Regiodivergent Radical Termination for Intermolecular Biocatalytic C-C Bond Formation

Mark R. Petchey, Yuxuan Ye, Victor Spelling, James D. Finnigan, Samantha Gittings, Magnus J. Johansson, Martin A. Hayes, Todd K. Hyster

Research output: Contribution to journalArticlepeer-review

Abstract

Radical hydrofunctionalizations of electronically unbiased dienes are challenging to render regioselective, because the products are nearly identical in energy. Here, we report two engineered FMN-dependent “ene”-reductases (EREDs) that catalyze regiodivergent hydroalkylations of cyclic and linear dienes. While previous studies focused exclusively on the stereoselectivity of alkene hydroalkylation, this work highlights that EREDs can control the regioselectivity of hydrogen atom transfer, providing a method for selectively preparing constitutional isomers that would be challenging to prepare using traditional synthetic methods. Engineering the ERED from Gluconabacter sp. (GluER) furnished a variant that favors the γ,δ-unsaturated ketone, while an engineered variant from a commercial ERED panel favors the δ,ϵ-unsaturated ketone. The effect of beneficial mutations has been investigated using substrate docking studies and the mechanism probed by isotope labeling experiments. A variety of α-bromo ketones can be coupled with cyclic and linear dienes. These interesting building blocks can also be further modified to generate difficult-to-access heterocyclic compounds.

Original languageEnglish (US)
Pages (from-to)5005-5010
Number of pages6
JournalJournal of the American Chemical Society
Volume146
Issue number7
DOIs
StatePublished - Feb 21 2024
Externally publishedYes

All Science Journal Classification (ASJC) codes

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

Fingerprint

Dive into the research topics of 'Regiodivergent Radical Termination for Intermolecular Biocatalytic C-C Bond Formation'. Together they form a unique fingerprint.

Cite this