Ni(II)-Mediated Asymmetric Synthesis of a Conjugated Diyne-Containing Non-Proteinogenic Amino Acid via Glaser Heterocoupling

Abstract

Non-proteinogenic amino acids bearing acetylenic motifs are valuable building blocks in medicinal chemistry and chemical biology due to their structural rigidity, synthetic versatility, and biological relevance. Herein, we report an asymmetric synthesis of (S)-2-amino-8-(3,4-dihydroisoquinolin-2(1H)-yl)octa-4,6-diynoic acid using a Belokon Ni(II) square-planar complex as a chiral scaffold. The synthetic route involves the preparation of a propargylglycine-derived Ni(II) complex followed by a Glaser heterocoupling reaction with 2-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroisoquinoline, enabling the stereocontrolled construction of a conjugated diyne side chain. Subsequent acidic hydrolysis of the Ni(II) complex, ion-exchange demineralization, and recrystallization from aqueous ethanol afforded the target non-proteinogenic amino acid in high purity with retention of the (S)-configuration. This work demonstrates the compatibility of oxidative alkyne coupling reactions with Ni(II)-mediated asymmetric amino acid synthesis and expands the synthetic toolbox for accessing structurally complex, acetylenic amino acid derivatives.