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 s creening 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-0 499, a potassium channel blocker targeted for the treatment of ventric ular arrhythmias. Process development studies, employing statistical e xploratory designs, yielded a 10-fold increase in the rate of bioreduc tion and improved the (S)-beta-tetralol enantiomeric excess from 71% t o 99%. The (S)-beta-tetralol enantiomeric excess was found to be highl y dependent on glucose catabolism by T. capitatum. Elevated enantiomer ic excesses were achieved when switching to a glycerol containing medi um. Other process parameters such as pH, temperature and medium compos ition were found to mostly influence the rate of bioreduction. The dev eloped shake flask process was scaled up to laboratory reactors (23-l scale) and supported the production of gram quantities of highly optic ally pure (S)-beta-tetralol.