ASYMMETRIC-SYNTHESIS OF A POTENT AND SELECTIVE COMPETITIVE NMDA ANTAGONIST

-2-Amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (15) has been prepared by an efficient nine-step route (16% overall yield) which use s chemoenzymatic processes to establish all absolute stereochemistry. This compound was found to be the most active isomer of the previously reported isomeric mixture, NPC 12626. In addition, synthetic routes w ere developed for the stereochemically unambiguous preparation of all the other cis isomers of this racemate. All of the synthetic pathways utilized enzymatic hydrolysis of a meso diester to prepare key optical ly pure building blocks. Pharmacological evaluation of the isomers ind icates that 15 is one of the most potent and least toxic NMDA antagoni sts discovered to date.