1,3‐Dipolar Cycloaddition between Dehydroalanines and C,N‐Cyclic Azomethine Imines: Application to Late‐Stage Peptide Modification

• Published in: Angewandte Chemie International Edition 2021-03, Vol.60 (10), p.5331-5338
• Main Authors: Bao, Guangjun, Wang, Peng, Li, Guofeng, Yu, Changjun, Li, Yiping, Liu, Yuyang, He, Zeyuan, Zhao, Tiantian, Rao, Jing, Xie, Junqiu, Hong, Liang, Sun, Wangsheng, Wang, Rui
• Format: Article
• Language: English
• Subjects: Amino acids; Conjugation; cyclic azomethine imines; Cycloaddition; dehydroalanines; dipolar cycloaddition; Imines; late-stage peptide modification; Peptides; Regioselectivity; Resins
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202012523

A non‐catalytic, mild, and easy‐to‐handle protecting group switched 1,3‐dipolar cycloaddition (1,3‐DC) between bi‐ or mono‐N‐protected Dha and C,N‐cyclic azomethine imines, which afford various quaternary amino acids with diverse scaffolds, is disclosed. Specifically, normal‐electron‐demand 1,3‐DC reaction occurs between bi‐N‐protected Dha and C,N‐cyclic azomethine imines, while inverse‐electron‐demand 1,3‐DC reaction occurs between mono‐N‐protected Dha and C,N‐cyclic azomethine imines. Above all, the reactions can be carried out between peptides with Dha residues at the position of interest and C,N‐cyclic azomethine imines, both in homogeneous phase and on resins in SPPS. It provides a new toolkit for late‐stage peptide modification, labeling, and peptide–drug conjugation. To shed light on the high regioselectivity of the reaction, DFT calculations were carried out, which were qualitatively consistent with the experimental observations. A non‐catalytic, mild, and easy‐to‐handle protecting group switching normal‐electron‐demand or inverse‐electron‐demand 1,3‐dipolar cycloaddition between bi‐ or mono‐N‐protected Dha and C,N‐cyclic azomethine imines is disclosed and applied in the late‐stage peptide modification, labeling, and peptide–drug conjugation.