-7), 123.4 (s, C-5), 126.3 (d, CHarom), 127.1 (d, CHarom),
128.1 (d, CHarom), 134.7 (s, Cqarom), 166.6 (s, C-3), 171.1 (s, COO).
endo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (endo-58b) (sbo-368a)
Ph
H3C
N
O
CO2CH3
O
OCH3
Yield: 23 %
1
δ ppm = 0.68 (t, J = 7.5 Hz, 3H, CH3 ), 1.55 (m, 1H, CH), 1.72 (s, 3H, CH3 ), 1.87 (m,
1H, CH), 3.74 (s, 3H, OCH3 ), 3.80 (s, 3H, OCH3 ), 7.21-7.37 (m, 5H, Harom).
13
128.1 (d, CHarom), 137.6 (s, Cqarom), 169.1 (s, C-3), 173.0 (s, COO).
exo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicylo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-58c) (sbo-361a)
359
___________________________________________________________________________
H3CO2C
O
N
H3C
O
Ph
OCH3
A solution of methyl phenylglyoxylate (0.82 g, 5 mmol) and 2-methyl-4-propyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
gel yielded 0.82 g of the exo-isomer (and 0.42 g of the endo-isomer) as a colorless oil.The
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 52 %
1
δ ppm = 0.71 (t, J = 7.1 Hz, 3H, CH3 ), 1.25 (m, 2H, CH2 ), 1.52 (m, 2H, CH2 ), 2.08 (s,
13
52.7 (q, OCH3 ), 83.0 (s, C-1), 92.6 (s, C-7), 123.3 (s, C-5), 126.3 (d, CHarom), 127.5
(d, CHarom), 128.5 (d, CHarom), 134.6 (s, Cqarom), 165.7 (s, C-3), 168.2 (s, COO).
HRMS: (C 17 H21 NO5 , M = 319.14 g/mol)
Calcd:
319.1367
Found:
319.1363
endo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicylo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (endo-58c) (sbo-361d)
Ph
H3C
N
O
CO2CH3
O
O CH3
Yield: 27 %
1
δ ppm = 0.87 (t, J = 7.5 Hz, 3H, CH3 ), 1.32 (m, 2H, CH2 ), 1.72 (s, 3H, CH3 ), 1.95 (m,
13
360
___________________________________________________________________________
(d, CHarom), 135.1 (s, Cqarom), 165.2 (s, C-3), 169.9 (s, COO).
exo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid methyl ester (exo-58d) (sbo-362)
H3CO2C
H3C
N
O
Ph
O
OCH3
A solution of methyl phenylglyoxylate (0.82 g, 5 mmol) and 4-isopropyl-2-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 48 %
1
6.8 Hz, 1H, CH), 2.04 (s, 3H, CH3 ), 3.67 (s, 3H, OCH3 ), 3.78 (s, 3H, OCH3 ), 7.337.62 (m, 5H, Harom).
13
endo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid ethyl ester (endo-58d) (sbo-362a)
Ph
H3C
N
O
CO2CH3
O
OCH3
Yield: 31 %
361
___________________________________________________________________________
1
6.8 Hz, 1H, CH), 1.78 (s, 3H, CH3 ), 3.54 (s, 3H, OCH3 ), 3.67 (s, 3H, OCH3 ), 7.277.34 (m, 5H, Harom).
13
exo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-58e) (sbo-366a)
H3CO2C
H3C
N
O
Ph
O
OCH3
A solution of methyl phenylglyoxylate (0.82 g, 5 mmol) and 4-isobutyl-2-methyl-5methoxyoxazole (0.82 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 50 %
1
CH), 1.35 (dd, J = 13.4, 5.7 Hz, 1H, CH), 2.08 (s, 3H, CH3 ), 2.33 (dd, J = 13.4, 6.1
Hz, 1H, CH), 3.71 (s, 3H, OCH3 ), 3.76 (s, 3H, OCH3 ), 7.27-7.55 (m, 5H, Harom).
13
(q, OCH3 ), 53.3 (q, OCH3 ), 81.9 (s, C-2), 91.8 (s, C-7), 123.4 (s, C-5), 126.3 (d,
CHarom), 127.5 (d, CHarom), 128.4 (d, CHarom), 134.5 (s, Cqarom), 165.8 (s, C-3),
169.2 (s, COO).
endo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid methyl ester (endo-58e) (sbo-366c)
362
___________________________________________________________________________
H3C
Ph
O
N
O
CO2CH3
OCH3
Yield: 25 %
1
CH), 1.62 (dd, J = 14.2, 7.8 Hz, 1H, CH), 1.73 (s, 3H, CH3 ), 2.07 (dd, J = 14.2, 4.7
Hz, 1H, CH), 3.69 (s, 3H, OCH3 ), 3.77 (s, 3H, OCH3 ), 7.24-7.49 (m, 5H, Harom).
13
169.9 (s, COO).
exo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methylester (exo-58f) (sbo-367a)
H3CO2C
H3C
N
O
Ph
O
OCH3
A solution of methyl phenylglyoxylate (0.82 g, 5 mmol) and 4-sec-butyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 48 %
1
δ ppm = 0.50 (t, J = 7.4 Hz, 3H, CH3 ), 0.68 (quintet, J = 7.4 Hz, 2H, CH2 ), 0.85 (d, J =
6.6 Hz, 3H, CH3 ), 1.35 (m, 1H, CH), 2.09 (s, 3H, CH3 ), 3.72 (s, 3H, OCH3 ), 3.80 (s,
3H, OCH3 ), 7.26-7.56 (m, 5H, Harom).
13
363
___________________________________________________________________________
169.0 (s, COO).
HRMS: (C 18 H23 NO5 , M = 333.16 g/mol)
Calcd:
333.1578
Found:
333.1572
endo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methylester (endo-58f) (sbo-367d)
Ph
N
O
H3C
CO2CH3
O
OCH3
Yield: 24 %
1
CH), 1.77 (s, 3H, CH3 ), 1.93 (m, 2H, CH2 ), 3.71 (s, 3H, OCH3 ), 3.78 (s, 3H,
OCH3 ), 7.27-7.52 (m, 5H, Harom).
13
170.2 (s, COO).
Photolyses of ethyl phenylglyoxylate with 5-methoxyoxazoles 36a-f:
exo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (exo-60a) (sbo-351)
C2H5O2C
H3C
N
O
Ph
O
CH3
OCH3
A solution of ethyl phenylglyoxylate (0.89 g, 5 mmol) and 2,4-dimethyl-5-methoxyoxazole
364
___________________________________________________________________________
0.65 g of the exo-isomer (and 0.41 g of the endo-isomer) as a colorless oil. The products were
Yield: 43 %
1
δ ppm = 1.06 (s, 3H, CH3 ), 1.24 (t, J = 7.2 Hz, 3H, CH3 ), 2.06 (s, 3H, CH3 ), 3.63 (s,
3H, OCH3 ), 4.21 (q, J = 7.2 Hz, 2H, OCH2 ), 7.23-7.52 (m, 5H, Harom).
13
δ ppm = 13.8 (q, CH3 ), 14.0 (q, CH3 ), 15.6 (q, CH3 ), 51.7 (q, OCH3 ), 61.7 (t, OCH2 ),
134.9 (s, Cqarom), 166.3 (s, C-3), 168.5 (s, COO).
HRMS: (C 16 H19 NO5 , M = 305.13 g/mol)
Calcd:
305.1271
Found:
305.1268
endo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (endo-60a) (sbo-351b)
Ph
H3C
N
O
CO2C2H5
O
CH3
OCH3
Yield: 27 %
1
δ ppm = 1.27 (t, J = 7.2 Hz, 3H, CH3 ), 1.51 (s, 3H, CH3 ), 1.70 (s, 3H, CH3 ), 3.67 (s,
13
δ ppm = 14.1 (q, CH3 ), 14.3 (q, CH3 ), 15.7 (q, CH3 ), 52.1 (q, OCH3 ), 61.9 (t, OCH2 ),
135.0 (s, Cqarom), 166.3 (s, C-3), 168.5 (s, COO).
exo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (exo-60b) (sbo-371a)
365
___________________________________________________________________________
C2H5O2C
N
O
H3C
A
solution
of
ethyl
phenylglyoxylate
Ph
O
OCH3
(0.89
g,
5
mmol)
and
4-ethyl-2-methyl-5-
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 42 %
1
δ ppm = 1.25 (t, J = 7.5 Hz, 6H, 2CH3 ), 1.58 (q, J = 7.5 Hz, 2H, CH2 ), 2.09 (s, 3H,
CH3 ), 3.67 (s, 3H, OCH3 ), 4.23 (q, J = 7.5 Hz, 2H, OCH2 ), 7.25-7.71 (m, 5H,
Harom).
13
δ ppm = 7.3 (q, CH3 ), 9.8 (q, CH3 ), 14.1 (q, CH3 ), 28.8 (t, CH2 ), 51.7 (q, OCH3 ), 61.8
(t, OCH2 ), 82.1 (s, C-1), 86.9 (s, C-7), 123.4 (s, C-5), 126.3 (d, CHarom), 127.5 (d,
CHarom), 128.0 (d, CHarom), 134.9 (s, Cqarom), 165.4 (s, C-3), 166.4 (s, COO).
endo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (endo-60b) (sbo-371b)
Ph
H3C
N
O
CO2C2H5
O
OCH3
Yield: 24 %
1
CH3 ), 1.85 (sextet, J = 7.5 Hz, 1H, CH), 2.08 (sextet, J = 7.5 Hz, 1H, CH), 3.69 (s,
13
366
___________________________________________________________________________
61.9 (t, OCH2 ), 81.9 (s, C-1), 90.9 (s, C-7), 123.8 (s, C-5), 126.3 (d, CHarom), 128.5
exo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (exo-60c) (sbo-354a)
C2H5O2C
H3C
N
O
Ph
O
OCH3
A solution of ethyl phenylglyoxylate (0.89 g, 5 mmol) and 2-methyl-4-propyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 44 %
1
CH2 ), 2.06 (s, 3H, CH3 ), 2.33 (m, 2H, CH2 ), 3.64 (s, 3H, OCH3 ), 4.20 (q, J = 7.5
Hz, 2H, OCH2 ), 7.25-7.67 (m, 5H, Harom).
13
(q, OCH3 ), 61.7 (t, OCH2 ), 86.4 (s, C-1), 92.5 (s, C-7), 123.4 (s, C-5), 126.3 (d,
168.2 (s, COO).
endo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (endo-60c) (sbo-354)
Ph
H3C
N
O
CO2C2H5
O
OCH3
Yield: 23 %
367
___________________________________________________________________________
1
CH2 ), 1.67 (m, 2H, CH2 ), 1.70 (s, 3H, CH3 ), 3.67 (s, 3H, OCH3 ), 4.25 (q, J = 7.5
Hz, 2H, OCH2 ), 7.27-7.37 (m, 5H, Harom).
13
169.1 (s, COO).
exo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid ethyl ester (exo-60d) (sbo-352b)
C2H5O2C
H3C
N
O
Ph
O
OCH3
A solution of ethyl phenylglyoxylate (0.89 g, 5 mmol) and 4-isopropyl-2-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 42 %
IR: (Film)
ν~ (cm-1 ) = 2983, 2895, 1725, 1612, 1600, 1558, 1435, 1085, 980, 770.
1
6.8 Hz, 1H, CH), 1.29 (t, J = 6.8 Hz, 3H, CH3 ), 2.08 (s, 3H, CH3 ), 3.72 (s, 3H,
OCH3 ), 4.25 (q, J = 6.8 Hz, 2H, OCH2 ), 7.33-7.82 (m, 5H, Harom).
13
368
___________________________________________________________________________
168.3 (s, COO).
HRMS: (C 18 H23 NO5 , M = 333.16 g/mol)
Calcd:
333.1570
Found:
333.1561
endo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid ethyl ester (endo-60d) (sbo-352d)
Ph
N
O
H3C
CO2C2H5
O
OCH3
Yield: 21 %
1
Hz, 3H, CH3 ), 1.77 (s, 3H, CH3 ), 2.27 (septet, J = 6.6 Hz, 1H, CH), 3.71 (s, 3H,
13
169.6 (s, COO).
exo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (exo-60e) (sbo-355a)
C2H5O 2C
H3C
N
O
Ph
O
OCH3
A solution of ethyl phenylglyoxylate (0.89 g, 5 mmol) and 4-sec-butyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
369
___________________________________________________________________________
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 43 %
1
Hz, 3H, CH3 ), 1.56 (m, 2H, CH2 ), 1.58 (m, 1H, CH), 2.04 (s, 3H, CH3 ), 3.64 (s, 3H,
13
(t, CH2 ), 51.6 (q, OCH3 ), 62.1 (t, OCH2 ), 81.7 (s, C-2), 91.5 (s, C-3), 123.3 (s, C-5),
C-3), 169.9 (s, COO).
HRMS: (C 19 H25 NO5 , M = 347.17 g/mol)
Calcd:
347.1717
Found:
347.1716
endo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid ethyl ester (endo-60e) (sbo-355d)
Ph
H3C
N
O
CO2C2H5
O
OCH3
Yield: 21%
1
CH), 1.27 (t, J = 7.2 Hz, 3H, CH3 ), 1.38 (m, 2H, CH2 ), 1.72 (s, 3H, CH3 ), 3.69 (s,
13
C-3), 169.3 (s, COO).
370
___________________________________________________________________________
exo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid ethylester (exo-60f) (sbo-356b)
C2H5O 2C
N
O
H3C
Ph
O
OCH3
A solution of ethyl phenylglyoxylate (0.89 g, 5 mmol) and 4-sec-butyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 41 %
1
Hz, 3H, CH3 ), 1.31 (m, 2H, CH2 ), 1.47 (m, 1H, CH), 2.08 (s, 3H, CH3 ), 3.73 (s, 3H,
13
C-3), 168.3 (s, COO).
endo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid ethylester (endo-60f) (sbo-356d)
Ph
H3C
N
O
CO2C2H5
O
OCH3
Yield: 21 %
1
371
___________________________________________________________________________
δ ppm = 0.78 (d, J = 6.8 Hz, 3H, CH3 ), 0.86 (t, J = 7.5 Hz, 3H, CH3 ), 1.18 (t, J = 7.4
Hz, 3H, CH3 ), 1.28 (m, 2H, CH2 ), 1.69 (s, 3H, CH3 ), 1.98 (m, 1H, CH), 3.64 (s, 3H,
13
C-3), 169.6 (s, COO).
Photolyses of isopropyl phenylglyoxylate with 5-methoxyoxazoles 36a-f:
exo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (exo-61a) (sbo-582a)
Pr iO2C
H3C
A
solution
of
isopropyl
N
O
Ph
O
phenylglyoxylate
CH3
OCH3
(0.96
g,
5
mmol)
and
2,4-dimethyl-5-
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 46 %
1
CH3 ), 1.99 (s, 3H, CH3 ), 3.72 (s, 3H, OCH3 ), 5.3 (septet, J = 6.2 Hz, 1H, OCH),
7.24-7.49 (m, 5H, Harom).
13
δ ppm = 14.5 (q, CH3 ), 15.9 (q, CH3 ), 21.8 (q, CH3 ), 21.9 (q, CH3 ), 52.2 (q, OCH3 ),
70.0 (d, OCH), 79.5 (s, C-1), 92.5 (s, C-7), 124.3 (s, C-5), 126.4 (d, CHarom), 127.7
endo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (endo-61a) (sbo-582b)
372
___________________________________________________________________________
CO2Pri
Ph
O
N
O
H3C
CH3
OCH3
Yield: 27 %
1
7.27-7.49 (m, 5H, Harom).
13
δ ppm = 14.3 (q, CH3 ), 15.8 (q, CH3 ), 21.6 (q, CH3 ), 21.7 (q, CH3 ), 52.0 (q, OCH3 ),
69.9 (d, OCH), 78.5 (s, C-1), 90.5 (s, C-7), 123.7 (s, C-5), 126.4 (d, CHarom), 127.7
exo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (exo-61b) (sbo-582c)
Pr iO2C
H3C
N
O
Ph
O
OCH3
A solution of isopropyl phenylglyoxylate (0.96 g, 5 mmol) and 4-ethyl-2-methyl-5methoxyoxazole (0.71 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 42 %
1
Hz, 3H, CH3 ), 1.43 (q, J = 7.2 Hz, 2H, CH2 ), 2.09 (s, 3H, CH3 ), 3.67 (s, 3H, OCH3 ),
5.02 (septet, J = 6.6 Hz, 1H, OCH), 7.25-7.71 (m, 5H, Harom).
13
373
___________________________________________________________________________
(q, OCH3 ), 71.0 (d, OCH), 82.2 (s, C-1), 86.5 (s, C-7), 123.6 (s, C-5), 126.3 (d,
167.4 (s, COO).
HRMS: (C 18 H23 NO5 , M = 333.16 g/mol)
Calcd:
333.1639
Found:
333.1638
endo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (endo-61b) (sbo-582d)
Ph
H3C
N
O
CO2Pri
O
OCH3
Yield: 23 %
1
Hz, 3H, CH3 ), 1.67 (m, 2H, CH2 ), 1.72 (s, 3H, CH3 ), 3.69 (s, 3H, OCH3 ), 5.28
(septet, J = 6.2 Hz, 1H, OCH), 7.27-7.31 (m, 5H, Harom).
13
169.3 (s, COO).
exo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (exo-61c) (sbo-584b)
Pr iO2C
O
N
H3C
O
Ph
OCH3
A solution of isopropyl phenylglyoxylate (0.96 g, 5 mmol) and 2-methyl-4-propyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
374
___________________________________________________________________________
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 43 %
IR: (Film)
ν~ (cm-1 ) = 2990, 2893, 1745, 1610, 1600, 1550, 1440, 1075, 980, 770.
1
Hz, 3H, CH3 ), 1.47 (m, 2H, CH2 ), 2.06 (s, 3H, CH3 ), 2.33 (m, 2H, CH2 ), 3.64 (s,
3H, OCH3 ), 5.20 (septet, J = 6.2 Hz, 1H, OCH), 7.25-7.67 (m, 5H, Harom).
13
(t, CH2 ), 51.6 (q, OCH3 ), 71.5 (t, OCH), 86.4 (s, C-1), 92.5 (s, C-7), 123.4 (s, C-5),
C-3), 168.2 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 347 (M+, 10), 305 (15), 262 (8), 260 (38), 173 (28), 155 (78), 130 (40),
105 (100), 102 (38), 91 (10), 77 (25), 71 (28), 57 (60).
HRMS: (C 19 H25 NO5 , M = 347.17 g/mol)
Calcd:
347.1726
Found:
347.1721
endo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (endo-61c) (sbo-584)
CO2Pri
Ph
H3C
N
O
O
OCH3
Yield: 25 %
1
Hz, 3H, CH3 ), 1.49 (m, 2H, CH2 ), 1.67 (m, 2H, CH2 ), 1.73 (s, 3H, CH3 ), 3.67 (s,
375
___________________________________________________________________________
13
(t, CH2 ), 51.7 (q, OCH3 ), 71.2 (d, OCH), 84.3 (s, C-1), 91.7 (s, C-7), 123.7 (s, C-5),
C-3), 169.1 (s, COO).
exo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid isopropyl ester (exo-61d) (sbo-577a)
Pr iO2C
H3C
N
O
Ph
O
OCH3
A solution of isopropyl phenylglyoxylate (0.96 g, 5 mmol) and 4-isopropyl-2-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 41 %
1
Hz, 3H, CH3 ), 0.98 (d, J = 6.2 Hz, 3H, CH3 ), 1.16 (septet, J = 6.8 Hz, 1H, CH), 2.08
(s, 3H, CH3 ), 3.72 (s, 3H, OCH3 ), 5.25 (septet, J = 6.2 Hz, 1H, OCH), 7.33-7.82 (m,
5H, Harom).
13
25.9 (d, CH), 51.6 (q, OCH3 ), 71.0 (d, OCH), 86.0 (s, C-1), 92.9 (s, C-7), 123.6 (s,
C-5), 127.2 (d, CHarom), 128.0 (d, CHarom), 128.7 (d, CHarom), 134.8 (s, Cqarom),
166.0 (s, C-3), 168.3 (s, COO).
endo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid isopropyl ester (endo-61d) (sbo-577b)
376
___________________________________________________________________________
CO2Pr i
Ph
H3C
N
O
O
OCH3
Yield: 23 %
1
Hz, 3H, CH3 ), 1.24 (d, J = 6.8 Hz, 3H, CH3 ), 1.77 (s, 3H, CH3 ), 2.27 (septet, J = 6.6
Hz, 1H, CH), 3.71 (s, 3H, OCH3 ), 5.22 (septet, J = 6.2 Hz, 1H, OCH), 7.25-7.34 (m,
5H, Harom).
13
165.4 (s, C-3), 169.6 (s, COO).
exo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (exo-61e) (sbo-578a)
Pr iO 2C
H3C
N
O
Ph
O
OCH3
A solution of isopropyl phenylglyoxylate (0.96 g, 5 mmol) and 4-isobutyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 42 %
1
377
___________________________________________________________________________
2.04 (s, 3H, CH3 ), 3.64 (s, 3H, OCH3 ), 5.22 (septet, J = 6.2 Hz, 1H, OCH), 7.267.52 (m, 5H, Harom).
13
25.7 (d, CH), 38.5 (t, CH2 ), 51.6 (q, OCH3 ), 70.1 (d, OCH), 81.7 (s, C-2), 91.5 (s,
C-3), 123.3 (s, C-5), 126.3 (d, CHarom), 127.3 (d, CHarom), 128.5 (d, CHarom), 134.2
(s, Cqarom), 165.5 (s, C-3), 169.9 (s, COO).
HRMS: (C 20 H27 NO5 , M = 361.19 g/mol)
Calcd:
361.1864
Found:
361.1860
endo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid isopropyl ester (endo-61e) (sbo-578b)
CO2Pr i
Ph
H3C
N
O
O
OCH3
Yield: 24 %
1
CH), 1.20 (d, J = 6.2 Hz, 3H, CH3 ), 1.25 (d, J = 6.2 Hz, 3H, CH3 ), 1.38 (m, 2H,
7.26-7.80 (m, 5H, Harom).
13
(s, Cqarom), 164.7 (s, C-3), 169.3 (s, COO).
exo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid isopropyl ester (exo-61f) (sbo-586g)
378
___________________________________________________________________________
Pr iO 2C
N
O
H3C
Ph
O
OCH3
A solution of isopropyl phenylglyoxylate (0.96 g, 5 mmol) and 4-sec-butyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 41 %
1
2.08 (s, 3H, CH3 ), 3.73 (s, 3H, OCH3 ), 5.25 (septet, J = 6.2 Hz, 1H, OCH), 7.227.38 (m, 5H, Harom).
13
(s, Cqarom), 165.8 (s, C-3), 168.3 (s, COO).
endo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid isopropyl ester (endo-61f) (sbo-586f)
CO2Pr i
Ph
H3C
N
O
O
OCH3
Yield: 22 %
1
Hz, 3H, CH3 ), 1.24 (d, J = 6.2 Hz, 3H, CH3 ), 1.28 (m, 2H, CH2 ), 1.69 (s, 3H, CH3 ),
379
___________________________________________________________________________
1.98 (m, 1H, CH), 3.64 (s, 3H, OCH3 ), 5.24 (septet, J = 6.2 Hz, 1H, OCH), 7.177.45 (m, 5H, Harom).
13
(s, Cqarom), 165.1 (s, C-3), 169.6 (s, COO).
Photolyses of tert-butyl phenylglyoxylate with 5-methoxyoxazoles 36a-f:
exo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (exo-62a) (sbo-445d)
But O2C
H3C
A
solution
of
tert-butyl
N
O
Ph
O
phenylglyoxylate
CH3
OCH3
(1.0
g,
5
mmol)
and
2,4-dimethyl-5-
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 46 %
1
δ ppm = 1.04 (s, 3H, CH3 ), 1.46 (s, 9H, 3CH3 ), 2.07 (s, 3H, CH3 ), 3.62 (s, 3H, OCH3 ),
7.23-7.67 (m, 5H, Harom).
13
δ ppm = 14.3 (q, CH3 ), 14.9 (q, CH3 ), 27.9 (q, 3CH3 ), 51.8 (q, OCH3 ), 78.8 (s, C-1),
82.9 (s, Cq), 91.1 (s, C-7), 123.4 (s, C-5), 126.2 (d, CHarom), 128.2 (d, CHarom),
134.9 (s, Cqarom), 166.2 (s, C-3), 167.4 (s, COO).
endo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (endo-62a) (sbo-445c)
380
___________________________________________________________________________
CO2But
Ph
O
N
O
H3C
CH3
OCH3
Yield: 22 %
1
δ ppm = 1.44 (s, 9H, 3CH3 ), 1.52 (s, 3H, CH3 ), 1.67 (s, 3H, CH3 ), 3.67 (s, 3H, OCH3 ),
7.25-7.49 (m, 5H, Harom).
13
δ ppm = 14.3 (q, CH3 ), 15.8 (q, CH3 ), 27.9 (q, 3CH3 ), 51.9 (q, OCH3 ), 78.2 (s, C-1),
83.1 (s, Cq), 90.5 (s, C-7), 123.7 (s, C-5), 126.4 (d, CHarom), 127.7 (d, CHarom),
135.0 (s, Cqarom), 165.2 (s, C-3), 168.0 (s, COO).
exo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (exo-62b) (sbo-583c)
But O2C
H3C
N
O
Ph
O
OCH3
A solution of tert-butyl phenylglyoxylate (1.0 g, 5 mmol) and 4-ethyl-2-methyl-5methoxyoxazole (0.71 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 41 %
IR: (Film)
ν~ (cm-1 ) = 2983, 2895, 1751, 1615, 1600, 1555, 1440, 1085, 980, 770.
1
δ ppm = 0.73 (t, J = 7.5 Hz, 3H, CH3 ), 1.21 (m, 1H, CH), 1.46 (s, 9H, 3CH3 ), 1.60 (m,
1H, CH), 2.09 (s, 3H, CH3 ), 3.65 (s, 3H, OCH3 ), 7.28-7.35 (m, 5H, Harom).
13
381
___________________________________________________________________________
δ ppm = 7.4 (q, CH3 ), 14.8 (q, CH3 ), 21.8 (t, CH2 ), 27.9 (q, 3CH3 ), 51.6 (q, OCH3 ),
81.9 (s, C-1), 82.9 (s, Cq), 91.4 (s, C-7), 123.4 (s, C-5), 126.3 (d, CHarom), 127.5 (d,
MS: (EI, 70 eV)
m/z (%) = 347 (M+, 10), 310 (4), 264 (40), 222 (25), 159 (75), 127 (40), 116 (100),
105 (80), 102 (38), 91 (10), 77 (25), 71 (28), 57 (60).
HRMS: (C 19 H25 NO5 , M = 347.17 g/mol)
Calcd:
347.1726
Found:
347.1722
endo-1-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (endo-62b) (sbo-583d)
Ph
H3C
N
O
CO2But
O
OCH3
Yield: 22 %
1
δ ppm = 0.93 (t, J = 7.5 Hz, 3H, CH3 ), 1.44 (s, 9H, 3CH3 ), 2.07 (s, 3H, CH3 ), 2.14 (m,
1H, CH), 2.18 (m, 1H, CH), 3.69 (s, 3H, OCH3 ), 7.27-7.49 (m, 5H, Harom).
13
exo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (exo-62c) (sbo-585a)
But O2C
O
N
H3C
O
Ph
OCH3
A solution of tert-butyl phenylglyoxylate (1.0 g, 5 mmol) and 2-methyl-4-propyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
382
___________________________________________________________________________
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 47 %
1
9H, 3CH3 ), 2.08 (s, 3H, CH3 ), 3.64 (s, 3H, OCH3 ), 7.25-7.69 (m, 5H, Harom).
13
δ ppm = 14.1 (q, CH3 ), 14.8 (q, CH3 ), 16.4 (t, CH2 ), 27.9 (q, 3CH3 ), 30.9 (t, CH2 ),
51.6 (q, OCH3 ), 81.6 (s, C-1), 82.9 (s, Cq), 91.4 (s, C-7), 123.3 (s, C-5), 126.3 (d,
167.5 (s, COO).
endo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (endo-62c) (sbo-585b)
CO2But
Ph
H3C
N
O
O
OCH3
Yield: 23 %
1
δ ppm = 0.93 (t, J = 7.5 Hz, 3H, CH3 ), 1.40 (m, 2H, CH2 ), 1.44 (s, 9H, 3CH3 ), 1.77 (s,
3H, CH3 ), 1.79-1.83 (m, 2H, CH2 ), 3.69 (s, 3H, OCH3 ), 7.27-7.48 (m, 5H, Harom).
13
51.9 (q, OCH3 ), 81.3 (s, C-1), 83.1 (s, Cq), 91.0 (s, C-7), 123.7 (s, C-5), 127.2 (d,
168.1 (s, COO).
exo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid tert-butyl ester (exo-62d) (sbo-579a)
383
___________________________________________________________________________
But O2C
N
O
H3C
Ph
O
OCH3
A solution of tert-butyl phenylglyoxylate (1.0 g, 5 mmol) and 4-isopropyl-2-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 42 %
1
3CH3 ), 2.09 (s, 3H, CH3 ), 3.72 (s, 3H, OCH3 ), 7.33-7.82 (m, 5H, Harom).
13
δ ppm = 14.2 (q, CH3 ), 15.9 (q, CH3 ), 16.7 (q, CH3 ), 25.9 (d, CH), 28.1 (q, 3CH3 ),
51.5 (q, OCH3 ), 82.9 (s, Cq), 85.8 (s, C-1), 92.6 (s, C-7), 123.2 (s, C-5), 127.2 (d,
CHarom), 128.0 (d, CHarom), 128.7 (d, CHarom), 134.8 (s, Cq), 166.0 (s, C-3), 168.3 (s,
COO).
MS: (EI, 70 eV)
m/z (%) = 361 (M+, 5), 348 (45), 334 (35), 278 (40), 236 (20), 218 (10), 173 (25),
130 (60), 105 (100), 102 (18), 91 (10), 77 (25), 71 (28), 57 (60).
HRMS: (C 20 H27 NO5 , M = 361.19 g/mol)
Calcd:
361.1882
Found:
361.1876
endo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid tert-butyl ester (endo-62d) (sbo-579b)
CO2But
Ph
H3C
N
O
O
OCH3
Yield: 26 %
384
___________________________________________________________________________
1
3CH3 ), 1.75 (s, 3H, CH3 ), 2.36 (septet, J = 6.6 Hz, 1H, CH), 3.72 (s, 3H, OCH3 ),
7.25-7.34 (m, 5H, Harom).
13
δ ppm = 14.3 (q, CH3 ), 17.4 (q, CH3 ), 17.7 (q, CH3 ), 27.5 (d, CH), 27.8 (s, 9H, 3CH3 ),
51.8 (q, OCH3 ), 83.0 (s, Cq), 84.5 (s, C-1), 92.4 (s, C-7), 123.9 (s, C-5), 126.7 (d,
168.5 (s, COO).
exo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (exo-62e) (sbo-580c)
ButO 2C
H3C
N
O
Ph
O
OCH3
A solution of tert-butyl phenylglyoxylate (1.0 g, 5 mmol) and 4-isobutyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 40 %
IR: (Film)
ν~ (cm-1 ) = 2983, 2895, 1755, 1610, 1607, 1558, 1440, 1075, 980, 778.
1
OCH3 ), 7.26-7.52 (m, 5H, Harom).
13
36.5 (t, CH2 ), 51.6 (q, OCH3 ), 82.4 (s, Cq), 86.7 (s, C-2), 93.5 (s, C-3), 123.3 (s, C-
385
___________________________________________________________________________
5), 126.3 (d, CHarom), 127.3 (d, CHarom), 128.5 (d, CHarom), 134.2 (s, Cqarom), 165.5
(s, C-3), 169.9 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 375 (M+, 10), 348 (12), 320 (8), 292 (20), 274 (20), 187 (40), 168 (20),
144 (80), 105 (100), 102 (18), 91 (10), 77 (25), 71 (28), 57 (60).
HRMS: (C 21 H29 NO5 , M = 375.20 g/mol)
Calcd:
375.2038
Found:
375.2034
endo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid tert-butyl ester (endo-62e) (sbo-580e)
CO2But
Ph
H3C
O
N
O
OCH3
Yield: 21 %
1
CH), 1.38 (m, 2H, CH2 ), 1.44 (s, 9H, 3CH3 ), 1.72 (s, 3H, CH3 ), 3.69 (s, 3H, OCH3 ),
7.26-7.80 (m, 5H, Harom).
13
37.3 (t, CH2 ), 51.9 (q, OCH3 ), 83.0 (s, Cq), 85.8 (s, C-2), 92.8 (s, C-3), 123.8 (s, C5), 126.4 (d, CHarom), 127.8 (d, CHarom), 129.9 (d, CHarom), 135.3 (s, Cqarom), 164.7
(s, C-3), 169.3 (s, COO).
exo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid tert-butyl ester (exo-62f) (sbo-586c)
ButO 2C
H3C
N
O
Ph
O
OCH3
A solution of tert-butyl phenylglyoxylate (1.0 g, 5 mmol) and 2-sec-butyl4-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
386
___________________________________________________________________________
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 41 %
1
OCH3 ), 7.22-7.38 (m, 5H, Harom).
13
(q, 3CH3 ), 34.4 (t, CH2 ), 51.7 (q, OCH3 ), 82.9 (t, OCH2 ), 86.0 (s, C-1), 92.5 (s, C7), 123.9 (s, C-5), 126.9 (d, CHarom), 127.4 (d, CHarom), 128.8 (d, CHarom), 135.6 (s,
Cqarom), 164.9 (s, C-3), 168.5 (s, COO).
endo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid tert-butyl ester (endo-62f) (sbo-586b)
CO2But
Ph
H3C
N
O
O
OCH3
Yield: 21 %
1
CH2 ), 1.44 (s, 9H, 3CH3 ), 1.69 (s, 3H, CH3 ), 1.98 (m, 1H, CH), 3.64 (s, 3H, OCH3 ),
7.17-7.45 (m, 5H, Harom).
13
(q, 3CH3 ), 32.8 (t, CH2 ), 51.6 (q, OCH3 ), 82.9 (s, Cq), 86.2 (s, C-1), 92.7 (s, C-7),
Cqarom), 165.4 (s, C-3), 167.2 (s, COO).
Photolyses of menthyl phenylglyoxylate with 5-methoxyoxazoles 36a-f:
387
___________________________________________________________________________
exo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (exo-63a) (sbo-373b)
CH3
O
H3C
CH3
Ph
O O
N
O
H3C
A
solution
of
menthyl
phenylglyoxylate
CH3
OCH3
(1.44
g,
5
mmol)
and
2,4-dimethyl-5-
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 46 %
1
Hz, 3H, CH3 ), 1.04 (s, 3H, CH3 ), 1.45 (m, 3H), 1.63 (m, 3H), 1.85 (m, 1H, CH),
1.99 (m, 1H), 2.05 (s, 3H, CH3 ), 3.63 (s, 3H, OCH3 ), 4.74 (ddd, J = 11.0, 4.4, 4.6
Hz, 1H, OCH), 7.31-7.52 (m, 5H, Harom).
13
23.6 (t, CH2 ), 26.0 (d, CH), 31.8 (d, CH), 34.6 (t, CH2 ), 41.1 (t, CH2 ), 47.2 (d, CH),
52.3 (q, OCH3 ), 76.6 (d, OCH), 79.4 (s, C-1), 91.9 (s, C-7), 123.7 (s, C-5), 126.6 (d,
HRMS: (C 24 H33 NO5 , M = 415.24 g/mol)
Calcd:
415.2425
Found:
415.2427
endo-5-Methoxy-1,3-dimethyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (endo-63a) (sbo-373)
388
___________________________________________________________________________
CH3
H3C
Ph
O
N
O
O
H3C
CH3
O
CH3
OCH3
Yield: 22 %
1
Hz, 3H, CH3 ), 1.02 (m, 2H, CH2 ), 1.23 (m, 1H, CH), 1.37 (m, 2H, CH2 ), 1.49 (s,
3H, CH3 ), 1.54 (m, 2H, CH2 ), 1.67 (m, 2H, CH2 ), 1.70 (s, 3H, CH3 ), 3.70 (s, 3H,
OCH3 ), 4.72 (ddd, J = 11.1, 4.6, 4.4 Hz, 1H, OCH), 7.32-7.58 (m, 5H, Harom).
13
23.7 (t, CH2 ), 26.2 (d, CH), 31.9 (d, CH), 34.8 (t, CH2 ), 41.3 (t, CH2 ), 47.4 (d, CH),
52.5 (q, OCH3 ), 76.8 (d, OCH), 80.2 (s, C-1), 91.2 (s, C-7), 123.5 (s, C-5), 126.7 (d,
exo-5-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (exo-63b) (sbo-374b)
CH3
O
H3C
H3C
CH3
O O
N
O
Ph
OCH3
A solution of menthyl phenylglyoxylate (1.44 g, 5 mmol) and 4-ethyl-2-methyl-5methoxyoxazole (0.71 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
Yield: 41 %
389
subsequently
hydrolyzed
to
give
the
___________________________________________________________________________
1
Hz, 3H, CH3 ), 0.85 (d, J = 6.6 Hz, 3H, CH3 ), 1.00 (m, 3H), 1.25 (m, 1H), 1.45 (m,
3H), 1.63 (m, 2H, CH2 ), 1.92 (m, 2H, CH2 ), 2.07 (s, 3H, CH3 ), 3.67 (s, 3H, OCH3 ),
4.73 (ddd, J = 11.0, 4.4, 4.6 Hz, 1H, OCH), 7.33-7.42 (m, 5H, Harom).
13
(d, CH), 21.9 (t, CH2 ), 23.2 (d, CH), 25.5 (t, CH2 ), 31.4 (t, CH2 ), 34.1 (t, CH2 ), 40.8
(t, CH2 ), 46.7 (d, CH), 51.7 (q, OCH3 ), 76.0 (d, OCH), 82.2 (s, C-1), 91.8 (s, C-7),
123.2 (s, C-5), 126.6 (d, CHarom), 128.4 (d, CHarom), 135.8 (s, Cqarom), 165.6 (s, C3), 168.3 (s, COO).
endo-5-Ethyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (endo-63b) (sbo-374)
CH3
H3C
Ph
O
N
O
O
H3C
CH3
O
OCH3
Yield: 22 %
1
Hz, 3H, CH3 ), 0.89 (d, J = 6.6 Hz, 3H, CH3 ), 1.03 (m, 3H), 1.27 (m, 1H), 1.50 (m,
3H), 1.57 (m, 2H, CH2 ), 1.65 (m, 2H, CH2 ), 1.73 (s, 3H, CH3 ), 1.93 (m, 2H, CH2 ),
3.70 (s, 3H, OCH3 ), 4.75 (ddd, J = 11.0, 4.4, 4.6 Hz, 1H, OCH), 7.35-7.78 (m, 5H,
Harom).
13
(d, CH), 22.0 (t, CH2 ), 23.5 (d, CH), 25.7 (t, CH2 ), 31.5 (t, CH2 ), 34.7 (t, CH2 ), 41.0
(t, CH2 ), 47.0 (d, CH), 51.9 (q, OCH3 ), 75.9 (d, OCH), 83.0 (s, C-1), 92.3 (s, C-7),
123.7 (s, C-5), 126.6 (d, CHarom), 128.4 (d, CHarom), 135.8 (s, Cqarom), 166.3 (s, C3), 168.1 (s, COO).
390
___________________________________________________________________________
exo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (exo-63c) (sbo-375c)
CH3
O
H3C
H3C
CH3
O O
N
O
Ph
OCH3
A solution of menthyl phenylglyoxylate (1.44 g, 5 mmol) and 2-methyl-4-propyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 43 %
1
Hz, 3H, CH3 ), 0.85 (d, J = 6.5 Hz, 3H, CH3 ), 1.14 (m, 2H, CH2 ), 1.17 (m, 3H), 1.45
(m, 3H), 1.62 (m, 2H, CH2 ), 1.68 (m, 2H, CH2 ), 2.06 (s, 3H, CH3 ), 3.67 (s, 3H,
13
21.9 (d, CH), 23.3 (t, CH2 ), 25.6 (d, CH), 30.7 (t, CH2 ), 31.4 (d, CH), 34.2 (t, CH2 ),
40.8 (t, CH2 ), 46.7 (d, CH), 51.7 (q, OCH3 ), 76.0 (d, OCH), 81.9 (s, C-1), 91.8 (s,
C-7), 123.2 (s, C-5), 126.6 (d, CHarom), 128.4 (d, CHarom), 135.8 (s, Cqarom), 165.4
(s, C-3), 168.4 (s, COO).
HRMS: (C 26 H37 NO5 , M = 443.27 g/mol)
Calcd:
443.2659
Found:
443.2654
endo-5-Methoxy-3-methyl-7-phenyl-1-propyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (endo-63c) (sbo-375):
391
___________________________________________________________________________
CH3
H3C
Ph
O
N
O
O
H3C
CH3
O
OCH3
Yield: 28 %
1
Hz, 3H, CH3 ), 0.87 (d, J = 6.6 Hz, 3H, CH3 ), 1.15 (m, 2H, CH2 ), 1.18 (m, 3H), 1.49
(m, 3H), 1.65 (m, 2H, CH2 ), 1.68 (s, 3H, CH3 ), 1.83 (m, 2H, CH2 ), 3.74 (s, 3H,
13
22.0 (d, CH), 23.5 (t, CH2 ), 25.8 (d, CH), 30.9 (t, CH2 ), 31.9 (t, CH2 ), 34.6 (t, CH2 ),
(s, C-3), 168.1 (s, COO).
exo-1-Isopropyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (exo-63d) (sbo-379d)
CH3
O
H3C
H3C
CH3
O O
N
O
Ph
OCH3
A solution of menthyl phenylglyoxylate (1.44 g, 5 mmol) and 4-isopropyl-2-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
392
subsequently
hydrolyzed
to
give
the
___________________________________________________________________________
Yield: 45 %
1
Hz, 3H, CH3 ), 0.85 (d, J = 6.5 Hz, 3H, CH3 ), 0.88 (d, J = 6.6 Hz, 3H, CH3 ), 1.03 (m,
2H, CH2 ), 1.22 (m, 1H, CH), 1.46 (m, 2H, CH2 ), 1.62 (m, 2H, CH2 ), 1.69 (m, 2H,
CH2 ), 1.79 (m, 2H, CH2 ), 2.07 (s, 3H, CH3 ), 3.79 (s, 3H, OCH3 ), 4.86 (ddd, J =
11.0, 4.4, 4.6 Hz, 1H, OCH), 7.34-7.61 (m, 5H, Harom).
13
21.9 (d, CH), 23.0 (d, CH), 25.2 (t, CH2 ), 26.0 (t, CH2 ), 31.4 (d, CH), 34.1 (d, CH),
(s, C-3), 167.6 (s, COO).
endo-1-Isoproyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (endo-63d) (sbo-379)
CH3
H3C
Ph
O
N
O
O
H3C
CH3
O
OCH3
Yield: 24 %
1
Hz, 3H, CH3 ), 0.86 (d, J = 6.5 Hz, 3H, CH3 ), 0.90 (d, J = 6.7 Hz, 3H, CH2 ), 1.05
(m, 3H), 1.23 (m, 1H), 1.48 (m, 2H, CH2 ), 1.64 (m, 2H, CH2 ), 1.70 (s, 3H, CH3 ),
1.75 (m, 2H, CH2 ), 1.85 (m, 2H, CH2 ), 3.74 (s, 3H, OCH3 ), 4.78 (ddd, J = 11.0, 4.4,
4.6 Hz, 1H, OCH), 7.35-7.61 (m, 5H, Harom).
13
393
___________________________________________________________________________
C-7), 123.7 (s, C-5), 126.6 (d, CHarom), 128.4 (d, CHarom), 134.2 (s, Cqarom), 164.7 (
s, C-3), 168.2 (s, COO).
exo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (exo-63e) (sbo-384c)
CH3
O
H3C
H3C
CH3
O O
N
O
Ph
OCH3
A solution of menthyl phenylglyoxylate (1.44 g, 5 mmol) and 4-isobutyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 42 %
IR: (Film)
ν~ (cm-1 ) = 2983, 2895, 1745, 1610, 1600, 1550, 1440, 1075, 980, 770.
1
CH2 ), 1.53 (m, 2H, CH2 ), 1.67 (m, 1H, CH), 1.83 (m, 2H, CH2 ), 2.04 (s, 3H, CH3 ),
3.67 (s, 3H, OCH3 ), 4.76 (ddd, J = 11.0, 4.4, 4.6 Hz, 1H, OCH), 7.26-7.49 (m, 5H,
Harom).
13
22.3 (d, CH), 23.0 (d, CH), 23.2 (t, CH2 ), 23.6 (d, CH), 24.1 (t, CH2 ), 34.1 (d, CH),
394
___________________________________________________________________________
(s, C-3), 168.3 (s, COO).
endo-1-Isobutyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (endo-63e) (sbo-384)
CH3
H3C
Ph
O
N
O
O
H3C
CH3
O
OCH3
Yield: 21 %
1
δ ppm = 0.62 (d, J = 6.9 Hz, 3H, CH3 ), 0.70 (d, J = 6.9 Hz, 3H, CH3 ), 75 (d, J = 6.9
2H,CH2 ), 1.12 (m, 2H), 1.17 (m, 1H), 1.45 (m, 2H, CH2 ), 1.55 (m, 2H, CH2 ), 1.70
(s, 3H, CH3 ), 1.87 (m, 2H, CH2 ), 3.74 (s, 3H, OCH3 ), 4.75 (ddd, J = 11.0, 4.4, 4.6
Hz, 1H, OCH), 7.27-7.45 (m, 5H, Harom).
13
23.1 (q, CH3 ), 23.8 (d, CH), 24.1 (t, CH2 ), 32.5 (t, CH2 ), 37.2 (t, CH2 ), 40.1 (t,
CH2 ), 47.1 (d, CH), 52.7 (q, OCH3 ), 76.1 (d, OCH), 84.1 (s, C-1), 92.8 (s, C-7),
123.7 (s, C-5), 126.6 (d, CHarom), 128.4 (d, CHarom), 134.7 (s, Cqarom), 165.1 ( s, C3), 168.1 (s, COO).
exo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (exo-63f) (sbo-385f)
CH3
O
H3C
H3C
CH3
O O
N
O
395
Ph
OCH3
___________________________________________________________________________
A solution of menthyl phenylglyoxylate (1.44 g, 5 mmol) and 4-sec-butyl-2-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 39 %
1
1H, CH), 1.10 (m, 2H, CH2 ), 1.38 (m, 2H, CH2 ), 1.40 (m, 2H, CH2 ), 1.43 (m, 1H,
CH), 1.47 (m, 2H, CH2 ), 1.64 (m, 1H, CH), 2.05 (s, 3H, CH3 ), 3.73 (s, 3H, OCH3 ),
4.87 (ddd, J = 11.0, 4.4, 4.5 Hz, 1H, OCH), 7.35-7.79 (m, 5H, Harom).
13
22.0 (q, CH3 ), 23.1 (d, CH), 23.3 (t, CH2 ), 25.3 (d, CH), 31.4 (t, CH2 ), 32.7 (d, CH),
34.1 (t, CH2 ), 40.9 (t, CH2 ), 46.6 (d, CH), 51.7 (q, OCH3 ), 75.7 (d, OCH), 86.5 (s,
C-1), 93.1 (s, C-7), 123.3 (s, C-5), 126.6 (d, CHarom), 128.4 (d, CHarom), 135.3 (s,
Cqarom), 165.1 (s, C-3), 167.8 (s, COO).
HRMS: (C 27 H39 NO5 , M = 457.28 g/mol)
Calcd:
457.2764
Found:
457.2760
endo-1-sec-Butyl-5-methoxy-3-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid 2-isopropyl-5-methyl-cyclohexyl ester (endo-63f) (sbo-385):
CH3
H3C
Ph
O
N
O
O
H3C
O
OCH3
Yield: 39 %
396
CH3
___________________________________________________________________________
1
Hz, 3H, CH3 ), 0.93 (t, J = 6.5 Hz, 3H, CH3 ), 0.97 (d, J = 7.2 Hz, 3H, CH3 ), 1.00 (m,
1H,CH), 1.07 (m, 2H), 1.18 (m, 2H), 1.27 (m, 2H, CH2 ), 1.39 (m, 2H, CH2 ), 1.47
(m, 2H, CH2 ), 1.53 (m, 1H, CH), 1.67 (m, 2H, CH2 ), 1.70 (s, 3H, CH3 ), 3.75 (s, 3H,
13
22.3 (q, CH3 ), 23.2 (q, CH3 ), 23.7 (t, CH2 ), 25.7 (d, CH), 31.7 (t, CH2 ), 32.9 (d,
CH), 34.3 (t, CH2 ), 41.0 (t, CH2 ), 47.0 (d, CH), 52.8 (q, OCH3 ), 76.0 (d, OCH), 85.7
(s, C-1), 92.5 (s, C-7), 123.7 (s, C-5), 126.6 (d, CHarom), 128.4 (d, CHarom), 135.7 (s,
Cqarom), 166.1 ( s, C-3), 168.2 (s, COO).
Photolyses of α -keto esters with 2-ethyl-4-methyl-5-methoxyoxazole 49a:
exo-3-Ethyl-5-methoxy-1,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-64a) (sbo-442b)
C2H5
H3C
O
N
O
CO2CH3
CH3
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 2-ethyl-4-methyl-5-methoxyoxazole
Yield: 70 %
IR: (Film)
ν~ (cm-1 ) = 2998, 2895, 1715, 1605, 1440, 1075, 980, 770.
1
CH2 ), 1.90 (s, 3H, CH3 ), 3.71 (s, 3H, OCH3 ), 3.76 (s, 3H, OCH3 ).
13
397
___________________________________________________________________________
53.1 (q, OCH3 ), 72.5 (s, C-1), 87.5 (s, C-7), 118.7 (s, C-5), 170.5 (s, C-3), 175.9 (s,
COO).
HRMS: (C 11 H17 NO5 , M = 243.11 g/mol)
Calcd:
243.1126
Found:
243.1122
exo-7-tert-Butyl-3-ethyl-5-methoxy-1-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-64b) (sbo-442b)
H3CO2C
N
O
C2H5
O
CH3
OCH3
A solution of methyl trimethylpyruvate (0.36 g, 5 mmol) and 2-ethyl-4-methyl-5methoxyoxazole (0.35 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
later).
Yield: 60 %
1
δ ppm = 1.01 (t, J = 7.5 Hz, 3H, CH3 ), 1.12 (s, 9H, 3CH3 ), 1.47 (s, 3H, CH3 ), 1.75 (q,
J = 7.5 Hz, 2H, CH2 ), 3.56 (s, 3H, OCH3 ), 3.76 (s, 3H, OCH3 ).
13
δ ppm = 8.5 (q, CH3 ), 17.8 (q, CH3 ), 27.9 (q, 3CH3 ), 31.4 (t, CH2 ), 51.6 (q, OCH3 ),
52.6 (q, OCH3 ), 78.5 (s, C-1), 97.5 (s, C-7), 120.7 (s, C-5), 170.5 (s, C-3), 175.9 (s,
COO).
exo-3-Ethyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-64c) (sbo-441d)
H3CO2C
C2H5
N
O
Ph
O
398
CH3
O CH3
___________________________________________________________________________
A
solution
of
methyl
phenylglyoxylate (0.82 g, 5 mmol) and 2-ethyl-4-methyl-5-
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 47 %
1
δ ppm = 1.05 (s, 3H, CH3 ), 1.29 (t, J = 7.4 Hz, 3H, CH3 ), 2.60 (q, J = 7.4 Hz, 2H,
CH2 ), 3.03 (s, 3H, OCH3 ), 3.45 (s, 3H, OCH3 ), 7.31-7.59 (m, 5H, Harom).
13
134.7 (s, Cqarom), 168.9 (s, C-3), 173.1 (s, COO).
HRMS: (C 16 H19 NO5 , M = 305.13 g/mol)
Calcd:
305.1258
Found:
305.1254
endo-3-Ethyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (endo-64c) (sbo-441d)
C2H5
Ph
O
N
O
CO2CH3
CH3
OCH3
Yield: 24 %
1
13
134.6 (s, Cqarom), 169.7 (s, C-3), 174.8 (s, COO).
399
___________________________________________________________________________
exo-3-Ethyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (exo-64d) (sbo-465)
C2H5O2C
N
O
C2H5
A
solution
of
ethyl
phenylglyoxylate
Ph
O
CH3
O CH3
(0.89
g,
5
mmol)
and
2-ethyl-4-methyl-5-
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 43 %
1
δ ppm = 1.05 (s, 3H, CH3 ), 1.26 (t, J = 7.4 Hz, 3H, CH3 ), 1.27 (t, J = 7.5 Hz, 3H,
CH3 ), 2.53 (q, J = 7.5 Hz, 2H, CH2 ), 3.60 (s, 3H, OCH3 ), 4.16 (q, J = 7.5 Hz, 2H,
OCH2 ), 7.28-7.63 (m, 5H, Harom).
13
δ ppm = 9.5 (q, CH3 ), 9.9 (q, CH3 ), 13.6 (q, CH3 ), 21.4 (t, CH2 ), 52.3 (q, OCH3 ), 61.6
(t, OCH2 ), 78.4 (s, C-1), 90.2 (s, C-7), 123.0 (s, C-5), 126.3 (d, CHarom), 128.2 (d,
CHarom), 134.5 (s, Cqarom), 169.6 (s, C-3), 170.4 (s, COO).
endo-3-Ethyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid ethyl ester (endo-64c) (sbo-465)
C2H5
Ph
O
N
O
CO2C2H5
CH3
OCH3
Yield: 22 %
1
OCH2 ), 7.26-7.53 (m, 5H, Harom).
400
___________________________________________________________________________
13
δ = 9.3 (q, CH3 ), 9.6 (q, CH3 ), 13.7 (q, CH3 ), 22.0 (t, CH2 ), 51.6 (q, OCH3 ), 61.7 (t,
OCH2 ), 80.2 (s, C-1), 92.1 (s, C-7), 123.4 (s, C-5), 126.4 (d, CH), 127.7 (d, CH),
135.6 (s, Cq), 168.4 (s, C-3), 170.1 (s, COO).
exo-3-Ethyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (exo-64e) (sbo-463)
Pr iO2C
N
O
C2H5
Ph
O
CH3
OCH3
A solution of isopropyl phenylglyoxylate (0.96 g, 5 mmol) and 2-ethyl-4-methyl-5methoxyoxazole (0.71 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 43 %
1
δ ppm = 1.05 (s, 3H, CH3 ), 1.12 (t, J=7.5 Hz, 3H, CH3 ), 1.17 (t, J=6.3 Hz, 3H, CH3 ),
1.19 (d, J=6.3 Hz, 3H, CH3 ), 2.13 (q, J=7.5 Hz, 2H, CH2 ), 3.65 (s, 3H, OCH3 ), 5.12
(septet, J= 6.3 Hz, 1H, OCH), 7.28-7.63 (m, 5H, Harom).
13
endo-3-Ethyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid isopropyl ester (endo-64e) (sbo-463a)
C2H5
Ph
O
N
O
CO2Pr i
CH3
OCH3
Yield: 24 %
401
___________________________________________________________________________
1
Hz, 3H, CH3 ), 1.53 (s, 3H, CH3 ), 2.26 (q, J = 7.5 Hz, 2H, CH2 ), 3.66 (s, 3H, OCH3 ),
13
δ ppm = 9.7 (q, CH3 ), 15.7 (q, CH3 ), 21.6 (q, CH3 ), 21.7 (t, CH2 ), 21.9 (q, CH3 ), 52.1
exo-3-Ethyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (exo-64f) (sbo-450c)
But O2C
C2H5
N
O
Ph
O
CH3
O CH3
A solution of tert-butyl phenylglyoxylate (1.0 g, 5 mmol) and 2-ethyl-4-methyl-5methoxyoxazole (0.71 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 42 %
1
δ ppm = 1.06 (s, 3H, CH3 ), 1.28 (s, 9H, 3CH3 ), 1.32 (q, J = 7.5 Hz, 3H, CH3 ), 2.52 (q,
J = 7.5 Hz, 2H, CH2 ), 3.62 (s, 3H, OCH3 ), 2.13 (q, J = 7.5 Hz, 2H, CH2 ), 3.62 (s,
3H, OCH3 ), 7.26-7.54 (m, 5H, Harom).
13
HRMS: (C 19 H25 NO5 , M = 347.17 g/mol)
Calcd:
347.1739
Found:
347.1734
402
___________________________________________________________________________
endo-3-Ethyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid tert-butyl ester (endo-64f) (sbo-450d)
C2H5
Ph
O
N
O
CO2But
CH3
OCH3
Yield: 21 %
1
J = 7.5 Hz, 2H, CH2 ), 3.66 (s, 3H, OCH3 ), 7.29-7.63 (m, 5H, Harom).
13
77.9 (s, C-1), 83.1 (s, C-1), 90.4 (s, C-7), 123.5 (s, C-5), 126.3 (d, CHarom), 129.2 (d,
Photolyses of α -keto esters with 2-isopropyl-4-methyl-5-methoxyoxazole 49b:
exo-3-Isopropyl-5-methoxy-1,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-65a) (sbo-460)
H3C
CO2CH3
O
N
O
CH3
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 2-isopropyl-4-methyl-5-methoxyoxazole
Yield: 46 %
1
CH3 ), 1.87 (septet, J = 6.7 Hz, 1H, CH), 1.91 (s, 3H, CH3 ), 3.70 (s, 3H, OCH3 ), 3.75
(s, 3H, OCH3 ).
403
___________________________________________________________________________
13
(q, OCH3 ), 53.0 (q, OCH3 ), 72.4 (s, C-1), 87.4 (s, C-7), 124.3 (s, C-5), 170.4 (s,
COO), 176.2 (s, C-3).
endo-3-Isopropyl-5-methoxy-1,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (endo-65a) (sbo-460a)
H3 CO2 C
O
N
O
CH3
CH3
OCH3
Yield: 33 %
1
CH3 ), 1.87 (septet, J = 6.7 Hz, 1H, CH), 1.91 (s, 3H, CH3 ), 3.70 (s, 3H, OCH3 ), 3.75
(s, 3H, OCH3 ).
13
COO), 176.2 (s, C-3).
exo-7-tert-Butyl-3-isopropyl-5-methoxy-1-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid methyl ester (exo-65b) (sbo-483b)
H3CO2C
O
N
O
CH3
OCH3
A solution of methyl trimethylpyruvate (0.36 g, 2.5 mmol) and 2-isopropyl-4-methyl-5methoxyoxazole (0.38 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
silica gel yielded 0.34 g of the exo-isomer (and 0.21 g of the endo-isomer) as a colorless oil.
Yield: 46 %
1
404
___________________________________________________________________________
δ ppm = 1.12 (s, 9H, 3CH3 ), 1.16 (d, J = 6.2 Hz, 6H, 2CH3 ), 1.51 (s, 3H, CH3 ), 2.53
(septet, J = 6.2 Hz, 1H, CH), 3.57 (s, 3H, OCH3 ), 3.73 (s, 3H, OCH3 ).
13
37.0 (s, Cq), 51.4 (q, OCH3 ), 51.6 (q, OCH3 ), 76.7 (s, C-1), 97.3 (s, C-7), 122.6 (s,
C-5), 170.7 (s, COO), 172.3 (s, C-3).
HRMS: (C 15 H25 NO5 , M = 299.17 g/mol)
Calcd:
299.1685
Found:
299.1681
endo-7-tert-Butyl-3-isopropyl-5-methoxy-1-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid methyl ester (endo-65b) (sbo-483)
CO2CH3
N
O
O
CH3
OCH3
Yield: 28 %
1
δ ppm = 1.05 (s, 9H, 3CH3 ), 1.18 (d, J = 6.3 Hz, 6H, 2CH3 ), 1.45 (s, 3H, CH3 ), 1.87
(septet, J = 6.3 Hz, 1H, CH), 3.56 (s, 3H, OCH3 ), 3.75 (s, 3H, OCH3 ).
13
38.1 (s, Cq), 51.5 (q, OCH3 ), 52.1 (q, OCH3 ), 75.4 (s, C-1), 97.2 (s, C-7), 123.3 (s,
C-5), 170.7 (s, COO), 179.2 (s, C-3).
exo-3-Isopropyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene7-carboxylic acid methyl ester (exo-65c) (sbo-458)
H3CO2C
N
O
Ph
O
CH3
OCH3
A solution of methyl phenylglyoxylate (0.82 g, 5 mmol) and 2-isopropyl-4-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
405
___________________________________________________________________________
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 47 %
1
CH3 ), 1.79 (septet, J = 6.8 Hz, 1H, CH), 3.54 (s, 3H, OCH3 ), 3.64 (s, 3H, OCH3 ),
7.35-7.54 (m, 5H, Harom).
13
endo-3-Isopropyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid methyl ester (endo-65c) (sbo-458d)
Ph
N
O
CO2CH3
O
CH3
OCH3
Yield: 25 %
1
δ ppm = 1.19 (d, J=6.8 Hz, 3H, CH3 ), 1.43 (d, J = 6.8 Hz, 3H, CH3 ), 1.96 (s, 3H,
7.30-7.64 (m, 5H, Harom).
13
406
___________________________________________________________________________
exo-3-Isopropyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid ethyl ester (exo-65d) (sbo-459e)
C2H5O2C
N
O
Ph
O
CH3
OCH3
A solution of ethyl phenylglyoxylate (0.89 g, 5 mmol) and 2-isopropyl-4-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 39 %
1
13
HRMS: (C 18 H23 NO5 , M = 333.16 g/mol)
Calcd:
333.1587
Found:
333.1581
endo-3-Isopropyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid ethyl ester (endo-65d) (sbo-459)
Ph
N
O
CO2C2H5
O
CH3
OCH3
Yield: 19 %
IR: (Film)
407
___________________________________________________________________________
ν~ (cm-1 ) = 2988, 2892, 1755, 1614, 1600, 1550, 1440, 1075, 980, 770.
1
13
exo-3-Isopropyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid isopropyl ester (exo-65e) (sbo-456d)
Pr iO2C
N
O
Ph
O
CH3
OCH3
A solution of isopropyl phenylglyoxylate (0.96 g, 5 mmol) and 2-isopropyl-4-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 25 %
1
δ ppm = 1.07 (s, 3H, CH3 ), 1.20 (d, J = 6.2 Hz, 3H, CH3 ), 1.22 (d, J = 6.2 Hz, 3H,
CH3 ), 1.26 (d, J = 6.9 Hz, 3H, CH3 ), 1.32 (d, J = 6.9 Hz, 3H, CH3 ), 2.68 (septet, J =
6.9 Hz, 1H, CH), 3.62 (s, 3H, OCH3 ), 5.07 (septet, J = 6.2 Hz, 1H, OCH), 7.257.51 (m, 5H, Harom).
13
C-5), 126.4 (d, CHarom), 128.2 (d, CHarom), 134.8 (s, Cqarom), 168.0 (s, C-3), 173.2
(s, COO).
408
___________________________________________________________________________
endo-3-Isopropyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid isopropyl ester (endo-65e) (sbo-456d)
Ph
O
N
O
CO2Pr i
CH3
OCH3
Yield: 42 %
1
5H, Harom).
13
C-5), 126.7 (d, CHarom), 127.4 (d, CHarom), 135.1 (s, Cqarom), 168.6 (s, C-3), 169.6
(s, COO).
exo-3-Isopropyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid tert-butyl ester (exo-65f) (sbo-453d)
ButO2C
N
O
Ph
O
CH3
OCH3
A solution of tert-butyl phenylglyoxylate (1.0 g, 5 mmol) and 2-isopropyl-4-methyl-5methoxyoxazole (0.75 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
Yield: 26 %
1
409
subsequently
hydrolyzed
to
give
the
___________________________________________________________________________
CH3 ), 1.45 (s, 9H, 3CH3 ), 2.58 (septet, J = 6.2 Hz, 1H, CH), 3.61 (s, 3H, OCH3 ),
CH2 ), 7.26-7.66 (m, 5H, Harom).
13
51.8 (q, OCH3 ), 78.2 (s, C-1), 82.8 (s, Cq), 90.3 (s, C-7), 123.0 (s, C-5), 125.9 (d,
MS: (EI, 70 eV)
m/z (%) = 332 (10), 278 (8), 260 (15), 105 (35), 86 (65), 84 (100), 77 (10), 57 (38).
endo-3-Isopropyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid tert-butyl ester (endo-65f) (sbo-453d)
CO2But
Ph
N
O
O
CH3
OCH3
Yield: 42 %
1
7.29-7.66 (m, 5H, Harom).
13
δ ppm = 15.1 (q, CH3 ), 18.8 (q, CH3 ), 18.9 (q, CH3 ), 27.9 (q, 3CH3 ), 52.0 (q, OCH3 ),
MS: (EI, 70 eV)
m/z (%) = 346 (M+-Me, 10), 324 (45), 306 (15), 278 (20), 260 (18), 254 (25), 154
(28), 105 (100), 102 (38), 91 (10), 77 (25), 71 (28), 57 (60).
HRMS: (C 20 H27 NO5 , M = 361.19 g/mol)
Calcd:
361.1882
Found:
361.1874
410
___________________________________________________________________________
Photolyses of α -keto esters with 2-tert-butyl-4-methyl-5-methoxyoxazole 49c:
exo-3-tert-butyl-5-methoxy-1,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-66a) (sbo-436c)
H3C
CO2CH3
O
N
O
CH3
OCH3
A solution of methyl pyruvate (0.51 g, 5 mmol) and 2-tert-butyl-4-methyl-5-methoxyoxazole
Yield: 28 %
1
3.76 (s, 3H, OCH3 ).
13
53.4 (q, OCH3 ), 75.6 (s, C-1), 87.2 (s, C-7), 122.7 (s, C-5), 171.2 (s, COO), 179.6
(s, C-3).
HRMS: (C 13 H21 NO5 , M = 271.14 g/mol)
Calcd:
271.1435
Found:
271.1433
endo-3-tert-Butyl-5-methoxy-1,7-dimethyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (endo-65f) (sbo-436c)
H3CO2C
O
N
O
Yield: 29 %
1
411
CH3
CH3
OCH3
___________________________________________________________________________
3.77 (s, 3H, OCH3 ).
13
53.4 (q, OCH3 ), 74.7 (s, C-1), 86.7 (s, C-7), 124.6 (s, C-5), 171.4 (s, COO), 179.2
(s, C-3).
exo-3,7-Di-tert-butyl-5-methoxy-1-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (exo-66b) (sbo-484c)
H3CO2C
N
O
O
CH3
OCH3
A solution of methyl trimethylpyruvate (0.36 g, 2.5 mmol) and 2-tert-butyl-4-methyl-5methoxyoxazole (0.42 g, 2.5 mmol) in benzene (20 mL) was irradiated for 24 h according to
silica gel yielded 0.33 g of the exo-isomer (and 0.25 g of the endo-isomer) as a colorless oil.
The products were thermally unstable and were subsequently hydrolyzed to give the
Yield: 40 %
1
δ ppm = 1.12 (s, 9H, 3CH3 ), 1.18 (s, 9H, 3CH3 ), 1.50 (s, 3H, CH3 ), 3.56 (s, 3H,
OCH3 ), 3.73 (s, 3H, OCH3 ).
13
δ ppm = 15.7 (q, CH3 ), 24.1 (q, 3CH3 ), 27.3 (q, 3CH3 ), 33.5 (s, Cq), 33.7 (s, Cq), 51.8
COO), 174.4 (s, C-3).
HRMS: (C 16 H27 NO5 , M = 313.19 g/mol)
Calcd:
313.1886
Found:
313.1882
412
___________________________________________________________________________
endo-3,7-Di-tert-Butyl-5-methoxy-1-methyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene -7carboxylic acid methyl ester (endo-66b) (sbo-484)
CO2CH3
O
N
O
CH3
OCH3
Yield: 32 %
1
OCH3 ), 3.77 (s, 3H, OCH3 ).
13
δ ppm = 15.2 (q, CH3 ), 23.8 (q, 3CH3 ), 28.1 (q, 3CH3 ), 33.6 (s, Cq), 33.9 (s, Cq), 51.3
COO), 179.2 (s, C-3).
exo-3-tert-Butyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid methyl ester (exo-66c) (sbo-432c)
H3CO2C
N
O
Ph
O
CH3
OCH3
A solution of methyl phenylglyoxylate (0.82 g, 5 mmol) and 2-tert-butyl-4-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 39 %
IR: (Film)
ν~ (cm-1 ) = 2993, 2885, 1725, 1608, 1600, 1558, 1440, 1085, 980, 775.
1
δ ppm = 1.09 (s, 3H, CH3 ), 1.25 (s, 9H, 3CH3 ), 3.63 (s, 3H, OCH3 ), 3.76 (s, 3H,
OCH3 ), 7.26-7.70 (m, 5H, Harom).
413
___________________________________________________________________________
13
δ ppm = 14.9 (q, CH3 ), 27.4 (q, 3CH3 ), 33.8 (s, Cq), 51.9 (q, OCH3 ), 52.5 (q, OCH3 ),
135.0 (s, Cqarom), 169.0 (s, COO), 175.6 (s, C-3).
HRMS: (C 18 H23 NO5 , M = 333.16 g/mol)
Calcd:
333.1576
Found:
333.1580
endo-3-tert-Butyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid methyl ester (endo-66c) (sbo-432)
Ph
O
N
O
CO2CH3
CH3
OCH3
Yield: 25 %
1
δ ppm = 1.27 (s, 9H, 3CH3 ), 1.56 (s, 3H, CH3 ), 3.62 (s, 3H, OCH3 ), 3.78 (s, 3H,
OCH3 ), 7.30-7.64 (m, 5H, Harom).
13
136.5 (s, Cqarom), 170.2 (s, Coo), 175.9 (s, C-3).
exo-3-tert-Butyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid ethyl ester (exo-66d) (sbo-451d)
C2H5O2C
O
N
O
Ph
CH3
OCH3
A solution of ethyl phenylglyoxylate (0.89 g, 5 mmol) and 2-tert-butyl-4-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
414
___________________________________________________________________________
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 40 %
1
δ ppm = 0.98 (s, 3H, CH3 ), 1.21 (t, J = 7.5 Hz, 3H, CH3 ), 1.27 (s, 9H, 3CH3 ), 3.75 (s,
13
(d, CHarom), 134.5 (s, Cqarom), 169.9 (s, COO), 172.9 (s, C-3).
endo-3-tert-Butyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid ethyl ester (endo-66d) (sbo-451)
Ph
N
O
CO2C2H5
O
CH3
OCH3
A solution of ethyl phenylglyoxylate (0.89 g, 5 mmol) and 2-tert-butyl-4-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 40 %
IR: (Film)
ν~ (cm-1 ) = 2983, 2895, 1745, 1610, 1600, 1550, 1440, 1075, 980, 770.
1
δ ppm = 1.12 (s, 9H, 3CH3 ), 1.23 (t, J = 7.5 Hz, 3H, CH3 ), 1.54 (s, 3H, CH3 ), 3.67 (s,
13
(d, CHarom), 134.6 (s, Cqarom), 169.3 (s, COO), 172.8 (s, C-3).
415
___________________________________________________________________________
HRMS: (C 19 H25 NO5 , M = 347.17 g/mol)
Calcd:
347.1698
Found:
347.1694
exo-3-tert-Butyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid isopropyl ester ( exo-66e) (sbo-457c)
Pr iO2 C
Ph
O
N
O
CH3
OCH3
A solution of isopropyl phenylglyoxylate (0.96 g, 5 mmol) and 2-tert-butyl-4-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 23 %
1
CH3 ), 1.35 (s, 9H, 3CH3 ), 3.76 (s, 3H, OCH3 ), 5.00 (septet, J = 6.2 Hz, 1H, OCH),
7.26-7.35 (m, 5H, Harom).
13
δ ppm = 21.5 (q, CH3 ), 22.6 (q, CH3 ), 24.0 (q, CH3 ), 27.5 (q, 3CH3 ), 33.4 (s, Cq), 52.5
CHarom), 127.2 (d, CHarom), 135.1 (s, Cqarom), 169.4 (s, COO), 172.9 (s, C-3).
endo-3-tert-Butyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid isopropyl ester (endo-66e) (sbo-457)
Ph
CO2Pr i
O
N
O
Yield: 40 %
416
CH3
OCH3
___________________________________________________________________________
1
δ ppm = 1.02 (s, 9H, 3CH3 ), 1.18 (d, J = 6.2 Hz, 3H, CH3 ), 1.21 (d, J = 6.2 Hz, 3H,
7.28-7.62 (m, 5H, Harom).
13
δ = 20.9 (q, CH3 ), 21.3 (q, CH3 ), 23.7 (q, CH3 ), 28.1 (q, 3CH3 ), 33.5 (s, Cq), 52.7
CHarom), 128.5 (d, CHarom), 134.6 (s, Cqarom), 165.7 (s, COO), 179.1 (s, C-3).
HRMS: (C 20 H27 NO5 , M = 361.20 g/mol)
Calcd:
361.1946
Found:
361.1941
exo-3-tert-Butyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2-ene 7-carboxylic acid tert-butyl ester (exo-66f) (sbo-444e)
But O2C
N
O
Ph
O
CH3
OCH3
A solution of tert-butyl phenylglyoxylate (1.0 g, 5 mmol) and 2-tert-butyl-4-methyl-5methoxyoxazole (0.84 g, 5 mmol) in benzene (50 mL) was irradiated for 24 h according to the
products
were
thermally
unstable
and
were
subsequently
hydrolyzed
to
give
the
Yield: 37 %
1
δ ppm = 1.07 (s, 3H, CH3 ), 1.26 (s, 9H, 3CH3 ), 1.43 (s, 9H, 3CH3 ), 3.60 (s, 3H,
OCH3 ), 7.22-7.36 (m, 5H, Harom).
13
δ ppm = 15.2 (q, CH3 ), 27.0 (q, 3CH3 ), 27.3 (q, 3CH3 ), 33.4 (s, Cq), 51.8 (q, OCH3 ),
CHarom), 135.9 (s, Cqarom), 167.1 (s, COO), 175.2 (s, C-3).
417
___________________________________________________________________________
endo-3-tert-Butyl-5-methoxy-1-methyl-7-phenyl-4,6-dioxa-2-aza-bicyclo[3.2.0]hept-2ene -7-carboxylic acid tert-butyl ester (endo-66f) (sbo-444e)
Ph
N
O
CO2But
O
CH3
OCH3
Yield: 42 %
1
OCH3 ), 7.48-7.67 (m, 5H, Harom).
13
CHarom), 135.4 (s, Cqarom), 167.9 (s, COO), 172.6 (s, C-3).
HRMS: (C 21 H29 NO5 , M = 375.20 g/mol)
Calcd:
375.1849
Found:
375.1847
418
___________________________________________________________________________
4.20 Synthesis of erythro (S*,R*) & threo (S*,S*) α -amino-β
derivatives
Ring-opening of the bicyclic oxetanes; (Typical hydrolysis procedure):
To a stirred solution of the bicyclic oxetane (2 mmol) in chloroform (10 mL) was added 1N
HCl (0.5 mL). After to 2h at room temperature, the course of reaction was monitored by TLC.
Upon complete conversion, the reaction mixture was diluted with chloroform, washed with
saturated sodium bicarbonate, water, and brine, dried (MgSO4 ), and concentrated in vacuo.
The crude product was purified by preparative thick-layer chromatography over silica gel
using a mixture of ethylacetate/n-hexane as an eluent.
Synthesis of erythro (S*,R*) α -acetamido-β
β -hydroxy succinic acid derivatives 67a-f:
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2,3-dimethyl-succinic acid dimethyl ester
(erythro-67a) (sbo-394c)
HO
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 55a (0.5 g, 2 mmol) was
colorless oil.
Yield: 81 %
1
δ ppm = 1.29 (s, 3H, CH3 ), 1.58 (s, 3H, CH3 ), 2.26 (s, 3H, CH3 CO), 3.52 (s, 3H,
OCH3 ), 3.82 (s, 3H, OCH3 ), 6.06 (s, 1H, NH).
13
79.1 (s, C-2), 89.1 (s, C-3), 169.6 (s, CON), 171.2 (COO), 171.9 (s, COO).
erythro
(2S*,3R*)
2-Acetylamino-2-ethyl-3-hydroxy-3-methyl-succinic
ester (erythro-67b) (sbo-399d)
419
acid
dimethyl
___________________________________________________________________________
HO
Ac HN
CO2CH3
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 55b (0.51 g, 2 mmol) was
colorless oil. A crystalline sample for X-ray crystal structure analysis could be obtained by
crystallization of the product from pentane at –10 °C.
Yield: 86 %
M.p: 67-69 °C.
1
δ ppm = 0.81 (t, J = 7.2 Hz, 3H, CH3 ), 1.49 (s, 3H, CH3 ), 1.55 (m, 1H, CH), 1.63 (m,
1H, CH), 2.13 (s, 3H, CH3 CO), 3.61 (s, 3H, OCH3 ), 3.81 (s, 3H, OCH3 ).
13
52.4 (q, OCH3 ), 81.2 (s, C-2), 89.1 (s, C-3), 169.5 (s, CON), 170.1 (COO), 171.3 (s,
COO).
HRMS: (C 11 H19 NO6 , M = 261.12 g/mol)
Calcd:
261.1207
Found:
261.1204
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-3-methyl-2-propyl-succinic acid dimethyl
ester (erythro-67c) (sbo-405b)
HO
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 55c (0.5 g, 2 mmol) was
colorless oil.
Yield: 82 %
1
420
___________________________________________________________________________
δ ppm = 0.88 (t, J = 7.5 Hz, 3H, CH3 ), 1.21 (m, 2H, CH2 ), 1.85 (dt, J = 11.0, 6.2 Hz,
1H, CH), 1.53 (s, 3H, CH3 ), 2.04 (s, 3H, CH3 CO), 2.42 (dt, J = 10.8, 6.2 Hz, 1H,
CH), 3.21 (s, 3H, OCH3 ), 3.80 (s, 3H, OCH3 ), 6.39 (s, 1H, NH).
13
(q, OCH3 ), 53.1 (q, OCH3 ), 74.1 (s, C-2), 81.9 (s, C-3), 169.3 (s, CON), 177.4
(COO), 178.3 (s, COO).
HRMS: (C 12 H21 NO6 , M = 275.14 g/mol)
Calcd:
275.1363
Found:
275.1359
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-isopropyl-3-methyl-succinic acid dimethyl
ester (erythro-67d) (sbo-406b)
HO
CO2 CH3
Ac HN
CO2 CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 55d (0.5 g, 2 mmol) was
colorless oil.
Yield: 78 %
IR: (Film)
ν~ (cm-1 ) = 3510, 3340, 2988, 2896, 1745, 1735, 1685, 1445, 1075, 980, 770.
1
OH), 1.61 (s, 3H, CH3 ), 2.02 (s, 3H, CH3 CO), 2.98 (septet, J = 6.8 Hz, 1H, CH),
3.67 (s, 3H, OCH3 ), 3.86 (s, 3H, OCH3 ), 7.04 (s, 1H, NH).
13
(COO), 174.9 (s, COO).
Anal: (C 12 H21 NO6 , M = 275.3 g/mol)
Calcd:
C 52.35 H 7.69 N 5.09
Found:
C 52.52 H 7.89 N 5.12
421
___________________________________________________________________________
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-isobutyl-3-methyl-succinic acid dimethyl
ester (erythro-67e) (sbo-407c)
HO
AcHN
CO2CH3
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 55e (0.54 g, 2 mmol) was
cleaved hydrolytically in 2.5h. Preparative chromatography yielded 0.5 g of the product as a
colorless oil.
Yield: 86 %
1
CH), 1.56 (s, 3H, CH3 ), 1.89 (m, 2H, CH2 ), 2.04 (s, 3H, CH3 CO), 3.66 (s, 3H,
OCH3 ), 3.68 (s, 3H, OCH3 ), 6.53 (s, 1H, NH).
13
(t, CH2 ), 52.4 (q, OCH3 ), 52.7 (q, OCH3 ), 82.4 (s, C-2), 89.7 (s, C-3), 164.7 (s,
CON), 171.3 (COO), 172.5 (s, COO).
erythro (2S*,3R*) 2-Acetylamino-2-sec-butyl-3-hydroxy-3-methyl-succinic acid dimethyl
ester (erythro-67f) (sbo-408a)
HO
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 55f (0.54 g, 2 mmol) was
colorless oil.
Yield: 80 %
1
CH2 ), 1.57 (s, 3H, CH3 ), 1.89 (m, 1H, CH), 1.96 (s, 3H, CH3 CO), 3.61 (s, 3H,
OCH3 ), 3.76 (s, 3H, OCH3 ), 6.60 (s, 1H, NH).
13
422
___________________________________________________________________________
(d, CH), 51.6 (q, OCH3 ), 52.6 (q, OCH3 ), 78.2 (s, C-2), 82.0 (s, C-3), 170.7 (s,
CON), 170.9 (COO), 173.2 (s, COO).
MS: (EI, 70 eV)
m/z (%) = 273 (M+-O, 5), 272 (M+-OH, 7), 246 (M+-MeCO, 15), 232 (5), 188 (55),
144 (15), 141 (100), 113 (90), 83 (27), 57 (25), 55 (30).
HRMS: (C 13 H23 NO6 , M = 289.15 g/mol)
Calcd:
289.1519
Found:
289.1515
Synthesis of threo (S*,S*) α -acetamido-β
β -hydroxy succinic acid derivatives 68a-f:
threo (2S*,3S*) 2-Acetylamino-3-tert-butyl-3-hydroxy-2-methyl-succinic acid dimethyl
ester (threo-68a) (sbo-387a)
HO
CO2CH3
AcHN
CO2CH3
colorless oil.
Yield: 73 %
IR: (Film)
ν~ (cm-1 ) = 3490, 3360, 2994, 2934, 1740, 1735, 1685, 1443, 1065, 985, 770.
1
δ ppm = 1.02 (s, 3H, CH3 ), 1.12 (s, 9H, 3CH3 ), 1.50 (s, 3H, CH3 ), 1.98 (s, 3H,
CH3 CO), 3.55 (s, 3H, OCH3 ), 3.73 (s, 3H, OCH3 ).
13
δ ppm = 14.6 (q, CH3 ), 15.6 (q, CH3 ), 25.7 (q, CH3 ), 41.3 (s, Cq), 51.4 (q, OCH3 ),
COO).
HRMS: (C 13 H23 NO6 , M = 289.15 g/mol)
Calcd:
289.1519
Found:
289.1512
423
___________________________________________________________________________
threo
(2S*,3S*)
2-Acetylamino-3-tert-butyl-2-ethyl-3-hydroxy-succinic
acid
dimethyl
ester (threo-68b) (sbo-390a)
HO
CO2CH3
AcHN
CO2CH3
colorless oil.
Yield: 89 %
1
δ ppm = 0.81 (t, J = 7.4 Hz, 3H, CH3 ), 1.12 (s, 9H, 3CH3 ), 1.92 (m, 1H, CH), 2.00 (s,
3H, CH3 CO), 2.13 (s, 1H, CH), 3.56 (s, 3H, OCH3 ), 3.72 (s, 3H, OCH3 ).
13
δ ppm = 8.0 (q, CH3 ), 14.6 (q, CH3 ), 21.8 (q, CH3 ), 26.4 (t, CH2 ), 37.9 (s, Cq), 51.2 (q,
OCH3 ), 52.0 (q, OCH3 ), 80.7 (s, C-2), 81.3 (s, C-3), 169.8 (s, CON), 177.5 (COO),
180.9 (s, COO).
threo (2S*,3S*) 2-Acetylamino-3-tert-butyl-3-hydroxy-2-propyl-succinic acid dimethyl
ester (threo-68c) (sbo-389d)
HO
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 56c (0.31 g, 1 mmol) was
cleaved hydrolytically in 3.5h. Preparative chromatography yielded 0.25 g of the product as a
colorless oil.
Yield: 80 %
1
δ ppm = 0.83 (t, J = 7.5 Hz, 3H, CH3 ), 1.06 (s, 9H, 3CH3 ), 1.23 (m, 2H, CH2 ), 1.53
(m, 2H, CH2 ), 2.02 (s, 3H, CH3 CO), 3.58 (s, 3H, OCH3 ), 3.77 (s, 3H, OCH3 ).
13
424
___________________________________________________________________________
δ ppm =13.6 (q, CH3 ), 14.3 (q, CH3 ), 14.8 (q, CH3 ), 21.6 (q, CH3 ), 25.4 (q, 3CH3 ),
32.9 (t, CH2 ), 37.5 (t, CH2 ), 39.9 (s, Cq), 52.4 (q, OCH3 ), 53.4 (q, OCH3 ), 80.5 (s,
C-2), 81.0 (s, C-3), 165.5 (s, CON), 171.4 (COO), 175.4 (s, COO).
HRMS: (C 15 H27 NO6 , M = 317.18 g/mol)
Calcd:
317.1786
Found:
317.1782
threo (2S*,3S*) 2-Acetylamino-3-tert-butyl-3-hydroxy-2-isopropyl-succinic acid dimethyl
ester (threo-68d) (sbo-574b)
HO
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 56d (0.31 g, 1 mmol) was
colorless oil.
Yield: 67 %
1
3CH3 ), 1.23 (m, 1H, CH), 2.12 (s, 3H, CH3 CO), 3.64 (s, 3H, OCH3 ), 3.73 (s, 3H,
OCH3 ).
13
δ ppm = 14.2 (q, CH3 ), 17.2 (q, CH3 ), 17.5 (q, CH3 ), 24.6 (d, CH), 38.7 (s, Cq), 52.3
(COO), 175.7 (s, COO).
threo (2S*,3S*) 2-Acetylamino-3-tert-butyl-3-hydroxy-2-isobutyl-succinic acid dimethyl
ester (threo-68e) (sbo-575c)
HO
CO2CH3
AcHN
CO2CH3
425
___________________________________________________________________________
According to the typical hydrolysis procedure, the bicyclic oxetane 56e (0.33 g, 1 mmol) was
colorless oil.
Yield: 73 %
1
δ ppm = 0.93 (d, J = 6.8 Hz, 6H, 2CH3 ), 1.05 (s, 9H, 3CH3 ), 1.23 (m, 1H, CH), 1.53
(m, 2H, CH2 ), 2.12 (s, 3H, CH3 CO), 3.63 (s, 3H, OCH3 ), 3.71 (s, 3H, OCH3 ).
13
δ =13.8 (q, CH3 ), 19.3 (q, CH3 ), 19.5 (q, CH3 ), 26.4 (q, 3CH3 ), 27.5 (d, CH), 39.5 (t,
CH2 ), 40.2 (s, Cq), 52.2 (q, OCH3 ), 53.2 (q, OCH3 ), 82.5 (s, C-2), 84.0 (s, C-3),
165.6 (s, CON), 171.8 (COO), 175.9 (s, COO).
threo (2S*,3S*) 2-Acetylamino-2-sec-butyl-3-tert-butyl-3-hydroxy-succinic acid dimethyl
ester (threo-68f) (sbo-576b)
HO
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane 56f (0.33 g, 1 mmol) was
colorless oil.
Yield: 87 %
1
3CH3 ), 1.23 (m, 1H, CH), 1.59 (m, 2H, CH2 ), 2.02 (s, 3H, CH3 CO), 3.58 (s, 3H,
OCH3 ), 3.75 (s, 3H, OCH3 ).
13
δ ppm =13.8 (q, CH3 ), 14.2 (q, CH3 ), 14.8 (q, CH3 ), 21.6 (d, CH), 27.4 (q, 3CH3 ),
32.9 (t, CH2 ), 39.9 (s, Cq), 52.2 (q, OCH3 ), 53.6 (q, OCH3 ), 87.5 (s, C-2), 89.3 (s, C3), 167.2 (s, CON), 173.4 (COO), 176.4 (s, COO).
426
___________________________________________________________________________
Synthesis of erythro (S*,R*) & threo (S*,S*) α -acetamido-β
derivatives 69a-f:
threo
(2S*,3S*)
2-Acetylamino-3-hydroxy-2-methyl-3-phenyl-succinic
acid
dimethyl
ester (threo-69a) (sbo-359e)
HO
AcHN
CO2CH3
Ph
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane exo-58a (0.58 g, 2 mmol)
was cleaved hydrolytically in 6h. Preparative chromatography yielded 0.51 g of the product as
a colorless oil.
Yield: 87 %
1
OCH3 ), 7.32-7.38 (m, 5H, Harom).
13
Cqarom), 168.7 (s, CON), 169.6 (s, COO), 174.7 (COO).
HRMS: (C 15 H19 NO6 , M = 309.12 g/mol)
Calcd:
309.1176
Found:
309.1172
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-methyl-3-phenyl-succinic acid dimethyl
(erythro-69a) (sbo-359c)
HO
Ph
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane endo-58a (0.29 g, 1
mmol) was cleaved hydrolytically in 4h. Preparative chromatography yielded 0.28 g of the
product as a colorless oil.
Yield: 91 %
427
___________________________________________________________________________
IR: (Film)
ν~ (cm-1 ) = 3500, 3346, 2983, 2890, 1745, 1735, 1670, 1600, 1550, 1440, 1075,
980, 770.
1
OCH3 ), 7.23-7.31 (m, 5H, Harom).
13
83.6 (s, C-3), 126.1 (d, CHarom), 127.0 (d, CHarom), 135.5 (s, Cqarom), 168.8 (s,
CON), 169.0 (s, COO), 172.0 (COO).
threo (2S*,3S*) 2-Acetylamino-2-ethyl-3-hydroxy-3-phenyl-succinic acid dimethyl ester
(threo-69b) (sbo-368a)
HO
AcHN
CO2CH3
Ph
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane exo-58b (0.61 g, 2 mmol)
a colorless oil.
Yield: 82 %
IR: (Film)
ν~ (cm-1 ) = 3540, 3446, 2993, 2898, 1748, 1739, 1678, 1605, 1554, 1435, 1085,
980, 770.
1
δ ppm = 1.10 (t, J = 7.2 Hz, 3H, CH3 ), 1.55 (m, 1H, CH), 2.25 (s, 3H, CH3 CO), 2.45
(m, 1H, CH), 3.05 (s, 3H, OCH3 ), 3.78 (s, 3H, OCH3 ), 7.27-7.55 (m, 5H, Harom).
13
87.1 (s, C-2), 92.6 (s, C-3), 126.4 (d, CHarom), 127.5 (d, CHarom), 128.0 (d, CHarom),
134.8 (s, Cqarom), 165.4 (s, CON), 168.7 (s, COO), 169.4 (s, COO).
HRMS: (C 16 H21 NO6 , M = 333.14 g/mol)
Calcd:
333.1363
428
___________________________________________________________________________
Found:
erythro
333.1356
(2S*,3R*)
2-Acetylamino-2-ethyl-3-hydroxy-3-phenyl-succinic
acid
dimethyl
ester (erythro-69b) (sbo-368c)
HO
Ph
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane endo-58b (0.31 g, 1
Yield: 90 %
1
δ ppm = 0.96 (t, J = 7.4 Hz, 3H, CH3 ), 1.73 (s, 3H, CH3 CO), 1.85 (m, 1H, CH), 2.07
(m, 1H, CH), 3.69 (s, 3H, OCH3 ), 3.77 (s, 3H, OCH3 ), 7.29-7.47 (m, 5H, Harom).
13
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-3-phenyl-2-propyl-succinic acid dimethyl ester
(threo-69c) (sbo-361b)
HO
AcHN
CO2CH3
Ph
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane exo-58c (0.63 g, 2 mmol)
a colorless oil.
Yield: 79 %
1
(m, 2H, CH2 ), 3.04 (s, 3H, OCH3 ), 3.78 (s, 3H, OCH3 ), 7.27-7.58 (m, 5H, Harom).
429
___________________________________________________________________________
13
52.9 (q, OCH3 ), 86.6 (s, C-2), 92.6 (s, C-3), 126.5 (d, CHarom), 128.4 (d, CHarom),
134.8 (s, Cqarom), 165.2 (s, CON), 168.7 (COO), 169.5 (s, COO).
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-3-phenyl-2-propyl-succinic acid dimethyl
ester (erythro-69c) (sbo-361a)
HO
AcHN
Ph
CO2CH3
CO2 CH3
According to the typical hydrolysis procedure, the bicyclic oxetane endo-58c (0.31 g, 1
Yield: 84 %
1
3H, CH3 CO), 3.71 (s, 3H, OCH3 ), 3.73 (s, 3H, OCH3 ), 7.26-7.36 (m, 5H, Harom).
13
138.3 (s, Cqarom), 166.4 (s, CON), 170.7 (COO), 172.4 (s, COO).
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-isopropyl-3-phenyl-succinic acid dimethyl
ester (threo-69d) (sbo-362g)
HO
AcHN
CO2 CH3
Ph
CO2 CH3
According to the typical hydrolysis procedure, the bicyclic oxetane exo-58d (0.63 g, 2 mmol)
a colorless oil.
Yield: 86 %
430
___________________________________________________________________________
1
CH), 2.04 (s, 3H, CH3 CO), 3.28 (s, 3H, OCH3 ), 3.77 (s, 3H, OCH3 ), 7.24-7.58 (m,
5H, Harom).
13
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-isopropyl-3-phenyl-succinic acid dimethyl
ester (erythro-69d) (sbo-362g)
HO
Ph
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane endo-58d (0.31 g, 1
Yield: 75 %
1
CH3 CO), 1.85 (septet, J = 6.8 Hz, 1H, CH), 3.67 (s, 3H, OCH3 ), 3.85 (s, 3H,
OCH3 ), 7.23-7.46 (m, 5H, Harom).
13
threo
(2S*,3S*)
2-Acetylamino-3-hydroxy-2-isobutyl-3-phenyl-succinic acid dimethyl
ester (threo-69e) (sbo-366b)
HO
AcHN
CO2 CH3
Ph
CO2CH3
431
___________________________________________________________________________
According to the typical hydrolysis procedure, the bicyclic oxetane exo-58e (0.67 g, 2 mmol)
a colorless oil.
Yield: 89 %
1
δ ppm = 0.88 (d, J = 6.6Hz, 3H, CH3 ), 0.95 (d, J = 6.6 Hz, 3H, CH3 ), 1.35 (dd, J =
13.3, 5.7 Hz, 1H, CH), 1.80 (septet, J = 6.6 Hz, 1H, CH), 2.27 (s, 3H, CH3 CO), 2.37
(dd, J = 13.3, 6.1 Hz, 1H, CH), 3.05 (s, 3H, OCH3 ), 3.78 (s, 3H, OCH3 ), 7.25-7.55
(m, 5H, Harom).
13
(q, OCH3 ), 52.8 (q, OCH3 ), 86.5 (s, C-2), 93.0 (s, C-3), 125.6 (d, CH), 126.4 (d,
CHarom), 127.5 (d, CHarom), 134.8 (s, Cqarom), 164.6 (s, CON), 168.6 (s, COO), 170.0
(s, COO).
HRMS: (C 18 H25 NO6 , M = 351.17 g/mol)
Calcd:
351.1657
Found:
351.1652
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-isobutyl-3-phenyl-succinic acid dimethyl
ester (erythro-69e) (sbo-366b)
HO
Ph
CO 2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane endo-58e (0.33 g, 1
Yield: 85 %
1
δ ppm = 0.81 (d, J = 6.6 Hz, 3H, CH3 ), 0.92 (d, J = 6.6 Hz, 3H, CH3 ), 1.61 (dd, J =
13.4, 5.8 Hz, 1H, CH), 1.72 (s, 3H, CH3 CO), 1.83 (m, 1H, CH), 2.02 (dd, J = 13.4,
6.1 Hz, 1H, CH), 3.69 (s, 3H, OCH3 ), 3.76 (s, 3H, OCH3 ), 7.26-7.37 (m, 5H, Harom).
13
432
___________________________________________________________________________
(q, OCH3 ), 52.3 (q, OCH3 ), 83.1 (s, C-2), 93.1 (s, C-3), 126.7 (d, CHarom), 127.3 (d,
(s, COO).
threo (2S*,3S*) 2-Acetylamino-2-sec-butyl-3-hydroxy-3-phenyl-succinic acid dimethyl
ester (threo-69f) (sbo-367)
HO
Ac HN
CO2CH3
Ph
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane exo-58f (0.67 g, 2 mmol)
a colorless oil.
Yield: 92 %
1
CH2 ), 1.35 (m, 1H, CH), 2.26 (s, 3H, CH3 CO), 3.05 (s, 3H, OCH3 ), 3.78 (s, 3H,
OCH3 ), 7.27-7.56 (m, 5H, Harom).
13
(COO).
erythro (2S*,3R*) 2-Acetylamino-2-sec-butyl-3-hydroxy-3-phenyl- succinic acid dimethyl
ester (erythro-69f) (sbo-367)
HO
Ph
CO2CH3
AcHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane endo-58f (0.33 g, 1 mmol)
a colorless oil.
433
___________________________________________________________________________
Yield: 80 %
1
δ ppm = 0.91 (t, J = 7.2 Hz, 3H, CH3 ), 0.97 (d, J = 6.6 Hz, 3H, CH3 ), 1.47-1.55 (m,
2H, CH2 ), 1.69 (m, 1H, CH), 2.21 (s, 3H, CH3 CO), 3.67 (s, 3H, OCH3 ), 3.78 (s, 3H,
OCH3 ), 7.28-7.54 (m, 5H, Harom).
13
CHarom), 134.5 (s, Cqarom), 166.1 (s, CON), 169.3 (s, COO), 172.1 (COO).
derivatives 70a-f:
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-methyl-3-phenyl-succinic acid 4-ethyl ester
1-methyl ester (threo-70a) (sbo-351b)
HO
CO2C2H5
Ph
AcHN
CO 2CH3
a colorless oil.
Yield: 90 %
1
δ ppm = 1.27 (t, J = 6.6 Hz, 3H, CH3 ), 1.66 (s, 3H, CH3 ), 2.23 (s, 3H, CH3 CO), 3.05
(s, 3H, OCH3 ), 4.22 (q, J = 6.6 Hz, 2H, OCH2 ), 7.25-7.35 (m, 5H, Harom).
13
δ ppm = 14.3 (q, CH3 ), 21.7 (q, CH3 ), 51.8 (q, OCH3 ), 62.3 (t, OCH2 ), 82.2 (s, C-2),
Anal: (C 16 H21 NO6 , M = 323.34 g/mol)
Calcd:
C 59.43 H 6.55 N 4.33
Found:
C 59.73 H 6.42 N 4.33
434
___________________________________________________________________________
erythro
(2S*,3R*)
acid
4-ethyl
ester 1-methyl ester (erythro-70a) (sbo-351a)
HO
AcHN
Ph
CO2C2H5
CO2CH3
Yield: 80 %
1
δ ppm = 1.25 (t, J = 7.2 Hz, 3H, CH3 ), 1.50 (s, 3H, CH3 ), 2.07 (s, 3H, CH3 CO), 3.66
13
δ ppm = 14.8 (q, CH3 ), 15.7 (q, CH3 ), 51.9 (q, OCH3 ), 61.8 (t, OCH2 ), 78.5 (s, C-2),
CON), 168.3 (s, COO), 169.2 (COO).
threo (2S*,3S*) 2-Acetylamino-2-ethyl-3-hydroxy-3-phenyl-succinic acid 4-ethyl ester 1methyl ester (threo-70b) (sbo-371a)
HO
AcHN
CO2C2H5
Ph
CO2CH3
a colorless oil.
Yield: 84 %
1
δ ppm = 0.72 (t, J = 7.5 Hz, 3H, CH3 ), 1.04 (t, J = 7.5 Hz, 3H, CH3 ), 1.52 (sextet, J =
7.5 Hz, 1H, CH), 2.26 (s, 3H, CH3 CO), 2.41 (sextet, J = 7.5 Hz, 1H, CH), 3.04 (s,
13
435
___________________________________________________________________________
62.2 (t, OCH2 ), 91.6 (s, C-2), 92.4 (s, C-3), 126.4 (d, CHarom), 127.5 (d, CHarom),
128.0 (d, CHarom), 134.6 (s, Cqarom), 168.2 (s, CON), 168.7 (s, COO), 169.4 (s,
COO).
MS: (EI, 70 eV)
m/z (%) = 320 (M+-OH, 5), 309 (M+-CH2 =CH2 , 10), 294 (M+-COMe, 15), 277 (7),
264 (25), 260 (12), 244 (5), 159 (53), 127 (26), 105 (100), 91 (20), 77 (30), 51 (45).
HRMS: (C 17 H23 NO6 , M = 337.15 g/mol)
Calcd:
337.1519
Found:
337.1511
erythro (2S*,3R*) 2-Acetylamino-2-ethyl-3-hydroxy-3-phenyl-succinic acid 4-ethyl ester
1-methyl ester (erythro-70b) (sbo-371c)
HO
AcHN
Ph
CO2C2H5
CO2CH3
Yield: 83 %
1
δ ppm = 0.71 (t, J = 7.5 Hz, 3H, CH3 ), 1.23 (t, J = 7.5 Hz, 3H, CH3 ), 1.51 (sextet, J =
7.5 Hz, 1H, CH), 1.82 (sextet, J = 7.5 Hz, 1H, CH), 2.16 (s, 3H, CH3 CO), 3.76 (s,
13
δ ppm = 7.9 (q, CH3 ), 8.2 (q, CH3 ), 14.6 (q, CH3), 22.4 (t, CH2 ), 51.6 (q, OCH3 ), 61.7
(t, OCH2 ), 90.8 (s, C-2), 92.3 (s, C-3), 126.2 (d, CH), 127.9 (d, CH), 128.8 (d, CH),
134.8 (s, Cq), 167.9 (s, CON), 169.1 (s, COO), 171.2 (s, COO).
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-3-phenyl-2-propyl-succinic acid 4-ethyl ester
1-methyl ester (threo-70c) (sbo-354b)
436
___________________________________________________________________________
HO
AcHN
CO2 C2 H5
Ph
CO2 CH3
a colorless oil.
Yield: 88 %
1
CH2 ), 2.23 (s, 3H, CH3 CO), 2.33 (m, 2H, CH2 ), 3.02 (s, 3H, OCH3 ), 4.21 (q, J = 7.4
Hz, 2H, OCH2 ), 6.39 (s, 1H, NH), 7.25-7.56 (m, 5H, Harom).
13
(q, OCH3 ), 62.2 (t, OCH2 ), 81.8 (s, C-2), 91.6 (s, C-3), 126.5 (d, CHarom), 128.4 (d,
CHarom), 134.9 (s, Cqarom), 166.2 (s, CON), 168.1 (COO), 169.6 (s, COO).
erythro
(2S*,3R*)
2-Acetylamino-3-hydroxy-3-phenyl-2-propyl-succinic
acid
4-ethyl
ester 1-methyl ester (erythro-70c) (sbo-354)
HO
AcHN
Ph
CO2C2H5
CO2CH3
mmol) was cleaved hydrolytically in 3.5h. Preparative chromatography yielded 0.26 g of the
Yield: 84 %
1
CH2 ), 2.17 (s, 3H, CH3 CO), 2.45 (m, 2H, CH2 ), 3.76 (s, 3H, OCH3 ), 4.27 (q, J=7.4
Hz, 2H, OCH2 ), 6.21 (s, 1H, NH), 7.27-7.48 (m, 5H, Harom).
13
437
___________________________________________________________________________
CHarom), 134.6 (s, Cqarom), 169.1 (s, CON), 170.1 (COO), 171.3 (s, COO).
threo
(2S*,3S*)
2-Acetylamino-3-hydroxy-2-isopropyl-3-phenyl-succinic
acid
4-ethyl
ester 1-methyl ester (threo-70d) (sbo-352)
HO
CO2C2H5
Ph
AcHN
CO2CH3
a colorless oil.
Yield: 89 %
1
Hz, 3H, CH3 ), 2.29 (s, 3H, CH3 CO), 2.96 (septet, J = 6.6 Hz, 1H, CH), 3.11 (s, 3H,
13
CHarom), 135.8 (s, Cqarom), 163.4 (s, CON), 167.5 (s, COO), 170.2 (s, COO).
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-isopropyl-3-phenyl-succinic acid 4-ethyl
ester 1-methyl ester (erythro-70d) (sbo-352a)
HO
AcHN
Ph
CO2 C2 H5
CO2CH3
Yield: 90 %
438
___________________________________________________________________________
1
Hz, 3H, CH3 ), 2.12 (s, 3H, CH3 CO), 2.71 (septet, J = 6.8 Hz, 1H, CH), 3.74 (s, 3H,
13
Anal: (C 18 H25 NO6 , M = 351.2 g/mol)
Calcd:
C 61.52 H 7.17 N 3.99
Found:
C 61.98
H 7.11
N 4.31
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-isobutyl-3-phenyl-succinic acid 4-ethyl ester
1-methyl ester (threo-70e) (sbo-355b)
HO
AcHN
CO2C2H5
Ph
CO2CH3
a colorless oil.
Yield: 87 %
IR: (Film)
ν~ (cm-1 ) = 3490, 3360, 2993, 2967, 1755, 1729, 1680, 1604, 1550, 1440, 1075,
980, 770.
1
δ ppm = 0.86 (d, J = 6.8Hz, 3H, CH3 ), 0.97 (d, J = 6.6 Hz, 3H, CH3 ), 1.28 (t, J = 7.2
Hz, 3H, CH3 ), 1.39 (dd, J = 13.4, 5.9 Hz, 1H, CH), 1.80 (septet, J = 6.6 Hz, 1H,
CH), 2.26 (s, 3H, CH3 CO), 2.38 (dd, J = 13.4, 6.0 Hz, 1H, CH), 3.05 (s, 3H, OCH3 ),
4.25 (q, J = 7.2 Hz, 2H, OCH2 ), 7.25-7.56 (m, 5H, Harom).
13
(t, CH2 ), 51.7 (q, OCH3 ), 62.2 (t, OCH2 ), 86.4 (s, C-2), 92.9 (s, C-3), 125.6 (d,
439
___________________________________________________________________________
CHarom), 126.4 (d, CHarom), 127.5 (d, CHarom), 134.8 (s, Cqarom), 164.7 (s, CON),
168.1 (s, COO), 170.1 (s, COO).
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-isobutyl-3-phenyl-succinic acid 4-ethyl
ester 1-methyl ester (erythro-70e) (sbo-355)
HO
AcHN
Ph
CO2C2H5
CO2CH3
Yield: 88 %
1
Hz, 3H, CH3 ), 1.41 (septet, J = 6.6 Hz, 1H, CH), 1.60 (m, 2H, CH2 ), 2.10 (s, 3H,
CH3 CO), 3.78 (s, 3H, OCH3 ), 4.25 (q, J = 7.5 Hz, 2H, CH2 ), 7.26-7.35 (m, 5H,
Harom).
13
169.2 (s, COO), 171.3 (s, COO).
threo
(2S*,3S*)
2-Acetylamino-2-sec-butyl-3-hydroxy-3-phenyl-succinic
acid
4-ethyl
ester 1-methyl ester (threo-70f) (sbo-356a)
HO
AcHN
CO2 C2H5
Ph
CO2CH3
a colorless oil.
Yield: 87 %
440
___________________________________________________________________________
1
δ ppm = 0.74 (d, J = 6.3 Hz, 3H, CH3 ), 0.88 (t, J = 6.6 Hz, 3H, CH3 ), 1.23 (t, J = 7.5
Hz, 3H, CH3 ), 1.25 (m, 1H, CH), 1.54 (m, 2H, CH2 ), 2.23 (s, 3H, CH3 CO), 3.05 (s,
13
169.1 (s, COO), 172.3 (COO).
erythro (2S*,3R*) 2-Acetylamino-2-sec-butyl-3-hydroxy-3-phenyl-succinic acid 4-ethyl
ester 1-methyl ester (erythro-70f) (sbo-356b)
HO
Ph
CO2C2H5
Ac HN
CO2CH3
a colorless oil.
Yield: 82 %
1
CH), 1.27 (t, J = 7.2 Hz, 3H, CH3 ), 1.62 (m, 2H, CH2 ), 2.12 (s, 3H, CH3 CO), 3.69
13
(COO).
MS: (EI, 70 eV)
m/z (%) = 354 (4), 316 (10), 277 (18), 169 (50), 141 (45), 140 (100), 105 (43), 91
(20), 77 (30), 59 (10).
HRMS: (C 19 H27 NO6 , M = 365.18 g/mol)
441
___________________________________________________________________________
Calcd:
365.1831
Found:
365.1827
derivatives 71a-f:
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-methyl-3-phenyl-succinic acid 4-isopropyl
ester 1-methyl ester (threo-71a) (sbo-562c)
CO2Pr i
Ph
HO
AcHN
CO2CH3
a colorless oil.
Yield: 89 %
1
CH3 ), 2.11 (s, 3H, CH3 CO), 3.05 (s, 3H, OCH3 ), 5.07 (septet, J = 6.6 Hz, 1H,
OCH), 7.32-7.38 (m, 5H, Harom).
13
δ ppm = 21.3 (q, CH3 ), 21.5 (q, CH3 ), 23.1 (q, CH3 ), 52.2 (q, OCH3 ), 70.2 (d, OCH),
135.2 (s, Cqarom), 165.7 (s, CON), 170.2 (s, COO), 174.7 (COO).
MS: (EI, 70 eV)
m/z (%) = 279 (M+-MeCONH, 4), 260 (M+-Ph, 5), 246 (8), 191 (71), 150 (10), 144
(10), 127 (60), 105 (100), 105 (50), 87 (6), 86 (50), 77 (60), 51 (45).
HRMS: (C 17 H23 NO6 , M = 337.15 g/mol)
Calcd:
337.1519
Found:
337.1514
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-methyl-3-phenyl-succinic acid 4-isopropyl
ester 1-methyl ester (erythro-71a) (sbo-562)
442
___________________________________________________________________________
HO
AcHN
Ph
CO2Pri
CO2CH3
Yield: 87 %
1
CH3 ), 2.00 (s, 3H, CH3 CO), 3.65 (s, 3H, OCH3 ), 5.23 (septet, J = 6.6 Hz, 1H,
OCH), 7.32-7.42 (m, 5H, Harom).
13
δ ppm = 21.5 (q, CH3 ), 21.8 (q, CH3 ), 23.5 (q, CH3 ), 52.3 (q, OCH3 ), 70.1 (d, OCH),
135.2 (s, Cqarom), 168.7 (s, CON), 171.2 (s, COO), 173.6 (COO).
threo
(2S*,3S*)
acid
4-isopropyl
ester 1-methyl ester (threo-71b) (sbo-582a)
HO
Ac HN
CO2Pri
Ph
CO2CH3
a colorless oil.
Yield: 85 %
1
Hz, 3H, CH3 ), 1.55 (m, 1H, CH), 2.25 (s, 3H, CH3 CO), 2.45 (m, 1H, CH), 3.05 (s,
13
443
___________________________________________________________________________
(q, OCH3 ), 70.9 (d, OCH), 86.4 (s, C-2), 91.6 (s, C-3), 126.4 (d, CHarom), 127.5 (d,
(s, COO).
erythro (2S*,3R*) 2-Acetylamino-2-ethyl-3-hydroxy-3-phenyl-succinic acid 4-isopropyl
ester 1-methyl ester (erythro-71b) (sbo-582c)
HO
AcHN
Ph
CO2Pr i
CO2CH3
Yield: 74 %
1
δ ppm = 0.96 (t, J = 7.4 Hz, 3H, CH3 ), 1.21 (d, J = 6.2 Hz, 3H, CH), 1.26 (d, J = 6.2
Hz, 3H, CH3 ), 1.85 (m, 1H, CH), 1.93 (s, 3H, CH3 CO), 2.07 (m, 1H, CH), 3.69 (s,
13
(s, COO).
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-3-phenyl-2-propyl-succinic acid 4-isopropyl
ester 1-methyl ester (threo-71c) (sbo-584b)
HO
AcHN
CO2Pr i
Ph
CO2CH3
a colorless oil.
444
___________________________________________________________________________
Yield: 82 %
1
Hz, 3H, CH3 ), 1.51 (m, 2H, CH2 ), 2.26 (s, 3H, CH3 CO), 2.34 (m, 2H, CH2 ), 3.04 (s,
13
(t, CH2 ), 51.7 (q, OCH3 ), 70.5 (d, OCH), 86.3 (s, C-2), 92.5 (s, C-3), 126.4 (d,
CHarom), 128.4 (d, CHarom), 134.9 (s, Cqarom), 165.4 (s, CON), 167.6 (COO), 169.7
(s, COO).
HRMS: (C 19 H27 NO6 , M = 365.18 g/mol)
Calcd:
365.1784
Found:
365.1781
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-3-phenyl-2-propyl-succinic acid 4-isopropyl
ester 1-methyl ester (erythro-71c) (sbo-584d)
HO
AcHN
Ph
CO2Pr i
CO2CH3
Yield: 89 %
1
δ ppm = 0.93 (t, J = 7.2 Hz, 3H, CH3 ), 1.18 (m, 2H, CH2 ), 1.23 (d, J = 6.2 Hz, 3H,
CH3 ), 1.26 (d, J = 6.2 Hz, 3H, CH3 ), 1.53 (m, 2H, CH2 ), 2.02 (s, 3H, CH3 CO), 3.65
(s, 3H, OCH3 ), 5.07 (septet, J = 6.2 Hz, 1H, OCH), 7.26-7.36 (m, 5H, Harom).
13
(t, CH2 ), 52.8 (q, OCH3 ), 70.3 (d, OCH), 76.7 (s, C-2), 82.7 (s, C-3), 126.3 (d,
CHarom), 128.1 (d, CHarom), 138.3 (s, Cqarom), 169.4 (s, CON), 170.7 (COO), 172.4
(s, COO).
445
___________________________________________________________________________
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-isopropyl-3-phenyl-succinic acid 4-isopropyl
ester 1-methyl ester (threo-71d) (sbo-577e)
HO
AcHN
CO2Pri
Ph
CO2CH3
a colorless oil.
Yield: 62 %
1
Hz, 3H, CH3 ), 1.19 (d, J = 6.2 Hz, 3H, CH3 ), 1.21 (m, 1H, CH), 2.04 (s, 3H,
CH3 CO), 3.08 (s, 3H, OCH3 ), 5.07 (septet, J = 6.2 Hz, 1H, OCH), 7.24-7.58 (m, 5H,
Harom).
13
34.7 (d, CH), 52.4 (q, OCH3 ), 70.8 (d, OCH), 88.3 (s, C-2), 91.2 (s, C-3), 125.6 (d,
(s, COO).
erythro
(2S*,3R*)
acid
4-
isopropyl ester 1-methyl ester (erythro-71d) (sbo-577d)
HO
AcHN
Ph
CO2Pr i
CO2CH3
Yield: 62 %
1
446
___________________________________________________________________________
Hz, 3H, CH3 ), 1.85 (septet, J = 6.8 Hz, 1H, CH), 2.18 (s, 3H, CH3 CO), 3.67 (s, 3H,
OCH3 ), 5.05 (septet, J = 6.2 Hz, 1H, OCH), 7.23-7.46 (m, 5H, Harom).
13
(s, COO).
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-isobutyl-3-phenyl-succinic acid 4-isopropyl
ester 1-methyl ester (threo-71e) (sbo-578c)
HO
AcHN
CO2Pr i
Ph
CO2CH3
a colorless oil.
Yield: 67 %
IR: (Film)
ν~ (cm-1 ) = 3500, 3370, 2993, 2898, 1745, 1728, 1670, 1600, 1550, 1440, 1075,
980, 770.
1
δ ppm = 0.88 (d, J = 6.6Hz, 3H, CH3 ), 0.95 (d, J = 6.6 Hz, 3H, CH3 ), 1.12 (m, 1H,
CH), 1.27 (d, J = 6.2 Hz, 3H, CH3 ), 1.38 (d, J = 6.2 Hz, 3H, CH3 ), 1.79 (dd, J =
13.3, 5.7 Hz, 1H, CH), 1.80 (septet, J = 6.6 Hz, 1H, CH), 2.27 (s, 3H, CH3 CO), 2.37
(dd, J = 13.3, 6.1 Hz, 1H, CH), 3.05 (s, 3H, OCH3 ), 5.10 (septet, J = 6.2 Hz, 1H,
OCH), 3.67 (s, 3H, OCH3 ), 7.25-7.55 (m, 5H, Harom).
13
164.6 (s, CON), 168.6 (s, COO), 170.0 (s, COO).
HRMS: (C 20 H29 NO6 , M = 379.20 g/mol)
447
___________________________________________________________________________
erythro
Calcd:
379.2018
Found:
379.2014
(2S*,3R*)
2-Acetylamino-3-hydroxy-2-isobutyl-3-phenyl-succinic
acid
4-
isopropyl ester 1-methyl ester (erythro-71e) (sbo-578b)
HO
AcHN
Ph
CO2Pri
CO2CH3
Yield: 58 %
1
Hz, 3H, CH3 ), 1.26 (d, J = 6.2 Hz, 3H, CH3 ), 1.61 (dd, J = 13.4, 5.8 Hz, 1H, CH),
1.72 (s, 3H, CH3 CO), 1.83 (m, 1H, CH), 2.02 (dd, J=13.4, 6.1 Hz, 1H, CH), 3.69 (s,
13
165.1 (s, CON), 168.6 (s, COO), 171.0 (s, COO).
threo (2S*,3S*) 2-Acetylamino-2-sec-butyl-3-hydroxy-3-phenyl-succinic acid 4-isopropyl
ester 1-methyl ester (threo-71f) (sbo-586h)
HO
AcHN
CO2Pr i
Ph
CO2CH3
a colorless oil.
Yield: 58 %
448
___________________________________________________________________________
1
2.26 (s, 3H, CH3 CO), 3.05 (s, 3H, OCH3 ), 5.18 (septet, J = 6.2 Hz, 1H, OCH), 7.277.56 (m, 5H, Harom).
13
(q, CH3 ), 37.9 (t, CH2 ), 51.8 (q, OCH3 ), 70.9 (d, OCH), 86.6 (s, C-2), 92.6 (s, C-3),
CON), 168.8 (s, COO), 169.5 (COO).
erythro
(2S*,3R*)
acid
4-
isopropyl ester 1-methyl ester (erythro-71f) (sbo-586i)
HO
AcHN
Ph
CO2Pr i
CO2CH3
a colorless oil.
Yield: 65 %
1
δ ppm = 0.91 (t, J = 7.2 Hz, 3H, CH3 ), 0.97 (d, J = 6.6 Hz, 3H, CH3 ), 1.47-1.55 (m,
2H, CH2 ), 1.69 (m, 1H, CH), 2.21 (s, 3H, CH3 CO), 3.67 (s, 3H, OCH3 ), 3.78 (s, 3H,
OCH3 ), 7.28-7.54 (m, 5H, Harom).
13
(q, CH3 ), 39.1 (t, CH2 ), 51.6 (q, OCH3 ), 70.3 (d, OCH), 86.2 (s, C-2), 93.5 (s, C-3),
126.7 (d, CHarom), 129.1 (d, CHarom), 134.5 (s, Cqarom), 166.1 (s, CON), 169.3 (s,
COO), 172.1 (COO).
449
___________________________________________________________________________
derivatives 72a-f:
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-methyl-3-phenyl-succinic acid 4-tert-butyl
ester 1-methyl ester (threo-72a) (sbo-455b)
HO
CO2But
Ph
AcHN
CO2CH3
a colorless oil.
Yield: 82 %
1
δ ppm = 1.49 (s, 9H, 3CH3 ), 1.71 (s, 3H, CH3 ), 2.13 (s, 3H, CH3 CO), 3.79 (s, 3H,
OCH3 ), 7.33-7.48 (m, 5H, Harom).
13
δ ppm = 16.4 (q, CH3 ), 24.2 (q, CH3 ), 27.8 (q, 3CH3 ), 52.7 (q, OCH3 ), 83.4 (s, Cq),
136.0 (s, Cq), 168.4 (s, CON), 169.9 (s, COO), 170.3 (COO).
MS: (EI, 70 eV)
m/z (%) = 334 (M+-OH, 40), 318 (100), 296 (12), 278 (72), 250 (8), 145 (10), 105
(80), 91 (20), 77 (30), 51 (10).
HRMS: (C 18 H25 NO6 , M = 351.17 g/mol)
Calcd:
351.1675
Found:
351.1669
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-methyl-3-phenyl-succinic acid 4-tert-butyl
ester 1-methyl ester (erythro-72a) (sbo-455a)
HO
Ph
CO2 But
AcHN
CO2 CH3
450
___________________________________________________________________________
Yield: 80 %
IR: (Film)
ν~ (cm-1 ) = 3500, 3346, 2983, 2890, 1745, 1738, 1662, 1605, 1558, 1441, 1085,
980, 778.
1
δ ppm = 1.50 (s, 3H, CH3 ), 1.53 (s, 9H, 3CH3 ), 1.95 (s, 3H, CH3 CO), 3.65 (s, 3H,
OCH3 ), 3.83 (s, 3H, OCH3 ), 7.23-7.31 (m, 5H, Harom).
13
δ ppm = 18.6 (q, CH3 ), 23.9 (q, CH3 ), 27.8 (q, CH3 ), 52.4 (q, OCH3 ), 66.5 (s, C-2),
CON), 171.3 (s, COO), 172.0 (COO).
threo
(2S*,3S*)
acid
4-tert-butyl
ester 1-methyl ester (threo-72b) (sbo-583b)
HO
AcHN
CO2But
Ph
CO2CH3
a colorless oil.
Yield: 89 %
1
δ ppm = 1.04 (t, J = 7.5 Hz, 3H, CH3 ), 1.47 (s, 9H, 3CH3 ), 1.56 (m, 1H, CH), 2.10 (s,
3H, CH3 CO), 2.25 (m, 1H, CH), 3.00 (s, 3H, OCH3 ), 7.27-7.55 (m, 5H, Harom).
13
82.9 (s, Cq), 86.7 (s, C-2), 92.6 (s, C-3), 126.5 (d, CHarom), 127.5 (d, CHarom), 128.0
(d, CHarom), 134.8 (s, Cqarom), 165.6 (s, CON), 166.9 (s, COO), 169.6 (s, COO).
451
___________________________________________________________________________
erythro (2S*,3R*) 2-Acetylamino-2-ethyl-3-hydroxy-3-phenyl-succinic acid 4-tert-butyl
ester 1-methyl ester (erythro-72b) (sbo-368c)
HO
AcHN
Ph
CO2But
CO2CH3
Yield: 79 %
1
δ ppm = 0.96 (t, J = 7.4 Hz, 3H, CH3 ), 1.49 (s, 9H, 3CH3 ), 1.73 (s, 3H, CH3 CO), 1.85
(m, 1H, CH), 2.07 (m, 1H, CH), 3.69 (s, 3H, OCH3 ), 7.29-7.47 (m, 5H, Harom).
13
77.2 (s, C-2), 82.0 (s, C-3), 83.4 (s, Cq), 126.4 (d, CHarom), 127.9 (d, CHarom), 128.8
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-3-phenyl-2-propyl-succinic acid 4-tert-butyl-1methyl ester (threo-72c) (sbo-585c)
HO
AcHN
CO2But
Ph
CO2CH3
a colorless oil.
Yield: 79 %
1
δ ppm = 0.92 (t, J = 7.5 Hz, 3H, CH3 ), 1.44 (m, 2H, CH2 ), 1.48 (s, 9H, 3CH3 ), 2.26
(s, 3H, CH3 CO), 2.34 (m, 2H, CH2 ), 3.04 (s, 3H, OCH3 ), 7.27-7.58 (m, 5H, Harom).
13
452
___________________________________________________________________________
51.8 (q, OCH3 ), 82.9 (s, Cq), 86.6 (s, C-2), 92.6 (s, C-3), 126.5 (d, CHarom), 128.4
(d, CHarom), 134.8 (s, Cqarom), 165.2 (s, CON), 168.7 (COO), 169.5 (s, COO).
erythro
(2S*,3R*)
acid
4-tert-
butyl-1-methyl ester (erythro-72c) (sbo-585d)
HO
AcHN
Ph
CO2But
CO2CH3
Yield: 88 %
1
9H, 3CH3 ), 1.78 (s, 3H, CH3 CO), 3.71 (s, 3H, OCH3 ), 7.26-7.36 (m, 5H, Harom).
13
52.8 (q, OCH3 ), 72.7 (s, C-2), 81.7 (s, C-3), 83.3 (s, Cq), 126.3 (d, CHarom), 128.1
(d, CHarom), 138.3 (s, Cqarom), 166.4 (s, CON), 170.7 (COO), 172.4 (s, COO).
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-isopropyl-3-phenyl-succinic acid 4-tert-butyl
1-methyl ester (threo-72d) (sbo-579c)
HO
AcHN
CO2 But
Ph
CO2 CH3
a colorless oil.
Yield: 89 %
IR: (Film)
453
___________________________________________________________________________
ν~ (cm-1 ) = 3543, 3349, 2993, 2899, 1740, 1735, 1670, 1608, 1559, 1448, 1075,
980, 770.
1
CH), 1.47 (s, 9H, 3CH3 ), 2.04 (s, 3H, CH3 CO), 3.08 (s, 3H, OCH3 ), 7.24-7.58 (m,
5H, Harom).
13
52.4 (q, OCH3 ), 83.2 (s, Cq), 90.3 (s, C-2), 91.2 (s, C-3), 125.6 (d, CHarom), 127.9
HRMS: (C 20 H29 NO6 , M = 379.20 g/mol)
Calcd:
379.2039
Found:
379.2034
erythro (2S*,3R*) 2-Acetylamino-3-hydroxy-2-isopropyl-3-phenyl-succinic acid 4-tertbutyl-1-methyl ester (erythro-72d) (sbo-579d)
HO
AcHN
Ph
CO2But
CO2CH3
Yield: 86 %
1
3CH3 ), 1.68 (s, 3H, CH3 CO), 1.85 (septet, J = 6.8 Hz, 1H, CH), 3.67 (s, 3H, OCH3 ),
7.23-7.46 (m, 5H, Harom).
13
82.9 (s, Cq), 83.1 (s, C-2), 90.4 (s, C-3), 126.7 (d, CHarom), 127.4 (d, CHarom), 135.6
(s, Cqarom), 168.1 (s, CON), 170.2 (s, COO), 171.4 (s, COO).
454
___________________________________________________________________________
threo (2S*,3S*) 2-Acetylamino-3-hydroxy-2-isobutyl-3-phenyl-succinic acid 4-tert-butyl
ester 1-methyl ester (threo-72e) (sbo-580c)
HO
AcHN
CO2But
Ph
CO2CH3
a colorless oil.
Yield: 63 %
1
δ ppm = 0.88 (d, J = 6.6Hz, 3H, CH3 ), 0.95 (d, J = 6.6 Hz, 3H, CH3 ), 1.35 (dd, J =
13.3, 5.7 Hz, 1H, CH), 1.49 (s, 9H, 3CH3 ), 1.81 (septet, J = 6.6 Hz, 1H, CH), 2.13
(s, 3H, CH3 CO), 2.37 (dd, J = 13.3, 6.1 Hz, 1H, CH), 3.05 (s, 3H, OCH3 ), 7.25-7.55
(m, 5H, Harom).
13
43.9 (t, CH2 ), 51.8 (q, OCH3 ), 83.7 (s, Cq), 86.1 (s, C-2), 93.2 (s, C-3), 125.6 (d,
164.9 (s, COO), 166.8 (s, COO).
erythro
(2S*,3R*)
2-Acetylamino-3-hydroxy-2-isobutyl-3-phenyl-succinic acid 4-tert-
butyl ester 1-methyl ester (erythro-72e) (sbo-580d)
HO
AcHN
Ph
CO2But
CO 2CH3
Yield: 65 %
1
455
___________________________________________________________________________
3CH3 ), 1.61 (dd, J = 13.4, 5.8 Hz, 1H, CH), 1.72 (s, 3H, CH3 CO), 1.83 (m, 1H,
CH), 2.02 (dd, J = 13.4, 6.1 Hz, 1H, CH), 3.69 (s, 3H, OCH3 ), 7.26-7.37 (m, 5H,
Harom).
13
168.6 (s, COO), 171.0 (s, COO).
threo (2S*,3S*) 2-Acetylamino-2-sec-butyl-3-hydroxy-3-phenyl- succinic acid 4-tert-butyl
ester 1-methyl ester (threo-72f) (sbo-586a)
HO
AcHN
CO2But
Ph
CO2CH3
a colorless oil.
Yield: 82 %
1
CH2 ), 1.35 (m, 1H, CH), 1.47 (s, 9H, 3CH3 ), 2.26 (s, 3H, CH3 CO), 3.05 (s, 3H,
OCH3 ), 7.27-7.56 (m, 5H, Harom).
13
168.8 (s, COO), 169.5 (COO).
HRMS: (C 21 H31 NO6 , M = 399.22 g/mol)
Calcd:
399.2236
Found:
399.2233
456
___________________________________________________________________________
erythro (2S*,3R*) 2-Acetylamino-2-sec-butyl-3-hydroxy-3-phenyl-succinic acid 4-tertbutyl 1-methyl ester (erythro-72f) (sbo-586d)
HO
AcHN
Ph
CO2But
CO2CH3
a colorless oil.
Yield: 72 %
1
3CH3 ), 1.47-1.55 (m, 2H, CH2 ), 1.69 (m, 1H, CH), 2.21 (s, 3H, CH3 CO), 3.67 (s,
3H, OCH3 ), 7.28-7.54 (m, 5H, Harom).
13
169.3 (s, COO), 172.1 (COO).
457
4. Eperimental part
___________________________________________________________________________
derivatives 73a-f:
threo
(2S*,3S*)
acid
4-(2-
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (threo-73a) (sbo-373d)
O
HO
Ac HN
O
Ph
CO2CH3
a colorless oil.
Yield: 75 %
IR: (Film)
ν~ (cm-1 ) = 3540, 3370, 2983, 2890, 1736, 1725, 1670, 1595, 1550, 1440, 1075,
980, 770.
1
Hz, 3H, CH3 ), 0.95 (m, 2H, CH2 ), 1.03 (m, 2H, CH2 ), 1.45 (m, 2H, CH2 ), 1.68 (s,
3H, CH3 ), 1.74 (m, 2H, CH2 ), 1.84 (m, 2H, CH2 ), 1.84 (m, 2H, CH2 ), 2.23 (s, 3H,
CH3 CO), 3.05 (s, 3H, OCH3 ), 4.66 (ddd, J = 11.0 , 4.6, 4.4 Hz, 1H, OCH), 7.257.35 (m, 5H, Harom).
13
21.9 (q, CH3 ), 22.9 (d, CH), 23.3 (d, CH), 25.5 (t, CH2 ), 26.1 (d, CH), 31.4 (d, CH),
33.9 (t, CH2 ), 40.2 (t, CH2 ), 46.9 (d, CH), 51.8 (q, OCH3 ), 77.2 (t, OCH), 82.1 (s, C2), 92.7 (s, C-3), 126.06 (d, CHarom), 127.6 (d, CHarom), 128.2 (d, CHarom), 135.3 (s,
458
4. Eperimental part
___________________________________________________________________________
erythro
(2S*,3R*)
acid
4-(2-
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (erythro-73a) (sbo-373a)
O
HO
AcHN
O
Ph
CO2CH3
Yield: 68 %
1
Hz, 3H, CH3 ), 0.87 (m, 2H, CH2 ), 1.00 (m, 2H, CH2 ), 1.34 (m, 2H, CH2 ), 1.47 (m,
2H, CH2 ), 1.53 (s, 3H, CH3 ), 2.12 (s, 3H, CH3 CO), 3.74 (s, 3H, OCH3 ), 4.74 (ddd, J
= 11.0 , 4.6, 4.4 Hz, 1H, OCH), 7.32-7.50 (m, 5H, Harom).
13
22.0 (q, CH3 ), 23.2 (q, CH3 ), 25.6 (d, CH), 25.8 (d, CH), 31.4 (d, CH), 34.2 (t,
CH2 ), 40.3 (t, CH2 ), 47.1 (d, CH), 52.2 (q, OCH3 ), 74.9 (t, OCH), 75.9 (d, OCH),
109.9 (s, C-3), 127.3(d, CHarom), 128.2 (d, CHarom), 134.1 (s, Cqarom), 164.9 (s,
CON), 169.0 (s, COO), 169.2 (COO).
threo (2S*,3S*) 2-Acetylamino-2-ethyl-3-hydroxy-3-phenyl-succinic acid 4-(2-isopropyl5-methyl-cyclohexyl) ester 1-methyl ester (threo-73b) (sbo-374a)
459
4. Eperimental part
___________________________________________________________________________
O
HO
Ac HN
O
Ph
CO2CH3
a colorless oil.
Yield: 60 %
1
Hz, 3H, CH3 ), 1.02 (t, J = 7.2 Hz, 3H, CH3 ), 1.12 (m, 2H, CH2 ), 1.25 (m, 1H, CH),
1.35 (m, 2H, CH2 ), 1.43 (m, 2H, CH2 ), 1.54 (m, 2H, CH2 ), 1.67 (m, 1H, CH), 1.83
(m, 2H, CH2 ), 2.22 (s, 3H, CH3 CO), 2.46 (m, 1H, CH), 3.03 (s, 3H, OCH3 ), 4.67
(ddd, J = 11.0, 4.5, 4.4 Hz, 1H, OCH), 7.26-7.48 (m, 5H, Harom).
13
(q, CH3 ), 25.5 (d, CH), 28.9 (t, CH2 ), 31.4 (d, CH), 33.9 (t, CH2 ), 40.3 (t, CH2 ), 46.9
(d, CH), 51.7 (q, OCH3 ), 81.9 (d, OCH), 86.8 (s, C-2), 92.7 (s, C-3), 126.4 (d,
CHarom), 127.4 (d, CHarom), 128.3 (d, CH), 134.9 (s, Cqarom), 165.5 (s, CON), 167.8
(s, COO), 169.5 (COO).
MS: (EI, 70 eV)
m/z (%) = 430 (M+ – OH), 392 (4), 388 (M+-CO2 Me, 6), 288 (30), 353 (7), 244 (8),
159 (30), 127 (15), 105 (40), 83 (100), 57 (43), 55 (62).
HRMS: (C 25 H37 NO6 , M = 447.26 g/mol)
erythro
Calcd:
447.2611
Found:
447.2605
(2S*,3R*)
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (erythro-73b) (sbo-374b)
460
acid
4-(2-
4. Eperimental part
___________________________________________________________________________
O
HO
AcHN
O
Ph
CO2CH3
Yield: 53 %
1
Hz, 3H, CH3 ), 1.03 (t,J = 7.2 Hz, 3H, CH3 ), 1.14 (m, 2H, CH2 ), 1.27 (m, 2H, CH2 ),
1.37 (m, 1H, CH), 1.45 (m, 2H, CH2 ), 1.57 (m, 2H, CH2 ), 1.68 (m, 1H, CH), 1.89
(m, 2H, CH2 ), 2.12 (s, 3H, CH3 CO), 3.67 (s, 3H, OCH3 ), 4.67 (ddd, J = 11.0 , 4.5,
4.4 Hz, 1H, OCH), 7.26-7.53 (m, 5H, Harom).
13
(q, CH3 ), 25.7 (q, CH3 ), 29.0 (t, CH2 ), 31.7 (d, CH), 33.5 (t, CH2 ), 40.7 (t, CH2 ),
CHarom), 127.6 (d, CHarom), 128.2 (d, CH), 134.7 (s, Cqarom), 169.1 (s, CON), 170.1
(s, COO), 171.3 (COO).
threo
(2S*,3S*)
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (threo-73c) (sbo-375a)
O
HO
AcHN
O
Ph
CO2CH3
461
acid
4-(2-
4. Eperimental part
___________________________________________________________________________
a colorless oil.
Yield: 64 %
1
1.37 (m, 2H, CH2 ), 1.43 (m, 1H, CH), 1.47 (m, 2H, CH2 ), 1.68 (m, 2H, CH2 ), 2.20
(s, 3H, CH3 CO), 3.00 (s, 3H, OCH3 ), 4.68 (ddd, J = 11.1, 4.6, 4.4 Hz, 1H, OCH),
7.20-7.52 (m, 5H, Harom).
13
165.5 (s, CON), 167.8 (s, COO), 168.6 (COO).
Anal: (C 21 H37 NO6 , M = 339.3 g/mol)
erythro
Calcd:
C 63.32 H 9.33 N 3.51
Found:
C 64.00 H 9.12 N 3.59
(2S*,3R*)
acid
4-(2-
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (erythro-73c) (sbo-375b)
O
HO
Ac HN
O
Ph
CO2CH3
462
4. Eperimental part
___________________________________________________________________________
Yield: 74 %
1
1.25 (m, 1H, CH), 1.29 (m, 2H, CH2 ), 1.34 (m, 2H, CH2 ), 1.45 (m, 2H, CH2 ), 1.56
(m, 2H, CH2 ), 2.06 (s, 3H, CH3 CO), 3.46 (s, 3H, OCH3 ), 4.72 (ddd, J = 11.1 , 4.5,
4.4 Hz, 1H, OCH), 7.26-7.68 (m, 5H, Harom).
13
21.9 (q, CH3 ), 23.9 (t, CH2 ), 25.9 (d, CH), 29.9 (d, CH), 31.5 (t, CH2 ), 34.1 (t, CH2 ),
C-2), 86.1 (s, C-3), 126.2 (d, CHarom), 127.6 (d, CHarom), 128.2 (d, CHarom), 137.9 (s,
threo
(2S*,3S*)
acid
4-(2-
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (threo-73d) (sbo-379a)
O
HO
AcHN
O
Ph
CO2CH3
a colorless oil.
Yield: 72 %
IR: (Film)
ν~ (cm-1 ) = 3500, 3346, 2956, 2873, 1738, 1732, 1683, 1600, 1550, 1494, 1055,
942, 640.
1
463
4. Eperimental part
___________________________________________________________________________
2H, CH2 ), 1.23 (m, 2H, CH2 ), 1.29 (m, 1H, CH), 1.34 (m, 2H, CH2 ), 1.44 (m, 2H,
CH2 ), 1.56 (m, 2H, CH2 ), 2.29 (s, 3H, CH3 CO), 3.15 (s, 3H, OCH3 ), 4.80 (ddd, J =
11.0, 4.5 , 4.4Hz, 1H, OCH), 7.23-7.31 (m, 5H, Harom).
13
21.9 (q, CH3 ), 23.2 (d, CH), 25.6 (d, CH), 31.4 (t, CH2 ), 31.5 (d, CH), 23.4 (t, CH2 ),
C-2), 91.3 (s, C-3), 126.6 (d, CHarom), 127.6 (d, CHarom), 128.2 (d, CHarom), 136.0 (s,
Anal: (C 26 H39 NO6 , M = 461.59 g/mol)
erythro
Calcd:
C 67.65 H 8.52 N 3.03
Found:
C 66.98 H 8.22 N 3.14
(2S*,3R*)
2-Acetylamino-3-hydroxy-2-isopropyl-3-phenyl-succinic acid 4-(2-
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (erythro-73d) (sbo-379b)
O
HO
Ac HN
O
Ph
CO2CH3
Yield: 88 %
1
2H, CH2 ), 1.34 (m, 2H, CH2 ), 1.37 (m, 1H, CH), 1.53 (m, 2H, CH2 ), 1.57 (m, 2H,
464
4. Eperimental part
___________________________________________________________________________
CH2 ), 1.60 (m, 2H, CH2 ), 1.83 (m, 2H, CH2 ), 2.18 (s, 3H, CH3 CO), 3.81 (s, 3H,
OCH3 ), 4.48 (ddd, J = 11.0 , 4.6, 4.4 Hz, 1H, OCH), 7.25-7.35 (m, 5H, Harom).
13
21.9 (q, CH3 ), 22.9 (d, CH), 23.0 (t, CH2 ), 25.6 (d, CH), 31.2 (t, CH2 ), 34.0 (d, CH),
34.2 (d, CH), 40.1 (t, CH2 ), 46.8 (d, CH), 52.4 (q, OCH3 ), 77.0 (t, OCH), 82.1 (s, C2), 92.7 (s, C-3), 126.3 (d, CHarom), 127.6 (d, CHarom), 128.2 (d, CHarom), 134.1 (s,
threo
(2S*,3S*)
acid
4-(2-
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (threo-73e) (sbo-384b)
O
HO
AcHN
O
Ph
CO2CH3
was cleaved hydrolytically ni 4h. Preparative chromatography yielded 0.85 g of the product as
a colorless oil.
Yield: 89 %
1
CH2 ), 1.67 (m, 2H, CH2 ),1.83 (m, 2H, CH2 ), 2.12 (s, 3H, CH3 CO), 3.03 (s, 3H,
OCH3 ), 4.74 (ddd, J = 11.0, 4.6 , 4.5Hz, 1H, OCH), 7.23-7.55 (m, 5H, Harom).
13
21.8 (q, CH3 ), 23.0 (d, CH), 23.4 (t, CH2 ), 24.1 (d, CH), 25.9 (d, CH), 31.2 (t, CH2 ),
33.9 (t, CH2 ), 40.1 (t, CH), 46.8 (d, CH), 52.3 (q, OCH3 ), 76.8 (d, OCH), 86.2 (s, C465
4. Eperimental part
___________________________________________________________________________
2), 93.3 (s, C-3), 126.7 (d, CHarom), 127.6 (d, CHarom), 128.2 (d, CHarom), 134.7 (s,
erythro
(2S*,3R*)
acid
4-(2-
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (erythro-73e) (sbo-384)
O
HO
Ac HN
O
Ph
CO2CH3
Yield: 84 %
1
CH2 ), 1.69 (m, 2H, CH2 ),1.87 (m, 2H, CH2 ), 2.13 (s, 3H, CH3 CO), 3.69 (s, 3H,
OCH3 ), 4.78 (ddd, J = 11.0, 4.6 , 4.5Hz, 1H, OCH), 7.28-7.55 (m, 5H, Harom).
13
21.8 (q, CH3 ), 23.2 (d, CH), 23.4 (t, CH2 ), 24.3 (d, CH), 25.8 (d, CH), 31.3 (t, CH2 ),
34.5 (t, CH2 ), 42.1 (t, CH), 47.0 (d, CH), 52.7 (q, OCH3 ), 76.9 (d, OCH), 87.3 (s, C2), 94.1 (s, C-3), 126.9 (d, CHarom), 127.6 (d, CHarom), 128.2 (d, CHarom), 135.1 (s,
threo
(2S*,3S*)
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (threo-73f) (sbo-385c)
466
acid
4-(2-
4. Eperimental part
___________________________________________________________________________
O
HO
AcHN
O
Ph
CO2CH3
a colorless oil.
Yield: 88 %
1
Hz, 3H, CH3 ), 0.83 (d, J = 6.9 Hz, 3H, CH3 ), 0.90 (t, J = 7.2 Hz, 3H, CH3 ), 1.03 (m,
CH2 ), 1.45 (m, 1H, CH), 1.89 (m, 2H, CH2 ), 2.29 (s, 3H, CH3 CO), 3.14 (s, 3H,
13
20.4 (q, CH3 ), 20.8 (t, CH2 ), 21.9 (d, CH), 23.2 (d, CH), 25.6 (t, CH2 ), 26.3 (d, CH),
31.5 (t, CH2 ), 34.0 (d, CH), 39.3 (t, CH2 ), 40.1 (t, CH2 ), 46.8 (d, CH), 51.6 (q,
OCH3 ), 76.3 (d, OCH), 88.5 (s, C-2), 90.8 (s, C-3), 125.7 (d, CHarom), 127.3 (d,
(COO).
erythro
(2S*,3R*)
isopropyl-5-methyl-cyclohexyl) ester 1-methyl ester (erythro-73f) (sbo-385)
O
HO
AcHN
O
Ph
CO2CH3
467
acid
4-(2-
4. Eperimental part
___________________________________________________________________________
a colorless oil.
Yield: 89 %
1
Hz, 3H, CH3 ), 0.85 (d, J = 7.2 Hz, 3H, CH3 ), 0.93 (t, J = 7.2 Hz, 3H, CH3 ), 1.17 (m,
CH2 ), 1.49 (m, 1H, CH), 1.93 (m, 2H, CH2 ), 2.17 (s, 3H, CH3 CO), 3.74 (s, 3H,
13
20.5 (q, CH3 ), 20.9 (t, CH2 ), 22.3 (d, CH), 27.4 (d, CH), 29.3 (t, CH2 ), 30.1 (d, CH),
34.1 (t, CH2 ), 37.2 (d, CH), 40.1 (t, CH2 ), 42.3 (t, CH2 ), 47.0 (d, CH), 52.7 (q,
OCH3 ), 76.0 (d, OCH), 89.1 (s, C-2), 92.3 (s, C-3), 125.7 (d, CHarom), 127.3 (d,
(COO).
Synthesis of erythro (S*,R*) & threo (S*,S*) α -propionylamino-β
derivatives 74a-f:
erythro
(2S*,3R*)
2,3-Dimethyl-3-hydroxy-2-propionylamino-succinic
acid
dimethyl
ester (erythro-74a) (sbo-442)
HO
CO2CH3
EtOCHN
CO2CH3
colorless oil.
Yield: 89 %
468
4. Eperimental part
___________________________________________________________________________
1
δ ppm = 1.12 (t, J = 7.2 Hz, 3H, CH3 ), 1.45 (s, 3H, CH3 ), 1.67 (s, 3H, CH3 ), 1.98 (q, J
= 7.2 Hz, 2H, CH2 ), 3.67 (s, 3H, OCH3 ), 3.76 (s, 3H, OCH3 ).
13
δ ppm = 7.9 (q, CH3 ), 19.2 (q, CH3 ), 25.7 (q, CH3 ), 35.2.4 (t, CH2 ), 52.9 (q, OCH3 ),
COO).
threo
(2S*,3S*)
3-tert-Butyl-2-propionylamino-3-hydroxy-2-methyl-succinic
acid
dimethyl ester (threo-74b) (sbo-442c)
HO
CO2CH3
EtOCHN
CO2CH3
colorless oil.
Yield: 81 %
1
J = 7.2 Hz, 2H, CH2 ), 3.69 (s, 3H, OCH3 ), 3.76 (s, 3H, OCH3 ).
13
δ ppm = 8.7 (q, CH3 ), 20.2 (q, CH3 ), 28.7 (q, 3CH3 ), 35.2.4 (t, CH2 ), 37.8 (s, Cq),
52.9 (q, OCH3 ), 53.2 (q, OCH3 ), 82.3 (s, C-2), 89.2 (s, C-3), 169.2 (s, CON), 172.1
(COO), 175.3 (s, COO).
threo (2S*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-propionylamino-succinic acid dimethyl
ester (threo-74c) (sbo-441c)
469
4. Eperimental part
___________________________________________________________________________
CO2CH3
Ph
HO
EtOCHN
CO2CH3
a colorless oil.
Yield: 85 %
1
13
168.4 (s, CON), 172.2 (s, COO), 173.9 (s, COO).
erythro
(2R*,3S*)
2-Hydroxy-3-methyl-2-phenyl-3-propionylamino-succinic
acid
dimethyl ester (erythro-74c) (sbo-441d)
HO
EtOCHN
Ph
CO2CH3
CO2CH3
Yield: 88 %
1
13
470
4. Eperimental part
___________________________________________________________________________
170.3 (s, CON), 172.6 (s, COO), 174.9 (s, COO).
threo (2S*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-propionylamino-succinic acid 1-ethyl
ester-4-methyl ester (threo-74d) (sbo-465b)
CO2C2H5
Ph
HO
EtOCHN
CO 2CH3
a colorless oil.
Yield: 76 %
IR: (Film)
ν~ (cm-1 ) = 3490, 3365, 2983, 2890, 1743, 1720, 1650, 1600, 1550, 1440, 1075,
980, 770.
1
OCH2 ), 7.26-7.32 (m, 5H, Harom).
13
HRMS: (C 17 H23 NO6 , M = 337.15 g/mol)
Calcd:
337.1468
Found:
351.1463
erythro (2R*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-propionylamino-succinic acid 1-ethyl
ester-4-methyl ester (erythro-74d) (sbo-465d)
471
4. Eperimental part
___________________________________________________________________________
Ph
CO2C2H5
HO
EtO CHN
CO2CH3
Yield: 76 %
1
OCH2 ), 6.38 (s, 1H, NH), 7.31-7.66 (m, 5H, Harom).
13
threo
(2S*,3S*)
acid
1-
isopropyl ester-4-methyl ester (threo-74e) (sbo-463)
CO2Pri
Ph
HO
EtOCHN
CO2CH3
a colorless oil.
Yield: 74 %
1
472
4. Eperimental part
___________________________________________________________________________
13
Anal: (C 18 H25 NO6 , M = 351.17 g/mol)
erythro
Calcd:
C 61.52 H 7.17 N 3.99
Found:
C 61.72 H 7.14 N 4.03
(2R*,3S*)
acid
1-
isopropyl ester-4-methyl ester (erythro-74e) (sbo-463a)
HO
EtOCHN
Ph
CO2Pr i
CO2CH3
Yield: 74 %
1
13
CH), 135.6 (s, Cqarom), 169.2 (s, CON), 172.1 (s, COO), 173.1 (s, COO).
473
4. Eperimental part
___________________________________________________________________________
threo
(2S*,3S*)
2-Hydroxy-3-methyl-2-phenyl-3-propionylamino-succinic acid 1-tert-
butyl ester-4-methyl ester (threo-74f) (sbo-450c)
HO
CO2But
Ph
EtOCHN
CO2CH3
a colorless oil.
Yield: 79 %
1
13
δ ppm = 10.1 (q, CH3 ), 21.6 (t, CH2 ), 21.7 (q, CH3 ), 27.9 (q, 3CH3 ), 52.8 (q, OCH3 ),
82.0 (s, C-2), 83.8 (s, Cq), 92.3 (s, C-3), 126.3 (d, CHarom), 129.2 (d, CHarom), 134.7
Anal: (C 19 H27 NO6 , M = 365.2 g/mol)
Calcd:
C 62.45 H 7.45 N 3.83
Found:
C 62.92 H 7.38 N 3.96
erythro (2R*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-propionylamino-succinic acid 1-tertbutyl ester-4-methyl ester (erythro-74f) (sbo-450a)
HO
EtOCHN
Ph
CO2But
CO2CH3
a colorless oil.
Yield: 82 %
474
4. Eperimental part
___________________________________________________________________________
1
δ ppm = 1.09 (t, J = 7.5 Hz, 3H, CH3 ), 1.50 (s, 3H, CH3 ), 1.55 (s, 9H, 3CH3 ), 2.19 (q,
13
δ ppm = 9.5 (q, CH3 ), 18.7 (q, CH3 ), 27.8 (q, 3CH3 ), 30.1 (t, CH2 ), 52.4 (q, OCH3 ),
Synthesis of erythro (S*,R*) & threo (S*,S*) α -isobutyrylamino-β
derivatives 75a-f:
erythro
(2R*,3S*)
2-Hydroxy-3-isobutyrylamino-2,3-dimethyl-succinic
acid
dimethyl
ester (erythro-75a) (sbo-460)
HO
Pr iOCHN
CO2CH3
CO2CH3
Yield: 82 %
1
CH3 ), 1.95 (s, 3H, CH3 ), 2.45 (septet, J = 6.8 Hz, 1H, CH), 3.64 (s, 3H, OCH3 ), 3.74
(s, 3H, OCH3 ).
13
(COO), 176.2 (s, COO).
475
4. Eperimental part
___________________________________________________________________________
threo (2S*,3S*) 2-Hydroxy-3-isobutyrylamino-2,3-dimethyl-succinic acid dimethyl ester
(threo-75a) (sbo-460a)
HO
Pr iOCHN
CO2CH3
CO2CH3
a colorless oil.
Yield: 84 %
1
CH3 ), 1.98 (s, 3H, CH3 ), 2.49 (septet, J = 6.8 Hz, 1H, CH), 3.67 (s, 3H, OCH3 ), 3.74
(s, 3H, OCH3 ).
13
(COO), 175.2 (s, COO).
threo
(2S*,3S*)
2-tert-Butyl-2-hydroxy-3-isobutyrylamino-3-methyl-succinic
acid
dimethyl ester (threo-75b) (sbo-461)
HO
Pr iOCHN
CO2CH3
CO2CH3
a colorless oil.
Yield: 86 %
1
476
4. Eperimental part
___________________________________________________________________________
3.74 (s, 3H, OCH3 ).
13
CON), 171.1 (COO), 176.2 (s, COO).
erythro
(2R*,3S*)
2-tert-Butyl-2-hydroxy-3-isobutyrylamino-3-methyl-succinic
acid
dimethyl ester (erythro-75b) (sbo-461a)
HO
CO2 CH3
PriOCHN
CO2CH3
According to the typical hydrolysis procedure, the bicyclic oxetane endo-65b (0.21 g, 0.8
Yield: 76 %
1
3.71 (s, 3H, OCH3 ).
13
CON), 174.1 (COO), 175.2 (s, COO).
threo (2S*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-isobutyrylamino-succinic acid dimethyl
ester (threo-75c) (sbo-458c)
477
4. Eperimental part
___________________________________________________________________________
HO
Pr iOCHN
CO2CH3
Ph
CO2CH3
a colorless oil.
Yield: 82 %
1
7.28-7.47 (m, 5H, Harom).
13
HRMS: (C 17 H23 NO6 , M = 337.15 g/mol)
Calcd:
337.1474
Found:
337.1470
erythro
(2R*,3S*)
2-Hydroxy-3-methyl-2-phenyl-3-isobutyrylamino-succinic
acid
dimethyl ester (erythro-75c) (sbo-458d)
HO
PriOCHN
Ph
CO2CH3
CO2CH3
Yield: 73 %
478
4. Eperimental part
___________________________________________________________________________
1
7.32-7.54 (m, 5H, Harom).
13
threo (2S*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-isobutyrylamino-succinic acid 1-ethyl
ester-4-methyl ester (threo-75d) (sbo-459e)
CO2C2H5
Ph
HO
Pr iOCHN
CO2CH3
a colorless oil.
Yield: 79 %
1
13
erythro (2R*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-isobutyrylamino-succinic acid 1-ethyl
ester-4-methyl ester (erythro-75d) (sbo-459a)
479
4. Eperimental part
___________________________________________________________________________
Ph
CO2C2H5
HO
Pr iOCHN
CO2CH3
Yield: 82 %
1
13
threo
(2S*,3S*)
acid
1-
isopropyl ester-4-methyl ester (threo-75e) (sbo-456c)
CO2Pr i
Ph
HO
Pr iOCHN
CO2CH3
a colorless oil.
Yield: 78 %
IR: (Film)
ν~ (cm-1 ) = 3525, 3370, 2983, 2890, 1756, 1730, 1645, 1605, 1550, 1440, 1075,
980, 770.
480
4. Eperimental part
___________________________________________________________________________
1
5H, Harom).
13
(s, COO).
erythro
(2R*,3S*)
acid
1-
isopropyl ester-4-methyl ester (erythro-75e) (sbo-456a)
Ph
CO2Pr i
HO
Pr iOCHN
CO2CH3
Yield: 84 %
1
5H, Harom).
13
481
4. Eperimental part
___________________________________________________________________________
(s, COO).
Anal: (C 19 H27 N O6 , M = 365.2 g/mol)
Calcd:
C 62.45 H 7.45 N 3.83
Found:
C 62.10 H 7.52 N 4.00
threo (2S*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-isobutyrylamino-succinic acid 1-tertbutyl ester-4-methyl ester (threo-75f) (sbo-453c)
CO2But
Ph
HO
Pr iOCHN
CO2CH3
a colorless oil.
Yield: 78 %
1
3CH3 ), 1.72 (s, 3H, CH3 ), 2.18 (septet, J=6.2 Hz, 1H, CH), 3.00 (s, 3H, OCH3 ),
7.28-7.54 (m, 5H, Harom).
13
51.8 (q, OCH3 ), 82.1 (s, Cq), 83.7 (s, C-2), 91.9 (s, C-3), 126.3 (d, CHarom), 129.2 (d,
erythro (2R*,3S*) 2-Hydroxy-3-methyl-2-phenyl-3-isobutyrylamino-succinic acid 1-tertbutyl ester-4-methyl ester (erythro-75f) (sbo-453a)
HO
Pr iOCHN
Ph
CO2But
CO2CH3
482
4. Eperimental part
___________________________________________________________________________
a colorless oil.
Yield: 90 %
1
δ ppm = 0.97 (d, J = 6.2 Hz, 6H, 2CH3 ), 1.50 (s, 3H, CH3 ), 1.52 (s, 9H, 3CH3 ), 2.32
(septet, J = 6.2 Hz, 1H, CH), 3.66 (s, 3H, OCH3 ), 7.28-7.60 (m, 5H, Harom).
13
δ ppm = 18.5 (q, CH3 ), 19.2 (q, 2CH3 ), 27.8 (q, 3CH3 ), 36.0 (d, CH), 52.5 (q, OCH3 ),
Anal: (C 20 H29 NO6 , M = 379.45 g/mol)
Calcd:
C 63.31 H 7.70 N 3.69
Found:
C 63.51 H 7.65 N 4.05
Synthesis of erythro (S*,R*) & threo (S*,S*) α -(2,2-dimethyl-propionylamino)-β
β -hydroxy
succinic acid derivatives 76a-f:
erythro
(2S*,3R*)
2-(2,2-Dimethyl-propionylamino)-3-hydroxy-2,3-dimethyl-succinic
acid dimethyl ester (erythro-76a) (sbo-436b)
HO
CO2 CH3
But OCHN
CO2CH3
a colorless oil.
Yield: 81 %
1
483
4. Eperimental part
___________________________________________________________________________
δ ppm = 1.36 (s, 9H, 3CH3 ),1.43 (s, 3H, CH3 ), 1.49 (s, 3H, CH3 ), 2.12 (s, 3H, CH3 ),
3.54 (s, 3H, OCH3 ), 3.67 (s, 3H, OCH3 ).
13
threo
(2S*,3S*) 2-(2,2-Dimethyl-propionylamino)-3-hydroxy-2,3-dimethyl-succinic acid
dimethyl ester (threo-76a) (sbo-436)
HO
CO2CH3
But OCHN
CO2CH3
Yield: 83 %
1
δ ppm = 1.33 (s, 9H, 3CH3 ), 1.44 (s, 3H, CH3 ), 1.53 (s, 3H, CH3 ), 2.23 (s, 3H, CH3 ),
3.65 (s, 3H, OCH3 ), 3.76 (s, 3H, OCH3 ).
13
erythro
(2R*,3S*)
2-tert-Butyl-3-(2,2-dimethyl-propionylamino)-2-hydroxy-3-methyl-
succinic acid dimethyl ester (erythro-76b) (sbo-484a)
HO
CO2CH3
But OCHN
CO2CH3
484
4. Eperimental part
___________________________________________________________________________
According to the typical hydrolysis procedure, the bicyclic oxetane endo-66b (0.25 g, 0.8
Yield: 87 %
1
δ ppm = 1.36 (s, 9H, 3CH3 ),1.43 (s, 9H, 3CH3 ), 1.56 (s, 3H, CH3 ), 3.54 (s, 3H,
OCH3 ), 3.67 (s, 3H, OCH3 ).
13
COO).
threo
(2S*,3S*)
2-tert-Butyl-3-(2,2-dimethyl-propionylamino)-2-hydroxy-3-methyl-
succinic acid dimethyl ester (threo-76b) (sbo-484b)
HO
CO2CH3
But OCHN
CO2CH3
a colorless oil.
Yield: 85 %
1
OCH3 ), 3.76 (s, 3H, OCH3 ).
13
485
4. Eperimental part
___________________________________________________________________________
COO).
threo
(2S*,3S*)
2-(2,2-Dimethylpropionylamino)-3-hydroxy-2-methyl-3-phenyl-succinic
acid dimethyl ester (threo-76c) (sbo-432a)
HO
But OCHN
CO2CH3
Ph
CO2CH3
a colorless oil.
Yield: 82 %
1
OCH3 ), 7.28-7.48 (m, 5H, Harom).
13
δ ppm = 18.1 (q, CH3 ), 27.9 (q, CH3 ), 38.1 (s, Cq), 52.1 (q, OCH3 ), 53.2 (q, OCH3 ),
169.1 (s, CON), 170.1 (s, COO), 171.3 (s, COO).
HRMS: (C 18 H25 NO6 , M = 351.17 g/mol)
erythro
Calcd:
351.1689
Found:
351.1683
(2S*,3R*)
2-(2,2-Dimethylpropionylamino)-3-hydroxy-2-methyl-3-phenyl-
succinic acid dimethyl ester (erythro-76c) (sbo-432b)
HO
Ph
CO2CH3
But OCHN
CO2CH3
486
4. Eperimental part
___________________________________________________________________________
Yield: 87 %
1
OCH3 ), 7.32-7.54 (m, 5H, Harom).
13
169.2 (s, CON), 172.1 (s, COO), 173.1 (s, COO).
threo
(2S*,3S*)
acid 4-ethyl ester-1-methyl ester (threo-76d) (sbo-451e)
HO
ButOCHN
CO2 C2 H5
Ph
CO2 CH3
a colorless oil.
Yield: 89 %
1
δ ppm = 1.25 (t, J = 7.5 Hz, 3H, CH3 ), 1.38 (s, 9H, 3CH3 ), 1.67 (s, 3H, CH3 ), 3.00 (s,
13
487
4. Eperimental part
___________________________________________________________________________
erythro
(2S*,3R*)
2(2,2-Dimethylpropionylamino)-3-hydroxy-2-methyl-3-phenyl-
succinic acid 4-ethyl ester-1-methyl ester (erythro-76d) (sbo-451b)
Ph
CO2C2H5
HO
ButOCHN
CO2CH3
Yield: 84 %
IR: (Film)
ν~ (cm-1 ) = 3530, 3420, 2993, 2898, 1755, 1724, 1675, 1600, 1558, 1440, 1078,
980, 770.
1
δ ppm = 1.11 (s, 9H, 3CH3 ), 1.32 (t, J = 7.5 Hz, 3H, CH3 ), 1.55 (s, 3H, CH3 ), 3.70 (s,
13
134.6 (s, Cq), 172.1 (s, CON), 172.7 (s, COO), 178.5 (s, COO).
Anal: (C 19 H27 NO6 , M = 365.42 g/mol)
threo
Calcd:
C 62.45 H 7.45 N 3.83
Found:
C 62.67 H 7.27 N 3.91
(2S*,3S*)
acid 4-isopropyl ester-1-methyl ester (threo-76e) (sbo-457d)
HO
CO2Pr i
Ph
ButOCHN
488
CO2CH3
4. Eperimental part
___________________________________________________________________________
a colorless oil.
Yield: 84 %
1
3CH3 ), 1.69 (s, 3H, CH3 ), 3.00 (s, 3H, OCH3 ), 5.03 (septet, J = 6.3 Hz, 1H, OCH),
7.26-7.55 (m, 5H, Harom).
13
erythro
(2S*,3R*)
succinic acid 4-isopropyl ester-1-methyl ester (erythro-76e) (sbo-457b)
Ph
CO2Pr i
HO
But OCHN
CO2 CH3
Yield: 88 %
1
CH3 ), 1.36 (s, 9H, 3CH3 ), 3.76 (s, 3H, OCH3 ), 5.00 (septet, J = 6.2 Hz, 1H, OCH),
7.28-7.59 (m, 5H, Harom).
13
489
4. Eperimental part
___________________________________________________________________________
CHarom), 134.7 (s, Cq), 169.1 (s, CON), 171.2 (s, COO), 176.2 (s, COO).
threo
(2S*,3S*)
acid 4-tert-butyl ester-1-methyl ester (threo-76f) (sbo-444d)
CO2But
Ph
HO
ButOCHN
CO2CH3
a colorless oil.
Yield: 70 %
1
OCH3 ), 7.28-7.54 (m, 5H, Harom).
13
erythro
(2S*,3R*)
succinic acid 4-tert-butyl ester-1-methyl ester (erythro-76f) (sbo-444c)
HO
ButOCHN
Ph
CO2But
CO2CH3
a colorless oil.
490
4. Eperimental part
___________________________________________________________________________
Yield: 69 %
IR: (Film)
ν~ (cm-1 ) = 3510, 3450, 2989, 2897, 1740, 1735, 1670, 1600, 1550, 1440, 1075,
980, 770.
1
δ ppm = 0.96 (s, 3H, CH3 ), 1.38 (s, 9H, 3CH3 ), 1.39 (s, 9H, 3CH3 ), 3.78 (s, 3H,
OCH3 ), 7.31-7.58 (m, 5H, Harom).
13
HRMS: (C 21 H31 NO6 , M = 399.22 g/mol)
Calcd:
399.2175
Found:
399.2171
491
___________________________________________________________________________
4.21 Synthesis of starting materials
4.21.1 Preparation of benzaldehyde -1-d (77)138 (sbo-461d)
O
D
To a stirred solution of benzil (13.9 g, 66.1 mmol) in p-dioxane (30 mL) was added deuterium
oxide (14.4 g, 0.719 mol) and then potassium cyanide (4.68 g, 71.9 mmol) in five portions
over 0.5 h. The mixture was stirred for another 0.5 h and then diluted with water (120 mL).
The mixture was extracted with ether (3 x 50 mL) and the ether solution washed with
saturated sodium bicarbonate (2 x 50 mL) and saturated sodium chloride (2 x 50 mL). After
evaporation of the dried (MgSO4 ) ether solution, distillation gave pure 4.32 g of the product
as a pale yellow oil.
Yield: 61 %
B.p: 74-76 °C, 22 mmHg (Lit.138 , 76-78 °C, 22 mmHg).
1
δ ppm = 7.45-7.51 (m, 2H, Harom), 7.55-7.61 (m, 1H, Harom), 7.81-7.85 (m, 1H, Harom).
13
δ ppm = 126.5 (d, CHarom), 128.9 (d, CHarom), 129.6 (d, CHarom), 136.2 (s, Cqarom),
192.0 (t, COD).
Preparation of nitropropane-1,1-d2 (78)139 (sbo-589)
D
D
NO2
A mixture of nitropropane (50 mL) and deuterium oxide (50 mL) containing 3 drops of NaOD
(40 wt. % solution in D2 O) was refluxed for two days. Then the layer of deuterated
nitropropane was separated and distilled off. The yield of colorless liquid was 26 mL. The
product was 85 % deuterated by 1 H-NMR analysis.
1
δ ppm = 0.88 (t, J = 7.5 Hz, 3H, CH3 ), 1.89 (q, J = 7.5 Hz, 2H, CH2 ).
492
___________________________________________________________________________
13
δ ppm = 10.7 (q, CH3 ), 20.9 (t, CH2 ), 76.4 (t, CD2 ).
4.21.2 Preparation of propanal-1-d (79)139 (sbo-589a)
O
D
Nitropropane-1,1-d2 (26 mL) was dissolved in 290 mL of ice-cold aqueous 15 % sodium
hydroxide in a separatory funnel. The solution was added slowly dropwise to a beaker
containing 53.2 mL of conc. sulfuric acid dissolved in 355 mL water. The sulfuric acid
solution was cooled in an ice-bath and stirred continuously while the solution of nitropropane1,1-d2 was added. After the addition was completed, the reaction was stirred an additional 30
min. The product, propanal-1-d (96 % D) was purified by distillation to give 2.5 g as a
colorless liquid.
Yield: 35 %
B.p: 43-45°C.
1
δ ppm = 0.87 (t, J = 7.5 Hz, 3H, CH3 ), 2.25 (q, J = 7.5 Hz, 2H, CH2 ).
13
δ ppm = 6.0 (q, CH3 ), 37.0 (t, CH2 ), 202.8 (t, COD).
4.21.3 Preparation of 5-deuterio-2,3-dihydrofuran (80)140 (sbo-566c)
O
D
To a stirred solution of a freshly distilled 2,3-dihydrofuran (0.9 g, 13 mmol) and TMEDA (0.3
g, 25 mmol) was added rapidly a solution of 1.6 M butyllithium (6.0 mL, 13 mmol) until the
precipitation of a solid began. The reaction mixture was cooled with an ice-bath and then the
addition of butyllithium was completed. The resulting solid was washed with hexane (3 x 4
mL) and then suspended in 1 mL of hexane. To this suspension was added 1 mL of D2 O. The
hexane layer was isolated and dried over MgSO4 and kept under N2 .
493
___________________________________________________________________________
1
δ ppm = 2.55 (dt, J = 2.5, 9.5 Hz, 2H, 3-H), 4.29 (t, J = 9.5 Hz, 2H, 2-H), 4.93 (t, J =
2.5, 1H, 4-H).
13
δ ppm = 28.4 (t, C-3), 69.5 (t, C-2), 99.2 (d, C-2), 145.6 (t, C-5).
4.21.4 Preparation of 1-trimethylsilyoxycycloalkenes (81-83); General procedure:141
Sodium iodide (9.3 g, 62 mmol) in acetonitrile (62 mL) was added dropwise (15 min), at
room temperature to a solution of the ketone (50 mmol); triethyl amine (6.26 g, 62 mmol) and
trimethylchlorosilane (6.72 g, 62 mmol) successively introduced in the reaction flask. An
exothermic reaction generally occured with concomitant formation of a white precipitation
(Et3 NH+I-), while the acetonitrile solution become brownish. The stirring was continued for 4
h. The reaction was quenched by adding cold pentane (50 mL) and then ice water (50 mL).
After decantation, the aqueous layer was extracted with pentane (2 x 50 mL) and the collected
organic layers were washed with ice water (2 x 50 mL) or with aqueous solution of NH4 Cl
until neutrality, dried over MgSO4 and evaporation under vacum gave the crude product.
Purification was carried out by Büchi distillation.
1-Trimethylsilyoxycyclopentene (81)142 (sbo-482)
OTM S
The reaction was carried out following the above general procedure using cyclopentanone
(4.2 g, 50 mmol). Distillation of the crude product under vacum afforded 5.8 g of the pure
product as a colorless liquid.
Yield: 75 %
B.p: 55-57°C, 10 torr (Lit.,142 99°C, 40 torr)
1
δ ppm = 0.17 (s, 9H, 3CH3 ), 1.77-1.87 (m, 2H, CH2 ), 2.19-2.26 (m, 4H, 2CH2 ), 4.58
(dd, J = 2.7, 1.6 Hz, 1H, CH=) .
13
494
___________________________________________________________________________
δ ppm = -0.06 (q, 3CH3 ), 21.3 (t, C-4), 28.7 (t, C-3), 33.5 (t, C-5), 102.0 (s, C-1),
154.9 (d, C-2).
1-Trimethylsilyoxycyclohexene (82)143 (sbo-481)
OTMS
The reaction was carried out following the above general procedure using cyclohexanone (4.9
g, 50 mmol). Distillation of the crude product under vacum afforded 7.0 g of the pure product
as a colorless liquid.
Yield: 82 %
B.p: 78-80°C, 10 torr (Lit.,143 60-62°C, 8 torr)
1
δ ppm = 0.14 (s, 9H, 3CH3 ), 1.45-1.49 (m, 2H, CH2 ), 1.60-1.64 (m, 2H, CH2 ), 1.931.99 (m, 4H, 2CH2 ), 4.82 (dd, J = 1.3, 1.3 Hz, 1H, CH=) .
13
δ ppm = 0.24 (q, 3CH3 ), 22.3 (t, CH2 ), 23.1 (t, CH2 ), 23.8 (t, CH2 ), 29.9 (t, CH2 ),
104.1 (s, C-2), 150.3 (d, C-2).
1-Trimethylsilyoxycyclopentene (83)144 (sbo-497)
OTMS
The reaction was carried out following the above general procedure using cycloheptanone
(5.6 g, 50 mmol). Distillation of the crude product under vacum afforded 7.8 g of the pure
product as a colorless liquid.
Yield: 85 %
B.p: 78-81°C, 10 torr (Lit.,144 73-74°C, 8 torr).
1
495
___________________________________________________________________________
δ ppm = 0.13 (s, 9H, 3CH3 ), 1.48-1.65 (m, 8H, 4CH2 ), 1.92-1.98 (m, 2H, CH2 ), 2.172.22 (m, 2H, CH2 ), 4.98 (t, J = 6.6 Hz, 1H, CH=) .
13
δ ppm = 0.13 (q, 3CH3 ), 25.2 (t, CH2 ), 25.3 (t, CH2 ), 27.8 (t, CH2 ), 31.5 (t, CH2 ),
35.5 (t, CH2 ), 108.6 (s, C-1), 155.9 (d, C-2).
4.22 General procedure for photolyses of benzaldehyde and benzaldehyde -1d with
cycloalkenes:
Under a nitrogen atmosphere, a solution of either benzaldehyde or benzaldehyde-1d (0.3 g, 3
mmol) and cyclic alkene (3 mmol) in 25 mL benzene was irradiated in a Rayonet photoreactor
(λ = 300 nm) for 24 h. After removal of the solvent under vacum, the crude photolysate was
subjected to 1 H-NMR analysis to determine the diastereoselectivity. Purification was carried
out by Büchi distillation.
Irradiation of benzaldehyde with 2,3-dihydrofuran (sbo-542)
A solution of benzaldehyde (0.3 g, 3 mmol) and 2,3-dihydrofuran (0.21 g, 3 mmol) in 25 mL
crude photolysate yielded 0.42 g (80 %) of inseparable mixture of oxetanes as a colorless oil.
Both 1 H-NMR and 13 C-NMR data was reported earlier (endo- & exo- 3a).
Irradiation of benzaldehyde-1-d with 2,3-dihydrofuran (sbo-464)
A solution of benzaldehyde-1d (0.3 g, 3 mmol) and 2,3-dihydrofuran (0.21 g, 3 mmol) in 25
mL benzene was irradiated for 24 h according to the above general procedure. Distillation of
the crude photolysate yielded 0.47 g (89 %) of inseparable mixture of oxetanes as a colorless
oil.
endo-7-Deuterio-7-phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-84b)
H
5 O
1 7
4
3
O
Ph
H D
IR: (Film, mixture of endo & exo)
ν~ (cm-1 ) = 3020, 2928, 1600, 1505, 1470, 1400, 1050, 835, 778.
496
___________________________________________________________________________
1
δ ppm = 1.62-1.70 (m, 2H, 4-H), 3.72-3.80 (m, 2H, 3-H), 5.00 (d, J = 3.8 Hz, 1H, 1H), 5.48 (dd, J = 4.1, 3.8 Hz, 1H, 5-H), 7.15-7.35 (m, 5H, Harom.).
13
δ ppm = 32.7 (t, C-4), 68.8 (t, C-3), 79.4 (d, C-1), 84.6 (d, C-5), 85.1 (t, C-7), 124.4
(d, CHarom.), 127.0 (d, CHarom.), 127.8 (d, CHarom.), 137.1 (s, Cqarom.).
GC-MS: (EI, 70 eV, endo & exo)
m/z (%) = 177 (M+, 15), 121 (20), 105 (20), 92 (50), 77 (10), 70 (100), 65 (4), 51
(10).
exo-7-Deuterio-7-phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-84b)
H
O
Ph
O
1
H D
δ ppm = 2.08-2.15 (m, 2H, 4-H), 3.97 (t, J = 8.4 Hz, 2H, 3-H), 4.57 (d, J = 4.3 Hz,
1H, 1-H), 5.44 (dd, J = 4.3, 4.4 Hz, 1H, 5-H), 7.20-7.50 (m, 5H, Harom.).
13
δ ppm = 32.1 (t, C-4), 67.3 (t, C-3), 82.9 (d, C-1), 84.7 (d, C-5), 85.8 (d, C-7), 125.2
Irradiation of benzaldehyde with 5-deuterio-2,3-dihydrofuran (sbo-567)
A solution of benzaldehyde (0.3 g, 3 mmol) and 5-deuterio-2,3-dihydrofuran (0.21 g, 3 mmol)
in 25 mL benzene was irradiated for 24 h according to the above general procedure.
Distillation of the crude photolysate yielded 0.51 g (94 %) of inseparable mixture of oxetanes
as a colorless oil.
endo-1-Deuterio-7-phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-84c)
H
O
Ph
O
D
497
___________________________________________________________________________
1
δ ppm = 1.48-1.75 (m, 2H, 4-H), 3.55-3.86 (t, J = 6.5 Hz, 2H, 3-H), 5.49 (d, J = 4.3
Hz, 1H, 5-H), 5.77 (s,1H, 7-H), 7.26-7.35 (m, 5H, Harom.).
13
δ ppm = 32.7 (t, C-4), 68.8 (t, C-3), 78.9 (t, C-1), 84.9 (d, C-5), 85.0 (d, C-7), 124.5
m/z (%) = 177 (M+, 10), 121 (17), 105 (14), 91 (30), 77 (10), 71 (100), 65 (4), 51
(10).
exo-1-Deuterio-7-phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-84c)
H
O
Ph
O
1
D
δ ppm = 1.78-2.12 (m, 2H, 4-H), 3.94 (t, J = 7.8 Hz, 2H, 3-H), 5.37 (s, 1H, 7-H), 5.44
(d, J = 4.4 Hz, 1H, 5-H), 7.26-7.42 (m, 5H, Harom).
13
δ ppm = 32.1 (t, C-4), 67.2 (t, C-3), 79.5 (t, C-1), 85.1 (d, C-5), 85.2 (d, C-7), 126.2
HRMS: (C 11 H11 DO2 , M = 177.1 g/mol)
Calcd:
177.0918
Found:
177.0913
Irradiation of benzaldehyde-1-d with 5-deuterio-2,3-dihydrofuran (sbo-568)
A solution of benzaldehyde-1-d (0.3 g, 3 mmol) and 5-deuterio-2,3-dihydrofuran (0.21 g, 3
as a colorless oil.
endo-1,7-Dideuterio-7-phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-84d)
498
___________________________________________________________________________
H
O
Ph
O
1
D D
1H, 5-H), 7.28-7.39 (m, 5H, Harom.).
13
δ ppm = 32.7 (t, C-4), 68.7 (t, C-3), 78.9 (t, C-1), 84.9 (d, C-5), 85.6 (t, C-7), 124.4 (d,
m/z (%) = 178 (M+, 10), 122 (20), 105 (21), 92 (20), 77 (10), 71 (100), 65 (4), 51
(12).
exo-1,7-Dideuterio-7-phenyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-84d)
H
O
Ph
O
1
D D
1H, 5-H), 7.26-7.38 (m, 5H, Harom.).
13
δ ppm = 31.3 (t, C-4), 67.3 (t, C-3), 79.0 (t, C-1), 85.2 (d, C-5), 87.1 (t, C-7), 124.4 (d,
HRMS: (C 11 H10 D2 O2 , M = 178.1 g/mol)
Calcd:
178.1348
Found:
178.1343
Irradiation of benzaldehyde with 5-methyl-2,3-dihydrofuran (sbo-474a)
A solution of benzaldehyde (0.3 g, 3 mmol) and 5-methyl-2,3-dihydrofuran (0.25 g, 3 mmol)
in 25 mL benzene was irradiated for 24 h according to the above general procedure.
499
___________________________________________________________________________
as a colorless oil. Both 1 H-NMR and 13 C-NMR data was reported earlier.
Irradiation of benzaldehyde-1-d with 5-methyl-2,3-dihydrofuran (sbo-474)
A solution of benzaldehyde-1-d (0.3 g, 3 mmol) and 5-methyl-2,3-dihydrofuran (0.25 g, 3
as a colorless oil.
endo-7-Deuterio-7-phenyl-1-methyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-84f)
H
O
Ph
O
1
D
δ ppm = 1.60 (s, 3H, CH3 ), 1.69-2.14 (m, 2H, 4-H), 3.71-3.82 (m, 2H, 3-H), 5.17 (d, J
= 4.0 Hz, 1H, 5-H), 7.23-7.39 (m, 5H, Harom.).
13
δ ppm = 21.7 (q, CH3 ), 33.8 (t, C-4), 68.9 (t, C-3), 75.1 (s, C-1), 89.0 (d, C-5), 91.1 (t,
m/z (%) = 191 (M+, 10), 135 (155), 105 (30), 92 (12), 84 (100), 77 (30), 69 (10), 63
(4), 52 (12).
exo-7-Deuterio-7-phenyl-1-methyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-84f)
H
O
Ph
O
1
D
δ ppm = 1.00 (s, 3H, CH3 ), 1.82-2.28 (m, 2H, 4-H), 4.21-4.38 (m, 2H, 3-H), 5.06 (d, J
= 4.1 Hz, 1H, 5-H), 7.20-7.35 (m, 5H, Harom.).
13
500
___________________________________________________________________________
δ ppm = 17.5 (q, CH3 ), 33.7 (t, C-4), 67.8 (t, C-3), 79.1 (s, C-1), 89.2 (d, C-5), 90.7 (t,
Irradiation of benzaldehyde with cyclopentene (sbo-474a)
A solution of benzaldehyde (0.3 g, 3 mmol) and cyclopentene (0.2 g, 3 mmol) in 25 mL
Both 1 H-NMR and 13 C-NMR data was reported earlier in literature.37
Irradiation of benzaldehyde-1-d with cyclopentene (sbo-474)
A solution of benzaldehyde-1d (0.3 g, 3 mmol) and cyclopentene (0.2 g, 3 mmol) in 25 mL
endo-7-Deuterio-7-phenyl-6-oxa-bicyclo[3.2.0]heptane (endo-84h)
H
O
Ph
H D
1
δ ppm = 1.25-2.38 (m, 6H), 3.31 (dd, J = 7.2 Hz, 5.6 Hz, 1H, 1-H), 5.39 (dd, J = 5.6,
3.4 Hz, 1H, 5-H), 7.20-7.50 (m, 5H, Harom.).
13
δ ppm = 24.7 (t), 25.1 (t), 34.6 (t), 42.8 (d, C-1), 83.7 (d, C-5), 85.4 (t, C-6), 124.4 (d,
exo-7-Deuterio-7-phenyl-6-oxa-bicyclo[3.2.0]heptane (exo-84h)
H
O
Ph
H D
1
501
___________________________________________________________________________
δ ppm = 1.25-2.40 (m, 6H), 2.98 (dd, J = 6.2, 6.2 Hz, 1H, 1-H), 5.30 (dd, J = 4.0, 6.2
Hz, 1H, 5-H), 7.25-7.48 (m, 5H, Harom.).
13
δ ppm = 23.8 (t), 30.3 (t), 34.1 (t), 46.8 (d, C-1), 83.6 (d, C-5), 85.3 (t, C-6), 125.6 (d,
Irradiation of benzaldehyde with cyclohexene (sbo-472a)
A solution of benzaldehyde (0.3 g, 3 mmol) and cyclohexene (0.25 g, 3 mmol) in 25 mL
Both 1 H-NMR and 13 C-NMR data was reported earlier in literature.37
Irradiation of benzaldehyde-1-d with cyclohexene (sbo-472)
A solution of benzaldehyde-1-d (0.3 g, 3 mmol) and cyclohexene (0.25 g, 3 mmol) in 25 mL
endo-8-Deuterio-8-phenyl-7-oxa-bicyclo[4.2.0]octane (endo-84j)
H
O
H
1
D
Ph
δ ppm = 0.92-1.49 (m, 8H), 2.99 (m, 2H, 1-H), 5.00 (m, 1H, 6-H), 7.22-7.48 (m, 5H,
Harom.).
13
δ ppm = 19.9 (t), 21.1 (t), 28.7 (t), 37.0 (d, C-7), 75.6 (d, C-6), 81.0 (t, C-8), 125.0 (d,
m/z (%) = 189 (M+, 5), 178 (10), 120 (15), 108 (27), 105 (100), 91 (15), 80 (30), 77
(60), 50 (27).
502
___________________________________________________________________________
exo-8-Deuterio-8-phenyl-7-oxa-bicyclo[4.2.0]octane (exo-84j)
H
O
H
1
D
Ph
δ ppm = 0.92-1.49 (m, 8H), 2.92 (m, 1H, 1-H), 4.95 (m, 1H, 6-H), 7.22-7.48 (m, 5H,
Harom.).
13
δ ppm = 19.8 (t), 20.9 (t), 29.0 (t), 40.3 (d, C-1), 76.7 (d, C-6), 85.6 (t, C-8), 126.6 (d,
Irradiation of benzaldehyde with 1-methylcyclohexene (sbo-473a)
A solution of benzaldehyde (0.3 g, 3 mmol) and 1-methylcyclohexene (0.29 g, 3 mmol) in 25
mL benzene was irradiated for 24 h according to the above general procedure. Distillation of
the crude photolysate yielded 0.54 g (89 %) of inseparable mixture of oxetanes as a colorless
oil. Both 1 H-NMR and 13 C-NMR data was reported earlier in literature.37
Irradiation of benzaldehyde-1-d with 1-methylcyclohexene (sbo-473)
A solution of benzaldehyde-1-d (0.3 g, 3 mmol) and 1-methylcyclohexene (0.29 g, 3 mmol) in
25 mL benzene was irradiated for 24 h according to the above general procedure. Distillation
of the crude photolysate yielded 0.53 g (87 %) of inseparable mixture of oxetanes as a
colorless oil.
endo-8-Deuterio-8-phenyl-1-methyl-7-oxa-bicyclo[4.2.0]octane (endo-84l)
H
O
Ph
D
1
δ ppm = 1.60 (s, 3H, CH3 ), 0.93-2.05 (m, 8H), 4.61 (m, 1H, 6-H), 7.18-7.48 (m, 5H,
Harom.).
503
___________________________________________________________________________
13
δ ppm = 19.5 (t), 20.2 (t), 21.0 (q), 28.3 (t), 35.0 (t), 42.0 (s, C-1), 84.1 (d, C-6), 88.6
(t, C-7), 124.8 (d, CHarom.), 126.8 (d, CHarom.), 128.1 (d, CHarom.), 139.7 (s, Cqarom.).
m/z (%) = 203 (M+, 5), 202 (M+-1, 9), 181 (21), 166 (30), 109 (53), 108 (75), 105
(24), 90 (11), 80 (100), 50 (20).
exo-8-Deuterio-8-phenyl-1-methyl-7-oxa-bicyclo[4.2.0]octane (exo-84l)
H
O
D
1
Ph
δ ppm = 0.68 (s, 3H, CH3 ), 0.93-2.05 (m, 8H), 4.55 (m, 1H, 6-H), 7.18-7.48 (m, 5H,
Harom.).
13
δ ppm = 19.7 (t), 20.2 (t), 23.9 (t), 27.8 (q, CH3 ), 28.9 (t), 42.4 (s, C-1), 81.5 (d, C-6),
87.3 (t, C-8), 126.5 (d, CHarom.), 128.5 (d, CHarom.), 129.3 (d, CHarom.), 140.5 (s,
Cqarom.).
Irradiation of benzaldehyde with 1-trimethylsilyoxycyclopentene (sbo-493)
A solution of benzaldehyde (0.3 g, 3 mmol) and 1-trimethylsilyoxycyclopentene (0.47 g, 3
as a colorless oil.
endo-7-Phenyl-1-trimethylsilyoxy-6-oxa-bicyclo[3.2.0]heptane (endo-84m)
H
O
Ph
OTMS
1
504
___________________________________________________________________________
δ ppm = 0.15 (s, 9H, 3CH3 ), 1.25-2.38 (m, 6H), 5.18 (d, J = 3.5 Hz, 1H, 5-H), 5.92 (s,
1H, 7-H), 7.20-7.45 (m, 5H, Harom.).
13
δ ppm = 1.2 (q, 3CH3 ), 24.7 (t), 24.9 (t), 34.3 (t), 81.0 (d, C-5), 85.4 (s, C-1), 98.1 (d,
exo-7-Phenyl-1-trimethylsilyoxy-6-oxa-bicyclo[3.2.0]heptane (exo-84m)
H
O
Ph
OTMS
1
δ ppm = - 0.12 (s, 9H, 3CH3 ), 1.25-2.42 (m, 6H), 5.05 (s, 1H, 7-H), 5.15 (d, J = 2.6
Hz, 1H, 7.20-7.45 (m, 5H, Harom.).
13
δ ppm = 1.3 (q, 3CH3 ), 24.1 (t), 30.6 (t), 34.8 (t), 85.6 (d, C-5), 86.3 (d, C-1), 90.1 (t,
C-7), 126.4(d, CHarom.), 127.3 (d, CHarom.), 129.2 (d, CHarom.), 134.2 (s, Cqarom.).
Irradiation of benzaldehyde-1-d with 1-trimethylsilyoxycyclopentene (sbo-494)
A solution of benzaldehyde-1-d (0.3 g, 3 mmol) and 1-trimethylsilyoxycyclopentene (0.47 g,
3 mmol) in 25 mL benzene was irradiated for 24 h according to the above general procedure.
as a colorless oil.
endo-7-Deuterio-7-phenyl-1-trimethylsilyloxy-6-oxa-bicyclo[3.2.0]heptane (endo-84n)
H
O
Ph
D
OTMS
1
δ ppm = 0.17 (s, 9H, 3CH3 ), 1.26-2.43 (m, 6H), 5.14 (d, J = 3.4 Hz, 1H, 5-H), 7.257.45 (m, 5H, Harom.).
13
505
___________________________________________________________________________
δ ppm = 1.6 (q, 3CH3 ), 21.2 (t), 23.3 (t), 28.6 (t), 84.4 (d, C-5), 90.5 (s, C-1), 101.2 (t,
C-7), 125.41(d, CHarom.), 126.8 (d, CHarom.), 129.1 (d, CHarom.), 139.3 (s, Cqarom.).
exo-7-Deuterio-7-phenyl-1-trimethylsilyoxy-6-oxa-bicyclo[3.2.0]he ptane (exo-84n)
H
O
Ph
D
OT MS
1
δ ppm = - 0.13 (s, 9H, 3CH3 ), 1.26-2.43 (m, 6H), 5.18 (d, J = 2.5 Hz, 1H, 5-H), 7.257.48 (m, 5H, Harom.).
13
δ ppm = 1.2 (q, 3CH3 ), 23.9 (t), 32.3 (t), 38.2 (t), 85.8 (d, C-5), 92.4 (s, C-1), 102.3 (t,
Irradiation of benzaldehyde with 1-trimethylsilyoxycyclohexene (sbo-495)
A solution of benzaldehyde (0.3 g, 3 mmol) and 1-trimethylsilyoxycyclohexene (0.51 g, 3
as a colorless oil.
endo-8-Phenyl-1-trimethylsilyoxy-7-oxa-bicyclo[4.2.0]octane (endo-84o)
H
O
OTMS
1
Ph
δ ppm = 0.17 (s, 9H, 3CH3 ), 0.92-1.99 (m, 8H), 5.00 (m, 1H, 6-H), 5.93 (s, 1H, 8-H),
7.23-7.48 (m, 5H, Harom.).
13
δ ppm = 0.14 (q, 3CH3 ), 20.1 (t), 21.2 (t), 24.2 (t), 30.1 (t), 74.4 (d, C-6), 86.1 (s, C1), 90.6 (s, C-8), 125.0 (d, CHarom.), 126.8 (d, CHarom.), 128.1 (d, CHarom.), 135.1 (s,
Cqarom.).
506
___________________________________________________________________________
exo-8-Phenyl-1-trimethylsilyoxy-7-oxa-bicyclo[4.2.0]octane (exo-84o)
H
O
OTMS
1
Ph
δ ppm = -0.12 (s, 9H, 3CH3 ), 0.90-1.99 (m, 8H), 5.10 (m, 1H, 6-H), 5.85 (s, 1H, 8H),
7.23-7.49 (m, 5H, Harom.).
13
δ ppm = 0.21 (q, 3CH3 ), 19.2 (t), 23.8 (t), 29.7 (t), 83.7 (d, C-6), 85.7 (d, C-8), 90.6 (s,
Irradiation of benzaldehyde-1d with 1-trimethylsilyoxycyclohexene (sbo-496)
A solution of benzaldehyde-1d (0.3 g, 3 mmol) and 1-trimethylsilyoxycyclohexene (0.51 g, 3
as a colorless oil.
endo-8-Deuterio-8-phenyl-1-trimethylsilyoxy-7-oxa-bicyclo[4.2.0]octane (endo-84p)
H
O
OTMS
1
Ph
D
δ ppm = 0.14 (s, 9H, 3CH3 ), 0.93-1.99 (m, 8H), 4.93 (m, 1H, 6-H), 7.19-7.38 (m, 5H,
Harom.).
13
δ ppm = 0.13 (q, 3CH3 ), 19.1 (t), 22.2 (t), 29.7 (t), 35.1(t), 74.4 (d, C-6), 86.9 (s, C-1),
104.1 (t, C-8), 124.8 (d, CHarom.), 126.8 (d, CHarom.), 128.1 (d, CHarom.), 139.7 (s,
Cqarom.).
exo-8-Deuterio-8-phenyl-1-trimethylsilyoxy-7-oxa-bicyclo[4.2.0]octane (exo-84p)
507
___________________________________________________________________________
H
O
OT MS
1
Ph
D
δ ppm = -0.17 (s, 9H, 3CH3 ), 0.92-1.99 (m, 8H), 4.98 (m, 1H, 6-H), 7.19-7.38 (m, 5H,
Harom.).
13
δ ppm = 0.20 (q, 3CH3 ), 21.2 (t), 23.9 (t), 26.0 (t), 29.7 (t), 76.9 (d, C-6), 83.9 (t, C-7),
107.8 (s, C-1), 126.6 (d, CHarom.), 127.8 (d, CHarom.), 129.3 (d, CHarom.), 134.6 (s,
Cqarom.).
Irradiation of benzaldehyde with 1-trimethylsilyoxycycloheptene (sbo-503)
A solution of benzaldehyde (0.3 g, 3 mmol) and 1-trimethylsilyoxycycloheptene (0.55 g, 3
as a colorless oil.
endo-9-Phenyl-1-trimethylsilyoxy-8-oxa-bicyclo[5.2.0]nonane (endo-84q)
H
O
OTMS
1
Ph
δ ppm = 0.13 (s, 9H, 3CH3 ), 1.12-2.44 (m, 10H), 4.75 (t, J = 8.4 Hz, 1H, 7-H), 5.22
(s, 1H, 9-H), 7.18-7.36 (m, 5H, Harom.).
13
δ ppm = 0.14 (q, 3CH3 ), 24.6 (t), 25.0 (t), 27.1 (t), 41.7 (t), 83.8 (d, C-7), 91.1 (d, C9), 93.4 (d, C-9), 125.0 (d, CHarom.), 126.8 (d, CHarom.), 128.1 (d, CHarom.), 134.6 (s,
Cqarom.).
exo-9-Phenyl-1-trimethylsilyoxy-8-oxa-bicyclo[5.2.0]nonane (exo-84p)
508
___________________________________________________________________________
H
O
OTMS
1
Ph
δ ppm = -0.26 (s, 9H, 3CH3 ), 1.12-2.45 (m, 10H), 4.80 (t, J = 8.2 Hz, 1H, 7-H), 5.07
(s, 1H, 9-H), 7.18-7.36 (m, 5H, Harom.).
13
δ ppm = 0.21 (q, 3 CH3 ), 23.7 (t), 25.7 (t), 28.1 (t), 42.1 (t), 81.6 (d, C-7), 90.3 (s, C1), 92.4 (d, C-9), 126.6 (d, CHarom.), 127.8 (d, CHarom.), 129.3 (d, CHarom.), 134.1 (s,
Cqarom.).
Irradiation of benzaldehyde-1d with 1-trimethylsilyoxycycloheptene (sbo-504)
A solution of benzaldehyde1-d (0.3 g, 3 mmol) and 1-trimethylsilyoxycycloheptene (0.55 g, 3
as a colorless oil.
endo-9-Deuterio-9-phenyl-1-trimethylsilyoxy-8-oxa-bicyclo[5.2.0]nonane (endo-84r)
H
O
OTMS
1
Ph
D
δ ppm = 0.19 (s, 9H, 3 CH3 ), 1.12-2.44 (m, 10H), 4.83 (t, J = 8.4 Hz, 1H, 7-H), 7.267.52 (m, 5H, Harom.).
13
δ ppm = 1.8 (q, 3 CH3 ), 24.1 (t), 25.2 (t), 26.9 (t), 30.4 (t), 41.6 (t), 81.3 (d, C-7), 90.3
(s, C-1), 93.4 (t, C-9), 124.7 (d, CHarom.), 126.8 (d, CHarom.), 128.1 (d, CHarom.),
134.7 (s, Cqarom.).
exo-9-Deuterio-9-phenyl-1-trimethylsilyoxy-8-oxa-bicyclo[5.2.0]nonane (exo-86r)
509
___________________________________________________________________________
H
O
OTMS
1
Ph
D
δ ppm = -0.18 (s, 9H, 3 CH3 ), 1.12-2.44 (m, 10H), 4.76 (t, J = 8.2 Hz, 1H, 7-H), 7.267.52 (m, 5H, Harom.).
13
δ ppm = 2.1 (q, 3CH3 ), 24.1 (t), 25.2 (t), 26.9 (t), 30.4 (t), 34.4 (t), 42.3 (t), 81.0 (d, C7), 90.7 (s, C-1), 92.3 (t, C-9), 126.6 (d, CHarom.), 127.8 (d, CHarom.), 129.3 (d,
4.23 Photolyses of propanal & propanal-1-d with 2,3-dihydrofuran & 5-deuterio-2,3dihydrofuran
Irradiation of propanal with 2,3-dihydrofuran (sbo-596)
Under a nitrogen atmosphere, a solution of propanal (0.17 g, 3 mmol) and 2,3-dihydrofuran
(0.21 g, 3 mmol) in 25 mL hexane was irradiated in a Rayonet photoreactor ( λ = 300 nm) for
24 h. Distillation of the residue after removal of the solvent afforded 0.37 g (96 %) of
inseparable mixture of oxetanes as a colorless oil. Both 1 H-NMR and
13
C-NMR data was
reported earlier (endo- & exo- 3c).
Irradiation of propanal-1-d with 2,3-dihydrofuran (sbo-596)
Under a nitrogen atmosphere, a solution of propanal-1-d (0.17 g, 3 mmol) and 2,3dihydrofuran (0.21 g, 3 mmol) in 25 mL hexane was irradiated in a Rayonet photoreactor ( λ
= 300 nm) for 24 h. Distillation of the residue after removal of the solvent afforded 0.36 g (93
%) of inseparable mixture of oxetanes as a colorless oil.
endo-7-Deuterio-7-ethyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-85)
H
O
Et
O
H D
510
___________________________________________________________________________
1
δ ppm = 0.78 (t, J = 7.5 Hz, 3H, CH3 ), 1.52 (m, 1H, 4-H), 1.54 (m, 2H, CH2 ), 1.96 (m,
1H, 4-H), 4.08-4.17 (m, 2H, 3-H), 4.64 (d, J = 3.8 Hz, 1H, 1-H), 5.22 (dd, J = 3.8,
3.8 Hz, 1H, 5-H).
13
δ ppm = 8.2 (q, CH3 ), 22.1 (t, CH2 ), 32.6 (t, C-4), 69.6 (t, C-3), 78.3 (d, C-1), 83.8 (d,
C-5), 85.7 (t, C-7).
exo-7-Deuterio-7-ethyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-85)
H
O
Et
O
1
H D
1H, 4-H), 4.08-4.16 (m, 2H, 3-H), 4.41 (d, J = 4.3 Hz, 1H, 1-H), 5.15 (dd, J = 4.3,
3.7 Hz, 1H, 5-H).
13
C-5), 87.5 (t, C-7).
HRMS: (C 7 H11 DO2 , M = 129.1 g/mol)
Calcd:
129.0947
Found:
129.0943
Irradiation of propanal with 5-deuterio-2,3-dihydrofuran (sbo-592)
Under a nitrogen atmosphere, a solution of propanal (0.17 g, 3 mmol) and 5-deuterio-2,3dihydrofuran (0.21 g, 3 mmol) in 25 mL hexane was irradiated in a Rayonet photoreactor ( λ
endo-1-Deuterio-7-ethyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-86)
511
___________________________________________________________________________
H
O
Et
O
1
D
1H, 4-H), 4.12-4.20 (m, 2H, 3-H), 4.53 (t, J = 7.5 Hz, 1H, 7-H), 5.27 (d, J = 4.0 Hz,
1H, 5-H).
13
C-5), 86.4 (t, C-7).
exo-1-Deuterio-7-ethyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-86)
H
O
Et
O
1
D
1H, 4-H), 4.12-4.19 (m, 2H, 3-H), 4.24 (t, J = 7.5 Hz, 1H, 7-H), 5.19 (d, J = 4.3 Hz,
1H, 5-H).
13
C-5), 88.2 (t, C-7).
Irradiation of propanal-1-d with 5-deuterio-2,3-dihydrofuran (sbo-593)
Under a nitrogen atmosphere, a solution of propanal-1-d (0.17 g, 3 mmol) and 5-deuterio-2,3dihydrofuran (0.21 g, 3 mmol) in 25 mL hexane was irradiated in a Rayonet photoreactor ( λ
endo-1,7-Dideuterio-7-ethyl-2,6-dioxa-bicyclo[3.2.0]heptane (endo-87)
512
___________________________________________________________________________
H
O
Et
O
1
D D
1H, 4-H), 4.06-4.15 (m, 2H, 3-H), 5.22 (d, J = 4.0 Hz, 1H, 5-H).
13
C-5), 85.8 (t, C-7).
exo-1,7-Dideuterio-7-ethyl-2,6-dioxa-bicyclo[3.2.0]heptane (exo-87)
H
O
O
1
Et
D D
1H, 4-H), 4.06-4.14 (m, 2H, 3-H), 5.14 (dd, J = 4.0 Hz, 1H, 5-H).
13
C-5), 87.6 (t, C-7).
HRMS: (C 7 H10 D2 O2 , M = 130.1 g/mol)
Calcd:
130.1345
Found:
130.1340
513
5. Appendix
___________________________________________________________________________
5. Appendix
“Crystal growth is a science and an art. The scientists role in the crystal growth process is that
of an assistant who helps molecules to crystallize.“177
39g
43df
45
Crystal data
39g
43df
45
Emperical formula
C7 H13 NO4
C12 H23 NO4
C8 H15 NO4
Formula mass
175.18
245.31
189.21
Size [mm]
0.25 x 0.15 x 0.15
0.15 x 0.08 x 0.05
0.25 x 0.20 x 0.20
a [Å]
4.831 (10)
6.434 (1)
6.163 (1)
b [Å]
11.381 (10)
14.945 (1)
7.834 (1)
c [Å]
8.634 (10)
15.721 (1)
11.184 (1)
α [°]
90
90
95.93 (1)
β [°]
105.17
90
95.28 (1)
γ [°]
90
90
105.65 (1)
V [Å3 ]
458.17 (12)
1511.7 (3)
513.11 (12)
Z
2
4
2
dcalcd. [g/cm3 ]
1.270
1.078
1.225
Crystal system
monoclinic
orthorhombic
triclinic
Space group 178
P-21
P21 21 21
P-1
No. refl. meas.
1022
3219
4338
No. uni. Refl.
1022
3219
2223
No. obs. Refl.[a]
815
1762
1570
R
0.0373
0.0605
0.0438
Rw
0.0746
0.1396
0.0685
0.123/-0.111
0.116/-0.134
0.155/-0.197
Largest diff. Peak /
hole [e/Å-3 ]
[a]
For I > 2σ (I)
514
5. Appendix
___________________________________________________________________________
67b
Crystal data
67b
Emperical formula
C11 H19 NO6
Formula mass
261.27
Size [mm]
0.35 x 0.08 x 0.08
a [Å]
7.319 (1)
b [Å]
21.573 (1)
c [Å]
8.799 (1)
α [°]
90
β [°]
108.02 (1)
γ [°]
90
V [Å3 ]
1321.2 (12)
Z
4
dcalcd. [g/cm3 ]
1.314
Crystal system
monoclinic
Space group 178
P-21 /c
No. refl. meas.
5302
No. uni. refl.
2722
No. obs. refl. [a]
1023
R
0.0559
Rw
0.0997
Largest diff. Peak /
0.150/-0.230
hole [e/Å-3 ]
[a]
For I > 2σ (I)
515
6. Summary
___________________________________________________________________________
6. Summary
This work was performed in order to study the mechanism and synthetic applications of the
Paternò-Büchi reaction: Spin-mapping of the stereoselectivity of [2+2]-photocycloaddition
via concentration, viscosity and temperature effects and, as a synthetic tool, the photo-aldol
reaction of 5-methoxyoxazoles.
The difference between the simple diastereoselectivities in the photocycloaddition reactions
following the singlet versus the triplet route were studied by determination of the
concentration dependence of the Paternò-Büchi reaction. Carbonyl substrates which have both
reactive singlet and triplet states, exhibit one characteristic substrate concentration where a
1:1 ratio of singlet and triplet reactivity, i.e isospinselectivity could be detected.a
O
O
EtCHO (1c)
hν
O
H
0.5 M
0.05 M in benzene
0.005 M
2
+
O
48
22
15
:
:
:
H
O
52
78
85
Scheme I
The effect of solvent viscosity and temperature on the spin-directed stereoselectivity of the
carbonyl-ene photocycloaddition was investigated. The variation of the solvent viscosity over
a large effective range (η = 0.3 to 1500 cp) resulted in a weak but significant increase in the
endo-selectivity of the (triplet) benzaldehyde cycloaddition to 2,3-dihydrofuran from 82 % to
91 %. For aliphatic aldehydes, the diastereoselectivity strongly increased with increasing
3,5
Figure I
3,0
2,5
benzaldehyde (1a)
acetaldehyde (1b)
propionaldehyde (1c)
3-methylbutraldehyde (1d)
2,0
1,5
1,0
0,5
1
10
100
Viscosity: log η (cP)
Figure II
1,4
1a
1c
1b
1d
1,3
+
+
+
+
2
2
2
2
1,2
1,1
1,0
0,9
0,8
-80
-60
-40
-20
0
20
40
Temperature: T (°C)
solvent viscosity. The temperature dependence of the endo/exo selectivity with aliphatic
aldehydes 1b-d showed characteristic non-linear curves with inversion points from which
activation parameters for singlet as well as the triplet photocycloaddition were determined.b
The concentration dependence of the photocycloaddition of cis- and trans-cyclooctene with
aliphatic aldehydes was studied.c The results showed that a moderate but still significant spin516
6. Summary
___________________________________________________________________________
correlation effect. The exo-diastereoisomer tc-18 was formed with similar probability as the
endo-diastereoisomer cc-18 in the singlet carbonyl manifold, whereas the triplet excited
aldehydes preferred the formation of the endo-diastereoisomer and trans fused product, tt-18.
O
Et
H
H
O
H
hν
H
Z-17
O
+
Et
O
+
Et
H
tc-18
cc-18
O
H
Et
hν
Et
H
H
E-17
tt-18
5M
42 : 44 : 14
1M
28 : 34 : 36
0.01M 24 : 34 : 42
Scheme II
The effect of hydrogen bonding in the first excited singlet versus the first excited triplet state
of aliphatic aldehydes in the photocycloaddition was compared for allylic alcohols and
acetates. The simple diastereoselectivity for oxetanes was nearly the same, but the presence of
hydrogen bonding interactions increased the rate of the Paternò-Büchi reaction. Moreover, the
effect of hydrogen bonding for simple diastereoselectvity was completely different than that
for the induced diastereoselectivity, what was confirmed by comparsion with the mesitylol
photocycloaddition to aliphatic aldehydes.d
OR
OH
O
hν
O
hν
OR
O
O
+
H
27c
d.r. > 95 : 5
HO
OR
R=
H
Ac
d.r. (cis : trans)
25c 86 : 14
26c 81 : 19
Scheme III
5-Methoxyoxazoles were prepared in three steps and evaluated with respect to their use as
dienes in stereoselective Paternò-Büchi reaction. The photocycloaddition of 2-methyl-5methoxyoxazole (glycine equivalent) with a series of aldehydes was investigated. In all cases
only one regioisomeric bicyclic oxetane was detected in the crude photolysis mixture and in
most cases also only one (exo)-diastereoisomer. Ring-opening of the bicyclic oxetanes
proceeded with retention of configuration to give erythro (S*,S*) α-acetamido-β-hydroxy
esters.e
517
6. Summary
___________________________________________________________________________
H
N
H
hν
H3C
O
H
32
H3C
O
OCH3
N
O
R
HO
H+/H2O
O
H
R
AcHN
OCH3
R
38a-f
37a-f
R = Ph(a), 2-Nph(b),
BnCH2(c), Et(d),
i-Pr(e), i-Bu(f)
CO2CH3
39a-f
Scheme IV
Acid-catalyzed water elimination from α-acetamido-β-hydroxy esters gave the (Z)-α,βdidehydroamino acid preferentially.
OH
CO2CH3
R
H+/CH2Cl2
NHAc
H
CO2CH3
R
NHAc
40a-d
Scheme V
Compound 40a, when treated with POCl3 in methylene chloride afforded methyl 1methylisoquinoline-3-carboxylate 41 in good yield via a Bischler-Napieralski cyclization.
CO2CH3
H
NHAc
CO2CH3
POCl3/CH2Cl2
N
40a
41
CH3
Scheme VI
Furthermore, the photocycloaddition of a series of 5-methoxyoxazoles as substrate with an
additional substituent at C-4 was studied. The primary photoadducts were formed with
excellent exo-diastereoselectivities except for the benzaldehyde addition to oxazole substrates
with bulky substituents R1. The products were hydrolyzed to give the erythro (S*,S*) αalkylated-α-acetamido-β-hydroxy esters.
N
R1
H3C
O
OCH3
H
hν
O
H R
36a-f
37a-f
R = Me(a), Et(b),
1
H3C
N
O
O
R
R1
OCH3
42aa-ff
H+/H2O
HO
AcHN
R
R1
CO2CH3
43aa-ff
n-Pr(c), i-Pr(d),
i-Bu(e), sec-Bu(f)
Scheme VII
Treatment of the photo aldol adducts with a catalytic amount of conc. HCl in chloroform led
to formation of transacylation products.
518
6. Summary
___________________________________________________________________________
HO
R
R1
CO2CH3
AcHN
AcO
R
H2N
R1
CO2CH3
H+/CHCl3
43da, 43dc & 43fc
44da, 44dc & 44fc
Scheme VIII
When compound 43c was heated in aqueous NaOH (10%), the retro-aldol cleavage product
45 was obtained. The structure of compound 45 was established by means of an X-ray
crystallographic analysis.
HO
NaOH (10%)
AcHN
CO2CH3
AcHN
43dc
OH
CO2CH3
45
Scheme IX
Following the semial work by Scharf et al., the photo aldol addition of 5-methoxyoxazoles to
aliphatic and aromatic α-keto esters was investigated in detail. Photolysis of methylpyruvate
with 5-methoxyoxazoles in benzene at 350 nm gave only one regio- and (exo)diastereoisomer in high chemical yield. Acid treatment of the bicyclic oxetanes furnished
erythro (S*,R*) α-acetamido-β-hydroxy succinic acid derivatives in quantitative chemical
yield. The erythro configuration of compound 67b was unambiguously established by means
of an X-ray structure analysis.
N
R1
H3C
O
OCH3
36a-f
1
R = Me(a), Et(b),
n-Pr(c), i-Pr(d),
CO2CH3
hν
H3C
O
N
O
OCH3
O
R1
OCH3
55a-f
HO
CO2CH3
AcHN
R1
CO2CH3
H+/H2O
O
54
i-Bu(e), sec-Bu(f)
Scheme X
In contrast to aliphatic α-keto ester, irradiation of alkyl phenylglyoxylate in the presence of 5methoxyoxazoles afforded two diastereoisomers with preferential formation of the exo-Ph
diastereoisomer. The exo/endo-Ph diastereoselectivity decreased with increasing steric
demand either at C-4 of oxazole and /or the alkyl group of the phenylglyoxylate. Acid
hydrolysis of the chromatographically separated exo-Ph and endo-Ph bicyclic oxetanes
afforded threo (S*,S*) and erythro (S*,R*) α-acetamido-β-hydroxy succinic acid derivatives
in high chemical yield, respectively.
519
6. Summary
___________________________________________________________________________
N
H3CO2C
R1
H3C
O
OCH3
OCH3
Ph
n-Pr(c), i-Pr(d),
57
+
N
H3C
O
OCH3
exo-Ph-58a-f
i-Bu(e), sec-Bu(f)
OCH3
endo-Ph-58a-f
CO2CH3
Ph
HO
R1
CO2CH3
AcHN
R1
H+/H2O
O
O
CO2CH3
O
+
H /H2O
36a-f
R1= Me(a), Et(b),
R1
N
H3C
O
Ph
Ph
O
hν
HO
Ph
CO2CH3
AcHN
R1
CO2CH3
threo (S*,S*)-69a-f
Scheme XI
Furthermore, the asymmetric induction in the Paternò-Büchi reaction of menthyl
phenylglyoxylate with 5-methoxyoxazoles was investigated. The simple exo/endo-Ph
diastereoselectivity was moderate, the facial selectivity for both exo and endo
diastereoisomers was low. Hydrolysis of the chromatographically isolated exo-Ph and endoPh bicyclic oxetanes led to formation of threo (S*,S*) and erythro (S*,R*) α-acetamido-βhydroxy succinic acid derivatives in high chemical yield, respectively.
N
R1
H3C
O
OCH3
R1
N
H3C
O
O
OR*
OCH3
exo-Ph-63a-f
n-Pr(c), i-Pr(d),
53
i-Bu(e), sec-Bu(f)
R* = menthyl
+
H3C
N
O
HO
AcHN
CO2R*
Ph
R1
CO2CH3
threo (S*,S*)-73a-f
CO2R*
O
R1
OCH3
endo-Ph-63a-f
H+/H2O
O
Ph
Ph
O
+
H /H2O
Ph
36a-f
R =Me(a), Et(b),
2
*RO2C
hν
HO
AcHN
Ph
CO2R*
R1
CO2CH3
Scheme XII
The effect of the substituent at C-2 of the oxazole substrates on the diastereoselectivity of the
triplet α-keto ester photocycloaddition was also studied. Surprisingly, the exo/endo-Ph
diastereoselectivity of the photocycloaddition of tert-butyl phenylglyoxate to 2-isopropy-4methyl-5-methoxyoxazole was inverted. This result indicated that secondary orbital
interactions (SOI) may play an important role for determining the stereoselectvity in the
triplet photocycloaddition reaction. Acid hydrolysis of the chromatographyically isolated exo
and endo-Ph bicyclic oxetanes led to the formation of threo (S*,S*) and erythro (S*,R*) αisobutyrylamino-β-hydroxy succinic acid derivatives in high chemical yields, respectively.
520
6. Summary
___________________________________________________________________________
N
O
ButO2C
CH3
hν
OCH3
O
OBut
Ph
49b
N
O
O
CH3
endo-Ph-65f
d.r. = 37 : 63
CO2But
Ph
PriOCHN
OCH3
+
H /H2O
H+/H2O
HO
CH3
O
exo-Ph-65f
52
O
N
+
OCH3
O
CO2But
Ph
Ph
HO
CO2CH3
Ph
CO2But
PriOCHN
CO2CH3
erythro (S*,R*)-75f
threo (S*,S*)-75f
Scheme XIII
Finally, a substantial magnetic isotope effect on stereoselectivity in the triplet [2+2]photocycloaddition of benzaldehyde-1-d to 2,3-dihydrofuran was measured. The results
revealed that spin-orbit coupling (SOC) is not the only responsible interaction for intersystem
crossing (ISC) as well as product distribution but also hyperfine coupling (HFC) plays an
additional role for ISC even for 1,4-biradical intermediate.f
hν
O
H
H
O
Ph
+
PhCHO
1a
Ph
O
O
2
hν
PhCDO
Ph
O
O
O
endo-3a
exo-3a
d.r. = 82 : 18 (GC)
O
D
D
+
endo-3a (7-d)
2
O
Ph
O
exo-3a (7-d)
d.r. = 93 : 7 (GC, NMR)
Scheme XIV
(a)
(b)
(c)
(d)
(e)
(f)
“Spin-Directed Stereoselectivity of Carbonyl-Alkene Photocycloadditions” Axel G. Griesbeck, Maren Fiege, Samir
Bondock and Murthy S.Gudipati, Organic Letters 2000, 2, 3623-3625.
“Temperatur- und Viskositätsabhängigkeit der spingesteuerten Stereoselektivität von Carbonyl-AlkenPhotocycloadditionen" Axel G. Griesbeck, Samir Bondock and Murthy S.Gudipati,
“Spin-Imposed Stereoselection in the Photocycloaddition of cis- and trans-Cyclooctene with Aliphatic Aldehydes"
Axel G. Griesbeck and Samir Bondock, Photochem. Photobiol. Sciences. 2002, 1, 81-83.
“Paternò-Büchi Reactions of Allylic Alcohols and Acetates with Aliphatic Aldehydes: Evidences for HydrogenBond Activation in the Excited Singlet and Triplet States?” Axel G. Griesbeck and Samir Bondock
J. Am. Chem. Soc. 2001, 123, 6191-6192.
“Photo Aldol Reactions with 5-Methoxyoxazoles: Highly Regio- and Diastereoselective Synthesis of α-Amino βHydroxy Carboxylic Acid Derivatives” Axel G. Griesbeck and Samir Bondock, Can. J. Chem. 2003, 81, 1-5.
"Substantial 2H-Magnetic Isotope Effects on the Diastereoselectivity of Triplet Photocycloaddition Reactions“
Axel G. Griesbeck and Samir Bondock, J. Am. Chem. Soc., 2003, submitted.
521
7. Zusammenfassung
___________________________________________________________________________
7. Zusammenfassung
In dieser Arbeit wurden mechanistische Aspekte und Syntheseanwendungen von PaternòBüchi-Reaktionen untersucht: „spin-mapping“ der Stereoselektivität von [2+2]-Cycloadditionen mittels Konzentrations-, Solvensviskositäts- und Temperaturvariation sowie, als
eine synthetische Anwendung, die Photo-Aldolreaktion von 5-Methoxyoxazolen.
Der Unterschied zwischen den einfachen (nicht-induzierten) Diastereoselektivitäten bei
Photocycloadditionreaktionen über die Singulett- und die Triplettroute wurden durch
Bestimmung
der
Konzentrationsabhängigkeit
der
Paternò-Büchi-Reaktion
bestimmt.
Carbonylsubstrate, die sowohl aus dem Singulett- als auch dem Triplettzustand reagieren
können, zeigen eine charakteristische Substratkonzentration, bei der ein 1:1-Verhältnis von
Singulett- und Triplettreaktivität, d.h. Isospinselektivität, nachgewiesen werden konnte.a
O
EtCHO (1c)
O
hν
2
0.5 M
0.05 M
0.005 M
H
O
+
O
48
22
15
in Benzol
:
:
:
H
O
52
78
85
Schema I
Der Effekt der Viskosität des Lösungsmittels und der Reaktionstemperatur auf die spingesteuerte Stereoselektivität der Carbonyl-En-Photocycloaddition wurde ebenfalls untersucht.
Eine Erhöhung der Lösungsmittelviskosität über einen grossen Bereich (η = 0.3 bis 1500 cp)
führte zu einem schwachen, aber signifikanten Anstieg der endo-Selektivität bei der Addition
von (Triplett) Benzaldehyd an 2,3-Dihydrofuran von 82% auf 91%. Bei aliphatischen
Aldehyden hingegen stieg die Diastereoselektivität stark mit der Lösungsmittelviskosität an.
Figure I
3,0
2,5
benzaldehyde (1a)
acetaldehyde (1b)
propionaldehyde (1c)
3-methylbutraldehyde (1d)
2,0
1,5
1,0
0,5
1
10
100
3,5
Viscosity: log η (cP)
Figure II
1,4
1a
1c
1b
1d
1,3
+
+
+
+
2
2
2
2
1,2
1,1
1,0
0,9
0,8
-80
-60
-40
-20
0
20
40
Temperature: T (°C)
Die Temperaturabhängigkeit der endo/exo-Selektivität mit den aliphatischen Aldehyden 1b-d
zeigte charakteristische nicht-lineare Korrelationen mit Inversionspunkten, aus denen die
Aktivierungsparameter sowohl für die Singulett- als auch die Triplettphotocycloadditionen
bestimmt wurden.b
522
7. Zusammenfassung
___________________________________________________________________________
Die Konzentrationsabhängigkeit der Photocycloaddition von cis- sowie trans-Cycloocten mit
aliphatischen Aldehyden wurde untersucht.c Die Ergebnisse zeigten einen schwachen, aber
aussagekräftigen Spin-Korrelationseffekt. Das exo-Diastereoisomer tc-18 wurde im Singulettbereich mit ähnlicher Wahrscheinlichkeit gebildet wie das endo-Diastereoisomer cc-18,
hingegen bevorzugten Triplett-angeregte Aldehyde die Bildung des endo-Diastereoisomers tt18 mit trans-Konfiguration.
O
Et
H
H
O
H
hν
H
Z-17
O
+
Et
O
+
Et
H
tc-18
cc-18
O
H
Et
hν
Et
H
H
E-17
tt-18
5M
42 : 44 : 14
1M
28 : 34 : 36
0.01M 24 : 34 : 42
Schema II
Der Effekt von Wasserstoffbrückenbindungen auf die Reaktivität und Selektivität von Photocycloadditionen erster angeregter Singulettzustände im Vergleich zu den ersten angeregten
Triplettzuständen wurde mit Allylalkoholen bzw. Acetaten untersucht. Die einfache, nichtinduzierte Diastereoselektivität für die Oxetanbildung war annähernd identisch, allerdings
erhöhten Wasserstoffbrückenwechselwirkungen die Effizienz der Paternò-Büchi Reaktion.
Darüberhinaus
war
der
Effekt
der
Wasserstoffbrückenbindung
auf
die
einfache
Diastereoselektivität verschieden vom Einfluß auf die induzierte Diastereoselektivität. Dies
wurde durch Vergleich von Photocycloadditionen mit Mesitylol und aliphatischen Aldehyden
gezeigt.d
OR
OH
O
hν
O
hν
OR
O
O
+
H
27c
d.r. > 95 : 5
HO
OR
R=
H
Ac
d.r. (cis : trans)
25c 86 : 14
26c 81 : 19
Schema III
Verschiedene 5-Methoxyoxazole wurden in einer Dreistufenreaktion hergestellt und auf ihre
Eignung als Diene in stereoselektiven Paternò-Büchi-Reaktionen getestet. Die Photocycloaddition von 2-Methyl-5-methoxyoxazol (einem Glycinäquivalent) wurde mit einer Serie von
Aldehyden untersucht. In allen Fällen wurde nur ein regioisomeres bicyclisches Oxetan mit
hoher exo-Diastereoselektivität gebildet. Die Ringöffnung der bicyclischen Oxetane verlief
523
7. Zusammenfassung
___________________________________________________________________________
mit Retention der Konfiguration unter Bildung der erythro (S*,S*) α-Acetamido-β-hydroxy
ester.e
H
N
H
hν
H3C
O
H3C
O
OCH3
H
32
R
N
O
R
HO
H+/H2O
O
H
AcHN
OCH3
38a-f
37a-f
R
CO2CH3
39a-f
R = Ph(a), 2-Nph(b),
BnCH2(c), Et(d),
i-Pr(e), i-Bu(f)
Schema IV
Die durch Brönsted-Säuren katalysierte Wassereliminierung ergab ausgehend von den αAcetamido-β -hydroxyestern bevorzugt die (Z)-α,β-Didehydroaminosäuren.
OH
CO2CH3
R
H+/CH2Cl2
NHAc
H
CO2CH3
R
NHAc
40a-d
Schema V
Aus der Verbindung 40a wurde durch Umsetzung mit POCl3 in Methylenchlorid das
Methylisoquinolin-3-carboxylat 41 in guten Ausbeuten über eine Bischler-NapieralskiCyclisierung gebildet.
CO2CH3
H
NHAc
CO2CH3
POCl3/CH2Cl2
N
40a
41
CH3
Schema VI
Weiterhin wurden Photocycloadditionen mit einer Serie von C-4-substituierten 5Methoxyoxazolen als Dienkomponenten studiert. Die Photoaddukte wurden mit exzellenten
exo-Diastereoselectivitäten gebildet. Eine Ausnahme stellten Benzaldehyd-Additionen an
Oxazole mit sterisch anspruchsvollen Substituenten R1 dar. Alle Produkte konnten leicht zu
den entsprechenden erythro (S*,S*) α-alkylierten α-Acetamido-β -hydroxy estern hydrolisiert
werden.
N
R1
H3C
O
OCH3
H
hν
O
H R
36a-f
37a-f
R1 = Me(a), Et(b),
H3C
N
O
O
R
R1
OCH3
42aa-ff
n-Pr(c), i-Pr(d),
i-Bu(e), sec-Bu(f)
524
H+/H2O
HO
AcHN
R
R1
CO2CH3
43aa-ff
7. Zusammenfassung
___________________________________________________________________________
Schema VII
Die Umsetzung der Photo-Aldol-Produkte mit katalytischen Mengen conc. HCl führte zur
quantitativen Bildung der Transacylierungsprodukte.
HO
R
R1
CO2CH3
AcHN
AcO
R
H2N
R1
CO2CH3
H+/CHCl3
43da, 43dc & 43fc
44da, 44dc & 44fc
Schema VIII
Bei der Umsetzung von Verbindung 43c mit wässriger NaOH (10%) wurde das Retro-Aldol
Spaltungsprodukt 45 erhalten. Die Struktur von Verbindung 45 wurde zusätzlich durch eine
Kristallstrukturanalyse bestätigt.
HO
NaOH (10%)
AcHN
CO2CH3
AcHN
43dc
OH
CO2CH3
45
Schema IX
In Analogie zu den bahnbrechenden Arbeiten von Scharf und Mitarbeitern, wurde die Photoaldolreaktion von 5-Methoxyoxazolen auch mit aliphatischen und aromatischen α-Ketoestern
untersucht. Die Belichtung von Methylpyruvat mit 5-Methoxyoxazol in Benzol bei 350 nm
ergab lediglich ein regio- und (exo)-diastereoisomerenreines Oxetan in hohen Ausbeuten. Die
Säurespaltung der bicyclischen Oxetane ergab quantitativ die erythro (S*,R*) α-Acetamido-βhydroxybernsteinsäurederivate. Die erythro-Konfiguration von Verbindung 67b wurde
zusätzlich durch eine Kristallstrukturanalyse bestätigt.
N
R1
H3C
O
OCH3
36a-f
1
R = Me(a), Et(b),
n-Pr(c), i-Pr(d),
CO2CH3
hν
H3C
O
N
O
OCH3
O
R1
OCH3
55a-f
HO
CO2CH3
AcHN
R1
CO2CH3
H+/H2O
O
54
i-Bu(e), sec-Bu(f)
Schema X
Im Gegensatz zu den aliphatischen α-Ketoestern, ergab die Belichtung von Alkylphenylglyoxylaten in Gegenwart von 5-Methoxyoxazolen zwei Diastereoisomere unter bevorzugter
Bildung des exo-Phenyl-Stereoisomeren. Die exo/endo-Phenyl-Diastereoselektivität nahm mit
zunehmenden Raumanspruch an C-4 der Oxazolkomponente und / oder der Alkylgruppe am
Phenylglyoxylat ab. Die saure Hydrolyse der chromatographisch getrennten exo-Ph- und
525
7. Zusammenfassung
___________________________________________________________________________
endo-Ph-Oxetane lieferte die threo (S*,S*) und erythro (S*,R*) α-Acetamido-β-hydroxybernsteinsäurederivate in hohen Ausbeuten.
N
R1
H3C
O
OCH3
H3CO2C
OCH3
n-Pr(c), i-Pr(d),
57
+
N
H3C
O
OCH3
exo-Ph-58a-f
i-Bu(e), sec-Bu(f)
OCH3
endo-Ph-58a-f
CO2CH3
Ph
HO
R1
CO2CH3
AcHN
R1
H+/H2O
O
O
CO2CH3
O
H+/H2O
Ph
36a-f
R = Me(a), Et(b),
1
R1
N
H3C
O
Ph
Ph
O
hν
HO
Ph
CO2CH3
AcHN
R1
CO2CH3
threo (S*,S*)-69a-f
Schema XI
Weiterhin wurde die asymmetrische Induktion bei der Paternò-Büchi-Reaktion von Menthylphenylglyoxylat mit 5-Methoxyoxazolen untersucht. Die einfache exo/endo-Ph-Diastereoselektivität war mässig, die induzierte Diastereoselektivtiät für beide exo- und endoDiastereoisomere gering. Die Hydrolyse der chromatographisch getrennten exo-Ph- und endoPh-Oxetane ergab in sehr guten Ausbeuten die threo (S*,S*) und erythro (S*,R*) αAcetamido-β -hydroxybernsteinsäurederivative.
N
R1
H3C
O
OCH3
R1
N
H3C
O
O
OR*
OCH3
exo-Ph-63a-f
n-Pr(c), i-Pr(d),
53
i-Bu(e), sec-Bu(f)
R* = menthyl
+
H3C
N
O
HO
AcHN
CO2R*
Ph
R1
CO2CH3
threo (S*,S*)-73a-f
CO2R*
O
R1
OCH3
endo-Ph-63a-f
H+/H2O
O
Ph
Ph
O
+
H /H2O
Ph
36a-f
R =Me(a), Et(b),
2
*RO2C
hν
HO
AcHN
Ph
CO2R*
R1
CO2CH3
Schema XII
Der Einfluss eines Substituenten an C-2 der Oxazolkomponente auf die Diastereoselektivität
bei der Photocycloaddition von Triplett-angeregten α-Ketoestern wurde untersucht.
Überraschenderweise drehte sich die exo/endo-Ph-Diastereoselektivität bei der Cycloaddition
von tert-Butylphenylglyoxat an 2-Isopropyl-4-methyl-5-methoxyoxazol um. Dieses Ergebnis
lässt vermuten, dass sekundäre Orbitalwechselwirkungen (SOI) eine wichtige Rolle bei der
Steuerung
der
Stereoselektivität
von
Triplett-Photocycloadditionen
spielen.
Die
säurekatalysierte Hydrolyse der chromatographisch getrennten exo and endo-Ph-Oxetane
526
7. Zusammenfassung
___________________________________________________________________________
ergab die threo (S*,S*) and erythro (S*,R*) α-Isobutyrylamino-β-hydroxybernsteinsäurederivate in guten Ausbeuten.
N
O
ButO2C
CH3
hν
OCH3
O
O
OBut
Ph
49b
N
O
CH3
endo-Ph-65f
d.r. = 37 : 63
CO2But
Ph
PriOCHN
OCH3
+
H /H2O
H+/H2O
HO
CH3
O
OCH3
52
O
N
+
exo-Ph-65f
O
CO2But
Ph
Ph
HO
CO2CH3
Ph
CO2But
PriOCHN
CO2CH3
erythro (S*,R*)-75f
threo (S*,S*)-75f
Schema XIII
Schliesslich wurde ein beachtlicher magnetischer Isotopeneffekt auf die Stereoselektivität der
Triplett-[2+2]-Photocycloaddition von Benzaldehyd-1-d an 2,3-Dihydrofuran bestimmt. Diese
Ergebnisse zeigten, dass die Spin-Bahn-Kopplung (SOC) nicht die einzige Wechselwirkung
ist, die für das Intersystem-Crossing (ISC) und somit auch für die Produktverteilung
verantwortlich ist, sondern dass auch die Hyperfeinkopplung (HFC) eine zusätzliche Rolle
beim ISC, sogar bei 1,4-Biradikalen, spielt.f
hν
O
H
H
O
Ph
+
PhCHO
1a
Ph
O
O
2
hν
PhCDO
Ph
O
O
O
endo-3a
exo-3a
d.r. = 82 : 18 (GC)
O
D
D
+
endo-3a (7-d)
2
O
Ph
O
exo-3a (7-d)
d.r. = 93 : 7 (GC, NMR)
Schema XIV
(a)
(b)
(c)
(d)
(e)
(f)
“Spin-Directed Stereoselectivity of Carbonyl-Alkene Photocycloadditions” Axel G. Griesbeck, Maren Fiege, Samir
Bondock und Murthy S.Gudipati, Organic Letters 2000, 2, 3623-3625.
“Temperatur- und Viskositätsabhängigkeit der spingesteuerten Stereoselektivität von Carbonyl-AlkenPhotocycloadditionen" Axel G. Griesbeck, Samir Bondock und Murthy S.Gudipati,
“Spin-Imposed Stereoselection in the Photocycloaddition of cis- and trans-Cyclooctene with Aliphatic Aldehydes"
Axel G. Griesbeck und Samir Bondock, Photochem. Photobiol. Sciences. 2002, 1, 81-83.
“Paternò-Büchi Reactions of Allylic Alcohols and Acetates with Aliphatic Aldehydes: Evidences for HydrogenBond Activation in the Excited Singlet and Triplet States?” Axel G. Griesbeck und Samir Bondock
J. Am. Chem. Soc. 2001, 123, 6191-6192.
“Photo Aldol Reactions with 5-Methoxyoxazoles: Highly Regio- and Diastereoselective Synthesis of α-Amino βHydroxy Carboxylic Acid Derivatives” Axel G. Griesbeck und Samir Bondock, Can. J. Chem. 2003, 81, 1-5.
"Substantial 2H-Magnetic Isotope Effects on the Diastereoselectivity of Triplet Photocycloaddition Reactions“
Axel G. Griesbeck und Samir Bondock, J. Am. Chem. Soc., 2003, eingereicht.
527
8. References
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Ich versichere, dass ich die von mir vorgelegte Dissertation selbständig angefertigt, die
benutzten Quellen und Hilfsmittel vollständig angegeben und die Stellen der Arbeit –
einschließlich Tabellen, Spektren und Abbildungen –, die anderen Werken im Wortlaut
oder dem Sinn nach entnommen wurden, in jedem Einzelfall als Entlehnung kenntlich
gemacht habe; dass diese Dissertation noch keiner anderen Fakultät oder Universität zur
Prüfung vorgelegen hat; dass sie – abgesehen von unten angegebenen Teilpublikationen –
noch nicht veröffentlicht worden ist, und dass ich eine solche Veröffentlichung vor
Abschluss des Promotionsverfahrens nicht vornehmen werde. Die Bestimmungen dieser
Promotionsordnung sind mir bekannt.
Die von mir vorgelegte Dissertation ist von Herrn Prof. Dr. Axel. G. Griesbeck betreut
worden.
Samir Bondock
Lebenslauf
Persönliche Daten
Name
Samir Bahgat Abd El-Razek Bondock
Geburtsdatum
20.09.1970
Geburtsort
Mansoura/Ägypten
Familienstand
ledig
Staatsangehörigkeit
ägyptisch
Schulbildung
1976-1982
Grundschule Meet El-Sarem
1982-1985
Mittelschule Ameria
1985-1988
El-Malek El-Kamel-Gymnasium
07/1988
Abitur
Studium
1988-1992
Studium der Chemie an der Mansoura Univerisität
05/1992
B.Sc. in Chemie
1992-1993
Magister-Vorprüfung
1993-1995
Magisterarbeit an der Mansoura Universität im Arbeitskreis
von Prof. Dr. Ahmed Fadda
Thema: “ Synthesis of Some New Azo Disperse Dyes for
Dyeing Synthetic Fiberes“
09/1995
M.Sc. in Chemie
1995-2000
Forschungsarbeit im Arbeitskreis von Prof. Dr. M.A.
Metwally
2000-2003
Promotionsstudium an der Universität zu Köln im
Arbeitskreis von Prof. Dr. Axel G. Griesbeck
Thema: “Mechanism and Synthetic Use of Paternò-Büchi
Reactions: Spin-Mapping and Photo-Aldol Reactions“
Berufserfahrung
1992-1995
Assistent an der Mansoura Universität
1995-2003
Oberassistent an der Mansoura Universität
2002-2003
Wissenschaftlicher Assistent an der Universität zu Köln

Mechanism and Synthetic Use of Paternò-Büchi

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