A light-driven enzymatic enantioselective radical acylation

Yuanyuan Xu, Hongwei Chen, Lu Yu, Xichao Peng, Jiawei Zhang, Zhongqiu Xing, Yuyan Bao, Aokun Liu, Yue Zhao, Changlin Tian (), Yong Liang () and Xiaoqiang Huang ()
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Yuanyuan Xu: Nanjing University
Hongwei Chen: Nanjing University
Lu Yu: Chinese Academy of Sciences
Xichao Peng: Nanjing University
Jiawei Zhang: Nanjing University
Zhongqiu Xing: Nanjing University
Yuyan Bao: Nanjing University
Aokun Liu: Chinese Academy of Sciences
Yue Zhao: Nanjing University
Changlin Tian: Chinese Academy of Sciences
Yong Liang: Nanjing University
Xiaoqiang Huang: Nanjing University

Nature, 2024, vol. 625, issue 7993, 74-78

Abstract: Abstract Enzymes are recognized as exceptional catalysts for achieving high stereoselectivities1–3, 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)6–8 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.

Date: 2024
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DOI: 10.1038/s41586-023-06822-x

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