Dynamic Enzymatic Resolution of Thioesters

Abstract

A detailed investigation of several issues related to the enzymatic resolution of thioesters under conditions of continuous racemization of substrate was conducted. The kinetic acidity of the α-protons of a series of α-substituted propionate thioesters was studied. It was found that the rate of α-proton exchange could be enhanced as much as 20-fold by variation of the thiol moiety, increasing the range of compounds to which enzymatic dynamic resolution may be applied. The relative rates of hydrolysis of ethyl butyrate and ethyl thiobutyrate by several enzymes commonly used in enzymatic resolution were determined. All of the enzymes studied exhibited similar rates of thioester and oxoester hydrolysis except for the esterase from pig liver, which showed very low activity in thioester hydrolysis. Dynamic resolution of the propargyl and trifluoroethyl thioesters of α-phenylpropionate was conducted using subtilisin Carlsberg as a catalyst. These examples demonstrated that enzymatic dynamic resolution can be applied even when the rate of α-proton exchange and the enantioselectivity of the enzyme are fairly low. A dynamic enzymatic transesterification procedure was demonstrated in the resolution of the trifluoroethyl thioester of α-(2,4-dichlorophenoxy)propionate, and product was obtained in 93% ee. This work helps expand and define the scope of enzymatic dynamic resolution of thioesters.