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.
Subject(s)
Amino Acids, Cyclic/chemistry , Amino Acids, Cyclic/metabolism , Glutamic Acid/analogs & derivatives , Glutamic Acid/chemistry , Receptors, Glutamate/chemistry , Receptors, Glutamate/metabolism , Ligands , Molecular Structure , Stereoisomerism , ThermodynamicsABSTRACT
The molecules of the title compounds, C(13)H(21)NO(4), (I), and C(15)H(26)NO(7)P, (II), are linked into chains along the c direction in (I) and along the b axis in (II) through O-H.O hydrogen bonds. The heteroatomic ring in (I) adopts a twist-boat conformation, while that in (II) has a conformation intermediate between boat and twist-boat. The P atom has a distorted tetrahedral geometry.
