Discovery of Racemization Organocatalysts and Biocatalysts for Ketoreductase-Catalyzed Dynamic Reductive Kinetic Resolution

Abstract Cyclic α-halo ketones and vicinal halohydrins serve as essential synthetic intermediates or structural motifs for a variety of pharmaceuticals. Ketoreductase-catalyzed dynamic reductive kinetic resolution (DYRKR) of cyclic α-halo ketones is an attractive strategy for the synthesis of chiral cyclic vicinal halohydrins. However, we found that the spontaneous racemization of the α-halo groups of 3-bromo-chroman-4-ones and 2-bromo-1-tetralones was less efficient than the ketoreductase-catalyzed reduction of the more reactive enantiomers, resulting in a low conversion and poor (dia)stereoselectivity. To address this challenge, two classes of racemization catalysts were identified: prolinol-derived organocatalysts and racemase-based biocatalysts, both of which could accelerate the racemization of cyclic α-halo ketones. Consequently, combining these catalysts with ketoreductases improved both the conversion and product (dia)stereoselectivity of the DYRKR. Based on the discovery of racemization catalysts, this work provides an efficient strategy for biocatalytic dynamic kinetic resolution and an operationally simple route for the synthesis of chiral cyclic vicinal halohydrins.