Asymmetric processes in the large-scale preparation of chiral drug candidates.

More than 50% of the 500 top selling drugs in the world today are single enantiomers. To address the production of enantiomerically pure drug candidates, several tools (chiral pool, asymmetric catalysis, chiral reagents, chiral auxiliaries, resolution and biotransformation) are becoming increasingly available to the process chemist for development and large-scale manufacturing. This article will document salient examples from the post-1998 literature that, in the opinion of the authors, best exemplify the utilization of these tools by process chemistry groups throughout the pharmaceutical industry.

Synthesis of novel inhibitors of the HIV-1 protease: difunctional enols of simple N-protected amino acids.

A series of enol HIV-1 protease inhibitors which show competitive inhibition and the structure-activity relationship study which led to the design of these compounds are reported. By systematically modifying simple amino acids, Boc-Phe enol and Boc-Tyr enol derivatives yield nanomolar Kiapp values (Kiapp = 0.485 microM and Kiapp = 0.425 microM, respectively). These enols are of low molecular weight (< 500 g/mol) and of non-peptidic nature. The enols are synthesized in a one step chemical synthesis and modifications to increase their potency could easily be performed. Boc-Phe enol and Boc-Tyr enol showed low inhibitory effect on pepsin, Kiapps of 23 and 149 microM, respectively, and Boc-Phe enol showed a Kiapp of 20 microM for cathepsin D. Neither of these two compounds inhibited renin (< 10% inhibition at 200 microM).