Fundamentals of Medicinal Chemistry

CH 2 OH

N CO

H

H H

HOOC C C

NH NH

H COOH

LiAlH 4

H CH

2 OH

(C 2 H 5 CO) 2 O

N−− COCH 2 CH 3

H

CH 2 OH

S-(−)-Proline The chiral

auxilary

The substrate

Hydrolysis

Chiral auxiliary removed

CH 3 CH 2 I

N

N

O−

CH 3

CH 3

CH 3

H

CH 3 CH 2 −I

O

CH 3

H

CH 3 CH 2

CH 3 CH 2 CH 3 CH 2

+I−

(I)

2LDA N−− C

H CH 2 −− O− Li+

C−− CH 3

H

2R-Methylbutanoic acid (84% e.e.)

O− Li+

Figure 10.10 The synthesis of 2R-methylbutanoic acid, illustrating the use of a chiral auxiliary.

The chiral auxiliary is 2S-hydroxymethyltetrahydropyrrole, which is readily prepared from the

naturally occurring amino acid proline. The chiral auxiliary is reacted with propanoic acid

anhydride to form the corresponding amide. Treatment of the amide with lithium diisopropyla-

mide (LDA) forms the corresponding enolate (I). The reaction almost exclusively forms the

Z-isomer of the enolate, in which the OLi units are well separated and possibly have the configur-

ation shown. The approach of the ethyl iodide is sterically hindered from the top (by the OLi units

or Hs) and so alkylation from the lower side of the molecule is preferred. Electrophilic addition to

the appropriate enolate is a widely used method for producing the enantiomers ofa-alkyl

substituted carboxylic acids

the R and S isomers of 2-bromobutane because addition has an equal chance of

occurring from either side of the C¼C bond.

H

H H

C

C

H+

Cl− Cl

Cl−

Cl

H C H

C

H

C 2 H 5 C 2 H 5

C 2 H 5

C 2 H 5

H

H H

C

C+

H

H

H C H

C

H

H

Butene

(±) 2-Bromobutane

The usefulness of these reactions in stereoselective synthesis will depend

on the nature of the product. If, for example, mixtures of enantiomers or

ASYMMETRY IN SYNTHESES 213