Systematic Study of the Synthesis of Macrocyclic Dipeptide β-Turn Mimics Possessing 8-, 9-, and 10- Membered Rings by Ring-Closing Metathesis

Abstract

[structures: see text] 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-membered [corrected] lactams having trans-amide and cis-olefin [corrected] 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. The 10-membered macrocycle was synthesized possessing cis- or trans-olefin geometry by employing similar metathesis conditions in the presence or absence of temporary benzyl amide protection, respectively [corrected]