Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans-tris(homoglutamic) acids
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Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans-tris(homoglutamic) acids. / Meyer, Udo; Bisel, Philippe; Bräuner-Osborne, Hans; Madsen, Ulf; Höfner, Georg; Wanner, Klaus Th; Frahm, August Wilhelm.
In: Chirality, Vol. 17, No. 2, 02.2005, p. 99-107.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans-tris(homoglutamic) acids
AU - Meyer, Udo
AU - Bisel, Philippe
AU - Bräuner-Osborne, Hans
AU - Madsen, Ulf
AU - Höfner, Georg
AU - Wanner, Klaus Th
AU - Frahm, August Wilhelm
N1 - Copyright 2005 Wiley-Liss, Inc.
PY - 2005/2
Y1 - 2005/2
N2 - 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.
AB - 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.
KW - Amino Acids, Cyclic
KW - Glutamic Acid
KW - Ligands
KW - Molecular Structure
KW - Receptors, Glutamate
KW - Stereoisomerism
KW - Thermodynamics
U2 - 10.1002/chir.20110
DO - 10.1002/chir.20110
M3 - Journal article
C2 - 15660439
VL - 17
SP - 99
EP - 107
JO - Chirality
JF - Chirality
SN - 0899-0042
IS - 2
ER -
ID: 45613574