Introduction of all-hydrocarbon i,i + 3 staples into α-helices via ring-closing olefin metathesis

The introduction of all-hydrocarbon i,i+3 staples into α-helical peptide scaffolds via ring-closing olefin metathesis (RCM) between two α-methyl,α-pentenylglycine residues incorporated at i and i+3 positions, which lie on the same face of the helix, has been investigated. The reactions were found to be highly dependent upon the side-chain stereochemistry of the amino acids undergoing RCM. The i,i+3 stapling system established here provides a potentially useful alternative to the well-established i,i+4 stapling system now in widespread use.