Using enzymes to tame nitrogen-centred radicals for enantioselective hydroamination

Yuxuan Ye, Jingzhe Cao, Daniel G. Oblinsky, Deeptak Verma, Christopher K. Prier, Gregory D. Scholes, Todd K. Hyster

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


The formation of C–N bonds—of great importance to the pharmaceutical industry—can be facilitated enzymatically using nucleophilic and nitrene transfer mechanisms. However, neither natural nor engineered enzymes are known to generate and control nitrogen-centred radicals, which serve as valuable species for C–N bond formation. Here we use flavin-dependent ‘ene’-reductases with an exogenous photoredox catalyst to selectively generate amidyl radicals within the protein active site. These enzymes are engineered through directed evolution to catalyse 5-exo, 6-endo, 7-endo, 8-endo, and intermolecular hydroamination reactions with high levels of enantioselectivity. Mechanistic studies suggest that radical initiation occurs via an enzyme-gated mechanism, where the protein thermodynamically activates the substrate for reduction by the photocatalyst. Molecular dynamics studies indicate that the enzymes bind substrates using non-canonical binding interactions, which may serve as a handle to further manipulate reactivity. This approach demonstrates the versatility of these enzymes for controlling the reactivity of high-energy radical intermediates and highlights the opportunity for synergistic catalyst strategies to unlock previously inaccessible enzymatic functions. [Figure not available: see fulltext.].

Original languageEnglish (US)
Pages (from-to)206-212
Number of pages7
JournalNature chemistry
Issue number2
StatePublished - Feb 2023

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Chemical Engineering


Dive into the research topics of 'Using enzymes to tame nitrogen-centred radicals for enantioselective hydroamination'. Together they form a unique fingerprint.

Cite this