Fu Wenzhen, Neris Natalia M, Fu Yue, Zhao Yunlong, Krohn-Hansen Benjamin, Liu Peng, Yang Yang
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA.
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Nat Catal. 2023 Jul;6(7):628-636. doi: 10.1038/s41929-023-00986-5. Epub 2023 Jul 20.
The effective induction of high levels of stereocontrol for free radical-mediated transformations represents a notorious challenge in asymmetric catalysis. Herein, we describe a novel metalloredox biocatalysis strategy to repurpose natural cytochromes P450 to catalyse asymmetric radical cyclisation to arenes through an unnatural electron transfer mechanism. Empowered by directed evolution, engineered P450s allowed diverse radical cyclisation selectivities to be accomplished in a catalyst-controlled fashion: P450 and P450 facilitated enantioconvergent transformations of racemic substrates, giving rise to either enantiomer of the product with excellent total turnover numbers (up to 12,000). In addition to these enantioconvergent variants, another engineered radical cyclase, P450, permitted efficient kinetic resolution of racemic chloride substrates ( factor = 18). Furthermore, computational studies revealed a proton-coupled electron transfer (PCET) mechanism for the radical-polar crossover step, suggesting the potential role of the haem carboxylate as a base catalyst. Collectively, the excellent tunability of this metalloenzyme family provides an exciting platform for harnessing free radical intermediates for asymmetric catalysis.
在不对称催化中，有效诱导自由基介导的转化实现高水平的立体控制是一个众所周知的挑战。在此，我们描述了一种新型的金属氧化还原生物催化策略，通过一种非天然的电子转移机制，将天然细胞色素P450重新用于催化不对称自由基环化生成芳烃。在定向进化的助力下，工程改造的细胞色素P450能够以催化剂控制的方式实现多种自由基环化选择性：P450和P450促进了外消旋底物的对映收敛转化，以优异的总周转数（高达12,000）生成产物的任意一种对映体。除了这些对映收敛变体之外，另一种工程改造的自由基环化酶P450能够对外消旋氯化物底物进行高效的动力学拆分（拆分因子 = 18）。此外，计算研究揭示了自由基 - 极性交叉步骤的质子耦合电子转移（PCET）机制，表明血红素羧酸盐作为碱催化剂的潜在作用。总的来说，这个金属酶家族出色的可调节性为利用自由基中间体进行不对称催化提供了一个令人兴奋的平台。
