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

Abstract

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.