ASYMMETRIC-SYNTHESIS OF A POTENT AND SELECTIVE COMPETITIVE NMDA ANTAGONIST

(2R,4R,5S)-2-Amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (15) has been prepared by an efficient nine-step route (16% overall yield) which uses 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 were 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 optically pure building blocks. Pharmacological evaluation of the isomers indicates that 15 is one of the most potent and least toxic NMDA antagonists discovered to date.