On-Resin Olefin Metathesis

Significance

Solid-phase synthesis of peptide macrocycles was achieved by using Grubbs’ ring closing metathesis (RCM) as key steps. Tetrapeptide 1, anchored on the Wang resin, was treated with the Grubbs’ 2^nd generation metathesis catalyst to give olefin-bridged (C-CH=CH-C) peptide macrocycle 2. Macrocycles B-ring and C-ring were synthesized via similar solid-phase peptide synthesis (standard Fmoc method) followed by the on-resin RCM. After cleavage of the resin, an overall yield of 0.5% (for 25 coupling steps and 3 RCM steps) of the desired lantibiotic peptide bearing the A-, B-, and C-rings, and the acyclic peptide chain of 15 amino acid units was obtained.