Oxidation 1

Sharpless Asymmetric Epoxidation
Asymmetric Epoxidation of Allylic Alcohols
R3
R2
Ti(OiPr)4, (+)-DET
OH
R1
R2
tBuOOH, 3Å MS,
CH2Cl2, -20°C
OH
R3
O
OH
CO2Et
EtO2C
OH
R1
(+)-DET
• 5-10 mol% catalyst
• 10-20 mol% excess tartrate vs. Ti(OiPr)4 required
• (+) and (-)-DET are readily available and inexpensive; (+) and (-) DIPT sometimes lead to higher selectivity
Mnemonic:
(+)-DET
R2
Sharpless, JACS, 1987, 5765
R3
R1
HO
(-)-DET
AE-(+)-DET
AE-(-)-DET
O
O
OH
86% ee
OH
OH
86% ee
Substrates for Shapless AE
Reactant
Tartrate
Product
%ee
O
OH
Ph
OH
(+)- DIPT
OH
(+)- DIPT
Ph
O
CH3
Ph
OH
(+)- DIPT
90
O
OH
>98
OH
>98
CH3
Ph
O
OH
OH
(+)- DET
CH3
Ph
OH
O
(-)- DET
Ph
Ph
91
CH3
OH
94
Ph
OH
O
(+)- DET
C7H15
Z-disubstituted olefins are least reactive and selective
OH
86
C7H15
JACS, 1987, 5764
Sharpless Asymmetric Epoxidation
(-)-DIPT
R2
R1
tBuOOH, Ti(Oi-Pr)4
OH
CH2Cl2, (+)-DET or
(-) DIPT
R3
R2
O
R1
R3
OH
(+)-DET
Ligand: Tartrates are C-2 symmetric. Such symmetry is useful in ligand
design, furnishing predictable and repetitive structural units which reduce RO
the number of diastereomeric transition states
The active catalyst is
dimeric, providing a chiral
environment for the substrate,
allowing distinction of the
enantiotopic faces of the alkene
O
OR
Ti
O
This is an example of LigandAccelerated Catalysis: The
reaction in the absence of the chiral
ligand is much slower than in its
presence, thus ensuring the enantioselective
pathway is the predominant one.
OH
OR
O
O
R3
E
RO
HO
E
O
O
Ti
EO O
O
R1
R2
only one face of the alkene
is presented to the coordinated peroxide
ligand.
The alkene pi bond attacks along the
O-O bond axis
The peroxide is activated by bidentate
coordination to the titanium
E
Sharpless, JACS, 1980, 102, 5974.
JACS, 1987, 109, 1279.
Chiral Substrates
anti
syn
O
O
+
OH
O
OH
O
O
OH
O
O
Ti(OiPr)4, TBHP
Ti(OiPr)4, (-)-DIPT, TBHP
Ti(OiPr)4, (+)-DIPT, TBHP
Tet, 1990, 245
O
1
1
22
:
:
:
2.3
90
1
Kinetic Resolution: using the Sharpless Mnemonic, contact between the C1 R substituent and the catalyst
predicts the slow reacting enantiomer:
(+)-DET
R2
(+)-DET
R3
R2
R1
H
R1
HO
HO
H
slow
OH
R3
R
R
fast
(-)-DIPT
OH
O
>95%ee
70% conversion
Pure Appl. Chem. 1983, 589.
• when krel=25, the ee of the unreacted alcohol is ~100% at 60% conversion
• allylic 3° alcohols are not oxidized
• disubstituted olefins are more reactive than monosubstituted
Chiral Substrates, Continued
OH
OBn
O
O
OH
OH
(+)-DIPT
O
O
OH
O
OBn
meso
OBn
Any minor diastereomer that is produced is rapidly removed by bis-epoxidation.
OBn
89%
JACS, 1987, 1525; JACS, 1987, 109, 4718.
Homoallylic, bishomoallylic substrates epoxidize slower, and the enantiofacial selectivity is lower:
H3C
OH
Ti(OiPr)4, (+)-DET
TBHP, -20°C, 1-4d
H3C
O
50%, 41%ee
OH
Transformations of 2,3-epoxy-alcohols
OH
HO
NaN3, NH4Cl
BnO
OH
H2, Pd/C
BnO
HO
NH2
N3
O
OH
OH
OH
LiAlH4
CH3
BnO
Aldrichimica Acta, 1983, 67
OH
OH
HO
(CH3)2CuLi
BnO
BnO
O
CH3
OH
OH
OTHP
Li
BnO
OTHP
OH
OH
KCN, CH3OH
CN
BnO
OH
The Payne Rearrangement
O
NaOH
HO
O
OH
H3C
H2O
CH3
H3C
CH3
JOC, 1962, 3819
Keq=98/2
OH
NaOH
O
equilibrium favors more substituted epoxide
BnO
BnO
BnO
OH
H2O
98:2
OH
t-BuSNa
O
StBu
NaOH, H2O
OH
fast-reacting isomer
(CH3)3OBF4
CH2Cl2; NaH
Aldrichimica Acta, 1983, 67.
OH
BnO
O
2,3-epoxy alcohols
Proposed TS:
Ti(OiPr)4 can catalyze the addition of nucleophiles to C3 of 2,3-epoxy alcohols
O
O
O
3
2
Nu
Nu
1 OH
3
1.5 eq Ti(OiPr)4
OH
2
+
OH
2
3
OH
Nu
OH
Nucleophile
C3:C2
yield
Et2NH
iPrOH
KCN
20:1
100:1
2.4:1
100:1
90
88
76
90
OH
Ti(OR)3
JOC, 1985, 1557.
Phenyl substitution at C3 of 2,3-epoxy alcohols can lead to high C-3 regioselectivity in uncatalyzed additions
O
2
Ph
3
H
H
OH
Nu
OH
Ph
OH
Chem Rev. 1991, 437
1
Reagent
Allyl magnesium bromide
R2CuLi
NaN3/ NH4Cl
ArONa
PhSH/NaOH
internal H-bonding:
Nu
Nu
Allyl
R
N3
ArO
PhS
H
yield
96
78-88
>95
83
81
O
Ph
H
O
H
weakened C-O
forming
bond
benzylic cation
Reductive Aluminum (Red-Al) Opening of Epoxides
MeO
OMe
Red-Al reduction of 2,3-epoxy alcohols is highly selective when C.4 is oxygenated:
Red-Al=
O
R
4
3
2
1
OH
H
+
R
0°C
R
H
OH
OH
OH
C2 reduction
epoxy alcohol
Li+
Al
OH
Red-Al, THF
O
O
C3 reduction
C2:C3
yield (%)
O
C6H13
94
1:1
OH
TL, 1982, 2719
O
BnOH2C
OH
O
BnO
5:1
89
40:1
98
OH
O
BnO
OH
O
O
O
BnO
HO
Red-Al
O
OH
THF, 22°C
OH
BnO
OH
JOC, 1982, 1378
Al
Li
78
>100:1
O
O
O
O
H O MeO
Regioselectivity vs. Organometallic Reagent
2
OH
BnO
3
O
CH3
(CH3)2CuLi
Et2O, -20°C
1
OH
TL, 1979, 4343
TL, 1983, 1377
BnO
OH
74-79%
2-addition
(CH3)3Al
OH
BnO
3
O
O
OH
2
OH
BnO
BnO
CH2Cl2
0-23°C
1
NaIO4, THF:
OH
H
H2O
69-73%
OH
3-addition
Utility of epoxy alcohols:
OH
Et2AlCN
O
NC
OTos
NaH
O
JOC, 1989, 1295
NC
OTos
Internal nucleophilic opening:
OH
JACS, 1980, 7986.
1. PhNCO, Et3N
O
O
C5H11
OH
C5H11
O
O
Ph
OH
O
N
1. PhNCO, iPr2NEt
2. tBuOK, THF
O
N
PhNCO =
O
2. aq HClO4
O
mechanism?
O
O
O
what's different?
JACS, 1982, 1109
OH
HO
O
CO2, Cs2CO3
O
DMF, 78°C
O
TL, 1988, 6389
O
CH3
OH
C
O
Jacobsen Asymmetric Epoxidation
Unactivated Alkenes:
R
R'
S,S -1 (4mol%)
NaOCl (aq)
JACS, 1991, 7063
R
CH2Cl2
H
R'
O
Ph
H
H
Ph
H
H
N
Me
Ph
H
disfavored by
phenyls
Ph
Me
disfavored by
phenyls
N
H
N
Mn
H
t-Bu
O
Mn
t-Bu
O
t-Bu
O
Cl
t-Bu
N
t-Bu
O
Cl
t-Bu
t-Bu
t-Bu
S,S-1
disfavored by tert-butyl groups
side-on perpendicular approach to metal oxo species
• Selectivity is determined through non-bonded interactions
• R=aryl, alkenyl, alkynyl, and R' is a bulky group
• Cis disubstituted alkenes are epoxidized with high levels of ee
• trans disubstituted alkenes are oxidized more slowly with lower ee
• terminal alkenes are poor substrates : styrene ~70%ee
• Addition of substoichiometric amounts of 4-phenylpyridine-N-oxide
improves both catalyst selectivity and turnover numbers.
Mnemonic:
S,S-1-"O"
R
R'
H
R,R-1-"O"
H
S,S-1-"O"
Trisubstituted alkenes are also excellent substrates for Jacobsen AE
R'
R''
R
H
R,R-1-"O"
Olefin
Epoxide
Yield
ee%
Catalyst
79
84
S,S-1
63
94
S,S-1
69
93
R,R-1
91
95
R,R-1
87
88
O
O
O
O
O
O
Ph
Ph
O
Ph
Ph
H3C
Ph
H3C
Ph
O
CH3
Ph
CH3
Ph
Ph
Ph
R,R-1
O
JOC, 1994, 4378
Cis-substituted styrenes afford cis epoxied as major products, but cis-enynes and cis dienes produce
Trans epoxides. Compare:
Ph
S,S-1
CH3
CH3
Ph
Ph
+
O
O
77%, 92%ee
Me3Si
S,S-1
CH3
6%, 83%ee
Me3Si
Me3Si
+
O
O
10%, 64% ee
55%, 98% ee
•Rotation of a radical intermediate is proposed to account for cis-trans isomerization:
MnLn
MnLn
O
O
H
H
H
R
R
R
R
JACS, 1991, 7063.
H
• For tetrasubstituted olefins, enantioselectivities are not yet high in many cases, and generality lacks
Kinetic Resolution using Jacobsen Catalysts
H
Hydrolytic Kinetic Resolution (HKR)
H
OAc
N
N
Co
t-Bu
O
t-Bu
O
OH2
OH
OH
R
O
+
H2O
R,R-5
t-Bu
H2O
S,S-5
O
OH
OH
R
R
R
O
+
t-Bu
S,S-5
R
S-epoxide
R-epoxide
racemic
Selective complexation of chiral cobalt to the epoxide oxygen atom of one enantiomer of the racemic pair
O
H2O
S,S-5
OH
OH
R
R
O
+
R
S-epoxide
R
CH3
(CH2)3CH3
Ph
H2C=CH
Epoxide ee, yield
>98, 44
98, 46
98, 38
84, 44
diol ee, yield
98, 50
98, 48
98, 39
94, 49
Science, 1997, 936.
Kinetic Resolution of Terminal Epoxides with Trimethylsily Azide
H
H
N
N
Cr
t-Bu
O
t-Bu
O
N3
OTMS
R
N3
O
+
t-Bu
TMSN3
R,R-7
O
TMSN3
S,S-7
R
R
OTMS
N3
R
O
+
R
S-epoxide
R-epoxide
racemic
High yields and ee's with a variety of substituents:
O
TMSN3 (0.5 eq)
R,R -7
R
R
CH2Cl
CH2CN
CH2Ph
OTMS
R
Yield
94
80
94
N3
ee%
95
92
93
JACS, 1996, 7420
t-Bu
R,R-7
2,2 Disubstituted Epoxides also Serve as Substrates for Jacobsen AE
• Sterically hindered epoxides (iPr, tBu substituted) are not reactive
R1
O
H3C
racemic
TMSN3
R,R-7
2 mol%
i-PrOH
TBME
23°C
H
R1
R1
OH
H3C
N3
+
H3C
N
O
N
Cr
t-Bu
O
t-Bu
O
N3
t-Bu
0.5 equivalents of HN3 are generated by mixing equimolar amounts of TMSN3 and iPrOH
R1
TBSOCH2CH2
PhCH2CH2
C5H11
cC6H11
H
epoxide Yield, ee
42, 99
44, 97
42, 99
46, 98
azido alcohol yield, ee
47, 90
45, 92
44, 95
40, 99
t-Bu
R,R-7
TL 2000, 7303
Kinetic Resolution of Terminal Epoxides via Highly Enantioselective Ring-Opening with Phenols
O
OH
+
O
H
N
R2
R2
OH2 N
Co
t-Bu
R1
R1
racemic
H
OH
R,R-8
TBME
O
t-Bu
2 equivalents
t-Bu
R,R-8
R1
H
H
p-CH3
o-Br
p-NO2
R2
CH2Cl
COCH2CH3
C4H9
C4H9
C4H9
yield
97
96
95
98
93
ee%
99
96
97
92
91
JACS, 1999, 6086
A remarkable dynamic kinetic resolution achieved with epibromohydrin:
O
Br
+
racemic
1.05 equivalents
OH
1.0 equivalent
R,R-8
TBME
4 mol% LiBr
CH3CN
3Å MS
OH
O
Br
t-Bu
O
OC(CF3)3
Enantioselective Opening of Meso Epoxides:
1. R,R-6, (2mol%)
Et2O, TMSN3
R
O
R
2. CSA, CH3OH
R
H
N3
H
N
R
N
Cr
OH
t-Bu
O
t-Bu
O
Cl
t-Bu
t-Bu
R,R-6
Substrate
Product
Yield
N3
O
ee (%)
72%
81
80
95
65
82
OH
N3
FmocN
O
FmocN
JACS, 1995, 5897
OH
H3C
H3C
N3
O
H3C
H3C
OH
• epoxides fused to five-membered rings show higher ee than those fused to 6-membered rings and acyclic substrates