Large ring-forming alkylations provide facile access to composite macrocycles.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Macrocyclic compounds show promise for targeting proteins with extended, solvent-exposed binding sites.
• Peptide-bound structures reveal strong surface complementarity and aromatic side-chain interactions at these sites.

Purpose of the Study:

• To develop a method for converting linear peptides into constrained macrocycles.
• To capture key features of peptide-protein interactions in small molecules for drug discovery.

Main Methods:

• Utilized designed templates to initiate Friedel-Crafts alkylation for macrocycle formation.
• Employed a room-temperature, protecting-group-free reaction compatible with polar functional groups.
• Demonstrated regiochemical tunability for diverse macrocycle connectivities.

Main Results:

• Achieved efficient, rapid macrocycle synthesis (minutes) at room temperature.
• Demonstrated the method's independence from protecting groups, metals, or air-free conditions.
• Showcased the ability to tune regiochemistry and further functionalize macrocycles.

Conclusions:

• The developed chemistry provides a foundation for synthesizing peptide-based macrocycles.
• This method facilitates studies correlating macrocycle size, shape, and composition with pharmacological properties.
• Enables exploration of macrocycles as drug candidates for challenging protein targets.