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

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Peptide Chemistry

Background:

• Late-stage modification of peptides enhances bioactivity and physicochemical properties for pharmaceutical applications.
• Tryptophan (Trp), with its unique indole ring, is crucial for peptide function, but its modification has been challenging.
• Previous methods for Trp modification primarily relied on transition-metal catalyzed C-H activation.

Purpose of the Study:

• To develop a novel, mild, and efficient method for the late-stage modification of tryptophan residues in peptides.
• To explore the utility of tertiary amine catalysis in peptide functionalization.
• To expand the toolbox for creating diverse peptide conjugates and cyclic peptides.

Main Methods:

• A tertiary amine catalyzed S_N2'-S_N2' allylation reaction between the N1 position of the indole ring of Trp and Morita-Baylis-Hillman (MBH) carbonates.
• The reaction proceeds under mild conditions, compatible with both solid-phase (on resin) and solution-phase synthesis.
• Demonstrated broad substrate scope for both Trp-containing peptides and MBH carbonates.

Main Results:

• Successfully synthesized a series of peptide conjugates and cyclic peptides via the developed method.
• The reaction exhibits a broad scope, accommodating various peptide sequences and MBH carbonate structures.
• The modified Trp residue serves as a versatile handle for further bioconjugation with other biomolecules.

Conclusions:

• Developed an unprecedented tertiary amine catalyzed allylation of tryptophan in peptides.
• The method provides a mild, efficient, and versatile approach for peptide modification and bioconjugation.
• This advancement opens new avenues for peptide pharmaceutical development and the creation of complex peptide-based molecules.