Mechanochemical Synthesis of Cysteine‐Containing Peptides via Native Chemical Ligation

Cysteine‐containing peptides are important building blocks for the preparation of artificially designed peptides. Therefore, the development of efficient methods for the synthesis of cysteine‐containing peptides is recognized as an important area of research. To achieve an efficient preparation method for cysteine‐containing peptides, we became interested in developing a mechanochemical native chemical ligation approach. First, amino acid thioesters, which are key reagents for native chemical ligation, were prepared in a ball‐mill reactor using a user‐friendly, odorless thiol reagent. Next, mechanochemical native chemical ligation between amino acid thioesters and cysteine derivatives was performed. As a result of these mechanochemical processes, cysteine‐containing peptides, including C ‐terminal unprotected peptides, were efficiently prepared.