Enantioselective Synthesis of Axial Chiral AllenesStructure and Spectroscopy of Allenes 1H NMR Spectroscopy: Typically in the same area as olefinic protons, but slightly upfield (~4.4

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


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.


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.


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 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


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)


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.


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)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%


t-BuOH (1.1 equiv)

THF53% C CO2Me

Racemic!

R'

OPO(OEt)2

CO2Me


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


R1

Br

CO2EtEtO2C

Me

CO2EtEtO2C

NHAcor+


dba (2 equiv to Pd)


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


R1

Br

CO2EtEtO2C

Me

CO2EtEtO2C

NHAcor+


dba (2 equiv to Pd)


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

Documents

Enantioselective Synthesis of Axial Chiral AllenesStructure and Spectroscopy of Allenes 1H NMR Spectroscopy: Typically in the same area as olefinic protons, but slightly upfield (~4.4