Stereoselective synthesis of 6,5-bicyclic reverse-turn peptidomimetics

Abstract

A flexible stereoselective synthetic scheme was developed to prepare 6,5-fused bicyclic lactams, that molecular mechanics calculations revealed to have a potential as reverse-turn mimetics. The convergence of the synthetic sequence was achieved by attachment of a properly substituted malonate unit to the (2 S)- cis-5-(2-hydroxyethyl)proline tert-butyl ester. Stereoselective intramolecular alkylation of the malonate afforded the 6-membered lactam fused to the 2-carbalkoxy pyrrolidine nucleus. X-ray diffraction analysis of a more advanced synthetic derivative allowed the unequivocal assignment of the configuration at the newly created quaternary stereocenter as R.