シクロプロパン環上の隣接置換基間の立体反発を利用する新規配座制御法とそのNMDA受容体特異的アンタゴニスト創製への展開

抄録

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.