Chiral Allenes - The Stoltz Group

Transcription

y
a
C
C
C
z
b
Orthogonal Bonding
Enantioselective Synthesis of
Axial Chiral Allenes
O
C
CO2Me
Andrew M. Harned
Monday, May 1, 2006
8 pm
147 Noyes
OPh
HO
Ph
HO NPh
OH
NPh D-camphorsulphonic
acid
Ph
Benzene, heat
Ph
NPh
C
NPh
Ph
[α]5461 = +437º
O
Pd(PPh3)4
CO (200 psi)
R2
5 examples
95% ee
OAc
O
O
MsO
R1
OAc
C
THF, R3OH
rt
R1
H
R2
C
CO2R3
80-86% yield
80-93% ee
Axial Chiral Allenes: Useful Curiosities
1) The basics of Allenes and Axial Chirality
a) A brief history of allenes
b) Spectroscopy
c) Types of chiral allenes
d) General axial chirality
e) Natural products with axial chiral allenes
f) Allenes as Pharmaceutical Agents
2) Methods of Synthesizing Axially Chiral Allenes
a) Propargyl alcohol derivatives
b) Elimination from allylic compounds
c) Stiochiometric chiral reagents
c) Kinetic resolution
d) Catalytic methods
3) Conclusions
General Allene Reviews:
(General reviews) Taylor, D. R. Chem. Rev. 1967, 67, 317-359. Pasto, D. J. Tetrahedron 1984, 40, 2805-2827.
(Electrophilic additions to allenes) Smadja, W. Chem. Rev. 1983, 83, 263-320.
(Synthesis with organometallics) Krause, N.; Hoffmann-Röder, A. Tetrahedron 2004, 60, 11671-11694.
(Synthesis of allenic esters) Miesch, M. Synthesis 2004, 746-752.
(Pd reactions of allenes) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Hkan, F. A. Chem. Rev. 2000, 100, 3067-3125.
(Selective reactions with transition metals) Hashmi, A. S. K. Angew. Chem. Int. Ed. 2000, 39, 3590-3593.
Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; Wiley & Sons: New York, 1984.
The Chemistry of the Allenes; Landor, S. R., Ed.; Academic Press: New York, 1982.
The Chemistry of Ketenes, Allenes and Related Compounds; Patai, S., Ed.; The Chemistry of Functional Groups; Wiley & Sons: New York, 1980.
Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004.
Bruneau, C.; Renaud, J.-L. Allenes and cumulenes. In Comprehensive Organic Functional Group Transformations II; Katritzky, A. R., Taylor, R. J. K., Eds.;
Elsevier: Oxford, 2005.
A Brief History of Allenes
1874-1875: Jacobus H. van't Hoff predicts the correct structures of alenes and cumulenes as well as their
axial chirality (La Chemie dans l'Espace, Bazendijk: Rotterdam, 1875).
1887: In an attempt to prove the nonexistence of these compounds, B. S. Burton and H. von Pechmann
report the first synthesis of an allene (Ber. Dtsch. Chem. Ges. 1887, 20, 145-149). The paucity of analytical
techniques make it very difficult to distinguish from the corresponding alkynes, and the structure is not proven
(E. R. H. Jones, G. H. Mansfield, M. L. H. Whiting J. Chem. Soc. 1954, 3208-3212) for almost 70 years!
1924: First naturally occuring allene, pyrethrolone, characterized by H. Staudinger and L. Ruzicka (Helv. Chim. Acta 1924, 7, 177).
HO
O
C
Me
Pyrethrolone
Me
1935: First axially chiral allene synthesized by P. Maitland and W. H. Mills (Nature 1935, 135, 994; J. Chem. Soc. 1936, 987-998).
NPh
Ph
Ph
HO NPh
D-camphorsulphonic
acid
Benzene, heat
Ph
NPh
[α]5461 = +437º
C
NPh
Ph
1952?: First cyclic allenes synthesized by A. T. Blomquist, R. E. Burge, Jr. and A. C. Sucsy (J. Am. Chem. Soc. 1952, 74, 36363642; J. Am. Chem. Soc. 1952, 74, 3643-47). Ring sizes above nine can be isolated. 1,2-Cyclooctadiene can be detected in small
amounts at low temperatures. Ring sizes of seven or below cannot be isolated or detected. Their intermediacy has been determined
through trapping/degradation studies. M. Regitz and coworkers have described a stable six membered cyclic allene, but is not a
hydrocarbon (Angew. Chem. Int. Ed. 2000, 39, 1261-1263).
Structure and Spectroscopy of Allenes
IR Spectroscopy: The diagnostic stretch can be found at 2000-1900 cm-1 (C=C=C asymm. stretch) and is usually strong.
For comparison, alkynes are at 2260-2100 cm-1 and olefins are at 1690-1635 cm-1.
Only other functional groups near this range are: diazo, cyanates, isocyanates, thiocyanates,
isothiocyanates, and ketenes; but are typically at slightly higher wavenumbers.
1H
NMR Spectroscopy: Typically in the same area as olefinic protons, but slightly upfield (~4.4 - 4.9 ppm).
13C
NMR Spectroscopy: Cα and Cγ are more upfield than typical olefin (~73 - 120 ppm).
Cβ is actually slightly more downfield than a ketone! (200-220 ppm)
sp
a
sp2
y
Cα Cβ
Cγ
b
z
O
y
a
O
C
C
C
b
Orthogonal Bonding
z
TMS
O
PhHN
C
O
Schultz-Fademrecht, C.; Wibbeling, B.; Fröhlich, R.;
Hoppe, D. Org. Lett. 2001, 3, 1221-1224.
H
N(i-Pr)2
Structure and Spectroscopy of Allenes
IR Spectroscopy: The diagnostic stretch can be found at 2000-1900 cm-1 (C=C=C asymm. stretch) and is usually strong.
For comparison, alkynes are at 2260-2100 cm-1 and olefins are at 1690-1635 cm-1.
Only other functional groups near this range are: diazo, cyanates, isocyanates, thiocyanates,
isothiocyanates, and ketenes; but are typically at slightly higher wavenumbers.
1H
NMR Spectroscopy: Typically in the same area as olefinic protons, but slightly upfield (~4.4 - 4.9 ppm).
13C
NMR Spectroscopy: Cα and Cγ are more upfield than typical olefin (~73 - 120 ppm).
Cβ is actually slightly more downfield than a ketone! (200-220 ppm)
sp
a
sp2
y
Cα Cβ
Cγ
b
z
O
O
a
y
TMS
O
z
b
Orthogonal Bonding
PhHN
C
O
Schultz-Fademrecht, C.; Wibbeling, B.; Fröhlich, R.;
Hoppe, D. Org. Lett. 2001, 3, 1221-1224.
H
N(i-Pr)2
Types of Chiral Allenes
Asymmetric allenes
(no element of symmetry)
A
H
H
•
A
B
D
H
B
H
D
A
B
H
•
B
(S)
A
•
A
H
D
H
D
A
•
A
D
D
B
D
•
A
B
E
B
(R)
Dissymmetric allene
(C2 proper axis of rotation)
A
A
•
B
B
H
H
•
A
B
(S)
D
D
A
B
(S)
Chiral Allene Reviews: Rossi, R.; Diversi, P. Synthesis 1973, 25-36. Runge, W. Stereochemistry of Allenes. In The Chemistry of Allenes; Landor, S. R., Ed.;
Academic Press: New York, 1982; 580-678. Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; Wiley & Sons: New York, 1984, 1-8. HoffmannRöder, A.; Krause, N. Angew. Chem. Int. Ed. 2002, 41, 2933-2935. Ohno, H.; Nagaoka, Y.; Tomioka, K. Enantioselective synthesis of Allenes. In Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; 141-181.
Types of Chiral Allenes
Asymmetric allenes
(no element of symmetry)
A
H
H
•
A
B
D
H
B
H
D
A
B
H
•
B
(S)
A
•
A
H
D
H
D
A
•
A
D
D
B
D
•
A
B
E
B
(R)
Not covered
Allene is not stereogenic
Dissymmetric allene
(C2 proper axis of rotation)
A
A
•
B
B
H
H
•
A
B
(S)
D
D
A
B
(S)
Chiral Allene Reviews: Rossi, R.; Diversi, P. Synthesis 1973, 25-36. Runge, W. Stereochemistry of Allenes. In The Chemistry of Allenes; Landor, S. R., Ed.;
Academic Press: New York, 1982; 580-678. Schuster, H. F.; Coppola, G. M. Allenes in Organic Synthesis; Wiley & Sons: New York, 1984, 1-8. HoffmannRöder, A.; Krause, N. Angew. Chem. Int. Ed. 2002, 41, 2933-2935. Ohno, H.; Nagaoka, Y.; Tomioka, K. Enantioselective synthesis of Allenes. In Modern Allene
Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; 141-181.
General Axial Chirality
Determining configuration
1
CO2H
4
H
3
CH3
CCW = (S)
2
C4H9
HO2C
H
•
C4H9
1
CH3
4
C4H9
3
CO2H
CH3
H
2
CCW = (S)
R=M
S=P
Predicting absolution configuration and magnitude of rotation (Lowe-Brewster Rule)
J. H. Brewster (Topics in Stereochemistry, 1967, 2, 1-72):
Through mathematical models, the actual optical rotation of optically pure chiral allenes can be calculated. At one time this
was a very common method to determine approximate optical purity (i.e. % ee). Not very amenable to more complicated
systems, and has now been supplanted by GC, HPLC, and NMR methods.
G. Lowe (J. Chem. Soc., Chem. Commun., 1965, 411-413):
The absolute configuration can be assignned based on the sign (+ or -) of rotation. From this, you can then assign S or R.
A
X
Y
B
Most polarizable group A is placed at the top. If Y is more polarizable than X, the allene will
be dextrorotatory (+). If X is more polarizable than Y, the allene will be levorotatory (-).
General Axial Chirality
Determining configuration
1
4
H
CO2H
HO2C
3
CH3
H
•
C4H9
CCW = (S)
2
1
CH3
4
C4H9
3
CO2H
CH3
C4H9
H
2
CCW = (S)
R=M
S=P
Predicting absolution configuration and magnitude of rotation (Lowe-Brewster Rule)
J. H. Brewster (Topics in Stereochemistry, 1967, 2, 1-72):
Through mathematical models, the actual optical rotation of optically pure chiral allenes can be calculated. At one time this
was a very common method to determine approximate optical purity (i.e. % ee). Not very amenable to more complicated
systems, and has now been supplanted by GC, HPLC, and NMR methods.
G. Lowe (J. Chem. Soc., Chem. Commun., 1965, 411-413):
The absolute configuration can be assignned based on the sign (+ or -) of rotation. From this, you can then assign S or R.
Ph
H
CO2H
Ph
HO2C
Ph
Cl
Me
t-Bu
H
H
H
(+)-S
(-)-R
(-)-S
Allenes as Natural Products
Not just curiosities anymore
CO2Me
O
NH3
nC8H17
C
H
C
O H
Br
~80% ee
H
H
C
CO2
Et
H
Br
H
H
OH
HO
H
Isolaurallene
Insect Pheromone
"Grasshopper Ketone"
OH
H
O
H
C
C
H
C
O
H
OH
HO
O
HO
H
O
C
Mimulaxanthin
H
H
Br
Okamurallene
C
AcO
OAc
C
H
O
O
OAc
O
O
OH
H
O
O
C C
O
O
HN
C
H
Acalycixeniolide E
Anti-angiogenic
Isodihydrohistrionicotixin
Nicotine acetylcholine receptor active
About 150 Natural Allenes are known. Most are chiral but not necessarily enantiopure.
Krause, N.; Hoffmann-Röder, A. Allenic Natural Products and Pharmaceuticals. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004; 997-1039.
Allenes as Pharmaceutical Agents
Not just curiosities anymore
H
CO2Na
CO2
O
C
C
CO2Me
C
NH3
OH
OPh
HO
OH
Vitamin B6-dependent
decarboxylase inhibitor
(suicide substrate)
Enprostil
Gastric acid inhibitor
OH
OH
OH
Anti-thrombotic agent
O
NH2
N
O
N
N
N
H
P(OEt)2
NH2
N
N
C
OH
H
(R)-Cytallene
C
H
C
OH
H
(R)-Adenallene
MeO
Sterol biosynthesis inhibitor
(AIDS-related pathogen)
Inhibitors of HIV and Hepatitis B replication
Krause, N.; Hoffmann-Röder, A. Allenic Natural Products and Pharmaceuticals. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004; 997-1039.
Chirality Transfer from Propargylic Alcohols
A) Copper-Mediated Methods
Alkylation
Halogenation
B) Rearrangements
D) SN2' reactions
C) Palladium (0)-Mediated Methods
anti-elimination
Nu
R1
R3
Nu
R2
R3
R1
R2
LG
R1
R2
Nu
C
R3
LG
syn-elimination
R1
R2
OH
R3
Z Nu
R2
R1
R3
O
Z
Nu
R1
R2
R3
C
Nu
The Beginnings
R1
R3
R1
LiCuR42
R3
C
R2
R2
OAc
R4
Rona, P.; Crabbé, P. J. Am. Chem. Soc. 1969, 91, 3289-3292.
anti-elimination
R2
R1
H
LG
MCuR22
H
R1
LG
Cu
R2
R2
R1
H
Cu
R2
Red.
Elim.
C
H
R1
H
R2
C
H
Luche, J.-L.; Barreiro, E.; Dollat, J.-M.; Crabbé, P. Tetrahedron Lett. 1975, 4615.
Dollat, J.-M.; Luche, J.-L.; Crabbé, P. J. Chem. Soc., Chem. Comm. 1977, 761-762.
Many studies with steriodal stystems. Complications due to racemization of product by dialkyl cuprates.
Proparglyic Esters
nonsteriodal, acyclic allenes
R1
H
R2CuBr⋅MgBr⋅LiBr
R1
H
[{RCuX}M]
LG
R1
[R2CuX][MgX]
H
H
R1
C
H
70-96% yield
>98% anti-selectivity
R1 = Ph, t-Bu, octyl, Me
LG = OS(O)Me or OSO2Me
R2
R2
R2
X
Cu
H
R1
R2
X
Cu
- LG
R1
H
LG
LG
III
Cu
R2
C
H
LG
- CuIX
L
Cu
dxz
px
R
R1
R1
C
H
σ*
C
π
H
H
R2
C
H
π*
O
Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726-3730.
Corey Tetrahedron Lett. 1984, 25, 3063-3066
Proparglyic Esters
CBr4
PPh3, Pyr
Cu
3
PO
THF
97%
D-Mannitol
CO2Me
C
88%
Br
H
3
CO2Me
H
(R)
>94% ee
25
[α] D -63.8° (c = 0.43, MeOH)
4 steps
TBDPSO
62%
PO
OH
>97% ee
Cu
TsCl, Et3N
3
PO
C
H
3
H
CO2Me
TBAF
96%
OTs
H
H
3
CO2Me
(S)
>94% ee
[α]25D +65.0° (c = 0.34, MeOH)
HO
C
THF
98%
PO
C
CH2Cl2
99%
TBDPSO
CO2Me
H
3
CO2Me
H
Antifungal constituent from
Sapium japonicum
lit. [α]12D -51.3° (c 0.94, CHCl3)
[α]25D -53.4° (c = 0.31, CHCl3)
Gooding, O. W.; Beard, C. C.; Jackson, D. Y.; Wren, D. L.; Cooper, G. F. J. Org. Chem. 1991, 56, 1083-1088.
Enantioenriched Propargyl Alcohols
O
PO
C7H15
OP = OSit-Bu2Ph
LiBr, Cu2I2
MeMgBr
THF, 0 °C
80%
Me
PO
THF, 20 °C
63%
CBr4, PPh3
Pyr, THF, 20 °C
OH
(R)-Alpine borane
PO
63%
C7H15
Br
PO
88% ee
Me
N N
H
C
C7H15
C8H17O
S
C7H15
52% ee
O
H
C
C7H15
liquid crystalline properties
Zab, K.; Kruth, H.; Tschierske, C. J. Chem. Soc., Chem. Comm. 1996, 977-978.
O
2.5 mol% [(p-cymene)RuCl2]2
(S,S)-TsDPEN, KOH, i-PrOH
OH
75%
Ph
Buisine, O.; Aubert, C.; Malacria, M. Synthesis 2000, 985-989.
Ph
>95% ee
a) BuLi,
THF, -78 °C
b) MsCl
c) MeCuCNMgBr
71%
C
Ph
Me
>95% ee
O
PO
C7H15
OP = OSit-Bu2Ph
LiBr, Cu2I2
MeMgBr
THF, 0 °C
80%
Me
PO
THF, 20 °C
63%
CBr4, PPh3
Pyr, THF, 20 °C
OH
(R)-Alpine borane
PO
63%
C7H15
PO
C7H15
88% ee
C8H17O
S
C7H15
52% ee
H
Me
N N
H
C
Br
C
O
C7H15
liquid crystalline properties
Zab, K.; Kruth, H.; Tschierske, C. J. Chem. Soc., Chem. Comm. 1996, 977-978.
BuLi, Ph2P(O)Cl
THF, -78 to 50 °C
C
Ph
CpCo
78%
Me
Ph
Me
PPh2
O
Buisine, O.; Aubert, C.; Malacria, M. Synthesis 2000, 985-989.
CpCo(CO)2
C
H
THF, Δ, hν
quant.
Ph2P
O
>95% ee
Me
Ph
O
H17C8
91%
MsCl
TEA
OH
(S)-BINAL-H
C8H17
OMs
C8H17
DCM, 0 ºC
95%
95% ee
H17C8
H
TMS
MgCl
LiBr, CuBr, THF
-60 ºC to rt
95%
C
TMS
H17C8
Cp2ZrCl2, BuLi
CO, 20 psi
H
THF
-78 ºC to rt to 0 ºC
39%
O
TMS
85% ee
Brummond, K. M.; Kerekes, A. D.; Wan, H. J. Org. Chem. 2002, 67, 5156-5163.
1) Ph
CHO
Ph
+
Me
HO
NMe2
Zn(OTf)2
PhMe, 23 ºC
2) MsCl, TEA
CH2Cl2, -40 ºC
80%
Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858.
1)
OMs
Boc
Ph
99% ee
N
CuCNLi
82%
2) TMSOTf
CH2Cl2, -40 ºC
99%
H
Ph
C
MeHN
83% ee
Enantioenriched Cyclic Allenes
OAc
Lipase
(Mucor miehei)
OAc
OH
+
n
Phosphate
Buffer
A, n = 1
B, n = 2
OAc
n
n
(S)-A-OAc
40% (64% ee)
(R)-A-OH
43% (91% ee)
(S)-B-OAc
50% (60% ee)
(R)-B-OH
20% (90% ee)
OAc
RMgX
CuBr, LiBr
THF, -70 ºC
(91% ee)
RMgX
C
R
(+)
R = Bu, i-Pr, t-Bu
(60% ee)
CuBr, LiBr
THF, -70 ºC
R = Bu, i-Pr, t-Bu
C
R
(-)
(60% ee)
% ee determined for R = Bu, t-Bu by GC,
Enantioseparation not achieved for others
Zelder, C.; Krause, N. Eur. J. Org. Chem. 2004, 3968-3971.
Silyl Cuprates
1a) HCCMgBr, DCM
-78 to 0 °C, 89%
b) Separate 2:1 dr
OBn
OHC
OBn
OTBS
OTBS
2) Ac2O, TEA, DMAP
DCM, 98%
or
DEAD, PPh3, HOAc
Pyr, THF
-45 °C to rt, 86%
CN
1) (Me2PhSi)2Cu(CN)Li2
THF, -96 °C, 84%
AcO H
CN
2) DIBALH, PhMe
-78 to 0 °C, 78%
OBn
Me2PhSi
C
H
OTBS
H
CHO
O
O
Br
N
PPh3
mesitylene
50 °C then reflux
H
Ar
N
SiPhMe2
H
H
C
OBn
OBn
Br
2) TBAF, THF, 0 °C
63% overall
N
H
OTBS
O
OTBS
O
OMe
O
O
OH
N H
(-)-coccinine
Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997, 119, 2050-2051.
For an alternative approach to allenyl silanes, see: Guintchin, B. K.;
Bienz, S. Organometallics 2004, 23, 4944-4951.
Propargylic Silanes
OMs
TMS
Me
H
TMS
HSiCl3, CuCl
C
R
DIEA, RCHO
DMF
OMs
Me
H
H
TMS
Me
"CuSiCl3"
reductive
elimination
Me
OH
TMS
H
C
CuX
TMS
H
XCu
SiCl3
C
Cl3Si
RCHO
Me
TMS
C
R
OH
H
Me
H
SiCl3
TMS
O
R
Me
H
SiCl3
TMS
SiCl3
TMS
55-92% yield
89:11 to 98:2
>95% chirality transfer
R
+
OH
TMS
- CuCl
Me
Me
Me
H
RCHO
TMS
C
Cl3Si
O
Me
Me
H
H
R
H
This Work: Marshall, J. A.; Adams, N. D. J. Org. Chem. 1997, 62, 8976-8977.
For similar chemistry with stannanes, see: Marshall, J. A.; Yu, R. H.; Perkins, J. F. J. Org. Chem. 1995, 60, 5550-5555.
R
TMS
OH
SN2' reaction
H
CO2Me
DIBAL-H
CH2Cl2
0 ºC
80%
O
HO
OH
C
HO
OH
O
enantiomerically pure
H
H
OBn
+
Br
OH
O
O
94% ee
91:9 dr
Et
1) AgNO3
2) H2, Pd/C
H
C9H19MgBr
CuBr (10 mol%)
Me
O
OH
peridinine
HO
Bn
N
N Al N
Tf
Tf
Me
10 mol %
O
C
Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S.
Angew. Chem. Int. Ed. 2002, 41, 1023-1026.
O
O
THF
-78 ºC
C
C9H19
Me
CO2H
OBn
BnO
Me
C9H19
O
O
94% ee
OH
(-)-malyngolide
antibiotic
Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470-10471.
Halogenations
Syn-halogenation
Me
48% aq HBr
CuBr, NH4Br
Cu powder
t -Bu
HO
H
1
"HCuCl2"
Me
t -Bu
H2O
L
Cu
L
Br
Original proposed mechanism
Syn
t -Bu
C
Me
H
Br
No 2H-exchange at C-1 in D2O/DBr,
or in H2O/HBr with 1-d alcohol
Landor, S. R.; Demetriou, B.; Evans, R. J.; Grzeskowiak, R.; Davey, P. J. Chem. Soc., Perkin Trans. 2 1972, 1995-1998.
Halogenations
Syn-halogenation
Me
48% aq HBr
CuBr, NH4Br
Cu powder
t -Bu
HO
t -Bu
Me
H
t -Bu
Syn
1
H
C
H
Cu Br
HO
"HCuCl2"
Br
Me
Br
No 2H-exchange at C-1 in D2O/DBr,
or in H2O/HBr with 1-d alcohol
Landor, S. R.; Demetriou, B.; Evans, R. J.; Grzeskowiak, R.; Davey, P. J. Chem. Soc., Perkin Trans. 2 1972, 1995-1998.
Syn or Anti-halogenation?
H
Ph
HCuCl2
H
Ph
H
C
I
HCuI2
syn
~6% ee
Ph
C
H
~4% ee
H
HO
optically
pure
Cl
anti
HCuBr2
H
Ph
Br
C
H
~22% ee
Authors conclude syn-elimination is not general for HCuX2.
Substituting for sulfinate ester gave better anti selectivity for X = Cl (24% ee) and X = Br (52% ee). X = I also gave anti, but
low selectivity (~6% ee).
Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1984, 49, 1649-1650.
Halogenations
Anti-halogenation
H
Ph
HO
81% ee
SOCl2
Et2O
0 ºC to rt
67%
H
Ph
Bu4NCuCl2
Acetone
62%
Cl
18% ee
Cl
H
C
Ph
H
[α]25D -94º (c 0.9, CHCl3)
Muscio, O. J.; Jun, Y. M.; Philip, Jr., J. B. Tetrahedron Lett. 1978, 2379-2382.
Ph
H
HO
a) BuLi, THF
-70 ºC
b) MsCl
Ph
H
c) cuprate
-70 to 20 ºC
Ph
H
MsO
50% ee
X
C
H
[α]20D deg (c 2, EtOH)
cuprate equiv. X = Cl X = Br X = I
Elsevier, C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos, H. J. T.;
Vermeer, P. J. Org. Chem. 1982, 47, 2194-2196.
LiCuX2
LiCu2X3
LiCu2X3
1.2
0.6
1.2
530
600
610
920
1220
1040 1350
1235 1550
Halogenations
OTs
1) TMSCCLi
HMPA, THF, -78 ºC
O
2) TsCl, TEA, DMAP
DCM, 0 ºC to rt
88%
CHO
O
H
CuBr
LiBr
NBoc
TMS
C
O
THF
60 ºC
70%
NBoc
Br
TMS
NBoc
OTs
1) TMSCCLi
HMPA, THF, -78 ºC
O
2) TsCl, TEA, DMAP
DCM, 0 ºC to rt
89%
H
CuBr
LiBr
NBoc
TMS
C
O
THF
60 ºC
75%
NBoc
TMS
Br
D'Aniello, F.; Schoenfelder, A.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 9631-9636.
H
O
1) t-BuOOH
(+)-tartrate, 94%
H
O
Cl
2) PPh3, NCS
84%
OH
TESO
Et
1) LDA, THF, 87%
2) ArSO2Cl, 96%
>98:2 dr
HO
H
H
O
O
H
H
LiCuBr2
67%
ArO2SO
OH
TESO
C
Br
H
1) PPTS, MeOH
2) CBr4, oct3P
58%
Et
H
H
Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123, 1533-1534
OH
Br
C
Et
Br
(-)-isolaurallene
H
Rearrangements
SOBr2
propylene
oxide
t-Bu
t-Bu
Me
Me
Me
Br
Et2O, 0 ºC
OH
S
C
O
Br
O
94% ee
t-Bu
H
t-Bu
+ Me
Br
52% yield, 90:10
Coery, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3055-3058.
Initial studies: Evans, R. J. D.; Landor, S. R.; Smith, R. T. J. Chem. Soc. 1963, 1506-1511.
Evans, R. J. D.; Landor, S. R. J. Chem. Soc. 1965, 2553-2559.
Ortho Claisen rearrangement
OH
EtC(OEt)3
t-Bu
Me
EtO
H
O
t-Bu
EtCO2H
E
98% ee
H
C
EtO2C
Me
A
H
EtO
t-Bu
H
E'
Me
O
H
t-Bu
EtO
Me
O
H
t-Bu
Z'
EtO
H
t-Bu
EtO2C
Me
B
O
t-Bu
Me
Z
rapid equilibrium, E reacts faster
Henderson, M. A.; Heathcock, C. H. J. Org. Chem. 1988, 53, 4736-4745.
H
C
A:B = 9:1
complete chirality transfer
Rearrangements
TMS
CHO
+
Sn(OTf)2
L* (cat)
O
TMSO
O
OTMS
1) deprotection
EtS
EtS
EtS
Me
Me
TMS
92% ee
2) MeC(OEt)3
EtCO2H
86%
C
Me
CO2Et
TMS
92% ee
Mukaiyama, T.; Furuya, M.; Ohtsubo, A.; Kobayashi, S. Chem. Lett. 1991, 989-992.
TBSO
O
CO2Et
MeC(OEt)3
H
OH
HCO2H
70%
OPh
THPO
C
OTHP
H
H
1 isomer
CO2Me
C
H
OPh
HO
OH
enprostil
1) CBr4, PPh3
2)
Cu
CO2Me
78%
C
H
CO2Me
H
1 isomer
Cooper, G. F.; Wren, D. L.; Jackson, D. Y.; Beard, C. C.; Galeazzi, E.; Van Horn, A. R.; Li, T. T. J. Org. Chem. 1993, 58, 4280-4286.
Rearrangements
H
H
OH
(CH2)6CH3
MeC(OEt)3
H+
71%
OTIPS
(CH2)6CH3
C
EtO2C
OTIPS
H
OH
2) CH2N2
80%
HO2C
O
C7H15
*
C
C7H15
dr 93:7
complete transfer
of chirality
Me
H
Me
1) CH2N2
2) LDA, Cp2ZrCl2
THF, -78 ºC, 57%
5
clavepictine A, R = Ac
clavepictine B, R = H
[2,3]-Wittig Rearrangement
MeO2C
Me
Me
Ha, J. D.; Lee, D.; Cha, J. K. J. Org. Chem. 1997, 62, 4550-4551.
Ha, J. D.; Cha, J. K. J. Am. Chem. Soc. 1999, 121, 10012-10020.
1) LDA
N
RO
One
diastereomer
C7H15
AgNO3
MeO2C
O
MeO
Me
O
M
O
Me
H
H
Me
H
O
Marshall, J. A.; Robinson, E. D.; Zapata, A. J. Org. Chem. 1989, 54, 5854-5855.
Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 55, 2995-2996.
Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1990, 56, 4913-4918.
Me
MeO
O
H
M Me
Favored
Rearrangements
H
HN
OH
NBSH
R2
R1
PPh3, DEAD
-15 ºC
N
SO2Ar
H
- HSO2Ar
R2
N
N
R2
R1
R1
- N2
R1
23 ºC
71-91%
H
H
C
R2
complete
transfer of
chirality
Meyers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-4493.
For a synthetic application of this, see: Shepard, M. S.Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 2597-2605.
OH
H
ClP(OEt)2
TEA
C
O
O
N
Boc
DCM
-10 ºC to rt
HO2C
N
Boc
Muller, M.; Mann, A.; Taddei, M. Tetrahedron Lett. 1993, 34, 3289-3290.
P(O)(OEt)2
H
PO3H2
NH2
AP5
NMDA antagonist
Palladium Catalysis
transmetallation
2.5-3.2 mol%
Pd(PPh3)4
PhZnCl
H
Ph
PhZnCl
C
Ph
THF/Et2O
-50 to 25 ºC
X
Ph
PdXL2
H
H
H
Ph
PdL2
C
L2XPd
28% ee
X = OAc, OTFA,
OS(O)Me
C
85% ee
Ph
H
Me
THF
C
Ph
H
82:18 anti/syn
(Determined by
correlation of rotations)
Elsevier, C. J.; Stehouwer, P. M.; Westmijze, H.; Vermeer, P. J. Am. Chem. Soc. 1983, 48, 1103-1105.
Bu
Ph
H
H
Ph
CuI, ZnCl2
i-Pr2NH, Pd(PPh3)4
Ph
H
OCO2Et
Bu
cat. Pd(PPh3)4
PhZnBr
H
Me
93% ee
C
THF
Substituting Ph at alkyne terminus resulting in lower stereoselectivity
Dixneuf, P. H.; Guyot, T.; Ness, M. D.; Roberts, S. M. J. Chem. Soc., Chem. Comm. 1997, 2083-2084.
Bu
Ph
83% ee
H
Me
Palladium Catalysis
transmetallation
H
Ph
conditions
C
H
X = OH
10% ee
X
Ph
10 mol%
Pd(PPh3)4
B(OH)2
+
92% ee
C
H
dioxane
100 ºC
10 min
76%
X = OCO2Me
H
H
Ph
92% ee
Yoshida, M.; Gotou, T.; Ihara, M. Tetrahedron Lett. 2004, 45, 5573-5575.
Ph
O
10 mol%
Pd(PPh3)4
B(OH)2
+
OH
2:1 dioxane/H2O
80 ºC, 1-3 h
92%
92% ee
Ph
C
92% ee
Yoshida, M.; Ueda, H.; Ihara, M. Tetrahedron Lett. 2005, 46, 6705-6708.
R
H
H
conditions
C
Ph
>95% ee
X
R
X = OBz
R = Me
+
Ph3In
H
100% ee
Riveiros, R.; Rodriguez, D.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 2006, 8, 1403-1406.
Pd(DPEphos)Cl2
R
THF, rt, 8h
70%
H
X = OAc, OBz
R = Ph
H
C
Ph
84-86% ee
Palladium Catalysis
Carbonylation
O
R4O
1 mol% Pd2(dba)3⋅CHCl3
8 mol% PPh3
CO (1-30 atm)
O
R1
(±)
R2
R3
R1
R1
C
L2Pd
R4OH, 20-100 ºC
1-44 h
R3
R2
OR4
R3
C
R1
R2
O
C
O
PdL2
OR4
(±)
44-99% yield
R4O
Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986, 27, 731-734.
OMOM
MeO2CO
3
C6H13
5 mol% Pd2(dba)3
20 mol% PPh3
CO (1 atm)
2:1 PhH/MeOH
50-60 ºC, 4.5 h
70% ee
MOMO
H
C6H13
3
C
CO2Me
70% yield
<5% ee
Possible racemization by PPh3
Marshall, J. A.; Wolf, M. A. J. Org. Chem. 1996, 61, 3238-3239.
Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997, 62, 367-371.
R3
R2
Palladium Catalysis
Carbonylation
O
R4O
1 mol% Pd2(dba)3⋅CHCl3
8 mol% PPh3
CO (1-30 atm)
O
R1
(±)
R2
R4OH, 20-100 ºC
1-44 h
R3
R1
R1
R3
C
C
R2
L2Pd
O
R3
R1
R2
C
O
PdL2
OR4
OR4
(±)
44-99% yield
R4O
Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986, 27, 731-734.
MsO
R2
R1
5 examples
95% ee
Pd(PPh3)4
CO (200 psi)
THF, R3OH
rt
R1
H
R2
R2
I
IBr
C
CO2R3
80-86% yield
80-93% ee
CH2Cl2
-78 ºC
1h
R1
O
O
89-97% yield
80-93% ee
Marshall, J. A.; Wolf, M. A. J. Org. Chem. 1996, 61, 3238-3239.
Marshall, J. A.; Wolf, M. A.; Wallace, E. M. J. Org. Chem. 1997, 62, 367-371.
Pd-catalyzed formation of butenolides from allenic acids with high chirality transfer: Ma, S.; Shi, Z. J. Chem. Soc., Chem. Commun. 2002, 540-541.
R3
R2
Palladium Catalysis
Carbonylation
OH
14 steps
BuLi
O
THFpentane
-78 ºC
88%
O
$$
MsCl
Et3N
CH2Cl2
-78 ºC
O
Pd(PPh3)4
CO (1 atm)
O
O
TMSCH2CH2OH
THF
75%
(2 steps)
MsO
PPh3
CH3CN
55 ºC
92 h
O
H
C
HO
H
R = OCH2CH2TMS
C
CO2R
1 diastereomer
1) TBAF, THF
93%
2) AgNO3
Acetone, 68%
CO2R
85:15
Marshall, J. A.; Wallace, E. M.; Coan, P. S. J. Org. Chem. 1995, 60, 796-797.
Marshall, J. A.; Bartley, G. S.; Wallace, E. M. J. Org. Chem. 1996, 61, 5729-5735.
O
O
O
(-)-kallolide B
(unnatural)
Palladium Catalysis
R
5 mol% Pd(OAc)2
7.5 mol% dppe
O
R
H
O
THF
S
O
S
O
Tol
87% ee
R = Me, Pentyl
insertion
H
H
C
R
PdL2
reductive
elimination
PdL2
H
H
C
R
SO2Tol
TolO2S
Tol
Hiroi, K.; Kato, F. Tetrahedron 2001, 57, 1543-1550.
2 mol% Pd(acac)2
Ph2Si
SiMe2Ph
C6H13
NC
8 mol%
O
Toluene, reflux
O SiPh2
then BuLi
SiMe2Ph
Me
C6H13
Me
97% ee
CHO
OH
TiCl4
Suginome, M.; Matsumoto, A.; Ito, Y. J. Org. Chem. 1996, 61, 4884-4885.
Me
THF, -78 ºC
86%
C6H13
76% yield
95:5 syn:anti
93% ee
H
Me
SiMe2Ph
C
C6H13
Allenylmetal Compounds
TMS
1.5 equiv Ti(Oi-Pr)4
3 equiv i-PrMgCl
Et2O, -50 to -40 ºC
R2
R1
TMS
(i-PrO)2XTi
C
A
TMS
X
R2
Ph
Ti(Oi-Pr)2
Ti(Oi-Pr)4
+
2 i-PrMgCl
Ti(Oi-Pr)2
R1
R2
Ti(Oi-Pr)2
TMS
X
R1 R2
R2
R1
PhCHO
R1
Ti(Oi-Pr)2
C
OH
OH
72-87% yield
A
Ph
R1
R1
X = OCO2Et or OPO(OEt)2
TMS
R2
PhCHO
R2
TMS
Okamoto, S.; An, D. K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551-4554.
(Mechanism) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 3207-3210.
X
TMS
Ti(Oi-Pr)2
%ee / Config.
TMS
Bu
H
97% ee
TMS
OCO2Et
Bu
H
97% ee OPO(OEt)
2
TMS
C
(i-PrO)2XTi
Bu
2
H
Me
OPO(OEt)2
Bu
H
49 / (1R,2S)
49 / (1S,2S)
Ph 1 OH
Ph 1 OH
(i-PrO)2XTi
C
TMS
Bu
2
H
C
(i-PrO)2XTi
R
Bu
94 / (1S,2R)
94 / (1R,2R)
Me
85 / (2S)
H
TMS
TMS
Me
2
OCO2Et
TMS
87% ee
TMS
TMS
Me
87% ee
TMS
Ph 1 OH
(i-PrO)2XTi
C
TMS
Ph 1 OH
R
TMS
Okamoto, S.; An, D. K.; Sato, F. Tetrahedron Lett. 1998, 39, 4551-4554.
(Mechanism) Nakagawa, T.; Kasatkin, A.; Sato, F. Tetrahedron Lett. 1995, 36, 3207-3210.
8.3 / (2R)
2
Me
Me
Oi-Pr
Oi-Pr
i-PrO Ti
(i-PrO)2XTi
anti
Bu
C
H
TMS
O
P
TMS
(OEt)2
i-PrO Ti
Bu
(i-PrO)2XTi
C
Me
H
TMS
2º phosphate
(high selectivity)
O
anti
O
P
TMS
(OEt)2
Bu
H
3º phosphate
(low selectivity)
O
TMS
i-PrO
i-PrO
Ti
O
R1
H
95 or 98% ee
C
O
OEt
TMS
TMS
syn
Me
(i-PrO)2XTi
Song, Y.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 3543-3545.
Me
2º or 3º carbonate
(moderate selectivity)
1.5 equiv Ti(Oi-Pr)4
3 equiv i-PrMgCl
Et2O, -50 to -40 ºC
OPO(OEt)2
R
CO2Et
R2
R2
TMS
CO2Et
CO2Et
R1
CO2Et
> 97:3 anti:syn
> 88 to 96% ee
For reviews of the synthesis and reactivity of allenylmetal compounds, see: Marshall, J. A. Chem. Rev. 1996, 96, 31-47. Marshall, J. A. Chem. Rev. 2000,
100, 3163-3185. Marshall, J. A.; Gung, B. W.; Grachan, M. L. Synthesis and reactions of allenylmetal compounds. In Modern Allene Chemistry; Krause, N.,
Hashmi, A. S. K., Eds.; Wiley-VCH: Weinheim, 2004; 493-592.
Allylic Elimination (β-elimination)
A) Chirality transfer from allylic position
LG
Z
R3
LG
X
"Activator"
Z
R1
R3
C
X
R1
R2
R1
R2
R2
H
R3
B) Chiral leaving groups
HR
R4
HS
Y
R1
R3
R2
Y = S, Se
O
oxidation
R4
HR
Y
HS
R3
R1
R2
- HOYR4
R1
C
R2
H
R3
Chirality at allylic position
Bu3SnH
AIBN
OH
Me
C6H13
OH
Me
neat
90 ºC
MsCl
TEA
C6H13
SnBu3
94% ee
CH2Cl2
0 ºC to rt
OH
O
CBS
reduction
Swern
Me
C6H13
SnBu3
H
Me
C6H13
SnBu3
H
C
C6H13
51% ee
anti elimination
Konoike, T.; Araki, Y. Tetrahedron Lett. 1992, 33, 5093-5096.
Me
Bu3SnH
AIBN
OH
Me
C6H13
OH
Me
neat
90 ºC
OH
Me
SnBu3
94% ee
81%
C6H13
CBS
reduction
Me
C6H13
SnBu3
SnBu3
OAc
Ac2O
DMAP
C6H13
O
Swern
TBAF
Me
C6H13
H
Me
H
C
C6H13
94±2% ee
anti elimination
SnBu3
F
Konoike, T.; Araki, Y. Tetrahedron Lett. 1992, 33, 5093-5096.
O
R
1) OHC
CO2Me
LDA, THF, -78 ºC
31% (78% brsm)
O
Tol
S
Tol
51%
H
-78 ºC
10 min
95%
C8H17
H
C
CO2Me
81% ee
O
C8H17
R
Tol
44%
Satoh, T.; Hanaki, N.; Kuramochi, Y.; Inoue, Y.;
Hosoya, K.; Sakai, K. Tetrahedron 2002, 58, 2533-2549.
OAc
C8H17
2) Ac2O
(R)
S
6 equiv
i-PrMgCl
S
6 equiv
i-PrMgCl
OAc
C8H17
-78 ºC
10 min
91%
CO2Me
H
C
C8H17
84% ee
H
1) Ph
O
R1
PPh2
N
Ph
Li
TMSCl, THF, -78 ºC
O
PPh2
R1
2) H2O
3) TBAF, THF
R1=Ph, R2=t-Bu, 87%, 28% ee
R1=t-Bu, R2=t-Bu, 58%, 51% ee
R2
OH
NaH
DMF
60 ºC
R1
R2
Ph Ph
P O
R2
O
H
R1
C
H
R1=Ph, R2=t-Bu, 89%, ~12% ee
R1=t-Bu, R2=t-Bu, 74%, ~23% ee
This work: Fox, D. J.; Medlock, J. A.; Vosser, R.; Warren, S. J. Chem. Soc., Perkin Trans. 1 2001, 2240-2249.
For related achiral systems, see: Nagaoka, Y.; Tomioka, K. J. Org. Chem. 1998, 63, 6428-6429. Inoue, H.; Tsubouchi, H.; Nagaoka, Y.; Tomioka, K.
Tetrahedron 2002, 58, 83-90.
Chiral leaving groups
R
Ts
Et3N
or
KOtBu
R
SAE
or
Davis
Ts Epoxidation
O
nC7H15
ArSe
H
- ArSeOH
nC7H15
SeAr
ArSe
H
C
H
H
Ts
Not isolated
Can racemize with H2O
Komatsu, N.; Murakami, T.; Nishibayashi, Y.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 3697-3702.
45 examples
9-100% yield
1-42% ee
Ts
Chiral leaving groups
R
Ts
Et3N
or
KOtBu
SAE
or
Davis
Ts Epoxidation
R
O
nC7H15
ArSe
H
nC7H15
- ArSeOH
SeAr
H
C
ArSe
H
H
Ts
Ts
45 examples
9-100% yield
1-42% ee
Not isolated
Can racemize with H2O
Komatsu, N.; Murakami, T.; Nishibayashi, Y.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 3697-3702.
Positioned away from
sidechain of Fc*
(FcSe)2
NaBH4
R
CO2Et
R
CO2Et
Se
EtOH
Fc*
R = Me, Et, Pr
- HOSeFc*
H
R
mCPBA
R
H
H
CH2Cl2
4Å MS
-78 to -20 ºC
H
O
CO2Et
Se
Fc*
Not isolated
Me2N
Me
C
CO2Et
38-59% yield
75-89% ee
Hishibayashi, Y.; Singh, J. D.; Fukuzawa, S.; Uemura, S. J. Org. Chem. 1995, 60, 4114-4120.
(FcSe)2 =
Fe
Me
Se Se
NMe2
Fe
(S,R)
Equilibration of allylic metal center
Bu
O
H
Cu
BuCu⋅MgBr2
S
Tol
H
THF
-70 to 20 ºC
then, Bu2Zn, 2 MgBr2
0 to 5 ºC
S O
then,
Tol
I
Bu
I
Bu
Bu
Bu
ZnBu
Bu
ZnBu
syn
Bu
C
H
S O
Tol
"Racemic" sp3
organometallic
H
S O
Tol
Thermodynmic
equilibration;
"Enantioenriched"
sp3 organometallic
Varghese, J. P.; Zouev, I.; Aufauvre, L.; Knochel, P.; Marek, I. Eur. J. Org. Chem. 2002, 4151-4158.
H
75% yield
65% ee
Bu
H
Stoichiometric Chiral Reagents and Auxilliaries
A) Asymmetric Deprotonation-Protonation
HR
B*
HS
HR
B*
HS
HS
R1
R1
R2
R1
R2
R2
C
E
E
B) Asymmetric Horner-Wadsworth-Emmons
O
O
(*RO)2
C
P
O
O
OR
C
Nu
Nu
R2
R1
R1
R2
R1
R2
H
C
CO2R
Asymmetric Deprotonation
HR
BuLi
(-)-sparteine
HS
CbO
O
pentane
-78 ºC
R1
N
N
Ti(Oi-Pr)3
TiCl(Oi-Pr)3
Li
CbO
INVERSION!
N
R1 = TMS, t-Bu
R1
O
R1
Precipitates from reaction
Equilibrates in THF
Ti(Oi-Pr)3
R1
AcOH
C
CbO
H
R1
OCb
TMS: 86% yield, 88% ee
t-Bu: 80% yield, 84% ee
H
H
R2CHO
R1
H
R2
OCb
TiX3
O
R1
C
R2
OCb
H
OH
1 diastereomer
This Work: Schultz-Fademrecht, C.; Wibbeling, B.; Fröhlich, R.; Hoppe, D. Org. Lett. 2001, 3, 1221-1224.
For inversion in Li-Ti exchange with allyl species, see: Paulsen, H.; Graeve, C.; Hoppe, D. Synthesis, 1996, 141-144.
73-86% yield
93->95% ee
Asymmetric Deprotonation
O
BuLi (2 equiv)
THF, -78 ºC, 2 h
O
Li
H
O
t-BuOH
O
O
R
H
C
O
H
R
R
H
O
R = Me, 55%, 20/1 dr
R = t-Bu, 65%, 3/1 dr
O
Me
N
H
O
Ph
BuLi
O
THF
-78 ºC
30 min
C
H
O
O
Li
t-Bu
δ
O
OH
+
Me
Ph
O
H
H
OH
H
OH
t-Bu
Ph
Me
O
OH
H
Ph
O
O
t-Bu
δ
H
t-Bu
O
C
t-Bu
HCl
(CF3)2CHOH
CF3CH2OH
H
Ph
Me
This Work: Harrington, P. E.; Murai, T.; Chu, C.; Tius, M. A. J. Am. Chem. Soc. 2002, 124, 10091-10100.
For examples with a fructose-derived auxilliary, see: Hausherr, A.; Orschel, B.; Scherer, S.; Reissig, H.-U. Synthesis 2001, 1377-1385.
Me
Asymmetric Protonation
O
H
1) (R)-BINOL-Ti
CH2Cl2, 95%
OPO(OEt)2
5 mol% Pd(PPh3)4
SmI2 (2 equiv)
t-BuOH (1.1 equiv)
+
2) BuLi
(EtO)2POCl
CO2Me
94%
CO2Me
THF
53%
C
Racemic!
Pd0
R1
H
R2
PdII
R2
C
PdII
R1
H
R1
R2
C
PdII
2 SmII
Pd0
R1
H
R2
SmIII
R2
C
SmIII
R1
H
R1
R2
C
SmIII
R*OH
R1
H
R2
C
H
Mikami, K.; Yoshida, A. Angew. Chem. Int. Ed. 1997, 36, 858-860.
Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889-898.
R*OH
H
R1
R2
C
H
CO2Me
Asymmetric Protonation
O
H
1) (R)-BINOL-Ti
CH2Cl2, 95%
OPO(OEt)2
5 mol% Pd(PPh3)4
SmI2 (2 equiv)
t-BuOH (1.1 equiv)
+
2) BuLi
(EtO)2POCl
CO2Me
94%
CO2Me
5 mol% Pd(PPh3)4
SmI2 (2 equiv)
+
O
OH
1.1 equiv
C
Racemic!
OPO(OEt)2
O
THF
53%
C
THF
68%
CO2Me
R'
R'
H
O
O
Sm
H
R'
O
O
Sm
H
R'
H
R
R
E
Mikami, K.; Yoshida, A. Angew. Chem. Int. Ed. 1997, 36, 858-860.
Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889-898.
CO2Me
H
>95% ee
racemic
H
H
H
E
Ph
Ph
HO
OH
with
71% yield
86% ee
CO2Me
Asymmetric HWE
R1
CO2BHT
BuLi
ZnCl2
R1
C O
THF
-78 ºC
R2
KHMDS
A
R1
C
THF
-78 ºC to rt
R2
R2
H
CO2Me
60-94% yield
4-84% ee
R1
CO2Ph
R2
LDA
ZnCl2
LDA
A
R1
R1
C O
THF
-78 ºC
R2
C
THF
-78 ºC to rt
R2
H
CO2Me
21-71% yield
32-89% ee
O
si face
Me
C
Me
O
O
P
O
Me
O
OMe
Zn2+
O
O P
O
S
L
O
OMe
Me
A
re face
blocked by Me
This work: Tanaka, K.; Otsubo, K.; Fuji, K. Tetrahedron Lett. 1996, 37, 3735-3738. Yamazaki, J.; Watanabe, T.; Tanaka, K. Tetrahedron: Asymmetry 2001, 12,
669-675.
For examples of Wittig-type olefinations of ketenes, see: Lang, R. W.; Hansen, H. J. Helv. Chim. Acta 1980, 63, 438-55. Tanaka, K.; Otsubo, K.; Fuji, K. Synlett
1995, 933-934. Tanaka, K.; Otsubo, K.; Fuji, K. Tetrahedron Lett. 1995, 36, 9513-9514.
Chiral Catalysis and Kinetic resolution
Kinetic Resolution
H
Sharpless
Asymmetric
Epoxidation
OH
OH
C
C7H15
H
run to ~60% conversion
C7H15
H
C
H
40% ee
Sharpless, K. B.; Behrens, C. H.; Katsuki, T.; Lee, A. W. M.; Martin, V. S.; Takatani, M.; Viti, S. M.; Walker, F. J.; Woodard, S. S. Pure Appl. Chem. 1983, 55,
589-604.
R
H
R
2 mol% cat
PhIO
H
C
H
C
R
Noguchi, Y.; Takiyama, H.; Katsuki, T. Synlett 1998, 543-545
CH2Cl2
-40 ºC
H
61-98% ee
57-83% conversion
Me Me
Me
Me
N
N
Mn+
O
Ph
O
Ph
R
Kinetic Resolution
H
R
NAr
Zr
C
H
R
1.8 equiv
C6H6
HAr
N
R
H
R
+
C
Zr
H
NAr
Zr
H
R
R
H
Zr
100% conv.
(S,S)
C
(S)
>95% recovery
85-93% ee
R
(S,S,R)
HAr
N
C
1 equiv
H
C
R
(R)
50-61% conv
78-98% ee
(S,S)
H
Ar
N
(S,S,R)
H
Zr
1 diastereomer!
R
C
R
C
H
Thought to involve stepwise
mechanism; therefore highly
stereoselective, not stereospecific
Only favored
approach
84% ee
93% yield
H
C
(S)
H
Sweeney, Z. K.; Salsman, J. L.; Anderson, R. A.; Bergman, R. G. Angew. Chem. Int. Ed. 2000, 39, 2339-2343.
Kinetic Resolution
deracemization
RO2C
H
C
H
RO2C
1 mol% Et3N
pentane
-20 ºC
2 days
CO2R
R = (-)-L-menthyl
5:4 dr
CO2R
C
H
H
(R) crystallizes
90% yield
>98% de
Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. J. Chem. Soc., Chem. Commun.1998, 2363-2364.
OR
RO2C
C
H
+ Et3N
CO2R
H
O
RO2C
- Et3N
(R)
H
Boc N
RO2C
C
H
CO2R
H
+
N Boc
CH2Cl2
-78 ºC
CO2R
H
C
+ Et3N
H
H
H
CO2R
(S)
H
N
CO2R
CO2R
RO2C
C
NEt3
Boc
H
AlCl3
- Et3N
H
Cl
H
N
N
CO2R
H
(-)-epibatidine
Kinetic Resolution
deracemization
RO2C
H
C
H
CO2R
R = (-)-L-menthyl
5:4 dr
1 mol% Et3N
pentane
-20 ºC
2 days
RO2C
C
H
CO2R
H
(R) crystallizes
90% yield
>98% de
Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. J. Chem. Soc., Chem. Commun.1998, 2363-2364.
i-PrO2C
H
C
H
CO2i-Pr
(+)-Eu(hfc)3
CDCl3
9 days
20 ºC
Naruse, Y.; Watanabe, H.; Ishiyama, Y.; Yoshida, T. J. Org. Chem. 1997, 62, 3862-3866
i-PrO2C
C
H
(S)
>95% ee
H
CO2i-Pr
Chiral Catalysis
The Beginning
t-Bu
H
BuLi
MX
t-Bu
H
C
cat Pd(R,R-DIOP)
PhI
t-Bu
C
H
H
THF
-60 ºC
H
-60 ºC to rt
M
(±)
"fast" reacting
enantiomer
-M+
H
C
t-Bu
H
C
M
H
t-Bu H
H
Warning!
Speculation by AMH
"slow" reacting
enantiomer
t-Bu
C
PhI
L2
I
t-Bu
C
H
H
t-Bu
Pd0
-M+
M
C
H
Ph
H
up to 25% ee
changing MX altered sense of induction
MX = ZnCl, MgCl, CuBr/LiBr
t-Bu
H
C
H
t-Bu
H
H
H
M
t-Bu
H
C
L2Pd
H
Ph
MI
PdL2
Ph
de Graaf, W.; Boersma, J.; van Koten, G.; Elsevier, C. J. J. Organometallic Chem. 1989, 378, 115-124.
-L2Pd0
t-Bu
C
H
H
Ph
Chiral Catalysis
R1
+
Br
EtO2C
CO2Et
or
EtO2C
Me
CO2Et
10 mol%
Pd[(R)-BINAP]2
dba (2 equiv to Pd)
H
R1
CsOt-Bu
CH2Cl2, 20 ºC
NHAc
CO2Et
R2
CO2Et
C
H
34-75% yield
54-89% ee
Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 2089-2090.
Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Org. Chem. 2005, 70, 5764-5767.
2
Pd0(BINAP)
R1
Br
R1
Br
R1
Pd
R1
P
2
Pd
P
(2R) P
Pd
P
34:66 dr
by NMR
(2S)
Nu
The presence of dba
does not affect the ratio of
2R to 2S, but accelerates the
interconversion 12-25 times.
P
P
Nu
H
C
H
H
R1
major
Nu
C
R1
Nu
H
minor
Chiral Catalysis
R1
EtO2C
+
CO2Et
Br
or
EtO2C
Me
CO2Et
10 mol%
Pd[(R)-BINAP]2
dba (2 equiv to Pd)
H
R1
CsOt-Bu
CH2Cl2, 20 ºC
NHAc
H
TMS
C
OMe
+
OMe
H
87% ee
C
H
34-75% yield
54-89% ee
CO2Et
NHAc
CO2Et
CO2Et
R2
CO2Et
CO2Et
NHAc
CO2Et
TiCl4
CH2Cl2
-78 ºC
t-Bu
MeO
H
(S)
90% yield
85% ee
Ogasawara, M.; Ueyama, K.; Nagano, T.; Mizuhata, Y.; Hayashi, T.
Org. Lett. 2003, 5, 217-219.
t-Bu
H
t-Bu
C
TMS
O
H
TMS
H
R
H H
C
H
R
O
Me
(S)
(R)
Me
H
Me
O
C
Favored
TMS
H H
t-Bu
Disfavored
R
Chiral Catalysis
R1
EtO2C
+
Br
CO2Et
or
EtO2C
Me
10 mol%
Pd[(R)-BINAP]2
dba (2 equiv to Pd)
CO2Et
H
R1
CsOt-Bu
CH2Cl2, 20 ºC
NHAc
H
TMS
C
OMe
+
H
87% ee
CH2Cl2
-78 ºC
H
CO2Et
NHAc
CO2Et
TiCl4
OMe
C
34-75% yield
54-89% ee
CO2Et
NHAc
CO2Et
CO2Et
R2
CO2Et
t-Bu
MeO
H
(S)
90% yield
85% ee
Ogasawara, M.; Ueyama, K.; Nagano, T.; Mizuhata, Y.; Hayashi, T.
Org. Lett. 2003, 5, 217-219.
R1
OPO(OEt)2
C
H
(±)
+
H
R2O2C
CO2R2
R3
1 mol%
Pd2(dba)3⋅CHCl3
4 mol%
(R)-MeOBIPHEP
H
BSA, THF, rt
R1
Imada, Y.; Ueno, K.; Kutsuwa, K.; Murahashi, S.-I. Chem. Lett. 2002, 5, 140-141.
CO2R2
R3
CO2R2
C
H
72-90% yield
69-90% ee
Chiral Catalysis
PdCl(Allyl)2/L
(1 mol% Pd)
R
+
HSiCl3
(neat)
R
20 ºC
H
MeMgBr
Me
Et2O
C
Cl3Si
H
R
C
TMS
Me
37-90% yield
68-90% ee
R
R
Cl3Si Pd H
Pd Me
Cl3Si
L
L
L
Cl3Si
H
R
+
Cl3Si Pd H
R
R
H
PhCHO
R
OH
C
Me
Ph
DMF
R
OH
+
Me
1:1 to 4:1
100% chirality transfer
C
Cl3Si
Ph
Me
Me
Fe
MeO
P
Fe
Ph
OMe
Me
Me
(S)-(R)-bisPPFOMe
Han, J. W.; Tokunaga, N.; Hayashi, T. J. Am. Chem. Soc. 2001, 123, 12915-12916.
For hydrosilylation of butadiynes with low selectivity, see: Tillack, A., Koy, C.; Michalix, D.; Fischer, C. J. Organometallic Chem. 2000, 603, 116-121.
For hydroboration of ene-ynes with low selectivity, see: Matsumoto, Y.; Naito, M.; Uozumi, Y.; Hayashi, T. J. Chem. Soc., Chem. Commun. 1993, 1468-1469.
Chiral Catalysis
O
OTMS
[RhCl(C4H4)2]2/L*
(3 or 10 mol% Rh)
ArTi(Oi-Pr)4Li
TMSCl
n
n
THF, 20 ºC
30 min
*
61->99% yield
26-93% ee
(configuration not reported)
C
Ar
R
R
[Rh]-Ar
TMSCl
ArTi(Oi-Pr)4Li
O
O
[Rh]
R
Ar
isomerization
determines
stereochemistry
[Rh]
C
*
Ar
O
R
O
PPh2
O
PPh2
L* =
O
Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305-307.
(R)-segphos
Conclusions
Presented a flavor of the methods known to construct axial chiral allenes in an enantioselective
manner, as well as a few reactions these products are useful for.
Many reliable methods for chirality transfer from pre-generated stereocenters with
stiochiometric reagents.
There is still a deficiency in catalytic asymmetric methods. The selectivities of these processes
are not as reliable, and scope has yet to be defined.
Allenes are not just theoretical curiosities and can be useful synthons for asymmetric synthesis
as well as potentially useful final targets for biologically relavant molecules.
Prof. Kay Brummond
University of Pittsburgh
Prof. James Marshall
University of Virginia
Prof. Tamio Hayashi
Kyoto University

Chiral Allenes - The Stoltz Group

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