Fundamentals of Medicinal Chemistry

O

HO

O

(iii) H+or OH−

(ii) CrO 3

(iv) H 2 /Pd

O

CH 3 COO

(i) CH 3 COOCOCH 3

Diosgenin Pregnenolone ethanoate

Oestrogens

Androgens

Corticoids Progesterone

Microbial

oxidation

Figure 10.1 An outline of the synthesis of progesterone from diosgenin

All approaches are based on a knowledge of the chemistry of functional

groups and their associated carbon skeletons. The design may be either alinear

synthesis, where one step in the pathway is immediately followed by another, or

aconvergent synthesis, where two or more sections of the molecule are synthe-

sized separately before being combined to form the target structure (Figure

10.2). Each of these approaches may involve steps where protecting groups

have to be used. These groups should be selected on the basis that they are

easy to attach, stable under the conditions that are used for the primary reaction

and easy to remove after the primary reaction(s) have been completed.

In both linear and convergent synthesis designs, common sense dictates that

the starting materials should be chosen on the basis of what will give the best

chance of reaching the desired product. In addition, they should be cheap and

A B C D E F G H I J Target structure

(a) Overall yield of the target structure 35%

A B C D E

Target structure

F G H I J

(b) Overall yield of the target structure 53%

A B C

D E F

J

G H I

(c) Overall yield of the target structure 66%

Target structure

Figure 10.2 A schematic representation of (a) linear and (b) and (c) convergent syntheses. The

overall yields are based on a 90%yield for each step. In general, convergent synthesis improves the

overall yield of the target structure

204 AN INTRODUCTION TO LEAD AND ANALOGUE SYNTHESES