Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans-tris(homoglutamic) acids |
| |
Authors: | Meyer Udo Bisel Philippe Bräuner-Osborne Hans Madsen Ulf Höfner Georg Wanner Klaus Th Frahm August Wilhelm |
| |
Affiliation: | Department of Pharmaceutical Chemistry, Albert-Ludwigs-Universit?t, Freiburg, Germany. |
| |
Abstract: | The second-generation asymmetric synthesis of the trans-tris(homoglutamic) acids reported herein proceeds via Strecker reaction of chiral ketimines, obtained from condensation of racemic 2-ethoxycarbonylmethylcyclopentanone and commercially available (S)- and (R)-1-phenylethylamine, respectively. In the key stereodifferentiating step, the cyanide addition leads to mixtures of diastereomeric alpha-amino nitrile-esters, the composition of which is independent of the reaction temperature and the type of the solvent, respectively. Hydrolysis of the alpha-amino nitrile-esters with concentrated H(2)SO(4) yielded diastereomeric mixtures of secondary alpha-amino amido-esters, which after separation were hydrogenolyzed and hydrolyzed each to the enantiomeric trans-1-amino-2-carboxymethylcyclopentanecarboxylic acids. Their configuration was completely established by NMR methods, CD spectra, and X-ray analysis of the trans-1S,2R-configured secondary alpha-amino amido-ester. In receptor binding assays and functional tests, trans-1S,2R-1-amino-2-carboxymethylcyclopentanecarboxylic acid hydrochloride was found to behave as a selective mGluR(2)-antagonist without relevant binding properties at iGluRs. |
| |
Keywords: | trans(homoglutamic) acids 2,3‐propanoglutamic acids α‐amino nitriles asymmetric Strecker synthesis X‐ray crystallography iGluRs binding assays mGluRs functional tests selective mGluR2‐antagonist |
本文献已被 PubMed 等数据库收录! |
|