Regioselective Radical Alkylation of Arenes Using Evolved Photoenzymes

Claire G. Page, Jingzhe Cao, Daniel G. Oblinsky, Samantha N. Macmillan, Shiva Dahagam, Ruth M. Lloyd, Simon J. Charnock, Gregory D. Scholes, Todd K. Hyster

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Substituted arenes are ubiquitous in molecules with medicinal functions, making their synthesis a critical consideration when designing synthetic routes. Regioselective C-H functionalization reactions are attractive for preparing alkylated arenes; however, the selectivity of existing methods is modest and primarily governed by the substrate's electronic properties. Here, we demonstrate a biocatalyst-controlled method for the regioselective alkylation of electron-rich and electron-deficient heteroarenes. Starting from an unselective "ene"-reductase (ERED) (GluER-T36A), we evolved a variant that selectively alkylates the C4 position of indole, an elusive position using prior technologies. Mechanistic studies across the evolutionary series indicate that changes to the protein active site alter the electronic character of the charge transfer (CT) complex responsible for radical formation. This resulted in a variant with a significant degree of ground-state CT in the CT complex. Mechanistic studies on a C2-selective ERED suggest that the evolution of GluER-T36A helps disfavor a competing mechanistic pathway. Additional protein engineering campaigns were carried out for a C8-selective quinoline alkylation. This study highlights the opportunity to use enzymes for regioselective radical reactions, where small molecule catalysts struggle to alter selectivity.

Original languageEnglish (US)
Pages (from-to)11866-11874
Number of pages9
JournalJournal of the American Chemical Society
Volume145
Issue number21
DOIs
StatePublished - May 31 2023

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry

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