New Methods to Prepare Complex Macrocyclic Peptidomimetics Directly from Unprotected Peptides

Peptidomimetic macrocycles are valuable research tools and serve as lead compounds in drug discovery. We have developed two synthetic methods to access distinct isomeric macrocycles from a given peptide sequence; internal palladium(0)-catalyzed allylation, and large-ring forming Friedel-Crafts alkylation. These methods utilize a lipophilic template designed to impart favorable drug-like properties to the composite macrocycles relative to their linear peptide precursors. Structurally diverse macrocyclic peptidomimetics derived from these methods have the potential to identify small molecules effective against challenging targets involved in exposed protein surfaces.