Ammonia-Ugi Reaction Employing α-Isocyanoacetamides: Synthesis of Sterically Congested Peptides.

The incorporation of sterically demanding α,α-disubstituted α-amino acids into peptide frameworks remains challenging because severe steric hindrance limits conventional coupling strategies. We herein report a robust synthetic method based on ammonia-Ugi reaction using α-isocyanoacetamide derivatives, including peptide-derived isocyanides, to construct sterically congested peptides. The reaction displayed broad compatibility with diverse ketones and N-protected α,α-disubstituted α-amino acids, delivering sterically congested tri- and tetrapeptides in high yields. Mechanistic studies revealed that the 2-adamantyl group at the α-carbon of isocyanides was crucial for suppressing their undesired 5-exo-dig cyclization. Furthermore, both C-to-N and N-to-C peptide elongation pathways were established, providing a streamlined platform for accessing peptides inaccessible by conventional methods.