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

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, labelling and peptide-drug conjugation. In addition, to shed light on the high regioselectivity of the reaction, DFT calculations were carried out, and showed qualitatively consistent with the experimental observations.