Systematic study of the synthesis of macrocyclic dipeptide β-turn mimics possessing 8-, 9-, and 10-membered rings by ring-closing metathesis

A systematic study was performed to establish general synthesis protocols for forming enantiomerically pure macrocyclic dipeptide lactams. Focusing on macrocycles of 8-, 9-, and 10-membered rings, effective syntheses were achieved by a sequence featuring peptide coupling of allyl- and homoallyl-glycine building blocks followed by ring-closing metathesis. The 8-membered lactam-possessing cis-amide and cis-olefin geometry as well as 9- and 10-membered lactams having trans-amide and trans-olefin configurations were effectively prepared by a general strategy employing the respective protected dipeptide, the first generation Grubbs' catalyst, and temporary protection of the central amide as a benzyl derivative.