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

Sustainable and scalable solution-phase synthesis of aza-tripeptide building-blocks was achieved by using resonant acoustic mixing (RAM). Hydrazinolysis gave <i>N</i>-(Fmoc)amino hydrazide without Fmoc cleavage, diacylation, epimerization, and chromatographic purification. <i>N</i>-(Suoc)amino esters and amides were made without hydantoin formation by using disuccinimidyl carbonate. Exceptional solubilizing properties of <i>N</i>-methylmorpholine and catalysis using 1-hydroxy-7-azabenzotriazole enabled RAM-assisted coupling of hydrazine and active carbamate components to afford aza-di-, -tri-, and -tetrapeptides. In solid-phase synthesis, aza-tripeptide coupled cleanly, giving access to biologically relevant azapeptides.