Scalable mechanochemical synthesis of a cyclic dehydroalanine peptide

Dehydroalanine derivatives are valuable building blocks in organic and biomolecular chemistry fields, and their scalable synthesis represents unmet needs. This work examined previously reported N-to-O acyl transfer-based condensation reactions of a diketopiperazine derivative (also known as cyclic glycine dimer or glycine anhydride) through a series of reaction optimization processes to identify scalable conditions. Liquid-assisted mechanochemistry proved important for the promotion of the overall efficiency and reproducibility of the condensation reaction between acetyl-diketopiperazine and paraformaldehyde.