The antiarrhythmic pharmaceutically active compound, (+)-N-[1'-(6-Cyano-1,2,3,4-tetrahydro-2-napthalenyl)-3,4-dihydro-4-hydroxy spiro[2H-1-benzopyran-2,4'-piperidin]yl]methanesulfonamide (Formula I) is a potent potassium channel blocker for treatment of life-threatening ventricular arrhythmia and the prevention of sudden cardiac death. It is currently undergoing intensive clinical trials. In order to support the on-going clinical study, a practical, asymmetric bioreduction of 6-bromo-2-tetralone (Formula II) to (S)-6-bromo-2-tetraol (Formula III) is highly desirable. The synthesis of the chiral alcohol of Formula I is challenging because it contains a unique spiro-fused ring system and two remote chiral centers which must be controlled independently. ##STR1##
As an alternative to asymmetric chemical synthesis of the intermediate (S)-6-bromo-2-tetraol, a bioconversion process, employing the yeast strain Trichosporon capitatum (MY 1890) and the substrate 6-bromo-2-tetralone is presented. This asymmetric bioreduction process yields to rapid process improvements, including rebalancing the cultivation medium and optimizing the bioconversion conditions. The use of 5 to 10% (v/v) ethanol to solubilize the substrate was found to be critical in maintaining high optical purity of the (S)-6-bromo-2-tetraol. Glucose present in the cultivation medium was found to have a negative effect on optical purity and was replaced by glycerol. When this process was scaled up to production size quantities, (S)-6-bromo-2-tetraol with an enantiomeric excess greater than 98% was obtained.