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.
Keywords: cyclic azomethine imines; dehydroalanines; dipolar cycloaddition; late-stage peptide modification; regioselectivity.
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