Alcohol dehydrogenases catalyzed asymmetric reductions of “difficult-to-reduce” ketones and the involved mechanism of stereoselective recognition and regulation

Alcohol dehydrogenases (ADHs) are widely used to prepare chiral alcohols because of their environmental benefits, high-cost effectiveness, broad substrate acceptance, and high enantioselectivity. However, the stereoselective reduction of "difficult-to-reduce" ketones, which are characterized by bulky substituents, similar steric and electronic properties at the α, α'-positions, or complex structures, remains a significant challenge. Understanding the interaction between these ketones and enzymes is crucial for overcoming catalytic limitations. This review summarized recent research advances in the asymmetric reduction of "difficult-to-reduce" ketones. We specifically discuss the stereoselective recognition mechanisms and outline strategies for regulating enzyme selectivity based on enzyme-substrate interactions. Finally, we propose future perspectives on the rational design of ADHs for the synthesis of high-value chiral chemicals.