Stereochemistry

Isomers are compounds with the same numbers of respective atoms, but different structures (and hence properties). Two molecules are said to be “chiral” if they are mirror image isomers (“stereoisomers”). The asymmetric atom (e.g. carbon) giving rise to the two stereoisomers is a “chiral centre”.

Individual stereoisomers are called “enantiomers” if they cannot be mapped onto each other by rotation and translation. The enantiomers (also called “optical isomers”) differ in their effect on polarised light. Each will rotate the plane of polarisation in an opposite direction. A mixture of two enantiomers is a “racemate” or “racemic mixture”.

The physical properties (melting point, boiling point etc.) of two enantiomers are the same (though not necessarily the same as those of the racemate, the mixture of the two). However, it has long been known that enantiomers can have vastly different pharmaceutical activity.

The most notorious example is Thalidomide™, a racemic drug, in which one enantiomer produces a desirable anti-emetic effect, whereas the other is mutagenic. In the case of Thalidomide, the enantiomers are converted into each other in the human body. Within four to six hours of exposure to human blood, an individual isomer is converted to an equal mixture of both enantiomers, so synthesis of the pure antiemetic enantiomer will not mitigate its dangers to the patient.

Warner-Lambert’s enantiomer: Atorvastatin

In the case of Atorvastatin, there are two enantiomers of interest:

Thalidomide™ inhibits the production of TNF-alpha that stimulates the immune system. For people with HIV, there is overproduction of TNF and that is also associated with the rapid progression of AIDS. As well as possible applications in fighting AIDS, Thalidomide is under study for its properties as an anti-angiogenic compound for the treatment of tumours and cancers.

The [R(R*R*)] isomer shown above was the subject of European Patent No. EP0409281B, of which the UK national part was revoked by the UK Patents Court. Incidentally, these are not the only stereoisomers. The upper lactone ring has two chiral centres and can additionally take the form of cis- and trans-isomers. It was conceded in the Warner-Lambert patent that only the trans- form was of interest