Multicopper Clusters Enable Oxidative Phenol Macrocyclization (OxPM) of Peptides

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Glycopeptide antibiotics like vancomycin are synthesized via enzymatic oxidative phenol macrocyclization.
• Existing biomimetic methods for this transformation are not sufficiently simple or step-economical.

Purpose of the Study:

• To develop a highly efficient and step-economical biomimetic method for synthesizing biaryl-bridged and diaryl ether-linked macrocyclic peptides.
• To demonstrate the utility of multicopper(II) clusters in catalyzing challenging macrocyclization reactions.

Main Methods:

• Utilized multicopper(II) clusters to promote intramolecular oxidative phenol coupling.
• Developed selective synthesis conditions for macrocyclic peptides.
• Synthesized ring models of vancomycin and the arylomycin cyclic core.

Main Results:

• Achieved highly efficient synthesis of biaryl-bridged and diaryl ether-linked macrocyclic peptides.
• Demonstrated the ability of multicopper(II) clusters to chelate diphenols and favor intramolecular coupling.
• Successfully synthesized complex antibiotic macrocyclic peptide models.

Conclusions:

• Multicopper(II) clusters offer a powerful catalytic system for biomimetic macrocyclization.
• This technology facilitates the assembly of challenging complex antibiotic macrocyclic peptides.
• Copper clusters can catalyze redox transformations beyond the scope of smaller metal catalysts.