Asymmetric bioreductions: application to the synthesis of pharmaceuticals

Abstract

Selected examples of asymmetric bioreductions of pharmaceutically relevant prochiral ketones are reviewed. These data show that microbial screens lead to the identification of appropriate biocatalysts, and that the use of miniaturized and semi-automated technology can greatly reduce both labor and lead times. The same data also highlight the need to evaluate a relatively large and/or diverse microbial population (highlighting biodiversity). We also found that in many instances the luxury of producing either enantiomers with high optical purity, enantiocomplementarity, can be achieved when employing different microbial strains. Process development studies reviewed here demonstrate that it is possible in some cases to understand and control the production of an unwanted enantiomer or by-product. Finally, a specific example, the asymmetric bioreduction of a ketone by Candida sorbophila, shows that process development studies which optimized, the bioreduction environmental conditions (pH, temperature…), the addition of ketone, and the implementation of a nutrient feeding strategy in conjunction with the use of a defined cultivation medium were key in achieving increased bioreduction rates and product titers. When scaled-up in pilot plant bioreactors, the bioreduction process supported the production of several kilograms of (R)-alcohol (enantiomeric excess (e.e.)>98%), with an isolated product yield of about 80%.