<i>N</i>-Acyl Benzotriazole Derivatives for the Synthesis of Dipeptides and Tripeptides and Peptide Biotinylation by Mechanochemistry

Abstract

An eco-friendly methodology for preparing Fmoc-, Z-, and Boc-N-protected dipeptides and tripeptides is described, from the corresponding N-protected-α-aminoacyl benzotriazoles and α-amino acid derivatives, with different C-terminal functionalities such as esters or amides, using vibrational ball-mill (VBM). The reactivity of a β-amino ester was also investigated. In some cases, the coupling was achieved by liquid-assisted grinding (LAG). α,α- and one α,β-dipeptide were obtained in good to excellent yields mainly by precipitation in water, resulting in an improved environmental impact compared to classical peptide synthesis in solution, as shown by green metric calculations. The method was extended to the biotinylation, via an aminohexanoyl spacer, of the pentapeptide RGDfV, which contains the well-known integrins recognition site arginine–glycine–aspartic acid (RGD) motif.