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

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.