Asymmetric Synthesis

-Substitution using chiral enolates

Outline

Requirements for stereoselective enolate alkylation Imposing facial bias on alkylation Chiral auxiliaries leading to acids or alcohols Chiral auxiliaries leading to ketones

Requirements for stereoselective enolate alkylation

Only one geometrical isomer must be formed

Chiral auxiliary

Stereoelectronic requirements for deprotonation and alkylation

Maximum overlap of orbitals during bond-breaking and formation Preferred conformation during deprotonation Electrophile approach is slightly away from perpendicular, towards the auxiliary
O R B A H Base
O B A H Base B

-O B

-O

Enolate geometry

OR

THF

OLi 'E enolate'

Ireland:
OR

LDA
THF/HMPT OR 'Z enolate'

LDA Solution structure

S Pri N Pri Li S Li N iPr iPr

S = tBuOMe THF HMPT DMPU: N

LDA TS in THF Solution

H R O R N THF H Li R R THF

LDA TS with HMPA

H
HMPA Pri N Pri Li HMPA Li N iPr iPr

Me O
+

Me Me + 2 HMPA CO2R
Pri Pri N

Li(HMPA)4

Li N

iPr iPr

Me OR Me O H Pri Li N N iPr iPr

Li(HMPA)4

Sun & Collum, J Amer Chem Soc 2000, 122, 2452-2458

Pri

Enolate stereochemistry (THF)

Enolate stereochemistry (HMPA)

Other effects

% HMPA Substituent (R) size [BuLi] % hexane [LiCl] or LiBr] Other bases

Examples
O OLi

R
MeO

Base

Solvent
THF(hexane) THF-23%HMPA THF(hexane) THF-23%HMPA THF THF-23%HMPA THF(hexane) THF(hexane)

Z:E
5:95 84:16 6:94 >95:5 20:80 77:23 30:70 >97:3

LDA LDA EtO LDA LHMDS BnO LDA tBuO LDA Et LDA [(PhCH2)2N]3SiLi

Effect of chiral auxiliary

OM R Aux
a

O Selective enolate formation R Aux

O R Aux
b

OM Selective enolate formation

R Auxb

Chiral Auxa directs alkylation to 'upper' face

Chiral Aux directs E alkylation to 'lower' face

O R Aux E
a

O XR X E

O R X E E XR

Aux

Example of facial bias on ring

Me

Me

O NH 2 OH H2N OH

MeO N

Me Me Me nC7H15Br MeO

Me O N H3O
+

Me

Me

LDA

MeO N

Li

NH 2 OMe OMe

N N OMe C7H15 OMe

H2N O C7H15

>95:5

Example of facial bias through chelation

O Me N

Ph LDA H2C

Ph R X
1

R1

Ph LDA 2 R X R
1

H C R
2

Ph

N OMe Li OMe

N Li OMe H R
1

N Li OMe

H3O OH HO

Ph

C R
2

H2N OMe

Stereoselectivity in alkylation
H C R
1

OH

R1X
MeI BuI BuI BuI PhCH2Cl EtI

R2X
BuI MeI Me2SO4 PhCH2Cl BuI Me2SO4

e.e. %
66 20 52 70 73 70

Evans Oxazolidinone
O R H2N OH HN O Me Me or O Me BuLi RCH2COCl or O O R N O O N O O O

Me Me or H2N OH (EtO)2CO K2CO3

Me

HN Me Ph Me

Ph

Me

Ph

Evans & Gage, Organic Syntheses 1989, 68, 77 Chemical Reviews 1996, 96, 835-875

Stereoselectivity by chelation
O R N O LDA O R N O Li O O E R N E Me Me O R N O O O LDA R N Me Ph Me Ph O E Me Ph Me Me Li O R E N O B O Me Me O O A O O

E-X
EtI PhCH2Br MeI H2C=CHCH2Br

A: d.e. %
92 98 80 96

B: d.e. %
76 96 74 96

Application: Antibiotic X-206

Me
20

OH
7 17

Me

Me

O H O
1

O H Me H OH H

O OH OH H

O Me HO O H Me O

OH

O Me N

O Me O Base H2C=CHCH2I
4

O
3

O Me N O 1. LiAlH4 2. TBSCl, Et3N

Et HO
OR

Me

Me

Ph

Me

Ph

Me

Me Ph3P

Me Cp2ZrH, I2

3
+

RO

PPh3I

RO

RO

Application: Antibiotic X-206

Me
20

OH
7 17

Me

Me

O H O
1

O H Me H OH H

O OH OH H

O Me HO O H Me

OH

O Me N

O Me O Base H2C=CBrCH2Br Br
18

O
17

O Me N O LiAlH4 Br
20 18 17

O
OH

Et HO

Me

20

Me

Ph

Me

Ph

Me

18

20

Me 1. COCl2, DMSO, Et3N + 2. Ph3P CH(Me)2I , BuLi HO

18

20

Me

17

Br

17

Br

Me

Evans et al., J Amer Chem Soc 1988, 110, 2506

Other electrophiles

Hydroxylation Bromination Amination Acylation

Hydroxylation

O R N

O R O NaHMDS, O PhHC Me Ph NSO 2Ph OH

O O N O Mg(OMe)2 R OMe OH

Me d.e. >90%

Ph

Bromination
Bu B O R N O O R Bu2BOTf DIPEA N O O O R N Br PhH2C PhH2C PhH2C O O NBS O Bu

O R N N3 PhH2C

Amination
Bu B O R N O O R Bu2BOTf DIPEA N O O O R N Br PhH2C PhH2C PhH2C O O NBS O Bu

O R N N3 PhH2C

Acylation
O Me N O O Me LDA RCOCl COR Me Me Me Me Me Me Me N O R N O O O O O O

Me R

OH

MeMgBr

Zn(BH4)2

N Me Me Me

OH

R Me Me

Me

Enantioselective ketone synthesis

Acyl converted to imine Stereochemistry controlled through chelation

R'O Li N

R'O N R R

R'O N

O R R

Chiral hydrazines

SAMP

RAMP

H N NH 2 S OMe

H R OMe N NH 2

Enders, In Asymmetric Synthesis (Ed. Morrison), Vol. 3, pp. 275-339.

SAMP Synthesis
H N H (S)-Proline CO2H LiAlH4 N H OH H tBuONO N NO OH NaH, MeI H

H N NH 2 SAMP OMe

LiAlH4 N NO

OMe

RAMP Synthesis

H HO 2C

CO2H NH 2

H2O, reflux

CH2N2 H HO 2C N H O H MeO2C N H LiAlH4 O

(R)-Glutamic acid

H N OMe NH 2

H N H OH

RAMP

Using RAMP/SAMP
H O H N NH 2 SAMP OMe + N R R' R R' N LDA OMe N R R' N Li
+

OMe

H N N H R'' R R'

R N R' N H Li R''X O Me

OMe

Stereoselectivity in alkylation
H N N H R'' R R' OMe

Hydrazone
R=H, R=Me R=H, R=CH2Ph R,R=-(CH2)3R,R=-(CH2)4R=Et, R=Me R=Et, R=Me R=Et, R=Me R=Ph, R=Me R=Ph, R=Ph

E
EtI MeI Me2SO4 H2C=CHCH2Br EtI MeHC=CMeCH2Br tBuOCOCH2Br MeI MeI

d.e. %
77(S) >90(R) 86(R) 73(S) 94(S) >95(S) >95(S) 30(S) 10(R)

Rationalization

Reaction with acyclic and cyclic ketones and aldehydes Methoxy group is important for high stereoselectivity Therefore chelation, as in oxazolines Removal by acid hydrolysis or ozonolysis

Removal of auxiliary
H N N H R'' R R' MeI OMe O3

O H R R'' R'' + N NO OMe H

H N N
+

H Me N N
+

H3O+

H N H2N
+

H + H2N+ Me N OMe

Me OMe H + R'' R R'

H R''

OMe

Me

OMe

R'

Application

H N N OMe

Br +

1. LDA 2. MeI + 3. H3O

'Daddy-long-legs' defense substance >95% ee

Leioburnum vittatum & L. calcar

Enders & Baus, Liebigs Ann Chem 1983, 1439

Antibiotic X-14547A
O H
H N N OMe H

I + OTBDMS

1. LDA 2. O3

OTBDMS

82 - 95% ee

O H O H CO2H H H N H

Nicolaou et al., J Amer Chem Soc 1981, 103, 6967, 6969

Questions ?