A3-Mannich coupling reaction via chiral propargylglycine Ni(ii) complex: an approach for synthesizing enantiomerically enriched unnatural α-amino acids

Abstract

A novel hybrid synthetic approach was developed for the enantioselective synthesis of unnatural α-amino acids, utilizing chiral square-planar Ni(II) Schiff base complexes in combination with an A³-coupling (Mannich-type) reaction. The methodology enabled the generation of a series of α-amino acid derivatives with excellent enantiomeric excess (≥99% ee) and high chemical yields under optimized reaction conditions involving CuI/FeCl₃ catalysis in toluene under argon. The reaction demonstrated strong dependence on the nature of the amine, with cyclic secondary amines yielding superior results compared to linear or primary analogs. The obtained products were structurally confirmed via X-ray crystallography and HPLC analysis, verifying the retention of stereochemical integrity. Molecular docking studies against collagenase indicated that all synthesized compounds could interact with the enzyme via various binding domains and interaction types, particularly hydrogen bonding. Subsequent in vitro collagenase inhibition assays revealed that all compounds, except 4a, exhibited inhibitory activity, with compound 4e demonstrating the highest potency (IC₅₀ = 0.75 mM), despite not having the most favorable docking score. This highlights the importance of complementary in silico and experimental evaluations for reliable biological profiling. The presented strategy provides a versatile platform for the synthesis of structurally diverse, enantiomerically pure non-proteinogenic amino acids with promising bioactivity, offering valuable prospects for drug discovery and enzymatic inhibition studies.