Enantiocomplementary Asymmetric Reduction of 2-Haloacetophenones Using TeSADH: Synthesis of Enantiopure 2-Halo-1-arylethanols.

Abstract

Enantiopure 2-halo-1-arylethanols are essential precursors for the synthesis of pharmaceuticals, agrochemicals, and fine chemicals. This study investigates the asymmetric reduction of 2-haloacetophenones and their substituted analogs to obtain their corresponding optically active 2-halo-1-arylethanols using secondary alcohol dehydrogenase from Thermoanaerobacter pseudethanolicus (TeSADH) mutants. Specifically, the ΔP84/A85G and P84S/A85G TeSADH mutants were evaluated for the asymmetric reduction of 2-haloacetophenones, generating their corresponding optically active halohydrins with high enantioselectivities. The asymmetric reduction of 2-haloacetophenones and their substituted analogs using the ΔP84/A85G TeSADH mutant yielded their corresponding (S)-2-halo-1-arylethanols with high enantiopurity in accordance with the anti-Prelog's rule. Conversely, the P84S/A85G TeSADH mutant produced (R)-alcohols when reducing 2-chloro-4'-chloroacetophenone, 2-chloro-4'-bromoacetophenone, and 2-bromo-4'-chloroacetophenone, while generating the (S)-configured halohydrin from 2-chloro-4'-fluoroacetophenone. Asymmetric reduction of the unsubstituted 2-bromoacetophenone, 2-chloroacetophenone, and 2,2,2-trifluoroacetophenone resulted in production of their (S)-halohydrins with the tested mutants, which reflects the importance of the nature of the substituent on the substrate's ring in controlling the stereopreference of these TeSADH-catalyzed reduction reactions. These findings contribute to the understanding and application of TeSADH in synthesizing optically active compounds and aid in the design of further mutants with the desired stereopreference.