Solid Phase Synthesis of Thioether‐linked Peptide Macrocycles via Palladium‐Catalyzed Intramolecular S‐Arylation and S‐Alkenylation

Abstract A new protocol for synthesis of thioether‐linked peptide macrocycles via Pd‐catalyzed intramolecular S ‐arylation and S ‐alkenylation on solid phase is developed. The use of PEGA resin in mixed solvents of CH 3 CN and H 2 O is critical to suppress the undesired S ‐arylation reactions with the XantPhos‐Pd‐G3 catalyst. Peptide macrocycles of varied ring size, composition, and with different thioether linkers can be prepared in moderate to good yield with one column chromatography purification.