Photoenzymatic Stereodivergent Synthesis of Chiral γ-Lactones via Decarboxylative and Desulfonylative Radical Hydroalkylation

Chiral γ-lactones are prominent structural motifs in natural products and pharmaceuticals. However, existing synthetic routes suffer from inherent limitations, ranging from expensive metal-catalyzed processes that require harsh reaction conditions to multi-step biocatalytic strategies. Especially, stereochemical control remains a daunting challenge. This study leveraged NADPH-dependent imine reductases (IREDs) to enable a photoinduced radical platform for the asymmetric synthesis of chiral γ-lactones via both decarboxylative and desulfonylative transformations. Guided by a concise directed evolution strategy, this platform provided access to complementary stereoisomers of γ-lactones with tailor-made R or S configurations on an optional basis, in good yields and stereoselectivity (up to >99% e.e.). Mechanistic experiments and computational studies revealed a radical-mediated pathway, with the tailor-made stereoselectivity arising from the controlled orientation of the pro-chiral radical intermediate and the subsequent HAT process within the catalytic pocket of the engineered IREDs.