Native chemical ligation (NCL), featuring the use of peptide thioesters and N-terminal Cys peptides, is one of the most powerful ligation techniques for chemical synthesis of proteins. In sequential NCL reactions to construct a large protein molecule, the N-terminal Cys residue of the middle segment must be protected to avoid the side reactions including cyclization though the intramolecular NCL. The use of 1,3-thiazolidine-4-carboxo (Thz) group as a protected Cys residue in the middle peptide segment can improve the efficiency of sequential NCL reactions by the applicability to one-pot synthesis. On the other hand, as a method for synthesizing a peptide thioester, a protocol utilizing peptide hydrazide as a precursor has attracted an attention because of the easy operation and compatibility with Fmoc chemistry. However, direct conversion from the N-terminal Thz peptide hydrazide to the corresponding thioester still remains difficult due to the decomposition of the Thz moiety during the hydrazide activation step. Therefore, practical protocols for the synthesis of peptide thioesters possessing an N-Thz moiety from peptide hydrazide have been required. In this symposium we will present a reaction condition to achieve facile conversion of a Thz peptide hydrazide to a Thz peptide thioester, involving the use of NaNO2-TFA-thioanisole-m-cresol-triisopropylsilane-H2O system. A successful application of the developed reaction to the synthesis of biologically active peptides will be also discussed.

Facile conversion of peptide hydrazide to peptide thioester without decomposition of N-terminal Thz moiety

256th National Meeting (2018)

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