NOVEL BICYCLIC LACTAMS AS XAAPRO TYPE-VI-BETA-TURN MIMICS - DESIGN, SYNTHESIS, AND EVALUATION

The design, enantioselective synthesis, and structural characterizatio n of novel bicyclic lactams as peptide mimics of the type VI beta turn is described. The mimics duplicate the conformation of the backbone a nd disposition of the side-chain atoms of the central two residues of the turn. The Gly L-Pro mimic, lactam 6, was prepared in good overall yield starting from (S)-2-(2'-propenyl)proline. H-1 NMR spectroscopy d efined the relative stereochemistry of the substituents and conformati onal characteristics of the six-membered ring of the lactam; X-ray cry stallographic analysis confirmed the conformational and stereochemical assignment. Examination of the crystal structure of lactam 6 revealed that the central amide bond was twisted appreciably out of planarity. The twisting of the amide bond was attributed to angle strain resulti ng from the presence of the sp(2)-hybridized nitrogen atom at the junc tion of the two rings. Alkylation of the enolate of the N,N-dimethylfo rmamidine derivative of lactam 6 with benzyl bromide afforded stereose lectively the formamidine 11, a mimic of an L-Phe L-Pro dipeptide in t he type VI turn conformation. The efficient synthetic route to highly functionalized peptidomimetics such as 11 will prove highly useful in peptide structure-function studies.