Polypeptide Preparation by β-Lactone-Mediated Chemical Ligation

• DOI: 10.1021/acs.orglett.4c01587
• Publication Date: 2024-06-20T18:45:28Z
• Authors: Xinhao Fan; Yuming Wen; Huan Chen; Baotong Tian; Qiang Zhang
• Keywords: Native chemical ligation; Epimer; Chemical Ligation; Thioester

Native chemical ligation (NCL) represents a cornerstone strategy in accessing synthetic peptides and proteins, remaining one of the most efficacious methodologies this domain. The fundamental requisites for achieving proficient NCL reaction involve chemoselective coupling between C-terminal thioester peptide thiol-bearing N-terminal peptide. However, at sterically congested residues remains challenging. In addition, while NCLs proceed without epimerization, β-branched (e.g., Ile, Thr, Val) Pro-derived thioesters react slowly can be susceptible to significant epimerization hydrolysis. Herein, we report an epimerization-free via β-lactone-mediated native which constructs Thr residues. constrained ring from β-lactone allows rapid detectable epimerization. method has broad side-chain tolerance was applied preparation cyclic polypeptidyl thioester, could difficult obtained otherwise.