Glaser Heterocoupling Reaction for the Synthesis of Enantiomerically Enriched Unnatural α-Amino Acids Incorporating Asymmetric Diyne Moieties: Mechanistic Insights and Optimization

The major challenge in synthesizing unsymmetrical 1,3-diynes lies in achieving high selectivity, as competing homocoupling reactions often complicate product isolation. To address this, we employed a Ni-(II) complex of the Schiff base derived from (<i>S</i>)-2 <i>N</i>-(<i>N</i>'-benzylprolyl)-aminobenzophenone (BPB) and propargylglycine to optimize the conditions for the Glaser coupling reaction. Systematic variations of the reaction parameters, including solvent, temperature, and reaction time, established an efficient protocol for synthesizing enantiomerically enriched α-amino acids. Mechanistic insights into the selectivity of the reaction were obtained through density functional theory (DFT) calculations, revealing that the stability of key intermediates, particularly O₁₃, plays a crucial role in driving the reaction toward the heterocoupling product. The reaction mechanism, including alkyne deprotonation, copper oxidation, and water extrusion steps, was thoroughly examined. This study extended to various phenylacetylene derivatives and an aliphatic alkyne, demonstrating the necessity of tailored reaction conditions for each alkyne to achieve optimal results. The developed protocol offers a versatile and efficient approach for the synthesis of unsymmetrical 1,3-diynes and enantiomerically enriched α-amino acids, with products retaining their chiral integrity, as confirmed by NMR, chiral HPLC, and circular dichroism (CD) spectroscopy.