Aza-propargylglycine installation by aza-amino acylation: Synthesis and ala-scan of an azacyclopeptide CD36 modulator

Abstract

Aza-propargylglycine (azaPra) peptides are branching points for the synthesis of azapeptide libraries. Efficient alkylation of N-(Fmoc)hydrazine in solution was found to provide N'-propargyl fluorenylmethyl carbazate 13, which on activation gave N-(Fmoc)-azaPra acid chloride for installation into peptides. Reducing the number of steps on resin for azaPra peptide synthesis, which previously necessitated alkylation of a semicarbazone protected aza-glycine residue, the new method offers potential for higher yield, as demonstrated by the synthesis of azacyclopeptide 1a, as well as by an alanine scan of this potent cluster of differentiation-36 receptor (CD36) modulator.