Synthetic Studies of Kobusine-type Aconite Alkaloids

乌头有一朵美丽的蓝紫色花，是一种众所周知的有毒草药，偶尔会因误食而导致死亡。乌头生物碱主要存在于乌头块根中，由于其药理活性和结构的复杂性，乌头生物碱一直受到研究人员的关注。1956年，钯催化甲酰基分子内α-芳基化反应成功地合成了一种从三叶乌头中分离得到的乌头生物碱（±）-诺米碱。以2-溴-5-甲氧基苯基碘化物为起始原料，总收率为0.15%，共合成40步，是首个全合成具有蛇头骨架的乌头生物碱，这是5种代表性乌头骨架[阿提丹、黄芪烷、环黄芪烷、乌头烷和蛇头碱（名称来源于蛇头碱）]中唯一一个全合成未能成功的乌头骨架。除上述α-芳基化反应外的关键步骤还有：(i)缩醛-烯反应形成C14-C20键，（ii）立体选择性氢氰化反应引入C19和氮功能，（iii）LiAlH_4还原氰基烯醇硅基醚形成N-C6键，（iv）炔前体自由基环化形成亚甲基双环[2.2.2]辛烷框架，(v)与seo_2 -叔丁醇烯丙基氧化引入15 - β- oh。（±）-Nominine的单晶x射线分析明确证实了合成的完成。

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.