Kinetic resolution of sulfoxides with pendant acetoxy groups using cholesterol esterase: substrate mapping and an empirical rule for chiral phenols

Abstract

Sulfoxides are valuable chiral auxiliaries because they direct the formation of carbon–carbon bonds. As a route to enantiomerically pure sulfoxides, we examined hydrolase-catalyzed kinetic resolution by hydrolysis of a pendant acetoxy group. Screening hydrolases for the enantioselective hydrolysis of the acetate in 2-(methylsulfinyl)phenyl acetate, 1b, identified cholesterol esterase (CE) as the most enantioselective enzyme. The enantiomeric ratio, E, ranged from 10 to 25, favoring the (R) configuration at sulfur. Competing chemical hydrolysis of 1b caused the large range in the measured values of E. A small-scale (250 mg) resolution of (±)-1b yielded (S)-1b with >99% ee (11% yield) after recrystallization. Changing the methyl substituent to phenyl or n-butyl did not significantly change the enantioselectivity (E = 10 and 15, respectively), but changing it to a chloromethyl substituent lowered the enantioselectivity slightly (E = 5). Changing the phenyl acetate to a naphthyl acetate (2-(phenylsulfinyl)phenyl acetate vs. 1-(phenylsulfinyl)-2-naphthyl acetate) increased the enantioselectivity from 10 to 19. In all cases CE favored the (R)-sulfoxide. To aid the design of new resolutions with CE, we propose an empirical rule that accounts for the observed enantiopreference of CE toward these 5 sulfoxides and 15 other chiral aryl acetates. This empirical rule uses both the size of the substituents and their conformational preferences to predict which enantiomer reacts faster. Keywords: kinetic resolution, lipase, cholesterol esterase, sulfoxides, empirical rule.