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e.g. silicon, nitrogen, phosphorus and sulphur, it is not surprising that optically active compounds of these elements are also known. In the case of trivalent derivatives of nitrogen the lone pair of electrons may be considered to be the fourth ligand. However, inversion of the pyramidal forms occurs very rapidly via a planar transition state (4.2^ 4.3^4.4), the activation energy for the inversion being very low, so that separation of enantiomers is not possible. However, the formation of quaternary ammonium compounds, e.g. the neuromuscular blocking agent atracurium besylate (4.5), or the formation of an amine oxide, e.g. A-ethyl-A-methylaniline A-oxide (4.6), results in the formation of a chiral centre.

In contrast to trivalent derivatives of nitrogen, trivalent pyramidal sulphur derivatives have a higher energy of activation for inversion and the rate is slow enough that the individual enantiomers are relatively stable. Examples of drug molecules containing

chiral sulphur and phosphorus centres include the non-steroidal anti-inflammatory prodrug sulindac (4.7) and the phosphamide mustard pro-drug cyclophosphamide (4.8).

Compounds which do not possess a chiral centre in their structure may also exist in enantiomeric forms as a result of an axis or plane of chirality. Such systems occur less frequently in compounds of pharmaceutical interest. Atropoisomerism (Greek, atropos inflexible) is a term used to characterise stereoisomers which are chiral due to hindrance of rotation about a single bond, e.g. suitably substituted biphenyl derivatives (4.9). In this case rotation about the carbon-carbon bond linking the two phenyl rings is restricted by the steric effect of the substitutents resulting in configurational stability. Examples of interest include the hypnotic methaqualone (4.10, 4.11) and the male antifertility agent gossypol (4.12).

The presence of adjacent double bonds as found in allenes also gives rise to enantiomerism, e.g. structures (4.13) and (4.14). In the case of these compounds the substituents lie in intersecting planes and the two structures are non-superimposable, such molecules possess a chiral axis. This type of isomerism is found in the naturally occurring antibiotic mycomycin (4.15).

Steric crowding in a molecule may also give rise to enantiomeric structures as a result of distortion, e.g. the helicenes. The simplest helicene consists of six ortho fused benzene rings (4.16) and as a result of steric crowding the molecule is not planar but helical. The

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