Switching the Stereopreference of <i>Te</i>SADH: Enabling Anti‐Prelog Asymmetric Reduction of Aryl‐Ring‐Containing Ketones

Abstract The biocatalytic asymmetric reduction of prochiral ketones offers a promising approach for producing optically active secondary alcohols. Alcohol dehydrogenases (ADHs) are enzymes that facilitate the reversible conversion of prochiral ketones into their corresponding optically active secondary alcohols, and thus are pivotal for this process. Most ADHs adhere to Prelog's rule in determining the stereopreference for the asymmetric reduction of prochiral ketones. This study focuses on the ΔP84/A85G mutation of Te SADH, demonstrating its capability to reduce aryl‐ring‐containing ketones to their corresponding alcohols in anti ‐Prelog mode with high stereoselectivities. The study also highlights the crucial role of P84 in switching the stereopreference of Te SADH in the asymmetric reduction of aryl‐ring‐containing ketones. Furthermore, this mutant exhibits a broad substrate scope, including substrates accepted by the previously reported W110 mutants of Te SADH with opposite stereopreference. The ability to create mutants of the same enzyme with opposite stereopreferences presents intriguing opportunities for fascinating transformations, such as bienzymatic racemization, which can be utilized in dynamic kinetic resolution, and stereoinversion using two enantiocomplementary mutants of the same enzyme.