Late-stage peptide modification and macrocyclization enabled by tertiary amine catalyzed tryptophan allylation

Abstract

Late-stage modification of peptides could potentially endow peptides with significant bioactivity and physicochemical properties, and thereby provide novel opportunities for peptide pharmaceutical studies. Since tryptophan (Trp) bears a unique indole ring residue and plays various critical functional roles in peptides, the modification methods for tryptophan were preliminarily developed with considerable progress via transition-metal mediated C–H activation. Herein, we report an unprecedented tertiary amine catalyzed peptide allylation via the S_N2′–S_N2′ pathway between the N1 position of the indole ring of Trp and Morita–Baylis–Hillman (MBH) carbonates. Using this method that proceeds under mild conditions, we demonstrated an extremely broad scope of Trp-containing peptides and MBH carbonates to prepare a series of peptide conjugates and cyclic peptides. The reaction is amenable to either solid-phase (on resin) or solution-phase conditions. In addition, the modified peptides can be further conjugated with other biomolecules at Trp, providing a new handle for bioconjugation.