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

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 CH3CN and H2O 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.

Automated summary

A new protocol for the synthesis of thioether-linked peptide macrocycles has been developed, using PEGA resin and a mixed solvent of CH3CN and H2O. This method allows for the preparation of peptide macrocycles of varied ring size, composition, and with different thioether linkers in moderate to good yield with one column chromatography purification.