Site-selective alcoholysis of oligopeptides through N-alkylation of a secondary amide unit by cooperative catalysis

We disclose a one-pot two-step protocol for site-selective cleavage of C–N bonds within oligopeptides. We demonstrate that by exploiting the cooperative functions of Sc(OTf) 3 and Barton’s base, N -alkylation of the oligopeptide’s specific secondary amide unit can be achieved. The resulting tertiary amide is “twisted” due to steric factors; its C–N bond is weakened by the disruption of amide resonance. Thus, when the oligopeptide derivative is subjected to Brønsted acid-mediated alcoholysis, only the N -alkylated residue undergoes C–N bond cleavage to afford an ester and an amine, while its secondary amides remain intact. Investigations aimed at elucidating the factors that influence the observed site-selectivity are described. One-Pot Two-Step Protocol: Introduces a streamlined, efficient method for the site-selective cleavage of C–N bonds in oligopeptides under mild conditions. Cooperative Catalysis: Utilizes a dual catalyst system—Sc(OTf) 3 and Barton’s base—to achieve selective N -alkylation of a specific secondary amide. Mechanistic Insights: Generates a "twisted" tertiary amide intermediate by disrupting the canonical amide resonance through steric hindrance, which weakens the C–N bond. Selective Transformation: Demonstrates that subsequent Brønsted acid-mediated alcoholysis selectively cleaves the N-alkylated amide, yielding an ester and an amine while preserving other secondary amides. Insight into Site-Selectivity: Provides mechanistic insights and analysis of factors influencing site-selectivity, potentially guiding further developments in peptide modification and organic synthesis.