Photoinduced chemomimetic biocatalysis for enantioselective intermolecular radical conjugate addition

Xiaoqiang Huang, Jianqiang Feng, Jiawen Cui, Guangde Jiang, Wesley Harrison, Xin Zang, Jiahai Zhou, Binju Wang, Huimin Zhao

Research output: Contribution to journalArticlepeer-review

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 conjugate 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. 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. [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)586-593
Number of pages8
JournalNature Catalysis
Volume5
Issue number7
DOIs
StatePublished - Jul 2022

ASJC Scopus subject areas

  • Catalysis
  • Bioengineering
  • Biochemistry
  • Process Chemistry and Technology

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