P-18 グルタミン酸拮抗阻害剤Kaitocephalinの大量合成法の開発(ポスター発表の部)
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概要
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Kitocephalin was isolated from Eupenicillim shearii PF1191 in 1997. This compound has the very unique framework in which three amino acids connect with C-C bonds. This compound exhibits potent inhibitory activity against neuronal cell death by the action of antagonist for NMDA and AMPA/KA receptors. Although this compound is expected to be the lead compound for development of therapentic agents against neuronal diseases, the fungus has stopped producing this compound. So, there is not the way to obtain this compound except for organic synthesis at present. These backgrounds made us develop the efficient synthetic route of kaitocephalin. Starting from known compound 1, homocoupling by treating with Grubbs 2^<nd> catalyst followed by Wacker oxidation readily provided ketone 3. Successive reductive amination and mono acylation with hydroxyl succinimide ester at primary amino group gave 4 preferentially. For the introduction of the right-hand moiety, we first tried dianion coupling, which was found to be unsuccessful. However, we tried Barbier reaction, after transforming 4 to imine 11 by treating with NBS and Et_3N, Barbier reaction proceeded to afford allylated compound 12 with desired stereoselectivity in almost quantitative yield. By exchanging the protective groups, followed by olefin-isomerization and allic oxidation, we obtained alcohol 15. Epoxidation of 15 proceeded with complete stereoselectivity and provided 16. Subsequent azidation under the Miyashita's condition gave desired product 17 along with debenzylated compound as a mixture. Rebenzylation of the mixture followed by reduction with indium and Cbz protection provided compound 18, which is an intermediate of our previous synthesis. After conducting oxidation and deprotection according to the known procedure, we obtained kaitocephalin. In summary, we achieved total synthesis of kaitocephalin in 6.5% overall yield (18 steps) from 1.
- 天然有機化合物討論会の論文
- 2007-08-24
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