Late-Stage Dehydroalanine Residue Modification of Peptides through Additive-Free [2 + 2] Annulation with N-Allenes

Late-stage modifications can significantly expand the structural and functional diversity of amino acids and peptides. Herein, we report an additive-free [2 + 2] annulation between dehydroalanine (Dha) residues and electron-rich N-allenes, enabling the synthesis of cyclobutane-incorporated amino acids and peptides. The stereoselectivity of this cycloaddition can be tuned by modifying the N-protection pattern of the Dha residue: bis-N-protected Dha affords a single stereoisomer, whereas mono-N-protected Dha yields separable diastereomeric products. This method exhibits good substrate compatibility, accommodating various N-allenes, dehydroalanine derivatives, and even peptides, offering a versatile strategy for peptide modification.