Enantiopure 4-and 5-aminopiperidin-2-ones: Regiocontrolled synthesis and conformational characterization as bioactive beta-turn mimetics

Starting from aspartic acid, we synthesized lactam-bridged beta- and gamma -amino acid equivalents. Using the 1,4-bis-electrophile Ib as a central int ermediate, the 4- and 5-aminopiperidin-2-ones 4 and 8, respectively, were a pproached by regioselective functionalization and subsequent lactamization. Diastereoselective C-alkylation was performed after N-protection of the la ctam functionality when exclusive trans configuration resulting in the form ation of 5a-f was observed in the 4-amino series. On the other hand, cis se lectivity was typical for the alkylations of the 5-amino lactams 5a,b. To i nvestigate the ability of the lactam building blocks to induce reverse-turn structures by intramolecular hydrogen bonding, the model peptidomimetics 1 2 sind 14 representing Homo-Freidinger lactams of type II and III were prep ared from 4a and 8a, respectively. Conformational analyses in dilute soluti on (1 mM) by IR and NMR spectroscopy at room temperature clearly indicated that the 4-aminopiperidin-2-one derivative 12 predominantly adopts a revers e-turn structure stabilized by a CO-HN hydrogen bond in an 11-membered ring . VT NMR experiments showed a substantial temperature dependency of the ter minal NK when Delta delta (NH)/DeltaT = -6.5 indicated that the amount of i ntramolecular hydrogen bonding is higher at low temperature. An application in the field of medicinal chemistry was demonstrated. Thus, starting from the Homo-Freidinger lactam Ile and the enantiomer ent-11c, we synthesized t he peptidomimetics 15c and 16c and investigated them as lactam-bridged anal ogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH2 (PLG). Bo th test compounds turned out to enhance significantly the agonist binding o f dopamine D2 receptors, when the isomer 15c revealed a potency comparable to the genuine ligand PLG.