diastereoisomers are formed, the usefulness of the reaction will also depend on
the ease of separation of these mixtures into their component isomers.
10.3 Designing organic syntheses
The synthetic pathway for a drug or analogue must start with readily available
materials and convert them by a series of inexpensive reactions into the target
compound. There are no obvious routes as each compound will present a
different challenge. The usual approach is to work back from the target struc-
ture in a series of steps until cheap commercially available materials are found.
This approach is formalized by a method developed by S Warren, which is
known as either thedisconnection approachorretrosynthetic analysis. In all cases
the final pathway should contain a minimum of stages, in order to keep costs to
a minimum and overall yields to a maximum.
10.3.1 An introduction to the disconnection approach
This approach starts with the target structure and then worksbackwardsby
artificially cutting the target structure into sections known assynthons. Each of
these backward steps is represented by a double shafted arrow (¼)) whilst
is drawn through the disconnected bond of the target structure. Each of the
possible synthons is converted on paper into a real compound known as a
reagent, whose structure is similar to that of the synthon. All the possible
disconnection routes must be considered. The disconnection selected for a step
in the pathway is the one that gives rise to the best reagents for a reconnection
reaction. This analysis is repeated with the reagents of each disconnection step
until readily available starting materials are obtained. The selection of the
reagents and the reactions for their reconnection may require extensive litera-
ture searches (Table 10.2).
In the disconnection approach, bonds are usually disconnected by either
homolytic or heterolytic fission (Figure 10.11(a) and (b) ). However, some
bonds may be disconnected by a reverse pericyclic mechanism (Figure 10.11(c) ).
Disconnections may involve either the carbon skeleton or functional groups.
Normally the first step is to disconnect the sections of a molecule that are held
together by functional groups such as esters, amides and acetals, as it is usually
easier to find reconnection reactions for these functional groups. Heterolytic
disconnections usually provide the most useful approach to synthesis design.
214 AN INTRODUCTION TO LEAD AND ANALOGUE SYNTHESES