An Enzymatic Platform for Asymmetric Synthesis of <i>Si</i> ‐Stereogenic Silanols

Abstract Chiral silanols are important synthetic targets and have garnered increasing attention in the materials and pharmaceutical industries over recent decades. A promising approach for their efficient synthesis is asymmetric silane oxidation. While chemists have developed several transition‐metal‐catalyzed systems for asymmetric hydrolytic oxidation of silanes, no biocatalytic methods have been available for enantioselective synthesis of Si ‐stereogenic compounds, including chiral silanols. Here, we present an enzymatic platform for the asymmetric aerobic mono‐oxidation of dihydrosilanes using an engineered P450 BM3 enzyme. Through six iterative rounds of directed evolution, we identified the optimal evolved variant, ASOx‐6, which exhibits a 54‐fold improvement in k cat / K M compared with the wild‐type enzyme. Moreover, a variety of aryl–alkyl substituted dihydrosilanes are accepted by ASOx‐6, including those bearing heteroaromatic rings. Finally, mechanistic insights obtained from kinetic isotope experiments and computational studies further elucidate the nature of this biocatalytic transformation.