Synthesis and N-Methyl-D-aspartate (NMDA) Antagonist Properties of the Enantiomers of α-Amino-5-(phosphonomethyl)[1,1′-biphenyl]-3-propanoic Acid. Use of a New Chiral Glycine Derivative

The enantiomers of the title compound, 7a and ent- 7a , and of substituted analogues are synthesized. The absolute configuration of 7a is deduced from that of (tert-butyl 2-tert-butyl)-3-methyl-4-oxoimidazolidin-1-carboxylate ( 15 ) and from the trans-configuration of the intermediate 17a which in turn is assigned on the basis of ¹H-NMR nuclear Overhauser effect (NOE) measurements. Instead of 15 , the 2-isopropyl-substituted analogue 21 can also be employed. Its preparation from glycine, methylamine, isobutyraldehyde, and (Boc)₂O, and the resolution through the bis-O,O′-(4-toluyl)tartrate salt 20 are described. In two functional tests (rat neocortical slice and frog hemisected spinal cord preparation) the (S)-enantiomer 7a (SDZ EAB 515) is shown to be a very potent, selective competitive NMDA antagonist.