ABSTRACT
Synthetic approach Technological approach (racemic mixture resolution and isolation)Stereoselective or asymmetric synthesis CrystallizationEnzymatic resolution Salt resolutionEnantioselective catalysis Chromatography (LC, SFC) Analytical chemistry has progressed to a point where it is used to distinguish and separate two isomers that are identical except for
their ability to rotate a plane of light. Over the years, techniques such as polarimetry, circular dichroism, and spectroscopic techniques have been used to determine enantiomeric purity and establish stereoselective identity. In today’s pharmaceutical industry, the vast majority of this work is now done by chiral chromatography. This need for chiral preparative separations makes chiral chromatography unique from achiral chromatography in that the preparative scale drives the innovations in the technique instead of analytical applications. Historically, the majority of the drugs on the market have been racemic. Yet, we know the human body only uses L-amino acids and the only bioactive form of Vitamin D3 is (+)-cholecalciferol. Traditionally, it was more economical to synthesize racemic forms and formulate the drug on the basis of the enantiomeric purity. This all changed after an unfortunate series of events in the 1960s led to the discovery of the dangers of this practice. It was discovered that women who took thalidomide as a prescribed sedative during their pregnancy were prone to have significant deformities in their fetuses [1, 2]. The cause of this tragedy was found to be a specific isomer of thalidomide; the (S)- stereoisomer was found to be a teratogen. In response to this incident, regulatory agencies have rightfully required the pharmaceutical industry to characterize the stereochemistry of their drugs in development. Today, thalidomide is approved for use in the United States solely as the (R)-stereoisomer. Today, more than 40% of the new chemical entities currently under development in the pharmaceutical industry are chiral and subject to these guidelines. The control of drug stereochemistry is significant business. As seen in Table 6.2, top selling pharmaceuticals that are chiral were worth almost $54 billion in 2004 [3].
