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Title: Photoinduced chemomimetic biocatalysis for enantioselective intermolecular radical conjugate addition

Abstract

Exploiting nature’s catalysts for non-natural transformations that are inaccessible to chemocatalysis is highly desirable but challenging. On the one hand, the widespread nicotinamide-dependent oxidoreductases have not been utilized for single-electron-transfer-induced bimolecular cross-couplings; on the other, the addition of catalytic asymmetric radical con- jugate to terminal alkenes remains a challenge owing to strong racemic background reaction and unselective termination of prochiral radical species. Here we report a chemomimetic biocatalysitic approach for construction of alpha-carbonyl stereocentres via an unnatural intermolecular conjugate addition of N-(acyloxy)phthalimides-derived radicals with acceptor-substituted terminal alkenes, by combination of visible-light excitation and nicotinamide-dependent ketoreductases (KREDs). Based on protein crystal structure, we engineered KREDs via a semi-rational mutagenesis strategy to improve reaction outcomes with a small and high-quality variants library. Here, mechanistic investigations combining wet experiments, crystallographic studies and computational simulations demonstrate that the repurposed biocatalyst can suppress racemic background reaction and unselected side reactions, yielding enantioselectivity that is challenging to achieve by chemocatalysis.

Authors:
 [1];  [2];  [3];  [4]; ORCiD logo [4];  [3];  [5]; ORCiD logo [2]; ORCiD logo [4]
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  1. Univ. of Illinois at Urbana-Champaign, IL (United States); Nanjing Univ. (China)
  2. Xiamen Univ. (China)
  3. Univ. of Chinese Academy of Sciences, Shanghai (China)
  4. Univ. of Illinois at Urbana-Champaign, IL (United States)
  5. Univ. of Chinese Academy of Sciences, Shanghai (China); Chinese Academy of Sciences, Shenzhen (China)
Publication Date:
Research Org.:
Univ. of Illinois at Urbana-Champaign, IL (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1902704
Grant/Contract Number:  
SC0018420
Resource Type:
Accepted Manuscript
Journal Name:
Nature Catalysis
Additional Journal Information:
Journal Volume: 5; Journal Issue: 7; Journal ID: ISSN 2520-1158
Publisher:
Springer Nature
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Biocatalysis; Enzyme mechanisms; Oxidoreductases; Protein design; X-ray crystallography

Citation Formats

Huang, Xiaoqiang, Feng, Jianqiang, Cui, Jiawen, Jiang, Guangde, Harrison, Wesley, Zang, Xin, Zhou, Jiahai, Wang, Binju, and Zhao, Huimin. Photoinduced chemomimetic biocatalysis for enantioselective intermolecular radical conjugate addition. United States: N. p., 2022. Web. doi:10.1038/s41929-022-00777-4.
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Huang, Xiaoqiang, Feng, Jianqiang, Cui, Jiawen, Jiang, Guangde, Harrison, Wesley, Zang, Xin, Zhou, Jiahai, Wang, Binju, & Zhao, Huimin. Photoinduced chemomimetic biocatalysis for enantioselective intermolecular radical conjugate addition. United States. https://doi.org/10.1038/s41929-022-00777-4
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Huang, Xiaoqiang, Feng, Jianqiang, Cui, Jiawen, Jiang, Guangde, Harrison, Wesley, Zang, Xin, Zhou, Jiahai, Wang, Binju, and Zhao, Huimin. Mon . "Photoinduced chemomimetic biocatalysis for enantioselective intermolecular radical conjugate addition". United States. https://doi.org/10.1038/s41929-022-00777-4. https://www.osti.gov/servlets/purl/1902704.
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@article{osti_1902704,
title = {Photoinduced chemomimetic biocatalysis for enantioselective intermolecular radical conjugate addition},
author = {Huang, Xiaoqiang and Feng, Jianqiang and Cui, Jiawen and Jiang, Guangde and Harrison, Wesley and Zang, Xin and Zhou, Jiahai and Wang, Binju and Zhao, Huimin},
abstractNote = {Exploiting nature’s catalysts for non-natural transformations that are inaccessible to chemocatalysis is highly desirable but challenging. On the one hand, the widespread nicotinamide-dependent oxidoreductases have not been utilized for single-electron-transfer-induced bimolecular cross-couplings; on the other, the addition of catalytic asymmetric radical con- jugate to terminal alkenes remains a challenge owing to strong racemic background reaction and unselective termination of prochiral radical species. Here we report a chemomimetic biocatalysitic approach for construction of alpha-carbonyl stereocentres via an unnatural intermolecular conjugate addition of N-(acyloxy)phthalimides-derived radicals with acceptor-substituted terminal alkenes, by combination of visible-light excitation and nicotinamide-dependent ketoreductases (KREDs). Based on protein crystal structure, we engineered KREDs via a semi-rational mutagenesis strategy to improve reaction outcomes with a small and high-quality variants library. Here, mechanistic investigations combining wet experiments, crystallographic studies and computational simulations demonstrate that the repurposed biocatalyst can suppress racemic background reaction and unselected side reactions, yielding enantioselectivity that is challenging to achieve by chemocatalysis.},
doi = {10.1038/s41929-022-00777-4},
journal = {Nature Catalysis},
number = 7,
volume = 5,
place = {United States},
year = {Mon May 02 00:00:00 EDT 2022},
month = {Mon May 02 00:00:00 EDT 2022}
}
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