A NEW METHOD FOR CONFORMATIONAL RESTRICTI ON BASED ON REPULSION BETWEEN ADJACENT SUBSTITUENTS ON A CYCLOPROPANE RING, AND ITS APPLICATION TO DESIGNING POTENT NMDA RECEPTOR ANTAGONISTS

Adjacent substituents on a cyclopropane ring mutually exert steric rep ulsion quite significantly, because they are fixed in eclipsed conform ation to each other. Based on this structural feature of the cycloprop ane ring, we devised a new method for restricting the conformation of cyclopropane derivatives. Using this strategy, conformationally restri cted analogs of milnacipran, a useful antidepressant, were designed as potent NMDA receptor antagonists, and were synthesized highly enantio selectively from chiral epichlorohydrins. Throughout the synthetic stu dy, we found that nucleophilic addition reactions on cyclopropylcarbal dehyde and -ketones proceeded highly stereoselectively via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl deri vatives. The structures of the conformationally restricted analogs det ected by the X-ray crystallographic analysis suggested that their conf ormations can be restricted as we hypothesized. Some of the synthesize d analogs were significantly effective compared with milnacipran as an NMDA receptor antagonists.