Polypeptide Preparation by β‑Lactone-Mediated Chemical Ligation

• Published in: Organic letters 2024-07, Vol.26 (26), p.5436-5440
• Main Authors: Fan, Xinhao, Wen, Yuming, Chen, Huan, Tian, Baotong, Zhang, Qiang
• Format: Article
• Language: English
• Subjects: Letter
• ISSN: 1523-7060; 1523-7052; 1523-7052
• DOI: 10.1021/acs.orglett.4c01587

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