Work

Catalyst-controlled regiodivergence in enantioselective synthesis of spirocyclic γ- versus δ-lactams

Year: 2026

Type: article

Abstract: We report an unprecedented regiodivergent strategy for the catalytic asymmetric synthesis of enantioenriched spirocyclic γ - and δ -lactams from a single alkyne-tethered β -ketoamide precursor. Critically, simply switching the catalyst system between Cu(I)/Pyrabox and Ni(II)/Box enables precise toggling of the cyclization between 5- exo -dig and 6- endo -dig modes, allowing direct and highly stereoselective access to either γ -lactam or δ -lactam spirocycles, each bearing a challenging quaternary spiro-stereocenter. The method exhibits broad functional group compatibility and allows for gram-scale synthesis. Mechanistic experiments and DFT calculations reveal that regioselectivity arises from the mode of metal coordination or the joint regulation by metal and ligand, whereas stereocontrol is governed by steric hindrance between the ligand and the substrate. This practical and atom-economical approach provides a powerful platform for the divergent synthesis of privileged spirocyclic pharmacophores.

Source: Nature Communications

DOI: 10.1038/s41467-026-77228-2