Work

Scaling Azapeptide with N -Fmoc-Aza-Tripeptide from Resonant Acoustic Mixing of N -Fmoc-Amino Hydrazide and N -Succinimidyl Carbamate

Year: 2026

Type: article

Abstract: Azapeptides feature semicarbazide motifs that can improve the metabolic stability and therapeutic performance of peptides. Azapeptide synthesis suffers however limitations due partly to hydrazide preparation and difficulty in acylating poor semicarbazide nucleophiles. A sustainable and scalable solution-phase method for aza-tripeptide building block assembly is reported featuring effective N -(Fmoc)amino hydrazide and N -succinyl carbamate (Suoc) amino ester synthesis and coupling using resonant acoustic mixing (RAM). N -(Fmoc)Amino acid hydrazinolysis was tuned to give hydrazide without Fmoc cleavage, diacylation by-product, epimerization, and chromatographic purification. N -(Suoc)Amino esters and amides were made in high yield without hydantoin formation using disuccinimidyl carbonate. Capitalizing on the exceptional solubilizing properties of N -methylmorpholine and catalysis using 1-hydroxy-7-azabenzotriazole, RAM-assisted coupling of hydrazine and active carbamate components provided effectively aza-di-, tri- and tetrapeptides. In solid-phase synthesis, aza-tripeptide coupled cleanly and gave effective access to biologically relevant azapeptide targets. In summary, RAM-assisted aza-building block assembly minimized dependence on hazardous reagents and toxic solvents providing sustainable and scalable access to azapeptides.

Source: Organic Letters

DOI: 10.1021/acs.orglett.6c00458