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 1b as a central intermediate, the 4- and 5-aminopiperidin-2-ones 4 and 8, respectively, were approached by regioselective functionalization and subsequent lactamization. Diastereoselective C-alkylation was performed after N-protection of the lactam functionality when exclusive trans configuration resulting in the formation of 5a-f was observed in the 4-amino series. On the other hand, cis selectivity was typical for the alkylations of the 5-amino lactams 5a,b. To investigate the ability of the lactam building blocks to induce reverse-turn structures by intramolecular hydrogen bonding, the model peptidomimetics 12 and 14 representing Homo-Freidinger lactams of type II and III were prepared from 4a and 8a, respectively. Conformational analyses in dilute solution (1 mM) by IR and NMR spectroscopy at room temperature clearly indicated that the 4-aminopiperidin-2-one derivative 12 predominantly adopts a reverse-turn structure stabilized by a CO-HN hydrogen bond in an 11-membered ring. VT NMR experiments showed a substantial temperature dependency of the terminal NH when Deltadelta(NH)/DeltaT = -6.5 indicated that the amount of intramolecular hydrogen bonding is higher at low temperature. An application in the field of medicinal chemistry was demonstrated. Thus, starting from the Homo-Freidinger lactam 11c and the enantiomer ent-11c, we synthesized the peptidomimetics 15c and 16c and investigated them as lactam-bridged analogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH(2) (PLG). Both test compounds turned out to enhance significantly the agonist binding of dopamine D2 receptors, when the isomer 15c revealed a potency comparable to the genuine ligand PLG.
Weber
K
K
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrabetae 19, D-91052 Erlangen, Germany.
Ohnmacht
U
U
Gmeiner
P
P
D000818:Animals; D002417:Cattle; D003342:Corpus Striatum / Q000378:metabolism; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000378:metabolism; D066298:In Vitro Techniques; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis*; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000378:metabolism; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
D015259:Dopamine Agents; D010880:Piperidines; D011954:Receptors, Dopamine