Optimized Ring Closing Metathesis Reaction Conditions To Suppress Desallyl Side Products in the Solid-Phase Synthesis of Cyclic Peptides Involving Tyrosine(O-allyl)

Abstract

We are exploring constraining aromatic residues in the kappa opioid receptor selective antagonist arodyn (Ac[Phe^1,2,3,Arg⁴,d-Ala⁸]dynorphin A(1-11)-NH₂) by ring closing metathesis (RCM) involving tyrosine(O-allyl) (Tyr(All)), but desallyl products limited the yields of the desired cyclic peptide. The model dipeptide Fmoc-Tyr(All)-Tyr(All) was used to explore different reaction conditions, including the use of isomerization suppressants, to minimize formation of the desallyl products and enhance formation of the desired RCM product. Reaction conditions were identified that enhanced the RCM product yield while suppressing desallyl products using both second-generation Grubbs and second-generation Hoveyda-Grubbs catalysts. These optimized reaction conditions were then applied to the cyclization of a tripeptide and an arodyn analog resulting in ≥70% conversion to the desired cyclic peptides. These strategies should be applicable to RCM involving Tyr(All) and similar residues in peptide and peptidomimetic cyclizations performed on solid phase.