Ni(II) Chiral Square-Complex–Mediated Mannich Alkynylation for the Synthesis of Enantiomerically Enriched Unnatural α-Amino Acids with Collagenase Inhibitory Activity

An efficient approach to enantiomerically enriched unnatural α-amino acids bearing propargylamine moieties has been developed based on a Mannich-type three-component alkynylation (A3 reaction). Under the optimized conditions, the Mannich adducts were obtained in up to 90% yield with complete stereochemical control at the Cα position (>99% ee). Subsequent acid hydrolysis of the Ni(II) square-complexes afforded the target α-amino acids in pure crystalline form (25–68% isolated yields) while allowing nearly quantitative recovery (>96%) and reuse of the chiral auxiliary without loss of optical activity. Molecular docking studies against collagenase were performed prior to isolation to prioritize compounds for biological evaluation. Selected α-amino acids exhibited favorable binding energies (−5.0 to −6.3 kcal/mol) and distinct binding modes within the catalytic, activator, or interdomain regions of the enzyme. In vitro collagenase inhibition assays revealed micromolar activity, with IC50 values as low as 0.64 mM/L, demonstrating a correlation between predicted binding sites and enzymatic inhibition.