Asymmetric Methods and Their Use in the Pharmaceutical Industry
The importance of chirality in drug development has increased rapidly over the past four decades. In response to this need a multitude of asymmetric reactions have been developed which have in turn greatly expanded the three dimensional design space accessible to medicinal chemists. This chapter highlights the importance of enantioselective synthesis as a means of attaining chirally pure compounds, important to modern drug discovery programmes. Several key stereoselective synthesis methods, which have found widespread application in the pharmaceutical industry, are discussed within. The first part of the chapter is concerned with asymmetric hydrogenation. This type of reaction can be used to facilitate the reduction of a wide range of substrate classes including alkenes, ketones, imines and heterocycles and has been used extensively in the synthesis of pharmaceuticals in early stage drug discovery programmes, process development and manufacture. The second part of this chapter discusses the use of chiral reagents for hydride reduction of ketones, a class of reaction widely used in the pharmaceutical industry. DIP-Cl and the CBS reagent are the focus of this section due to their extensive utility in drug discovery programmes. The third section of the chapter discusses the catalytic enantioselective oxidation of olefins. Asymmetric epoxidation and dihydroxylation, in particular the catalytic systems developed by Sharpless, Jacobson and Shi, are explored. The reliability of these systems for the enantioselective oxidation of double bonds and the utility of the resultant molecules have made the reactions hugely impactful in pharmaceutical chemistry. The chapter concludes with a review of the use of chiral auxiliaries and organocatalysis in an industrial setting. Chiral auxiliaries have been used extensively, and are particularly relevant in the early stages of drug discovery where robustness and broad applicability are more important than atom efficiency and cost. In contrast there have, thus far, been relatively few examples of organocatalysis in the industrial setting due, largely, to the relative infancy of the field. It is obvious, however, that there is massive potential for the application of this technology in the drug discovery arena in the years ahead.