ClCOC(CH 3 ) 3NHCOCH 2 PhNHCOCH 2 CH 2 CH 2 OCH 2 CH 3NHCOC(CH 3 ) 3ClCOCH 2 PhClCOCH 2 CH 2 CH 2 OCH 2 CH 3NH 2Figure 10.3 A stage in a hypothetical drug design pathway illustrating some of the possibilities
provided by the presence of an amino group in the structure of an intermediate. The products of
the reactions illustrated could be either the final products of the design pathway or they could be
intermediates for the next stage(s) in the synthetic pathway
separation of the resulting stereoisomers or the use ofstereoselective reactions
that mainly produce one of the possible enantiomers. This section introduces
some of the general methods used to incorporate stereospecific centres into a
target molecule. However, for a more comprehensive discussion the reader is
referred toSelectivity in Organic Synthesisby R. S. Ward, published by Wiley
(1999).
10. 2. 1 The use of non-stereoselective reactions to produce stereospecific
centres
Non-stereoselective reactions produce either a mixture of diastereoisomers or a
racemic modification. Diastereoisomers exhibit different physical properties.
Consequently, techniques utilizing these differences may be used to separate
the isomers. The most common methods of separation are fractional crystalliza-
tion and chromatography.
The separation (resolution) of a racemic modification into its constituent
enantiomers is normally achieved by converting the enantiomers in the racemate
into a pair of diastereoisomers by reaction with a pure enantiomer (Figure
10.4.). Enantiomers of acids are used for racemates of bases whilst enantiomers
of bases are used for racemates of acids (Table 10.1). Neutral compounds may
sometimes be resolved by conversion to an acidic or basic derivative which is
suitable for diastereoisomer formation. The diastereoisomers are separated
using methods based on the differences in their physical properties and the
pure enantiomers are regenerated from the corresponding diastereoisomers by
suitable reactions.
206 AN INTRODUCTION TO LEAD AND ANALOGUE SYNTHESES