Post on 11-Sep-2020
Enantioselective Synthesis ofAxial Chiral Allenes
Andrew M. HarnedMonday, May 1, 2006
8 pm147 Noyes
b
CC
C
y
z
a
Orthogonal Bonding
C
OOO
OAc
OAc
NPh
PhPhNPhHO
D-camphorsulphonicacid
Benzene, heatC
Ph
NPhPh
NPh[α]5461 = +437º
R2MsO
R1
5 examples95% ee
Pd(PPh3)4CO (200 psi)
THF, R3OHrt 80-86% yield
80-93% ee
CCO2R3
R2
HR1
OPh
CO
HO
CO2Me
OH
Axial Chiral Allenes: Useful Curiosities
General Allene Reviews:
1) The basics of Allenes and Axial Chirality
2) Methods of Synthesizing Axially Chiral Allenes
a) A brief history of allenesb) Spectroscopyc) Types of chiral allenesd) General axial chiralitye) Natural products with axial chiral allenesf) Allenes as Pharmaceutical Agents
a) Propargyl alcohol derivativesb) Elimination from allylic compoundsc) Stiochiometric chiral reagentsc) Kinetic resolutiond) Catalytic methods
3) Conclusions
(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 Allenes1874-1875: Jacobus H. van't Hoff predicts the correct structures of alenes and cumulenes as well as theiraxial chirality (La Chemie dans l'Espace, Bazendijk: Rotterdam, 1875).
1935: First axially chiral allene synthesized by P. Maitland and W. H. Mills (Nature 1935, 135, 994; J. Chem. Soc. 1936, 987-998).
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
MeC Me Pyrethrolone
NPh
PhPhNPhHO
D-camphorsulphonicacid
Benzene, heatC
Ph
NPhPh
NPh[α]5461 = +437º
1952?: First cyclic allenes synthesized by A. T. Blomquist, R. E. Burge, Jr. and A. C. Sucsy (J. Am. Chem. Soc. 1952, 74, 3636-3642; 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).
b
Structure and Spectroscopy of Allenes
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)
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.
Cα Cβ Cγ
z
ya
b
CC
C
y
z
a
Orthogonal Bonding
sp
sp2
TMS CH
ON(i-Pr)2
O
O
O
PhHN
Schultz-Fademrecht, C.; Wibbeling, B.; Fröhlich, R.;Hoppe, D. Org. Lett. 2001, 3, 1221-1224.
Structure and Spectroscopy of Allenes
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)
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.
Cα Cβ Cγ
z
ya
b
Orthogonal Bonding
sp
sp2
TMS CH
ON(i-Pr)2
O
O
O
PhHN
Schultz-Fademrecht, C.; Wibbeling, B.; Fröhlich, R.;Hoppe, D. Org. Lett. 2001, 3, 1221-1224.
a
b
zy
Types of Chiral Allenes
B•
A
A
D
B•
A
E
D•
H
H
H
A
B D
•H
H
A
B D
Asymmetric allenes(no element of symmetry)
A B
D •H H
A
B D D B
A
B•
A
B
A
Dissymmetric allene(C2 proper axis of rotation)
•H H
A
B D A B
D
(S) (R)
(S) (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. Hoffmann-Röder, 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
B•
A
A
D
B•
A
E
D•
H
H
H
A
B D
•H
H
A
B D
Asymmetric allenes(no element of symmetry)
A B
D •H H
A
B D D B
A
B•
A
B
A
Dissymmetric allene(C2 proper axis of rotation)
•H H
A
B D A B
D
(S) (R)
(S) (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. Hoffmann-Röder, 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.
Not coveredAllene is not stereogenic
General Axial Chirality
C4H9•
HO2C
CH3
H
Determining configuration
CO2H
C4H9
CH3H
CCW = (S)
1
2
34CH3
H
CO2HC4H9
1
2
34
CCW = (S)R = MS = 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
B
YX Most polarizable group A is placed at the top. If Y is more polarizable than X, the allene willbe dextrorotatory (+). If X is more polarizable than Y, the allene will be levorotatory (-).
General Axial Chirality
C4H9
•HO2C
CH3
HCH3
H
CO2HC4H9
1
2
34
CCW = (S)
CO2H
C4H9
CH3H
1
2
34
CCW = (S)
Determining configuration
R = MS = 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
PhH
(+)-S
CO2H
H
PhHO2C
(-)-R
Cl
H
t-BuMe
(-)-S
nC8H17 C
H
H
CO2Me
Insect Pheromone
~80% eeC CO2
NH3
HOOH
C
HC
H
OHHO
Mimulaxanthin
HOOH
C
HO
"Grasshopper Ketone"
O
O
H
HBrEt
CH
H
H
Br
Isolaurallene
O
O
H
H
O
Okamurallene
C
OOO
OAc
OAc
HNC
OH
IsodihydrohistrionicotixinNicotine acetylcholine receptor active
O
O
AcO
C
O
H
H
H
Acalycixeniolide EAnti-angiogenic
OCC O
C
H
H
Br
H
Allenes as Natural ProductsNot just curiosities anymore
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 AgentsNot just curiosities anymore
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.
C
P(OEt)2
O
MeO
Sterol biosynthesis inhibitor(AIDS-related pathogen)
OPh
CO
HO
CO2Me
OHEnprostil
Gastric acid inhibitorOH OH
C
HCO2Na
Anti-thrombotic agent
OH
OH
CCO2
NH3
Vitamin B6-dependent decarboxylase inhibitor
(suicide substrate)
N
N N
N
NH2
COH
N
COH
N
NH2
O
(R)-Cytallene (R)-Adenallene
H
H
H
H
Inhibitors of HIV and Hepatitis B replication
Chirality Transfer from Propargylic AlcoholsA) Copper-Mediated Methods
B) Rearrangements
C) Palladium (0)-Mediated Methods
AlkylationHalogenation
D) SN2' reactions
anti-elimination
syn-elimination
LG
R1R2
R3
LG
R1R2
R3Nu
Nu
CR3
Nu
R2R1
OH
R1R2
R3
O
R1R2
R3 CNu
R3
R2R1
Z Nu
Z Nu
The Beginnings
LG
R1
H
CuR2R2
MCuR22
LG
HR1
CHR1
H
CuR2
R2 Red.Elim.
CHR1
H
R2
OAc
R1
R2
LiCuR42
R3
CR3
R4R2
R1
anti-elimination
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.
Rona, P.; Crabbé, P. J. Am. Chem. Soc. 1969, 91, 3289-3292.
Many studies with steriodal stystems. Complications due to racemization of product by dialkyl cuprates.
Proparglyic Esters
Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726-3730.
LG
R1
H CHR1
H
CuR2
R2
CHR1
H
R2
LG
R1
H CHR1
H
R2
R1 = Ph, t-Bu, octyl, MeLG = OS(O)Me or OSO2Me
R2CuBr⋅MgBr⋅LiBr
70-96% yield>98% anti-selectivity
[R2CuX][MgX]
LG
R1H
CuR2 X
LG
R1H
CuR2 X
- LGIII
- CuIX
C C HH
R1
O
Cu RL
pxdxz
π π*σ*
Corey Tetrahedron Lett. 1984, 25, 3063-3066
nonsteriodal, acyclic allenes
[{RCuX}M]
Proparglyic Esters
Gooding, O. W.; Beard, C. C.; Jackson, D. Y.; Wren, D. L.; Cooper, G. F. J. Org. Chem. 1991, 56, 1083-1088.
D-Mannitol4 steps
62% OHTBDPSO
>97% ee
CBr4PPh3, Pyr
BrPO
THF97%
TsCl, Et3N
CH2Cl299% OTs
PO
CPO
H HCO2Me3
Cu CO2Me3
(R)>94% ee
[α]25D -63.8° (c = 0.43, MeOH)
CPO
H
H
3
Cu CO2Me3
(S)>94% ee
[α]25D +65.0° (c = 0.34, MeOH)
CO2Me
88%
96%
CTBDPSO
H HCO2Me3
TBAF
THF98%
CHO
H HCO2Me
3
[α]25D -53.4° (c = 0.31, CHCl3)
Antifungal constituent fromSapium japonicum
lit. [α]12D -51.3° (c 0.94, CHCl3)
Enantioenriched Propargyl Alcohols
Buisine, O.; Aubert, C.; Malacria, M. Synthesis 2000, 985-989.
PO
O
C7H15
(R)-Alpine borane
THF, 20 °C63% PO
OH
C7H15
CBr4, PPh3Pyr, THF, 20 °C
63%
88% ee
LiBr, Cu2I2MeMgBr
THF, 0 °C80%
CH
C7H15
MePO
52% ee
CH
C7H15
MeO
NN
SC8H17O
OP = OSit-Bu2PhPO
Br
C7H15
liquid crystalline properties
Zab, K.; Kruth, H.; Tschierske, C. J. Chem. Soc., Chem. Comm. 1996, 977-978.
O
Ph
2.5 mol% [(p-cymene)RuCl2]2(S,S)-TsDPEN, KOH, i-PrOH
75%
OH
Ph>95% ee
a) BuLi, THF, -78 °C b) MsCl
c) MeCuCNMgBr71%
>95% ee
C
MePh
Enantioenriched Propargyl Alcohols
Buisine, O.; Aubert, C.; Malacria, M. Synthesis 2000, 985-989.
PO
O
C7H15
(R)-Alpine borane
THF, 20 °C63% PO
OH
C7H15
CBr4, PPh3Pyr, THF, 20 °C
63%
88% ee
LiBr, Cu2I2MeMgBr
THF, 0 °C80%
CH
C7H15
MePO
52% ee
CH
C7H15
MeO
NN
SC8H17O
OP = OSit-Bu2PhPO
Br
C7H15
liquid crystalline properties
Zab, K.; Kruth, H.; Tschierske, C. J. Chem. Soc., Chem. Comm. 1996, 977-978.
C
MePh
CpCoBuLi, Ph2P(O)ClTHF, -78 to 50 °C
78%C
MePh
PPh2
O
Ph2P Me
PhH
O>95% ee
CpCo(CO)2
THF, Δ, hνquant.
Enantioenriched Propargyl Alcohols
Brummond, K. M.; Kerekes, A. D.; Wan, H. J. Org. Chem. 2002, 67, 5156-5163.
H17C8
O (S)-BINAL-H
91% C8H17
OH MsClTEA
DCM, 0 ºC95%
C8H17
OMs
95% ee
TMS MgCl
LiBr, CuBr, THF-60 ºC to rt
95%
CH
H17C8
TMS
Cp2ZrCl2, BuLiCO, 20 psi
THF-78 ºC to rt to 0 ºC
39% TMS
O
H17C8
H
85% ee
CHO Ph+
1)
NMe2
MePh
HOZn(OTf)2
PhMe, 23 ºC
2) MsCl, TEA CH2Cl2, -40 ºC 80%
OMs
Ph99% ee
1) NBoc
CuCNLi
2) TMSOTf CH2Cl2, -40 ºC 99%
CPh
MeHN
H82%
83% ee
Dieter, R. K.; Yu, H. Org. Lett. 2001, 3, 3855-3858.
Enantioenriched Cyclic Allenes
Zelder, C.; Krause, N. Eur. J. Org. Chem. 2004, 3968-3971.
OAc Lipase(Mucor miehei)
PhosphateBuffern
A, n = 1B, n = 2
OAc
n
OH
n
(S)-A-OAc40% (64% ee)
(S)-B-OAc50% (60% ee)
(R)-A-OH43% (91% ee)
(R)-B-OH20% (90% ee)
+
OAc
(91% ee)
RMgX
CuBr, LiBrTHF, -70 ºC
C
R(+)
R = Bu, i-Pr, t-Bu
OAc
(60% ee)
RMgX
CuBr, LiBrTHF, -70 ºC
C
R(-)
(60% ee)R = Bu, i-Pr, t-Bu
% ee determined for R = Bu, t-Bu by GC,Enantioseparation not achieved for others
Silyl Cuprates
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.
OHC
OBn
OTBS
CN
1a) HCCMgBr, DCM -78 to 0 °C, 89% b) Separate 2:1 dr
2) Ac2O, TEA, DMAP DCM, 98% or DEAD, PPh3, HOAc Pyr, THF -45 °C to rt, 86%
OBn
OTBS
CNAcO H
1) (Me2PhSi)2Cu(CN)Li2 THF, -96 °C, 84%
OBn
OTBS
CHO
CH
Me2PhSi
H
2) DIBALH, PhMe -78 to 0 °C, 78%
O
O
Br
NPPh3
mesitylene50 °C then reflux
C
SiPhMe2H
OBn
HH
OTBS
NAr
OBn
OTBSNH
OO
Br2) TBAF, THF, 0 °C 63% overall
N
OMe
OHH
O
O
(-)-coccinine
Propargylic Silanes
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.
TMSOMs
HMe
HSiCl3, CuCl
DIEA, RCHODMF
CHMeTMS
OHR
RMe
OHTMS
55-92% yield89:11 to 98:2
>95% chirality transfer+
OMs
TMSHMe "CuSiCl3" C
HMeTMS
XCuSiCl3
CuXTMS
HMe
SiCl3
reductiveelimination
CHMeTMS
Cl3SiSiCl3
TMS
HMe
- CuCl
RCHO RCHO
CHMeTMS
Cl3SiSiCl3
TMS
HMe
ORHO
RH
RMe
OHTMS
CHMeTMS
OHR
SN2' reaction
Furuichi, N.; Hara, H.; Osaki, T.; Mori, H.; Katsumura, S.Angew. Chem. Int. Ed. 2002, 41, 1023-1026.
HOO
enantiomerically pure
CO2MeDIBAL-H
CH2Cl20 ºC80%
HO
C
OH
HOH
HO
C
OH
H OO
OH
O
peridinine
O
HOBn
O
Br Et
+
NN
N
Bn
AlMe TfTf
10 mol %O
Me
O
BnO94% ee91:9 dr
CH
CO2HMe
C9H19
OBn
C9H19MgBrCuBr (10 mol%)
THF-78 ºC
OO
Me
OHC9H19
1) AgNO3
2) H2, Pd/C(-)-malyngolide
antibiotic
94% ee
Wan, Z.; Nelson, S. G. J. Am. Chem. Soc. 2000, 122, 10470-10471.
Halogenations
Landor, S. R.; Demetriou, B.; Evans, R. J.; Grzeskowiak, R.; Davey, P. J. Chem. Soc., Perkin Trans. 2 1972, 1995-1998.
HO
Met -Bu
48% aq HBrCuBr, NH4BrCu powder
Syn-halogenation
H2O
Met -Bu
CuL
L
Br
SynC
t -Bu
Me BrH
"HCuCl2"
Original proposed mechanism No 2H-exchange at C-1 in D2O/DBr,or in H2O/HBr with 1-d alcohol
1H
Halogenations
Landor, S. R.; Demetriou, B.; Evans, R. J.; Grzeskowiak, R.; Davey, P. J. Chem. Soc., Perkin Trans. 2 1972, 1995-1998.
HO
Met -Bu
48% aq HBrCuBr, NH4BrCu powder
Syn-halogenation
SynC
t -Bu
Me BrH
"HCuCl2"
No 2H-exchange at C-1 in D2O/DBr,or in H2O/HBr with 1-d alcohol
1H
HO
Met -Bu
Cu BrBr
H
Syn or Anti-halogenation?
CI
H
PhH
Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1984, 49, 1649-1650.
HO
PhH
opticallypure
~6% ee
HCuI2
syn
CH
Cl
PhH
CH
Br
PhH
~4% ee
~22% ee
HCuCl2
HCuBr2
anti
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).
HalogenationsAnti-halogenation
HO
PhH SOCl2
81% ee
Et2O0 ºC to rt
67%Cl
PhH
18% ee
Bu4NCuCl2
Acetone62%
CH
Cl
PhH
Muscio, O. J.; Jun, Y. M.; Philip, Jr., J. B. Tetrahedron Lett. 1978, 2379-2382.
HO
HPh
50% eeMsO
PhH c) cuprate
-70 to 20 ºCC
H
X
HPh
a) BuLi, THF -70 ºC
b) MsCl
[α]25D -94º (c 0.9, CHCl3)
LiCuX2LiCu2X3LiCu2X3
1.20.61.2
530600610
92010401235
122013501550
cuprate equiv. X = Cl X = Br X = I
[α]20D deg (c 2, EtOH)
Elsevier, C. J.; Meijer, J.; Tadema, G.; Stehouwer, P. M.; Bos, H. J. T.;Vermeer, P. J. Org. Chem. 1982, 47, 2194-2196.
Halogenations
D'Aniello, F.; Schoenfelder, A.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 9631-9636.
CHOO
NBoc
1) TMSCCLi HMPA, THF, -78 ºC
2) TsCl, TEA, DMAP DCM, 0 ºC to rt 88%
1) TMSCCLi HMPA, THF, -78 ºC
2) TsCl, TEA, DMAP DCM, 0 ºC to rt 89%
ONBoc
OTs
TMS
ONBoc
OTs
TMS
CuBrLiBr
THF60 ºC70%
CuBrLiBr
THF60 ºC75%
ONBoc
C
H
TMSBr
ONBoc
C
H
BrTMS
O
O
EtTESO
H
H
H 1) t-BuOOH (+)-tartrate, 94%
2) PPh3, NCS 84%
HOCl
O
1) LDA, THF, 87%
2) ArSO2Cl, 96% ArO2SO>98:2 dr
LiCuBr2
O
O
EtTESO
H
H
H
C
H
Br H
67%
1) PPTS, MeOH
2) CBr4, oct3P 58%
O
O
EtBr
H
H
H
C
H
Br H(-)-isolaurallene
Crimmins, M. T.; Emmitte, K. A. J. Am. Chem. Soc. 2001, 123, 1533-1534
Me
Me EtO
Rearrangements
Henderson, M. A.; Heathcock, C. H. J. Org. Chem. 1988, 53, 4736-4745.
MeOH
t-Bu MeO
t-Bu
SBr
O
SOBr2propylene
oxideC
Me
Br t-BuH
MeBr
t-Bu+
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.
t-Bu
OH EtC(OEt)3
EtCO2H t-Bu
O
EtO t-Bu
O
Me
H
H Ot-Bu
HEtO
Ot-Bu
HEtO
Me
E E'
Z' Z
CH
t-BuH
MeEtO2C
CH
t-BuH
MeEtO2C
94% eeEt2O, 0 ºC
98% ee
A
B
A:B = 9:1complete chirality transfer
rapid equilibrium, E reacts faster
Ortho Claisen rearrangement
Rearrangements
Mukaiyama, T.; Furuya, M.; Ohtsubo, A.; Kobayashi, S. Chem. Lett. 1991, 989-992.
CHOTMS+
Me
TMSO
EtS
Sn(OTf)2L* (cat)
EtS
O OTMS
Me TMS92% ee
1) deprotection
2) MeC(OEt)3 EtCO2H 86%
EtS
O
CMe
TMSCO2Et
92% ee
TBSO
THPOOPh
OTHP
OHHMeC(OEt)3
HCO2H70%
O
HOOPh
OH
CH
CO2Me
enprostil
CHH
CO2Et
1) CBr4, PPh3
2)Cu
CO2Me CHH
CO2Me
78%
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.
1 isomer
1 isomer
Rearrangements
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.
(CH2)6CH3
OH
OTIPS
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.
MeC(OEt)3
H+71%
(CH2)6CH3COTIPS
H
H
EtO2C N
H
MeRO Me
5
clavepictine A, R = Acclavepictine B, R = H
C7H15
OHO2C
Me
1) LDA
2) CH2N2 80%
CC7H15
MeO2COH
HMe
dr 93:7complete transfer
of chirality
AgNO3
O MeMeO2C
C7H15
1) CH2N2
2) LDA, Cp2ZrCl2 THF, -78 ºC, 57%
Onediastereomer
O
Me
OMeO M
H Me
H
O
MeMe
H
O MMeO
H
*
Favored
[2,3]-Wittig Rearrangement
Rearrangements
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
R2
R1
NBSH
PPh3, DEAD-15 ºC
N
R2
R1
HN SO2Ar
23 ºC71-91%
CR2
H
HR1
OH
ON
Boc
ClP(OEt)2TEA
CON
Boc
H
HP(O)(OEt)2
HO2CPO3H2
NH2AP5
NMDA antagonist
Muller, M.; Mann, A.; Taddei, M. Tetrahedron Lett. 1993, 34, 3289-3290.
DCM-10 ºC to rt
H
N
R2
R1
NH
- HSO2Ar - N2
completetransfer of
chirality
Palladium Catalysis
Elsevier, C. J.; Stehouwer, P. M.; Westmijze, H.; Vermeer, P. J. Am. Chem. Soc. 1983, 48, 1103-1105.
X
PhH
28% eeX = OAc, OTFA,
OS(O)Me
2.5-3.2 mol%Pd(PPh3)4
PhZnCl
THF/Et2O-50 to 25 ºC
CPh
H
H
PdXL2
L2XPd
PhH
PhZnClC
PhH
H
PdL2
Ph
CPh
H
H
Ph
82:18 anti/syn(Determined by
correlation of rotations)
transmetallation
BuOCO2Et
MeH
cat. Pd(PPh3)4PhZnBr
THFC
Bu
Ph MeH
93% ee 83% ee
CuI, ZnCl2i-Pr2NH, Pd(PPh3)4
Ph
THFC
Bu
MeH
Ph85% ee
Dixneuf, P. H.; Guyot, T.; Ness, M. D.; Roberts, S. M. J. Chem. Soc., Chem. Comm. 1997, 2083-2084.
Substituting Ph at alkyne terminus resulting in lower stereoselectivity
Yoshida, M.; Gotou, T.; Ihara, M. Tetrahedron Lett. 2004, 45, 5573-5575.
X
HPh
92% ee
B(OH)2+
10 mol%Pd(PPh3)4
dioxane100 ºC10 min
76%
CH
HPh
92% ee
X = OCO2Me
CH
HPh
10% eeX = OH
92% ee
B(OH)2+
10 mol%Pd(PPh3)4
2:1 dioxane/H2O80 ºC, 1-3 h
92% 92% ee
PhO
COH
Ph
Yoshida, M.; Ueda, H.; Ihara, M. Tetrahedron Lett. 2005, 46, 6705-6708.
X
HR
+Pd(DPEphos)Cl2
THF, rt, 8h70%
CH
PhHR
84-86% eeX = OAc, OBz
R = Ph
Ph3In
100% ee
conditions
conditions
X = OBzR = Me
CH
PhHR
>95% ee
Riveiros, R.; Rodriguez, D.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 2006, 8, 1403-1406.
Palladium Catalysistransmetallation
Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986, 27, 731-734.
R1O
R2 R3
OR4O
1 mol% Pd2(dba)3⋅CHCl38 mol% PPh3CO (1-30 atm) C
R1
L2Pd R2R3
OR4
CR1
R2R3
PdL2
O
R4O
CR1
R2R3
OR4O
(±) (±)
R4OH, 20-100 ºC1-44 h
44-99% yield
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.
MeO2CO
C6H13
OMOM
3
70% ee
5 mol% Pd2(dba)320 mol% PPh3
CO (1 atm)
2:1 PhH/MeOH50-60 ºC, 4.5 h
70% yield<5% ee
CCO2MeC6H13
H
MOMO
3
Possible racemization by PPh3
Palladium CatalysisCarbonylation
Tsuji, J.; Sugiura, T.; Minami, I. Tetrahedron Lett. 1986, 27, 731-734.
R1O
R2 R3
OR4O
1 mol% Pd2(dba)3⋅CHCl38 mol% PPh3CO (1-30 atm) C
R1
L2Pd R2R3
OR4
CR1
R2R3
PdL2
O
R4O
CR1
R2R3
OR4O
(±) (±)
R4OH, 20-100 ºC1-44 h
44-99% yield
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.
Palladium CatalysisCarbonylation
R2MsO
R1
5 examples95% ee
Pd(PPh3)4CO (200 psi)
THF, R3OHrt 80-86% yield
80-93% ee
CCO2R3
R2
HR1 IBr
CH2Cl2-78 ºC
1 hO
R2I
OR1
89-97% yield80-93% ee
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.
OO
OH
$$
BuLi
THF-pentane-78 ºC88%
O
HO
MsClEt3N
CH2Cl2-78 ºC
O
MsO
O
C
Pd(PPh3)4CO (1 atm)
TMSCH2CH2OHTHF75%
(2 steps)
H
CO2R1 diastereomer
R = OCH2CH2TMS
PPh3
CH3CN55 ºC92 h
O
CH
CO2R85:15
1) TBAF, THF 93%
2) AgNO3 Acetone, 68%
O
O
O(-)-kallolide B(unnatural)
14 steps
Palladium CatalysisCarbonylation
Palladium Catalysis
Suginome, M.; Matsumoto, A.; Ito, Y. J. Org. Chem. 1996, 61, 4884-4885.
O
Me
C6H13Ph2SiSiMe2Ph
97% ee
NC8 mol%
2 mol% Pd(acac)2
Toluene, reflux
SiPh2O
SiMe2Ph
C6H13
Methen BuLi
THF, -78 ºC86%
CMe
H
C6H13
SiMe2Ph
CHO
TiCl4 Me
OH C6H1376% yield
95:5 syn:anti93% ee
O
R
STolO
5 mol% Pd(OAc)27.5 mol% dppe
THF
87% eeR = Me, Pentyl
O
R
STolO
H
PdL2
CRH H
PdL2TolO2S
CRH H
SO2Tol
reductiveeliminationinsertion
Hiroi, K.; Kato, F. Tetrahedron 2001, 57, 1543-1550.
Allenylmetal Compounds
X
TMS
R1R2
X = OCO2Et or OPO(OEt)2
1.5 equiv Ti(Oi-Pr)43 equiv i-PrMgCl
Et2O, -50 to -40 ºCTMS
R1R2
OHPh
C(i-PrO)2XTi
TMS R1R2 PhCHO
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.
Ti(Oi-Pr)4 +
2 i-PrMgCl
Ti(Oi-Pr)2Ti(Oi-Pr)2 TMS
X
R2R1
A
Ti(Oi-Pr)2A
CTMS
Ti(Oi-Pr)2R1
R2Ti(Oi-Pr)2
TMS
X
R2R1TMS
R1R2
OHPh
PhCHO
72-87% yield
Allenylmetal Compounds
OCO2Et
TMS
HBu
TMS
HBu
OHPh
CTMS
(i-PrO)2XTi HBu
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.
OPO(OEt)2
TMS
HBu
OCO2Et
TMS
Me
OPO(OEt)2
TMS
Me
C(i-PrO)2XTi
TMS HBu
CTMS
(i-PrO)2XTi MeR
C(i-PrO)2XTi
TMS MeR
TMS
BuH
OHPh
TMSMe
OHPh
TMS
Me
%ee / Config.
1
2
1
Ph OH1
1
2
2
2
97% ee
97% ee
87% ee
87% ee
49 / (1R,2S)49 / (1S,2S)
94 / (1S,2R)94 / (1R,2R)
85 / (2S)
8.3 / (2R)
Allenylmetal Compounds
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.
OPO(OEt)2
TMS
HR1
1.5 equiv Ti(Oi-Pr)43 equiv i-PrMgCl
Et2O, -50 to -40 ºCTMS
Song, Y.; Okamoto, S.; Sato, F. Org. Lett. 2001, 3, 3543-3545.
CO2Et
CO2EtR2
R1
R2
CO2Et
CO2Et
> 97:3 anti:syn> 88 to 96% ee
95 or 98% ee
OH
BuTi
TMS
Oi-Pri-PrO
PO
(OEt)22º phosphate
(high selectivity)
C(i-PrO)2XTi
TMS HBu
OMe
Ti
TMS
Oi-Pri-PrO
PO
(OEt)2
C(i-PrO)2XTi
TMS HBu
3º phosphate(low selectivity)
anti anti
2º or 3º carbonate(moderate selectivity)
syn
OTi
TMS
i-PrO
i-PrOO
OEt
Me CTMS
(i-PrO)2XTi MeR
Allylic Elimination (β-elimination)
A) Chirality transfer from allylic position
B) Chiral leaving groups
Z
R2R1
R3
LG X"Activator"
X
Z
R2R1
R3
LG
CR1
R2 R3H
Y
R2R1
R3 CR1
R2 R3H
R4
HR HSoxidation
Y = S, Se
Y
R2R1
R4
HR
R3HS
O
- HOYR4
Allylic Elimination (β-elimination)Chirality at allylic position
Me
OH
C6H13
Bu3SnHAIBN
neat90 ºC
Me
OH
SnBu3
C6H13
SwernMe
O
SnBu3
C6H13
CBSreduction
Me
OH
SnBu3
C6H13
94% ee
MsClTEA
CH2Cl20 ºC to rt
CMe
H H
C6H13
51% eeanti elimination
Konoike, T.; Araki, Y. Tetrahedron Lett. 1992, 33, 5093-5096.
Allylic Elimination (β-elimination)Chirality at allylic position
Me
OH
C6H13
Bu3SnHAIBN
neat90 ºC
Me
OH
SnBu3
C6H13
SwernMe
O
SnBu3
C6H13
CBSreduction
Me
OH
SnBu3
C6H13
94% ee
Konoike, T.; Araki, Y. Tetrahedron Lett. 1992, 33, 5093-5096.
Ac2ODMAP
Me
OAc
SnBu3
C6H1381%
TBAF
F
CMe
H H
C6H1394±2% ee
anti elimination
S
C8H17
Tol
OLDA, THF, -78 ºC31% (78% brsm)
OHCCO2Me
1)
2) Ac2O
51%
44%
S
C8H17
Tol
O
(R)
OAc
R
S
C8H17
Tol
O
OAc
R
6 equivi-PrMgCl
-78 ºC10 min
95%
6 equivi-PrMgCl
-78 ºC10 min
91%
CC8H17
H H
CO2Me81% ee
CC8H17
H
H
84% ee
CO2Me
Satoh, T.; Hanaki, N.; Kuramochi, Y.; Inoue, Y.;Hosoya, K.; Sakai, K. Tetrahedron 2002, 58, 2533-2549.
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.
R1
R2 OH
PPh2
O
NaHDMF60 ºC
CH
R1R2
HR1 PPh2
OPh N Ph
LiTMSCl, THF, -78 ºC
1)
2) H2O3) TBAF, THF
R1=Ph, R2=t-Bu, 87%, 28% eeR1=t-Bu, R2=t-Bu, 58%, 51% ee
R1=Ph, R2=t-Bu, 89%, ~12% eeR1=t-Bu, R2=t-Bu, 74%, ~23% ee
OP
R2
R1 Ph Ph
O
Allylic Elimination (β-elimination)Chirality at allylic position
Allylic Elimination (β-elimination)Chiral leaving groups
H
Ts
ArSe
R Ts
ArSe
R
SAEor
DavisEpoxidation
nC7H15 SeAr
H Ts
O - ArSeOHC
H
Ts
nC7H15
H
45 examples9-100% yield
1-42% ee
Komatsu, N.; Murakami, T.; Nishibayashi, Y.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 3697-3702.
Et3Nor
KOtBu
Not isolatedCan racemize with H2O
Allylic Elimination (β-elimination)Chiral leaving groups
H
Ts
ArSe
R Ts
ArSe
R
SAEor
DavisEpoxidation
nC7H15 SeAr
H Ts
O - ArSeOHC
H
Ts
nC7H15
H
45 examples9-100% yield
1-42% ee
Komatsu, N.; Murakami, T.; Nishibayashi, Y.; Sugita, T.; Uemura, S. J. Org. Chem. 1993, 58, 3697-3702.
Et3Nor
KOtBu
Not isolatedCan racemize with H2O
Hishibayashi, Y.; Singh, J. D.; Fukuzawa, S.; Uemura, S. J. Org. Chem. 1995, 60, 4114-4120.
Fe FeSe Se
Me
MeMe2N
NMe2
(FcSe)2 =
(S,R)
RCO2Et
(FcSe)2NaBH4
EtOH
R = Me, Et, Pr
R CO2EtSe
Fc*
mCPBA
CH2Cl24Å MS
-78 to -20 ºCO Se
H CO2Et
Fc*
RH
CCO2Et
H
RH- HOSeFc*
38-59% yield75-89% ee
Not isolated
Positioned away from sidechain of Fc*
Allylic Elimination (β-elimination)Equilibration of allylic metal center
Varghese, J. P.; Zouev, I.; Aufauvre, L.; Knochel, P.; Marek, I. Eur. J. Org. Chem. 2002, 4151-4158.
H STol
O BuCu⋅MgBr2
THF-70 to 20 ºC
Bu Cu
H STol
O
BuI
I
then, Bu2Zn, 2 MgBr20 to 5 ºC
then,
Bu
H STol
O
ZnBuBu
Bu
H STol
O
ZnBuBu
"Racemic" sp3
organometallicThermodynmicequilibration;
"Enantioenriched"sp3 organometallic
synC
H
Bu
HBu
75% yield65% ee
Stoichiometric Chiral Reagents and Auxilliaries
A) Asymmetric Deprotonation-Protonation
B) Asymmetric Horner-Wadsworth-Emmons
C
R1 R2
O P(*RO)2
O
OR
O
C
R1 R2
O
Nu Nu CCO2R
H
R1R2
R1
R2
HR HS B*
R2
B* HR
R1HS
E
CE
R2
R1HS
Asymmetric Deprotonation
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.
N NLi
OR1
O
N
CbOR1
HR HS BuLi(-)-sparteine
pentane-78 ºC
Precipitates from reactionEquilibrates in THF
TiCl(Oi-Pr)3CbO
R1
Ti(Oi-Pr)3
R1 = TMS, t-Bu
INVERSION!
CbOR1
Ti(Oi-Pr)3
R2CHO R1H
TiX3
OCb
OR2
HC
HOCbR1
OHR2
73-86% yield93->95% ee
1 diastereomer
CHOCbR1
H
AcOH TMS: 86% yield, 88% eet-Bu: 80% yield, 84% ee
Asymmetric Deprotonation
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.
O
OR
BuLi (2 equiv)THF, -78 ºC, 2 h
O
OR
LiH
OH
OO
CR
H
Ht-BuOH
R = Me, 55%, 20/1 drR = t-Bu, 65%, 3/1 dr
OO
C
Li
Ht-Bu
BuLi
THF-78 ºC30 min
N
O
O
Me
Ph
CO
O
H
t-Bu
MePh
OH
H
δ OO
H
OH
Me
t-Bu
δHCl(CF3)2CHOHCF3CH2OH
H
Ph
O
OH
Me
t-Bu
H
Ph
O+
HO
OH
Me
H
t-Bu
Ph
Asymmetric Protonation
Mikami, K.; Yoshida, A. Angew. Chem. Int. Ed. 1997, 36, 858-860.Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889-898.
O
HCO2Me
+
1) (R)-BINOL-Ti CH2Cl2, 95% OPO(OEt)2
CO2Me2) BuLi (EtO)2POCl 94%
5 mol% Pd(PPh3)4SmI2 (2 equiv)
t-BuOH (1.1 equiv)
THF53% C CO2Me
Racemic!Pd0
R1R2
PdII
CR2
PdIIR1H
CR2
PdIIHR1
Pd0
2 SmII
R1R2
SmIII
CR2
SmIIIR1H
CR2
SmIIIHR1
R*OH R*OH
CR2
HR1H
CR2
HHR1
Asymmetric Protonation
Mikami, K.; Yoshida, A. Angew. Chem. Int. Ed. 1997, 36, 858-860.Mikami, K.; Yoshida, A. Tetrahedron 2001, 57, 889-898.
O
HCO2Me
+
1) (R)-BINOL-Ti CH2Cl2, 95% OPO(OEt)2
CO2Me2) BuLi (EtO)2POCl 94%
5 mol% Pd(PPh3)4SmI2 (2 equiv)
t-BuOH (1.1 equiv)
THF53% C CO2Me
Racemic!
R'
OPO(OEt)2
CO2Me
5 mol% Pd(PPh3)4SmI2 (2 equiv)
THF68%
C CO2Me
racemic H
HO
O OH1.1 equiv
+
>95% ee
RH
E
SmO O
H
H
R'
R'
HR
E
SmO O
H
H
R'
Ph
OHHO
Ph
71% yield86% ee
with
Asymmetric HWE
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.
CO2PhR1
R2
LDAZnCl2
THF-78 ºC
Me
Me
O
OP
O O
OMe
A
C OR2
R1 LDAA
THF-78 ºC to rt
CR2
R1
CO2MeH
21-71% yield32-89% ee
CO2BHTR1
R2
BuLiZnCl2
THF-78 ºC
C OR2
R1 KHMDSA
THF-78 ºC to rt
CR2
R1
CO2MeH
60-94% yield4-84% ee
C
O
S L
OMe
OPO
Zn2+
OO
Me
Me
si face
re faceblocked by Me
Chiral Catalysis and Kinetic resolution
Kinetic Resolution
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.
CH
H
C7H15
OHC
H
OH
HC7H15
SharplessAsymmetricEpoxidation
run to ~60% conversion40% ee
C
R
R
C
R
R
HH
H H
2 mol% catPhIO
CH2Cl2-40 ºC
61-98% ee57-83% conversionNoguchi, Y.; Takiyama, H.; Katsuki, T. Synlett 1998, 543-545
OMn+
N
O
N
PhPh
Me
MeMe
Me
Kinetic Resolution
Sweeney, Z. K.; Salsman, J. L.; Anderson, R. A.; Bergman, R. G. Angew. Chem. Int. Ed. 2000, 39, 2339-2343.
ZrNAr
(S,S)
C RR
H
H
C6H6
Zr
HArN H
RR
1.8 equivC
H
R
RH
(R)
+
50-61% conv78-98% ee
ZrN
Ar
CR
H
HR
Only favoredapproach
(S,S,R)
CR
H
RH
(S)>95% recovery
85-93% ee
C
ZrNAr
(S,S)
C1 equiv
Zr
HArN
(S,S,R)
H
100% conv.
1 diastereomer!
C
C(S)H H
84% ee93% yield
Thought to involve stepwisemechanism; therefore highlystereoselective, not stereospecific
Kinetic Resolution
Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. J. Chem. Soc., Chem. Commun.1998, 2363-2364.
CH
RO2C H
CO2RR = (-)-L-menthyl
5:4 dr
1 mol% Et3N
pentane-20 ºC2 days
CH
RO2C CO2RH
(R) crystallizes90% yield>98% de
CH
RO2C CO2RH
(R)
+ Et3N
- Et3NH
RO2C
NEt3
ORO
H
+ Et3N
- Et3NC
H
RO2C HCO2R
(S)
CH
RO2C CO2RH
N Boc
+ C
CO2R
H
CO2RHNBoc
AlCl3
CH2Cl2-78 ºC
NBoc
CO2R
H CO2R
HHN
H
N
Cl
(-)-epibatidine
deracemization
Kinetic Resolution
Node, M.; Nishide, K.; Fujiwara, T.; Ichihashi, S. J. Chem. Soc., Chem. Commun.1998, 2363-2364.
CH
RO2C H
CO2RR = (-)-L-menthyl
5:4 dr
1 mol% Et3N
pentane-20 ºC2 days
CH
RO2C CO2RH
(R) crystallizes90% yield>98% de
deracemization
CH
i-PrO2C H
CO2i-Pr
(+)-Eu(hfc)3
CDCl39 days20 ºC
CH
i-PrO2C HCO2i-Pr
(S)>95% ee
Naruse, Y.; Watanabe, H.; Ishiyama, Y.; Yoshida, T. J. Org. Chem. 1997, 62, 3862-3866
Chiral Catalysis
de Graaf, W.; Boersma, J.; van Koten, G.; Elsevier, C. J. J. Organometallic Chem. 1989, 378, 115-124.
The Beginning
Ct-Bu
H
H
H
BuLiMX
THF-60 ºC
Ct-Bu
M
H
H(±)
cat Pd(R,R-DIOP)PhI
-60 ºC to rt
up to 25% eechanging MX altered sense of inductionMX = ZnCl, MgCl, CuBr/LiBr
L2Pd0
PhI L2PdI
Ph
MI
Ct-Bu
H M
H
Ct-Bu
H M
H
Ct-Bu
H PdL2
H
Ph
Ct-Bu
H Ph
H-L2Pd0
-M+
Ct-Bu
H
H
Ht-Bu
Ct-Bu
H H
M -M+
Ct-Bu
H H
Ht-Bu
"fast" reactingenantiomer
"slow" reactingenantiomer
Ct-Bu
H PhH
Warning!Speculation by AMH
Chiral Catalysis
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.
R1
Br
CO2EtEtO2C
Me
CO2EtEtO2C
NHAcor+
10 mol%Pd[(R)-BINAP]2
dba (2 equiv to Pd)
CsOt-BuCH2Cl2, 20 ºC
CR1H
H
CO2Et
CO2EtR2
34-75% yield54-89% ee
Pd0(BINAP)R1
Br
R1
PPd
Br
PR1
PPd
P
2
(2R)
R1
PPd
P
2
(2S)34:66 drby NMR
CH
R1
H
Nu
CH
R1 H
Nu
NuNu
major minor
The presence of dbadoes not affect the ratio of
2R to 2S, but accelerates the interconversion 12-25 times.
Chiral Catalysis
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.
R1
Br
CO2EtEtO2C
Me
CO2EtEtO2C
NHAcor+
10 mol%Pd[(R)-BINAP]2
dba (2 equiv to Pd)
CsOt-BuCH2Cl2, 20 ºC
CR1H
H
CO2Et
CO2EtR2
34-75% yield54-89% ee
CH
H
CO2Et
CO2EtNHAc
TMSOMe
OMe+
TiCl4
CH2Cl2-78 ºC
CO2Et
CO2EtNHAc
HMeOt-Bu
t-Bu
OHC
HR
Favored
(S)87% ee
90% yield85% ee
(S)
t-Bu
OHC
H
TMS
R
Disfavored
t-Bu
O
HCH
TMS
R
(R)H
H
TMSMe
MeMe
H
Ogasawara, M.; Ueyama, K.; Nagano, T.; Mizuhata, Y.; Hayashi, T. Org. Lett. 2003, 5, 217-219.
Chiral Catalysis
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.
R1
Br
CO2EtEtO2C
Me
CO2EtEtO2C
NHAcor+
10 mol%Pd[(R)-BINAP]2
dba (2 equiv to Pd)
CsOt-BuCH2Cl2, 20 ºC
CR1H
H
CO2Et
CO2EtR2
34-75% yield54-89% ee
CH
H
CO2Et
CO2EtNHAc
TMSOMe
OMe+
TiCl4
CH2Cl2-78 ºC
CO2Et
CO2EtNHAc
HMeOt-Bu
(S)87% ee
90% yield85% ee
Ogasawara, M.; Ueyama, K.; Nagano, T.; Mizuhata, Y.; Hayashi, T. Org. Lett. 2003, 5, 217-219.
CO2R2R2O2C
R3+
1 mol%Pd2(dba)3⋅CHCl3
4 mol% (R)-MeOBIPHEP
BSA, THF, rtC
R1H
H
CO2R2
CO2R2R3
72-90% yield69-90% ee
CH
R1
H
OPO(OEt)2
(±)
Imada, Y.; Ueno, K.; Kutsuwa, K.; Murahashi, S.-I. Chem. Lett. 2002, 5, 140-141.
Chiral Catalysis
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.
R HSiCl3+
PdCl(Allyl)2/L(1 mol% Pd)
(neat) 20 ºCC
H
Me
R
Cl3Si
MeMgBr
Et2OC
H
Me
R
TMS
Fe
MeO
Me
PPh
Fe
Me
OMe
(S)-(R)-bisPPFOMe
R
Pd HCl3SiL
+
R
Pd HCl3SiL
R
MeCl3Si
PdL
CH
Me
R
Cl3Si
37-90% yield68-90% ee
CH
Me
R
Cl3Si
PhCHO
DMF Ph
OH
Me
R
Ph
OH
Me
R
1:1 to 4:1100% chirality transfer
+
Chiral Catalysis
Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett. 2004, 6, 305-307.
O
R
n
[RhCl(C4H4)2]2/L*(3 or 10 mol% Rh)
ArTi(Oi-Pr)4LiTMSCl
THF, 20 ºC30 min
n
OTMS
C
RAr
61->99% yield26-93% ee
(configuration not reported)
O
O
O
O
PPh2
PPh2
(R)-segphos
L* =
[Rh]-Ar
O
[Rh]
ArR
isomerizationdetermines
stereochemistry
O
C Ar
R
*
*
[Rh]
TMSClArTi(Oi-Pr)4Li
ConclusionsConclusionsPresented 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 BrummondUniversity of Pittsburgh
Prof. James MarshallUniversity of Virginia
Prof. Tamio HayashiKyoto University