A Stereoselective Entry to Enantiopure (<i>S</i>)-2-Amino-2-methyl-5-arylpent-4-ynoic Acids and Evaluation of Their Inhibitory Activity against Bacterial Collagenase G

Abstract

Nowadays, amino acids (AAs) and peptides with bulky side chains hold significant interest for organic synthesis and the modern pharma industry. Non-proteinogenic (or unnatural) AAs are key building blocks used for obtaining pharmaceutically relevant peptides and for the development of chiral molecular catalysts, and they are extensively used in the total synthesis of complex natural compounds. Thus, an elaboration of cost-effective methods for the preparation of novel unnatural AAs to increase their structural diversity is highly desirable. In this context, herein, we present an asymmetric metal-templated synthesis of a number of enantiomerically pure (S)-2-amino-2-methyl-5-arylpent-4-ynoic acids starting from commercially available reagents and Belokon’s chiral auxiliary (S)-BPB, namely (S)-2-(N-benzylprolyl)aminobenzophenone. The construction of a chiral Ni(II) complex from alanine (Ala) and the subsequent propargylation, arylation by the Sonogashira cross-coupling reaction using various aryl halides, and, finally, an acidic decomposition of the obtained complexes deliver to the target complex α,α-disubstituted AAs featuring a triple bond in a side chain. Next, the Fmoc-protected α-AAs and dipeptide were synthesized. Finally, we examined the obtained α-AAs and peptide as collagenase inhibitors.

Keywords

• amino acids
• asymmetric synthesis
• Sonogashira cross-coupling
• peptides
• Ni(II) complex
• triple bond