10 An Introduction to Lead and Analogue Syntheses
10.1 Introduction
Once the structure of a lead has been decided it is necessary to design a synthetic
pathway to produce that lead. These pathways may be broadly classified as
eitherpartialorfullsynthetic routes. However, partial synthetic routes tend to
be more concerned with the large scale production of proven drugs rather than
the synthesis of lead compounds. This chapter is intended to introduce some of
the strategies used, and the challenges associated with the design of these
synthetic routes.
Partial synthetic pathways use biochemical and other methods to produce the
initial starting materials and traditional organic synthesis to convert these
compounds to the target structure. These methods are used to produce the
initial starting materials because it usually cuts down the cost of production
and produces compounds whose structures have the required configurations.
For example, the total synthesis of steroidal drugs is not feasible because of the
many chiral centres found in their structures. Consequently, partial synthesis is
the normal approach to producing new analogues and manufacturing steroidal
drugs. For example, the starting material for the production of progesterone is
diosgenin obtained from a number ofDioscorea species(a plant source). Dios-
genin may beconverted to pregnenolone ethanoate by a series of steps (Figure
10.1). This compound serves as the starting material for the synthesis of a
number of steroidal drugs including progesterone.
The full synthetic routes start with readily available compounds, both syn-
thetic and naturally occurring, but only utilize the standard methods of organic
synthesis to produce the desired product. These methods are discussed in
sections 10.2 and 10.3.
Fundamentals of Medicinal Chemistry, Edited by Gareth Thomas
#2003 John Wiley & Sons, Ltd
ISBN 0 470 84306 3 (Hbk), ISBN 0 470 84307 1 (pbk)