STEREOSELECTIVE MICROBIAL REDUCTION OF N-(4-(1-OXO-2-CHLOROACETYL ETHYL) PHENYL METHANE SULFONAMIDE

Several microbial cultures were screened for the ability to catalyse t he reduction of N-(4-(1-oxo-2-chloroacetyl ethyl) phenyl methane sulfo namide (1). The chiral intermediate (+)N-(4-(1-hydroxy-2-chloroethyl) phenyl methane sulfonamide (2) was prepared by the stereoselective mic robial reduction of the parent ketone 1. Compound 2 is a potential chi ral intermediate for synthesis of 4-(2-isopropylamino-1-hydroxyethyl) phenyl methanesulfonanilide (D-sotalol), a beta-receptor antagonist. M icroorganisms from the genera Rhodococcus, Nocardia, and Hansenula red uced 1 to 2. A reaction yield of >50% and optical purities of >90% wer e obtained. The best strain (H. polymorpha ATCC 26012) effectively red uced compound 1 to compound 2 in 95% reaction yield and 99% optical pu rity. Compound 2 (8.2 g) was isolated from a 3-1 preparative batch in 68% overall yield. Isolated compound 2 had a specific rotation of +20 degrees (CH2Cl2, C-1), an optical purity of 99.5%, and a chemical puri ty of 97% as analyzed by gas chromatography and HPLC. The nuclear magn etic resonance and mass spectra of compound 2 prepared by bioreduction and a standard chemical sample of 2 were virtually identical. Cell ex tracts of H. polymorpha in the presence of glucose dehydrogenase, gluc ose and nicotinamide adenine dinucleotide (NAD(+)) catalyzed the reduc tion of 1 to 2 with 98% reaction yield and resulted in an optical puri ty of 99.4%.