Fundamentals of Medicinal Chemistry

COOH

HOOC

CH 3 CH^3

H 2 N

H

COCl 2

HN O

O

CH 3 O

HN

H

N

O

H

HOOC H H L-Proline

Ph

Ph Ph

COOC 2 H 5

O

N

C C 2 H 5 OOC

CH 3

O

N H COOH COOH

H 2

Raney Ni C 2 H 5 OOC N

CH 3

O

N

H H

C

H

L-Alanine

Enalapril

S configuration S configuration

Figure 10.9 A synthetic route for the preparation of the ACE inhibitor enalapril (S-1-[N-

(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-L-proline). The configurations of L-alanine and

L-proline, the reagents for stage 2, are retained in the final product. The reduction of the

intermediate A is stereoselective, giving the S,S,S-isomer in 87%yield

products of these types of reaction range from a single enantiomer to a

mixture of diastereoisomers, which may be separated into their constituents

(see section 10.2.1). In all cases, the reactions used in further stages of the

synthesis should not affect the configurations of the chiral centres of the

building blocks. However, in some instances reactions that cause an inver-

sion of configuration may be used.

2. Using a chiral auxiliary. The achiral substrate is combined with a pure

enantiomer known as achiral auxiliaryto form a chiral intermediate. Treat-

ment of this intermediate with a suitable reagent produces the new asymmet-

ric centre. The chiral auxiliary causes, by steric or other means (see section

10.2.2), the reaction to favour the production of one of the possible stereo-

isomers in preference to the others. Completion of the reaction is followed by

removal of the chiral auxiliary, which may be recovered and recycled, thereby

cutting down development costs (Figure 10.10). An advantage of this

approach is that where the reaction used to produce the new asymmetric

centre has a poor stereoselectivity the two products of the reaction will be

diastereoisomers, as they contain two different asymmetric centres. These

diastereoisomers may be separated by crystallization or chromatography (see

section 10.2.1) and the unwanted isomer discarded.

3. Using achiral substrates and reagents. A wide variety of achiral substrates and

reagents can give rise to asymmetric centres. For example, electrophilic

addition of hydrogen chloride to butene gives rise to a racemic mixture of

212 AN INTRODUCTION TO LEAD AND ANALOGUE SYNTHESES