Mechano‐Biocatalytic Stereoselective Reduction of Ketones With Baker's Yeast Under Solvent‐Minimized Conditions

Mechanochemistry and biocatalysis offer complementary routes to greener synthesis, yet their combination remains challenging, as enzymes and whole-cell systems often lose activity under low-solvent and mechanically demanding conditions. Here we demonstrate that Baker's yeast, a widely used whole-cell biocatalyst, retains catalytic activity and high stereoselectivity under ball-milling conditions. This enables a highly stereoselective whole-cell mechano-biocatalytic reduction of α-keto esters and aryl-alkyl ketones, affording chiral alcohols with enantiomeric excesses up to >99% under solvent-minimized conditions. Both lyophilized and fresh yeast operate effectively, delivering E-factors substantially lower than those obtained under conventional aqueous conditions (>1000 in solution vs. 104-76 under mechano-biocatalytic conditions). The process is scalable, as demonstrated by translation to a twin-screw extrusion protocol, and significantly reduces waste compared with traditional whole-cell reductions. These results establish whole-cell mechanochemical biocatalysis as a practical and sustainable platform for asymmetric synthesis.