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

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 ( Te SADH) mutants. Specifically, the ΔP84/A85G and P84S/A85G Te SADH 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 Te SADH mutant yielded their corresponding ( S )-2-halo-1-arylethanols with high enantiopurity in accordance with the anti -Prelog's rule. Conversely, the P84S/A85G Te SADH 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 Te SADH-catalyzed reduction reactions. These findings contribute to the understanding and application of Te SADH in synthesizing optically active compounds and aid in the design of further mutants with the desired stereopreference.