Asymmetric Synthesis

The manufacture of fine chemicals, particularly drugs, fragrances, and flavors, is undergoing a major revolution now as a result of the capability of chemists to prepare these chemicals, mainly drugs, in their purest isomeric forms (as stereoisomers). This shift to pure forms has been described by Brown in the following words (1990) (see also Deutsch, 1991): “A mixture of stereoisomers in a medicine will (now) need to be justified just the same way as any other mixture of compounds.” Indeed, in the United States today (as in many other advanced countries), the use of pure enantiomeric forms is practically a requirement since extensive justification is needed to continue with racemates (FDA, 1992). As a consequence, the combined sales of the “chiral top ten” drugs (ammoxycillin, enalapril, ampicillin, captopril, pravastatine, diltiazem, ibuprofen, lovastatin, naproxen, and fluoxetine) in 1994 amounted to more than 16 billion dollars (Sheldon, 1996). (Of these, ibuprofen and fluoxetine are still sold as racemates.) Because patent expiry for a racemate tends to proliferate the drug as generics, product line extension for an existing racemate technology can be obtained by switching to a single stereoisomeric form (the racemic switch). This is an incentive to produce the drugs in their pure enantiomeric forms. The use of homogeneous catalysis in organic synthesis and technology was considered in the previous chapter. A particularly useful application of homogeneous catalysis is in the production of stereoisomers in pure forms by a rapidly expanding technique known as chiral (asymmetric) synthesis or chirotechnology. Note, however, that the term asymmetric synthesis is much broader in scope, and the use of homogeneous catalysis to achieve chirality is only one of the methods of doing so. When applied to this specific case, it is generally referred to as chiral or asymmetric catalysis. This again is a much broader term and includes both homogeneous and heterogeneous catalyses. Although chirality is not a prerequisite for biological activity, the presence of stereogenic centers in bioactive molecules gives rise to large differences in the activities of the individual enantiomers. It is this fact that is exploited in the production of the desired pure enantiomers.