Angew Chem Int Ed Engl. 2026 Mar 19:e00006. doi: 10.1002/anie.202600006. Online ahead of print.
ABSTRACT
We describe a photoenzymatic hydroalkylation reaction that enables the efficient and stereocontrolled synthesis of aryl glutarimide precursors-chemically and configurationally robust entry points to bioactive agents for targeted protein degradation. Screening of flavin-dependent “ene”-reductases identified GluER HArac, a G. oxydans variant, as an efficient and substrate-tolerant catalyst, granting access to >30 (hetero)aryl glutarimide precursors. A directed evolution campaign then furnished a hexamutant, GluER HAent, that delivers the products in up to 93:7 enantiomeric ratio. Mechanistic experiments revealed a pathway that departs from the hydrogen atom transfer mechanism previously established for related systems, proceeding instead via radical-polar crossover followed by enantioselective proton transfer from an active-site tyrosine residue. Collectively, these studies establish a biocatalytic platform for advancing the synthesis and diversification of glutarimide-containing degraders.
PMID:41854164 | PMC:PMC13021314 | DOI:10.1002/anie.202600006