# Photoenzymatic Hydroalkylation Enables Streamlined Access to Aryl Glutarimide Precursors

## TL;DR

A new photoenzymatic method efficiently creates aryl glutarimide precursors for drug development with high stereocontrol.

## Contribution

A novel biocatalytic platform for synthesizing glutarimide precursors with high enantioselectivity and stereocontrol.

## Key findings

- GluER HA rac enables synthesis of over 30 aryl glutarimide precursors.
- GluER HA ent achieves up to 93:7 enantiomeric ratio through directed evolution.
- The reaction proceeds via radical–polar crossover and enantioselective proton transfer.

## 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 HA
rac
, 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 HA
ent
, 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.

We report a photoenzymatic hydroalkylation that enables streamlined, stereocontrolled access to aryl glutarimide precursors relevant to targeted protein degradation. Engineered flavin‐dependent “ene”‐reductases provide broad scope and high enantioselectivity through a distinct electron transfer–enantioselective proton transfer pathway.