chiral allylsilanes as enantioselective allylation reagents for aldehydes focusing on work by james...

Chiral Allylsilanes as Enantioselective Allylation Reagents for Aldehydes

Chiral Allylsilanes as Enantioselective Allylation Reagents for Aldehydes

Focusing on work by

James BullGroupe Charette, Réunion de littérature, 4 Décembre 2007

James S. Panek and James L. Leighton

SiR3 R

RRSi

L**L

LR

R

Outline

I. Introduction to allylation chemistryStereocontrol features for allylsilanesIntroduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States

II. James S. Panek1. Background/ Concept2. Aldehyde Crotylation3. Synthesis of chiral allyl silanes4. Use in complex molecule synthesis

III. James L. Leighton1. Background/ Concept2. Synthesis of chiral allyl silanes3. Allylation/Crotylation4. Imine electrophiles

Si

L**L

LR

R

SiR3 R

RR

The importance of allylation/crotylation chemistry

O O

MO

R

SE2' OH

Rcontrol ofchirality

R1

R2 R1 R2

OOH

RR1 R2

H

Common (Excellent) Enantioselective Methods

Brown Roush

Excellent enantio/diastereocontrol Unstable to storagePrepared in situUsed at low temperature

B R 2

R1O

O

iPrCO2

iPrCO2

OB

L*

L*

R

R2

R1

Well defined cyclic TS’s (Type I class)

L*2B Me

L*2B

Me

OH

R

OH

R

Me

Me

B R 2

R1

Common (Excellent) Enantioselective Methods

Keck

Lewis Base catalysed enantioselective allylation

Denmark, S. E.; Fu, J. Chem. Rev. 2003, 103, 2763

SnBu3

O

RR1

R

R1OH

OH

OH

Ti(OiPr)4

2 eq

4 A MS, CH2Cl2rt, 1h

SiCl3

O

R R

OHTi(OiPr)4

4 A MS, CH2Cl2R2

R1

5 mol %

PN

N N N

N

NP

5

R2 R1

HHHH

OO

Allylsilanes

SE2’ antiStereospecific

Stereocontrol??• New Chiral Centre• Double bond geometry• When E+ = aldehyde, diastereoselectivity

R1R

ROH

R3

SiR3

R1

R

R

E+

R1R

RELewis Acid

What is SE2’ reactivity??What is SE2’ reactivity??

Stereospecific ≠ 100% stereoselective Defined by mechanism

Determined by Structure/steric effectsConformation effects

What is a stereospecific reaction??What is a stereospecific reaction??

SE2’ reactivity

SN2

InversionStereospecific

A

CBX

N

SE2’ reactivity

SN2


A

CBX

N

SN1 AB

C*N

Non stereospecificMay be stereoselective

SE2’ reactivity

SN2


A

CBX

N

SN1 AB

C*N

Non stereospecificMay be stereoselective

SN2’Direct SN2 usually fasterStereospecifically Syn (depending on nucleophile)

LG

Nu

Stork:

OCOAr

NHN

OCOAr

N

Stork, G.; White. W. N. J. Am. Chem. Soc. 1956, 78, 4609.

SE2’ reactivity

SN2


A

CBX

N

E+A

CBM

A

CBM

Grignards: non stereospecificLi, inversion or retention depending on electrophile

stereodefined C-M bonds

A

CBE M

Inversion

RetentionE

SE2

MeO

N

OtBuO

Ph

HH BuLi

sparteine

MeO

N

OtBuO

Ph

LiH

MeO

N

OtBuO

Ph

H

MeO

N

OtBuO

Ph

H

Br

O

OMe

CO2Me

CHOCHO

Retention

Inversion

Park, Y. S.; Beak. P. J. Org. Chem. 1997, 62, 1574.

SE2’ reactivity

SN2


A

CBX

N

SN2’ LG

Nu

Stereospecifically SYNDirect SN2 usually faster

SE2 A

CBE M

Inversion

Retention

SE2’M

E+

For M = Si Stereospecifically ANTIM = Si, B, Mg, Sn, Ti, Cr, Zn, ….

Stereocontrol for allylsilanes

Parallel bonds for max interaction

Hyperconjugation: -conjugation

R3Si

R H

R2

R1

R3Si

RH

R2

R1

R3Si

R H

R2R1

E

ANTIR

H

R2R1

E

trans

RRR> >

H CH3 M

closer in energypoor energy matchpoor geometry

< <<

If there is no clearly prefered ground state conformationstereoselectivity will be reduced But reaction still occurs stereospecifically anti

Hg HgSiR3

Stereocontrol for allyl silanes

R3Si

R H

R2

R1

R3Si

RH

R2

R1

R3Si

R H

R2R1

E

ANTIR

H

R2R1

E

trans

No preorganisation by Lewis Acid

Open Transition State (Type II class)

SiR3

R1

R2

R

Lewis Acid

R1R2

ROH

R3

O

H R3

LA

Open TS for crotylsilane reagents

E-silane

Z-silane

SYN diastereoselective

SYN diastereoselective ANTI diastereoselective

ANTI diastereoselective

Antiperiplanar Transition States for crotyl silanes

Relative energy differences between antiperiplanar and synclinal TS are negligible

SYN product preferred

TS may adopt an antiperiplanar or synclinal arrangement

Open TS for crotylsilane reagents

Both antiperiplanar and synclinal TS predict syn selectivity

Synclinal Transition States

Z-silane

E-silane

SYN diastereoselective ANTI diastereoselective

Outline

I. Introduction to allylation chemistry,Stereocontrol features for allylsilanesIntroduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States



Si

L**L

LR

R

SiR3 R

RR

James S. Panek

b. 19561979 BSc Chemistry (SUNY Buffalo)1984 PhD Medicinal Chemistry (Kansas) with Dale Boger1984-86 Post Doc (Yale) with Danishefsky1986 Boston University

Chiral E-crotylsilane:Well behaved SE2’ Anti additionComplete transfer of chiralityProvides easily functionalised products

Able to control reaction pathway by control of temperature and Lewis acid

RCO2Me

SiMe2Ph

R X

http://www.bu.edu/chemistry/images/faculty/panek.jpg

Crotylation using syn-selectivity

Panek, J. S.; Yang. M. J. Am. Chem. Soc. 1991, 113, 6594.

Complete chirality transfer from silane, no other diastereoisomers observedAnti SE2’E double bondSyn Selective

OMe

OMe 92%, 40:1, 95% ee

OMe

OMe

MeCO2Me

SiMe2Ph

OMeO

OMe

CO2MeMe

OMe

OMe

Ar OMe

TMSOTf

OMe

CO2Me

OMe

Major

Minor

90%, 13:1, 95% ee–78 ºC, CH2Cl2

Crotylation using Syn-selectivity

Panek, J. S.; Yang. M. J. Org Chem. 1991, 56, 5755.

OMe

CO2Me

86%, 30:1, 96% ee

BnO

OMe

CO2Me

OMe

O

70%, 30:1, 96% ee

OMe

CO2Me

OMe

BnO

96%, 20:1, 96% ee

MeCO2Me

SiMe2Ph

MeOMe

CO2Me

Me

TMSOTf

88%, 30:1, 96% ee

–78 ºC, CH2Cl216 h

OMe

OMeBnO BnO

Crotylation using Syn-selectivity

Panek, J. S.; Yang. M.; Solomon J. S. J. Org. Chem. 1993, 58, 1003.

Form oxonium in situOMe

CO2Me

OAc

O

85%, 20:1

OBn

CO2Me

OAc

87%, 20:1

OBn

CO2Me

OAc

BnO

PdCl2 (20 mol%)CH2Cl2, rt

OBn

CO2MeBnO

OAc

36 h

86%

Pd catalysed allylic transposition to form 1,3-diols

MeCO2Me

SiMe2Ph

OAc OBn

CO2Me

OAcTMSOTf

51%, 20:1

–78 ºC to –35 ºC CH2Cl2

BnOO

BnO

TMSOBn

complete preservation of chirality1,3-syn diol

MeCO2Me

SiMe2Ph

OAcTMSOTf

–78 ºC to –70 ºC CH2Cl2

OMe

CO2Me

OAc PdCl2 (20 mol%)CH2Cl2, rt

OMe

CO2MeBnO

OAc

36 h

96%

OMe

BnO BnO

54%, 20:1

OMe

Acyclic Diastereoselectivity - Reversing Syn Selectivity

Panek, J. S.; Cirillo, P. F. J. Org. Chem. 1993, 58, 999.

OH

CO2Me

6.5:1syn:anti

BnOBF3.OEt2, –78 ºCMe

CO2Me

SiMe2Ph

O

BnO

Me

Re face attack

MgBr2.OEt2, –25 ºCMe

CO2Me

SiMe2Ph

O

BnO

MeOH

CO2Me

1: 12.2syn:anti

BnO

Si face attack

Chiral Aldehydes - Double stereodifferentiation

Chirality of the aldehyde controls the absolute stereochemistry of the oxygen bearing stereogenic centre.Chelation control with OBn, Felkin control with OTBDPS

R = Me, 64%, 10:1R = Et, 35%, 15:1

R = Me, 85%, 1:30R = Et, 69%, 1:10

Syn:Anti

R = H, 90%, >30:1R = Me, 79%, >30:1R = Et, 74%, 15:1

R = Me,98 %, 1:8R = Et, 79%, 1:10

MeCO2Me

SiMe2Ph

RO

BnO

TiCl4 (1.1 eq)CH2Cl2, –78 ºC

OH CO2MeR

BnO

MeCO2Me

SiMe2Ph

RO

BnO


OH CO2MeR

BnO

OH CO2MeR

TBDPSO

O

TBDPSO

O

TBDPSO MeCO2Me

SiMe2Ph

R

MeCO2Me

SiMe2Ph

R TiCl4 (1.1 eq)CH2Cl2, –78 ºC


OH CO2MeR

TBDPSO

Chiral Aldehydes - Double stereodifferentiation

Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475.

O

TBDPSOMe

CO2Me

SiMe2Ph


OH CO2MeR

BnO

O

TBDPSOMe

CO2Me

SiMe2Ph


OH CO2MeR

TBDPSO

Chiral Aldehydes - 1,3-induction?

Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475.

Silane reagents override 1,3-induction of the chiral aldehydePredisposed to local Felkin induction to determine hydroxy stereochemistry

MeCO2Me

SiMe2Ph

R

MeCO2Me

SiMe2Ph

R

MeCO2Me

SiMe2Ph

R

MeCO2Me

SiMe2Ph

R





Synthesis of chiral silanes

Johnson-Claisen

Complete preservation of chirality

Beresis, R. T.; Solomon J. S.; Yang. M.; Jain, N. F.; Panek, J. S.; Org. Synth. 1998, 75, 78.Panek, J. S.; Yang. M. J. Am. Chem. Soc. 1991, 113, 6594

HOH

HSiPhMe2 (1.1 eq)THF, 50 ºC

SiO

Si

SiPhMe2

OHPttBu3P

Lipase (0.5 eq)

SiPhMe2

OH

SiPhMe2

OAc

vinyl acetate

86%

46%

48%

MeCO2Me

SiMe2Ph

SiPhMe2

OH

(MeO)3CCH3cat. propionic acid

toluenereflux

SiPhMe2

O

OMe 86%96% ee


Enolate

Ireland-Claisen

Sparks, M. A.; Panek, J. S. Org. Chem. 1991, 56, 3431. Panek, J. S.; Yang. M.; Solomon J. S. J. Org. Chem. 1993, 58, 1003Panek, J. S.; Beresis, R.; Xu, F.; Yang, M. Org. Chem. 1991, 56, 7341.

SiPhMe2

OH

Me SiPhMe2

O

O

R

HO

O

R

MeCO2Me

SiMe2Ph

R

DCCDMAP

1. LDA, TMSCl

–78 ºC to rt

R = Me 1:12 81%R = OH >25:1 65%R = OMe 23:1 81%

syn:anti

LDA, HMPS, TMSCl R = Me 16:1 69%

2. SOCl2/MeOH

MeCO2Me

SiMe2Ph

MeCO2Me

SiMe2Ph

R

Anti:synMeI 100:1BnBr 75:1

LDA

electrophile

.

.


Huang, H.; Panek, J. S. Org. Lett. 2003, 5, 1991.

OHPhMe2Si

D-(–)-DETTi(OiPr)4,MS

CH2Cl2, –20 ºC

91%, 97% eeOHPhMe2Si

O1. TMSCl, Et3N

DMAP, CH2Cl2, –20 ºC

2. MgBrCuI, THF–50 ºC

OTMS

OH

SiMe2Ph

OAc

OH

SiMe2Ph

1. Citric acidMeOH

2. Ac2O, pyrDMAP, CH2Cl2

85%

71%

Synthesis of Oleandolide - Retrosynthesis

Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 1999, 121, 9229.Hu, T.; Takenada; N.; Panek, J. S. J. Am. Chem. Soc. 2002, 124, 12806.

MeCO2Me

SiMe2Ph

MeCO2Me

SiMe2Ph

R

R-2 S-3, R = HS-4, R = Me

PO

OP OP

[M]

OP

O

OP OP

MeH

7 81 13

Synthesis of Oleandolide


90%, >30:1 Syn:AntiFelkin approach

TBDPSO H

O

TiCl4, CH2Cl2–78 ºC to –35 ºC

TBDPSO

OH CO2MeMe

CO2Me

SiMe2PhR-2

1. 2% HCl/MeOH, 92%2. tBuSi(OTf)2, 2,4-lutidine3. O3, Me2S, MeOH/pyr (90%, 2 steps)

O O

O

SitBu tBu

H

TiCl4, CH2Cl2–78 ºC to –35 ºC

MeCO2Me

SiMe2PhS-3

O OSi

tBu tBu

OH CO2Me

87%, >30:1 Anti:SynFelkin approach

TBDPSO

O O

I

1. O3, Me2S, MeOH/pyr2. NaBH4, MeOH,90% (2 steps)3. I2, PPh3, Imid, 98%

TBDPSO

O O CO2Me1. HF.py2. TBDPSCl, 92% (2 steps)3. Me2C(OMe)2, PPTS, 99%


TBSOH

O

BF3.Et2O, CH2Cl2

–78 ºC to 0 ºC

HO

OH CO2MeMe

CO2Me

SiMe2PhR-2

82%, >30:1 Anti:Syn

TBSO

OTBS

O

1. TBSOTf, 2,6-lutidine2. O3,Me2S (93% 2 steps)

TiCl4, CH2Cl2–50 ºC

MeCO2Me

SiMe2PhS-3

CO2Me

Me

TBSO

TBSO OH

82%, >20:1 Syn:Anti

O

TBSO

TBSO OHO3, Me2S90%

1. Me4NBH(OAc)3MeCN, AcOH, –20 ºC, 89%2. PhCH(OMe)2, CSA, 89%

3. HF.py, py, 96%4. Dess Martin 95%

O

O

TBSO O

Ph



TBDPSO

O O O

O

TBSO O

Ph

tBuLi

TBDPSO

O O

I

O

O

TBSO O

Ph

Oleandolide


Alternative Reaction Pathways

Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113, 9868.

1,2 silyl migration competes with elimination

OH

CO2Me

6.5:1syn:anti

BnOBF3.OEt2, –78 ºCMe

CO2Me

SiMe2Ph

O

BnO

Me

If allowed to warm..

Me

CO2Me

SiMe2Ph

O

BnO

Me

Me

CO2Me

O

BnO

MeSiR3

F3BF3B

BF3.OEt2,Me

CO2Me

SiMe2Ph

O

BnO

Me

OBnO CO2Me

SiMe2Ph

H H

80%, 30:1 syn:anti, 96%de

–78 ºC to –30 ºC

Same concepts apply….

Masse, C. E.; Panek. J. S. Chem. Rev. 1995, 95, 1293, Fleming, I.; Barbero, A.; Walter, D. Chem. Rev. 1997, 97, 2063. Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000, 122, 9836

RCO2Me

SiMe2Ph

R Z

NR'O2C

HR

O

HR

LA

LA

CO2Me

Me

OH

R

CO2Me

Me

NHCO2R'

R

CO2MeE

Me

E+

XRCO2Me

SiMe2Ph

H H

Me

O

HCHO

Me

R3Si

MeO2C

O

HR

OH H

RMeO2C

Me

Outline

I. Introduction to allylation chemistry,Stereocontrol features for allylsilanesIntroduce SE2’ reactivity/stereospecificity Hyperconjugation, Open Transition States



Si

L**L

LR

R

SiR3 R

RR

James L. Leighton

Si

L**L

LR

R

b. 19641987 BSc Chemistry (Yale)1994 PhD Chemistry (Harvard) with David Evans1994-96 Post Doc (Harvard) with Eric Jacobsen1996 Columbia University

Cyclic transition state

Concept

B reagents - Type I cyclic TS Si Reagents - Type II open TS

OB

L*

L*

R

R2

R1

Make Si more Lewis-acidic to encourage a cyclic transition state

OSi

L*

L*

R

R2

R1

“Strain-Release Lewis Acidity”

Myers and Denmark Utimoto

Strained Silacycles: New reagents for allylation

Supports idea that ring strain is importantRing strain still exists due to long Si-O and short C-O bondsProceeds via cyclic TS

OSi

O

Cl

O

HPh

Tol

rt

OH

Ph

52%Uncatalysed

O

HPh

Tol

rt

O

HPh

Tol

rt

OSi

O

Cl

SiCl

O

O

N. R.

N. R.

Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920. Zhang, X.; Houk, K. N.; Leighton, J. L, Angew. Chem. Int. Ed. 2005, 44, 938.

Synthesis of Chiral Allyl Silanes

Screen chiral 1,2-diols, amino-alcohols and diamines

NSi

O

Cl

Ph

Me

Easily prepared Stable to storageConvenient work-up

Mixture of diastereoisomersInterconvert? React in same way?

Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920.

NSi

O

Cl

Ph

Me

NH

OHPh

Me

SiCl3

DBU, CH2Cl2

88% 2:1 dr

Scope - optimised conditions

Table 1

Kinnaird, J. W. A.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L, J. Am. Chem. Soc. 2002, 124, 7920.

NSi

O

Cl

Ph

Me (s,s)R

O

H

Toluene–10 ºC, 2h

R

OH

Diamine ligand

NSi

N

Cl

Br

Br

Best eeBr confers crystallinityStable solid (moderate air sensitivity)Straightforward synthesisSingle crystallisation to purify

Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946.Zhang, X.; Houk, K. N.; Leighton, J. L, Angew. Chem. Int. Ed. 2005, 44, 938

Scope

Excellent ee“among highest observed for this reaction”CH2Cl2 best solvent for allylation. Much longer reaction time 20h vs 2h

Aromatic Substrates

Aliphatic Substrates

NSi

N

Cl

pBrPh

pBrPh

R

O

H

CH2Cl2–10 ºC, 20h

R

OH

(R,R)

Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946

Scope - Chiral substrate

Chiral substrate:

Overrides 1,3 induction of chiral aldehyde

Kubota, K.; Leighton, J. L, Angew. Chem. Int. Ed. 2003, 42, 946

NSi

N

Cl

pBrPh

pBrPh

(R,R)

CH2Cl2–10 ºC, 20h

OH

(R,R) Ph

OBn

O

Ph

OBn

OH

Ph

OBn

86%, 95:5 dr

86%, 98:2 dr(S,S)

Crotylation - Cis reagent

Hackman, B. M.; Lombardi, P. J.; Leighton, J. L, Org. Lett. 2004, 6, 4375

Syn:Antidr >15:1

NSi

N

Cl

pBrPh

pBrPh

R

O

H

CH2Cl20 ºC, 20h

R

OH

(R,R)

1.1 equiv

Crotylation - Trans reagent

Hackman, B. M.; Lombardi, P. J.; Leighton, J. L, Org. Lett. 2004, 6, 4375

NSi

N

Cl

pBrPh

pBrPh

R

O

H

CH2Cl20 ºC, 20h

R

OH

(R,R)

Anti:Syndr >25:1

Reagents are crystalline solids but moisture sensitive - storable eg in glove boxHigh MW diamine. - 90% recoverable

Imine electrophiles - Aldimine allylation

NSi

O

Cl

Ph

Me (s,s)R

N

H

CH2Cl210 ºC, 16h

NH

O

1.5 eq

R

HNNH

O

Requires NHAc directing group

Berger, R.; Rabbat, P.M.; Leighton, J. L, J. Am. Chem. Soc. 2003, 125, 9596.

Single recrystallisation allowsaccess to enantiopure compounds

Imine electrophiles - Ketimine allylation

Berger, R.; Duff, K.; Leighton, J. L, J. Am. Chem. Soc. 2004, 126, 5686.

NSi

O

Cl

Ph

Me (s,s) R1

N

R2

CHCl340 ºC, 24h

NH

O Ph

R1

NHNHBzR2

Imine electrophiles - Aldimine crotylation

Trans reagent Syn product89%, 95:5, 97%22

Berger, R.; Rabbat, P.M.; Leighton, J. L, J. Am. Chem. Soc. 2003, 125, 9596.Berger, R.; Duff, K.; Leighton, J. L, J. Am. Chem. Soc. 2004, 126, 5686.

NSi

O

Cl

Ph

Me (s,s) R

N

H

CH2Cl210 ºC, 16h

NH

O Ph

R

HNNH

O Ph

Me

Imine electrophiles - directing groups

NSi

O

Cl

Ph

Me (s,s)R

N

H

CH2Cl2rt, 16h

HO

R

HN

HOR1

R2

R1 R2

HN

HO

HN

HO

HN

HO

64%98:2 dr98%ee

85%92%ee

83%96%ee

NSi

O

Cl

Me N

HN

R

NR1

N

HN

HNR1Toluene

23 ºC R

N

HN

HN

80%87%ee N

HN

N

71%88%ee

O

86%91%eeN

HN

HNMe

Rabbat, P. M.; Valdez, S. C.; Leighton, J. L, Org. Lett. 2006, 8, 6119.Perl, N. R.; Leighton, J. L, Org. Lett. 2007, 9, 3699.

Imine electrophiles - Cinnamylation

Huber, J. D..; Leighton, J. L, J. Am. Chem. Soc. 2007, 129, 14552.

NSi

O

Cl

Ph

Me

R

N

H

HO

Ph

DCE, reflux

R

N

H

DCE, reflux

HO

R

HN

Ph

R

HN

Ph

ArAr

Summary

Panek: Chiral allyl silanes for acyclic stereocontrol

Leighton: Chiral allyl silanes allowing cyclic stereocontrol

MeCO2Me

SiMe2Ph

RO

BnO


OH CO2MeR

BnO

85%, dr 1:30

NSi

N

Cl

pBrPh

pBrPhO

H

CH2Cl2–10 ºC, 20h OH

(R,R)

TBSO TBSO

61%, 98% ee

chiral allylsilanes as enantioselective allylation reagents for aldehydes focusing on work by james...

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