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Synthetic Studies of Kobusine-type Aconite Alkaloids

科布辛型附子生物碱的合成研究

基本信息

批准号：
16590025
负责人：
MURATAKE Hideaki
金额：
$ 1.6万
依托单位：
Research Foundation ITSUU Laboratory
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590025/
关键词：
Aconite alkaloid nominine total synthesis natural product 合成化学とりかぶと

项目摘要

Aconitum, which has a beautiful blue-purple flower, is well-known as a poisonous herb, which occasionally results in fatalities following accidental ingestion. The aconite alkaloids, mainly contained in the tuberous root, have long been of interest to researchers, because of both their pharmacological activities and their structural complexity.Our palladium-catalyzed intramolecular α-arylation of formyl group was successfully applied to a total synthesis of (±)-nominine, a hetisine-type aconite alkaloid isolated from Aconitum sanyoense Nakai in 1956. The synthesis consists of forty-steps from 2-bromo-5-methoxyphenethyl iodide in 0.15% overall yield, and constitutes the first total synthesis of an aconite alkaloid having the hetisan framework, the sole aconite skeleton whose total synthesis has long remained unsuccessful among five representative aconite skeletons [atidane, veatchane, cycloveatchane, aconitane, and hetisan (the name of which is derived from hetisine)].Key steps other than the above α-arylation are (i)acetal ene-reaction to form the C14-C20 bond, (ii)stereoselective hydrocyanation to introduce C19 and nitrogen functions, (iii)LiAlH_4 reduction of cyano-enol silyl ether to form the N-C6 bond, (iv)radical cyclization from enyne precursor to construct the methylenebicyclo[2.2.2]octane framework, and (v)allylic oxidation with SeO_2-tert-BuOOH to introduce 15β-OH. Completion of the synthesis was verified unequivocally by single crystal X-ray analysis of (±)-Nominine.

蒲公英，有一个美丽的蓝紫色的花，是众所周知的有毒草药，偶尔会导致死亡后意外摄入。乌头类生物碱主要存在于块根中，由于其药理活性和结构的复杂性，一直受到研究者的关注。1956年，我们成功地将钯催化的分子内甲酰基α-芳基化反应应用于（±）-nominine的全合成。该合成由2-溴-5-甲氧基苯乙基碘以0.15%的总产率进行了40步，并且构成了具有Hetisan骨架的乌头生物碱的第一个全合成，Hetisan骨架是五种代表性乌头骨架[乌头碱，乌头烷，环乌头烷，乌头烷，和赫蒂森除了上述α-芳基化以外的关键步骤是（i）缩醛烯反应以形成C14-C20键，（ii）立体选择性氢氰化以引入C19和氮官能团，（iii）LiAlH_4还原氰基烯醇硅醚形成N-C6键，（iv）烯炔前体自由基环化形成亚甲基双环[2.2.2]辛烷骨架，（v）用SeO_2-tert-BuOOH烯丙基氧化引入15β-OH。通过（±）-诺米宁的单晶X射线分析明确验证了合成的完成。