SYNTHESES OF 6-OXODECAHYDROISOQUINOLINE-3-CARBOXYLATES - USEFUL INTERMEDIATES FOR THE PREPARATION OF CONFORMATIONALLY DEFINED EXCITATORY AMINO-ACID ANTAGONISTS

We have prepared three of the four possible diastereomers of ethyl 6-oxo-2-(methoxycarbonyl)decahydroisoquinoline-3-carboxylic acid (two cis- ring and one trans ring juncture ketones, 3a-c) by a convergent route from (+/-)-m-tyrosine. These ketones are useful intermediates for the preparation of conformationally constrained acidic amino acids as N-methyl-D-aspartic acid (NMDA) receptor antagonists, e.g., LY274614 and LY233536 (1 and 2, respectively). The cis ring juncture ketones were prepared selectively by hydrogenation of a key tetrahydroisoquinoline intermediate 7, while the corresponding trans ring juncture ketone was prepared selectively by consecutive dissolving metal reductions of the tetrahydroisoquinoline 8. One of the ketones, 3b, that possesses the optimal stereochemical array for NMDA antagonist activity, was resolved via the alpha-methylbenzylamine salts of the corresponding acid to allow for determination of the active optical isomer of these amino acids. The synthesis and resolution of the keto esters can easily be performed on a multigram scale.