Facing chirality in the 21st century: Approaching the challenges in the pharmaceutical industry

How is process R&D organized and operated in today's pharmaceutical industry at the dawn of the 21st century? A way to respond to the challenges with regard to reduced time to market is to build on early involvement and a front‐loading approach. This means that activities are initiated during the lead optimization phase starting up to 2 years ahead of candidate drug nomination and a model built on this concept covering the stages through to commercial launch is advocated as the appropriate way forward. However, given the high attrition rate in a pharma R&D pipeline focused risk management needs to be applied and options judiciously evaluated. From a molecular perspective, the chemical targets in many instances present a formidable complexity both with regard to the overall structure but increasingly also when it comes to their stereochemical features. Thus, a novel triazolo pyrimidine compound with six stereogenic centers requiring 28 transformations for its assembly is examined to underscore this, but also the difficulties in designing a feasible route for the relatively simple ( S )‐azetidinecarboxylic acid are highlighted. Furthermore, the successful development of a unique and highly efficient catalytic asymmetric sulfide oxidation to the corresponding ( S )‐sulfoxide esomeprazole is discussed, together with the remarkable effect that normal sea sand has on the stereoselectivity of a steroid trans‐acetalization. Chirality 15:S128–S142, 2003. © 2003 Wiley‐Liss, Inc.