An Enzymatic Platform for Asymmetric Synthesis of Si‐Stereogenic Silanols

• Published in: Angewandte Chemie International Edition Vol. 64; no. 25; pp. e202501524 - n/a
• Main Authors: Dai, Shuang‐Yu, Chen, Xiahe, Yang, Yun‐Fang, Liu, Zhen
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 17.06.2025
• Edition: International ed. in English
• Subjects: Asymmetric synthesis; Asymmetry; Biocatalysis; Computational modeling; Directed evolution; Enantiomers; Oxidation; Pharmaceutical industry; Silanes; Silicon; Synthesis; Silicon; Biocatalysis; Directed evolution; Asymmetric synthesis; Computational modeling
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202501524

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 P450BM3 enzyme. Through six iterative rounds of directed evolution, we identified the optimal evolved variant, ASOx‐6, which exhibits a 54‐fold improvement in kcat/KM 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. Engineered P450 enzymes were employed to catalyze the asymmetric oxidation of dihydrosilanes, producing Si‐stereogenic chiral silanols with good yields and high enantioselectivies. The evolved variant ASOx‐6 exhibits a 54‐fold activity increase compared to the wild‐type enzyme on the model substrate. A combination of experimental and computational mechanistic studies provided detailed insights into this biocatalytic process.