Peptide segment coupling through in situ construction of unnatural α,α-disubstituted α-amino acid residues

Peptide segment coupling is a powerful strategy for diversity-oriented synthesis, particularly in the early stages of drug discovery. However, its broader application is often limited by racemization or epimerization at C-terminal stereocenters, as well as by the challenges associated with peptide bond formation between sterically hindered amino acids. Herein, we report an ammonia-Ugi reaction-based peptide segment coupling employing readily available C-terminal carboxylic acids, ammonia, ketones, and peptide-derived isocyanides. This approach enables the direct formation of N-unsubstituted peptide bonds without the need for conventional condensing agents, while simultaneously constructing sterically demanding α,α-disubstituted α-amino acid residues in situ from simple ketones. The method accommodates a broad range of substrates to provide penta- to hepta-peptides in good yields, although asymmetric induction at the newly formed stereogenic center has not yet been achieved when unsymmetrical ketones are employed. Importantly, the stereochemical integrity of the C-terminal amino acid residues remained completely unaffected. Furthermore, sequential ammonia-Ugi reactions allowed peptide elongation and ligation to be integrated with the construction of unnatural α,α-disubstituted α-amino acid residues. Overall, this strategy represents a conceptually distinct and practical approach for accessing peptides containing unnatural α,α-disubstituted α-amino acid residues.