Highly Stereoselective Synthesis of α-Substituted β-Hydroxy Sulfones via Ketoreductase-Catalyzed Dynamic Reductive Kinetic Resolution

The enzymatic syntheses of chiral alcohols containing multiple stereocenters via ketoreductase (KRED)-catalyzed dynamic reductive kinetic resolution (DYRKR) represent an efficient and simple synthetic strategy in recent years. Herein, we report the engineering of a KRED from Chryseobacterium sp. CA49 (ChKRED20) for the efficient asymmetric synthesis of α-substituted β-hydroxy sulfones through DYRKR of the corresponding α-substituted β-keto sulfone precursors. By minimizing mutagenesis efforts at active-site amino acid residues while selectively targeting a single residue, one of the fourth-generation ChKRED20 variants named M4C4 (Q97L+S153L+Y188N+H145A) was obtained, demonstrating markedly enhanced catalytic performance toward α-substituted β-keto sulfones (up to 99% yield, >99% e.e., >99% d.e.), in contrast to its third-generation parent M3C4 (Q97L+S153L+Y188N), which exhibited negligible activity (<1% yield). Additionally, diverse α-substituted β-hydroxy sulfones were also prepared by using the fourth-generation ChKRED20 variants M4C4, M4B1 (Q97L+S153L+Y188C+H145A), M4C3 (Q97L+S153L+Y188G+H145A), and M4C6 (Q97L+S153L+Y188T+H145A) (20 examples, up to 99% yield, > 99% e.e., >99% d.e.).