Engineered Alcohol Dehydrogenases-Catalyzed Enantiodivergent Atroposelective Synthesis of Axially Chiral Biaryl Phenols via Dynamic Kinetic Resolution

Axially chiral biaryl phenols are prominent motifs in natural products, bioactive compounds, chiral ligands, and catalysts, yet biocatalytic enantiodivergent synthetic routes remain rare. Herein, we report a biocatalytic dynamic kinetic resolution (DKR) strategy leveraging transient lactol/aldehyde tautomerization and engineered alcohol dehydrogenases (ADHs)-catalyzed stereoselective reduction for enantiodivergent synthesis of atropisomeric biaryl benzyl alcohols bearing phenol units. Two engineered ADHs provide complementary stereoselectivity (up to 99% yield and highly enantioselectivity, > 99:1 or e.r.)). Furthermore, the experimental results suggest that the lactol-aldehyde equilibrium ratio may be connected to both the stereoselectivity and catalytic efficiency of the reaction. This approach represents a versatile and practical biocatalytic method for synthesizing enantiocomplementary axially chiral biaryl phenols, thus offering a valuable complement to existing chemical methodologies.