Conformationally restricted peptide mimetics: The incorporation of 6,5-bicyclic lactam ring skeletons into peptides

This manuscript describes a convenient procedure for the synthesis of peptide fragments containing 6,5-bicyclic lactam-based conformational constraints. The syntheses capitalize on an electrochemical oxidation to functionalize a substituted proline derivative, an N-acyliminium ion-initiated cyclization in order to form a transient seven-membered-ring lactam, and a rearrangement reaction to form the desired six-membered-ring lactam. The bicyclic lactam products were converted into peptide building blocks and the stereochemistry of the building blocks assigned using two-dimensional NMR techniques. Once synthesized, the building blocks were readily incorporated into peptide fragments with the use of standard peptide synthesis techniques. The synthetic route employed was shown to be compatible with both aryl and branched amino acid side chains.