Asymmetric bioreduction of a beta-tetralone to its corresponding (S)-alcohol by the yeast Trichosporon capitatum MY 1890

The yeast Trichosporon capitatum MY 1890 was identified by microbial screening as a suitable biocatalyst for the asymmetric bioreduction of 6-bromo-beta-tetralone to its corresponding (S)-alcohol (beta-tetralol). This beta-tetralol is a precursor to the chiral drug candidate MK-0499, a potassium channel blocker targeted for the treatment of ventricular arrhythmias. Process development studies, employing statistical exploratory designs, yielded a 10-fold increase in the rate of bioreduction and improved the (S)-beta-tetralol enantiomeric excess from 71% to 99%. The (S)-beta-tetralol enantiomeric excess was found to be highly dependent on glucose catabolism by T. capitatum. Elevated enantiomeric excesses were achieved when switching to a glycerol containing medium. Other process parameters such as pH, temperature and medium composition were found to mostly influence the rate of bioreduction. The developed shake flask process was scaled up to laboratory reactors (23-l scale) and supported the production of gram quantities of highly optically pure (S)-beta-tetralol.