1997 Volume 55 Issue 10 Pages 868-876
Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, we devised a new method for restricting the conformation of cyclopropane derivatives. Using this strategy, conformationally restricted analogs of milnacipran, a useful antidepressant, were designed as potent NMDA receptor antagonists, and were synthesized highly enantioselectively from chiral epichlorohydrins. Throughout the synthetic study, we found that nucleophilic addition reactions on cyclopropylcarbaldehyde and -ketones proceeded highly stereoselectively via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized.
Some of the synthesized analogs were significantly effective compared with milnacipran as an NMDA receptor antagonists.
