Engineering Size-Complementary Alcohol Dehydrogenase Mutants for Highly Stereoselective Synthesis of Bulky Diaryl and Aliphatic Diols

Abstract Chiral 1,4-diols serve as crucial intermediates in the pharmaceutical industry, yet their asymmetric synthesis remains challenging. Through size-complementary engineering of alcohol dehydrogenase from Saccharomyces kudriavzevii, bulky diaryl and aliphatic chiral 1,4-diols were synthesized with high stereoselectivity. Mutant M5 showed a 181-fold enhancement in catalytic efficiency toward 1,4-diphenyl-1,4-butanedione, whereas mutant N2 delivered a space–time yield of 1065 g L–1 d–1 for (2S,5S)-hexanediol. This work provides a valuable platform for accessing bulky diaryl and aliphatic diols.