Vinylphosphonites for Staudinger-induced chemoselective peptide cyclization and functionalization

Area of Science:

• Organic Chemistry
• Bioconjugation Chemistry
• Medicinal Chemistry

Background:

• Chemoselective reactions are crucial for modifying biomolecules.
• Staudinger reactions offer a versatile platform for chemical ligation.
• Targeting cysteine residues is a common strategy in peptide and protein modification.

Purpose of the Study:

• To develop vinylphosphonites for chemoselective Staudinger-phosphonite reactions (SPhR) with azides.
• To enable subsequent modification of cysteine residues in peptides and proteins.
• To demonstrate applications in peptide stapling and macrocyclization.

Main Methods:

• Synthesis of vinylphosphonites.
• Chemoselective Staudinger-phosphonite reaction (SPhR) with azides.
• Thiol addition to vinylphosphonamidates.
• One-pot SPhR and thiol addition reactions.
• Application in peptide stapling and macrocyclization.

Main Results:

• Vinylphosphonites react chemoselectively with azides to form vinylphosphonamidates.
• Vinylphosphonamidates exhibit electrophilic reactivity towards thiols.
• Reactivity can be tuned by varying the phosphonamidate ester substituent.
• One-pot reactions with thiol substrates significantly enhance thiol addition efficiency.
• Successful stapling of a BCL9-beta-catenin PPI inhibitor and macrocyclization of CPPs.

Conclusions:

• Vinylphosphonites are effective reagents for chemoselective SPhR and subsequent cysteine modification.
• The developed method allows for fine-tuning of reactivity and functional properties.
• The one-pot approach enhances efficiency for intramolecular cyclizations.
• This strategy is valuable for developing therapeutic peptides and enhancing protein delivery.