Enantiodivergent C3-Selective Reduction of Arylvinyl-Substituted 3,5-Dicarbonyl Esters Enabled by Engineered Ketoreductases.

Chiral arylvinyl-substituted 3-hydroxy-5-oxo esters are valuable motifs in pharmaceuticals, yet their enantiocontrolled synthesis remains challenging. Herein, we report a biocatalytic system using ketoreductases (KREDs) for the highly C3-selective reduction of arylvinyl-substituted 3,5-dicarbonyl esters. Through semirational protein engineering, RasADH-E189D afforded the representative (S)-products in 89-99% conversion and 93-99% ee. Complementary (R)-products were obtained using KmCR2 and several other variants with up to 97% conversion and >99% ee, including a key intermediate for the synthesis of pitavastatin. Preparative-scale reactions (greater than 100 mg) further demonstrated the practicality of this platform. Protein-ligand docking among the substrate, cofactor, and KREDs provided mechanistic insights for great stereoselectivity.