Novel Bicyclic Lactams as XaaPro Type VI β Turn Mimics:  Design, Synthesis, and Evaluation

The design, enantioselective synthesis, and structural characterization of novel bicyclic lactams as peptide mimics of the type VI β turn is described. The mimics duplicate the conformation of the backbone and 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. ¹H NMR spectroscopy defined the relative stereochemistry of the substituents and conformational characteristics of the six-membered ring of the lactam; X-ray crystallographic 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 resulting from the presence of the sp²-hybridized nitrogen atom at the junction of the two rings. Alkylation of the enolate of the N,N-dimethylformamidine derivative of lactam 6 with benzyl bromide afforded stereoselectively the formamidine 11, a mimic of an l-Phe l-Pro dipeptide in the type VI turn conformation. The efficient synthetic route to highly functionalized peptidomimetics such as 11 will prove highly useful in peptide structure−function studies.