AN ENANTIOSELECTIVE SYNTHESIS OF CIS PERHYDROISOQUINOLINE LY235959

A novel synthesis of NMDA receptor antagonist LY235959 (1) has been ac hieved in 13% overall yield and 17 steps from (R)-pantolactone (7). Hi ghlights of the synthesis include (a) use of a chiral auxiliary contro lled asymmetric Diels-Alder reaction to provide the desired absolute a nd relative stereochemistry at C-4a, C-6, and C-8a, (b) an efficient a lkylation of hindered iodide 13 using a novel amide benzophenone imine , (c) oxidative ring opening of the [2.2.2] bicyclic system to simulta neously functionalize the molecule for intramolecular cyclization and phosphonate introduction, and (d) an increased understanding of how th e C-3 stereochemistry may be controlled by thermodynamic equilibration . Synthesis of epimer 20 in high overall yield makes this synthetic ro ute attractive for future development efforts.