Late-Stage Dehydroalanine Residue Modification of Peptides through Additive-Free [2 + 2] Annulation with <i>N</i> -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 <i>N</i>-allenes, enabling the synthesis of cyclobutane-incorporated amino acids and peptides. The stereoselectivity of this cycloaddition can be tuned by modifying the <i>N</i>-protection pattern of the Dha residue: bis-<i>N</i>-protected Dha affords a single stereoisomer, whereas mono-<i>N</i>-protected Dha yields separable diastereomeric products. This method exhibits good substrate compatibility, accommodating various <i>N</i>-allenes, dehydroalanine derivatives, and even peptides, offering a versatile strategy for peptide modification.