Asymmetric bioreductions: application to the synthesis of pharmaceuticals

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 min iaturized and semi-automated technology can greatly reduce both labor and l ead times. The same data also highlight the need to evaluate a relatively l arge and/or diverse microbial population (highlighting biodiversity). We al so found that in many instances the luxury of producing either enantiomers with high optical purity, enantiocomplementarity, can be achieved when empl oying different microbial strains. Process development studies reviewed her e demonstrate that it is possible in some cases to understand and control t he production of an unwanted enantiomer or by-product. Finally, a specific example, the asymmetric bioreduction of a ketone by Candida sorbophila, sho ws that process development studies which optimized, the bioreduction envir onmental conditions (pH, temperature...), the addition of ketone, and the i mplementation 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 bi oreduction process supported the production of several kilograms of (R)-alc ohol (enantiomeric excess (e.e.). 98%), with an isolated product yield of a bout 80%. (C) 2001 Elsevier Science B.V. All rights reserved.