Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans-tris(homoglutamic) acids.
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.
Meyer
Udo
U
Department of Pharmaceutical Chemistry, Albert-Ludwigs-Universität, Freiburg, Germany.
Bisel
Philippe
P
Bräuner-Osborne
Hans
H
Madsen
Ulf
U
Höfner
Georg
G
Wanner
Klaus Th
KT
Frahm
August Wilhelm
AW
D000598:Amino Acids, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D017470:Receptors, Glutamate / Q000737:chemistry* / Q000378:metabolism*; D013237:Stereoisomerism; D013816:Thermodynamics
D000598:Amino Acids, Cyclic; D008024:Ligands; D017470:Receptors, Glutamate; D018698:Glutamic Acid