Synthesis and utilization of non ribosomal amino acids consisting of carbon carbon double bonds in the design of hybrid peptide foldamers

Abstract

Designing protein secondary structure mimetics using non-natural amino acids has significant importance in understanding protein folding, as well as from the perspective of medicinal chemistry. Various backbone-modified synthetic amino acids have been explored over the years to design functional foldamers. These include acyclic beta- and gamma-amino acids, carbocyclic beta- and gamma-amino acids, sugar-modified beta- and gamma-amino acids, and dialkyl beta- and gamma-amino acids. In contrast to saturated gamma-amino acids, alpha, betaunsaturated gamma-amino acids have been frequently found in many biologically active peptide natural products. Our interest lies in understanding the reactivity and conformational properties of these gamma-amino acids, which consist of carbon-carbon double bonds in the backbone. In this work, we have demonstrated the stereoselective synthesis of amino acids with conjugative multiple double bonds in the backbone using the Wittig reaction. We thoroughly investigated the stereochemistry and substrate scope of the Wittig reaction in the synthesis of conjugative multiple double bonds and successfully isolated amino acids with multiple conjugated double bonds with complete E-selectivity in excellent yields. Furthermore, we explored these amino acids for the design of helix-turn-helix type foldamers.