Sandwich-SuFEx Cyclization Enables One-Pot Synthesis of Multicyclic Peptides with Tunable Topologies

Area of Science:

• Chemical Biology
• Organic Synthesis
• Supramolecular Chemistry

Background:

• Peptide macrocyclization is crucial for drug discovery and materials science.
• Existing methods often require harsh conditions or lack efficiency in aqueous environments.
• A need exists for rapid, versatile, and aqueous-compatible peptide assembly techniques.

Purpose of the Study:

• To introduce Sandwich-SuFEx (sulfur(VI) fluoride exchange) cyclization as a novel method for peptide macrocycle synthesis.
• To demonstrate the reaction's compatibility with aqueous conditions and its complementary nature to other click chemistry reactions.
• To showcase the ability to rapidly assemble complex multi-cyclic peptides with tunable topologies.

Main Methods:

• Utilizing di- or triarmed aryl sulfonyl fluorides to react with peptide phenols.
• Employing Sandwich-SuFEx cyclization in aqueous media.
• Combining Sandwich-SuFEx with thioether formation in one-pot procedures.

Main Results:

• Sandwich-SuFEx selectively captures peptide phenols, forming terphenyl-bridged macrocycles.
• The reaction successfully produces macrocycles ranging from 5- to 12-mers, accommodating diverse side chains and linkers.
• One-pot reactions efficiently assembled bi-, tri-, and tetracyclic peptides with controllable topologies in less than one hour.

Conclusions:

• Sandwich-SuFEx cyclization provides a rapid and efficient route for aqueous peptide macrocycle assembly.
• This method expands the synthetic toolbox for creating complex, multi-cyclic peptide architectures.
• The reaction's versatility and speed offer significant advantages for peptide-based research and development.