南京大学黄小强团队报道了一种光驱动的酶对映选择性自由基酰化。相关研究成果发表在2023年12月18日出版的《自然》。

酶被认为是实现高立体选择性的特殊催化剂，但它们控制自由基的反应性和立体诱导的能力落后于化学催化剂。硫胺二磷酸（ThDP）依赖性酶是表征良好的系统，激发了N-杂环卡宾（NHCs）的发展，但尚未被证明在不对称自由基转化中是可行的。缺乏生物相容性和通用的自由基产生机制，因为大自然更喜欢避免可能对生物系统有害的自由基。

该文中，研究人员通过蛋白质工程和与有机光氧化还原催化剂的组合，将ThDP依赖性裂解酶重新用作立体选择性自由基酰基转移酶（RAT）。酶结合的ThDP衍生缩酮基通过光激发有机染料的单电子氧化选择性地产生，然后与具有高对映选择性的前手性烷基交叉偶联。通过这种方法，从醛和氧化还原活性酯（35个实例，高达97%的对映体过量（e.e.））制备了多种手性酮。机制研究表明，这种以前难以捉摸的双酶催化/光催化以独特的ThDP辅因子和可进化的活性位点引导自由基。

该项工作不仅扩展了生物催化的范围，而且为用酶控制自由基提供了一种独特的策略，补充了现有的化学工具。

附：英文原文

Title: A light-driven enzymatic enantioselective radical acylation

Author: Xu, Yuanyuan, Chen, Hongwei, Yu, Lu, Peng, Xichao, Zhang, Jiawei, Xing, Zhongqiu, Bao, Yuyan, Liu, Aokun, Zhao, Yue, Tian, Changlin, Liang, Yong, Huang, Xiaoqiang

Issue&Volume: 2023-12-18

Abstract: Enzymes are recognized as exceptional catalysts for achieving high stereoselectivities1,2,3, but their ability to control the reactivity and stereoinduction of free radicals lags behind that of chemical catalysts4. Thiamine diphosphate (ThDP)-dependent enzymes5 are well-characterized systems that inspired the development of N-heterocyclic carbenes (NHCs)6,7,8 but have not yet been proved viable in asymmetric radical transformations. There is a lack of a biocompatible and general radical-generation mechanism, as nature prefers to avoid radicals that may be harmful to biological systems9. Here we repurpose a ThDP-dependent lyase as a stereoselective radical acyl transferase (RAT) through protein engineering and combination with organophotoredox catalysis10. Enzyme-bound ThDP-derived ketyl radicals are selectively generated through single-electron oxidation by a photoexcited organic dye and then cross-coupled with prochiral alkyl radicals with high enantioselectivity. Diverse chiral ketones are prepared from aldehydes and redox-active esters (35 examples, up to 97% enantiomeric excess (e.e.)) by this method. Mechanistic studies reveal that this previously elusive dual-enzyme catalysis/photocatalysis directs radicals with the unique ThDP cofactor and evolvable active site. This work not only expands the repertoire of biocatalysis but also provides a unique strategy for controlling radicals with enzymes, complementing existing chemical tools.

DOI: 10.1038/s41586-023-06822-x

Source: https://www.nature.com/articles/s41586-023-06822-x