Development of Enzymatic Desymmetrization Process for Preparing Enantiomeric 3-Substituted Glutarates

Enzyme-catalyzed kinetic resolution is to enantioselectively resolve the racemate such that the resulting chiral product can be separately from remaining chiral substrate via conventional unit operation processes. In the past years, this laboratory has employed substrate engineering approach for developing lipase-catalyzed kinetic resolution processes, finding that the enzyme enantioselectivity and activity could be greatly improved by using (R,S)-N-acylazoles as the substrate. Yet the largest bottleneck for all kinetic resolution processes is the maximum 50% yield for the chiral product or remaining substrate. Aside from the asymmetric synthesis of prochiral compounds and the dynamic kinetic resolution of racemates, enzymatic desymmetrization of prochiral compounds represent an efficient method to overcome this shortcoming, and hence induce the motivation to submit the present proposal. In the following two years, we will focus on the “development of enzymatic desymmetrization platform”for preparing useful industrial chiral intermediates derived from 3-substituted glutarates. In the first year with 3-methyl and 3-phenyl glutaric acids as the representative prochiral compounds of 3-alkyl and 3-aryl glutaric acids, respectively, we intend to study the reaction conditions (such as temperature, organic solvent, reaction type, leaving azole, and acyl acceptor) on the enzyme activity and enantioselectivity. In the second year, we will investigate the kinetic and thermodynamic analysis at the best reaction condition obtained in the first year, and elucidate effects of different 3-substituted moieties on the enzymatic catalysis. Moreover, we will study the separation and purification of resulting chiral products via (reactive) extraction.

Project ID:PB10501-3719
External Project ID:MOST104-2221-E182-058-MY2