Simple one-pot peptide cleavage and spontaneous macrocyclization through Paal- Knorr-like reactions using 2,5-dialkylfuran derivatives

Macrocyclic peptides show enhanced properties as compared to linear peptides (e.g., enhanced target affinity, resistance toward degradation), making them attractive candidates for therapeutic applications and for interfering with protein-protein interactions (PPIs).Synthetic techniques have revolutionized peptide macrocyclizations, relying on the use of both natural and unnatural amino acids to achieve chemoselective ligations on protected or unprotected peptides.Recently, research has been oriented toward one-pot chemistries that rely on simple reaction conditions or reagent-less approaches.Despite the notable progress in peptide stapling techniques, challenges persist in existing methodologies, particularly in controlling the reaction order at multiple sites and achieving precise positional selectivity.