Versatile Synthetic Route for the Hetisan-type Aconite Alkaloids

乌头是日本三大有毒植物之一，长期以来一直被用作有用的中药材。几年前，随着钯催化的酮、醛和硝基的α-芳基化反应的发现，我们开始了Hetisine类型的乌头生物碱的合成研究，这是唯一的乌头代表框架，其全合成仍然没有成功。我们的合成研究首次实现了(±)-诺明的全合成。然而，这种合成是由40个步骤组成的，因此需要巨大的能量和专业的合成技能。因此，我们对合成路线进行了综述，并对合成路线进行了改进，为光学活性生物碱的制备提供了线索。尝试对合成路线进行了改进：虽然应用Taber方法对2-甲氧基苯甲酸转化为2-烷酮衍生物进行了详细的研究，以缩短向2-苯乙基环己酮中间体的路线，但从起始的苯乙基二碘衍生物通过脱氢碘化得到了不需要的苯乙烯衍生物。另一方面，设计了一种新的定量合成起始的2-溴-5-甲氧基苯亚甲基的方法，并尝试了中间体的光学拆分：在所有文献方法下，硝基甲烷与环己酮中间体的不对称加成反应根本没有进行。在极端条件下得到的少量产物是外消旋的。同时，通过高效液相色谱分析发现，由硝基甲烷加合物和酒石酸二甲酯衍生的缩醛可以分离出四个非对映异构体。但在相同的洗脱溶剂下，尝试用开柱层析分离失败。因此，手性高效液相色谱分离(±)-Nominine衍生的苯甲酸酯是制备光学活性Nominine最实用的方法。

Aconitum, one of the Japanese three major poisonous plants, has long been used as a useful Chinese medicine. We commenced, several years ago, synthetic studies of the hetisine-type aconite alkaloid, the sole aconite representative framework whose total synthesis has remained unsuccessful, in the wake of the finding of the palladium catalyzed α-arylation reaction of ketone, aldehyde, and nitro groups. Our synthetic studies culminated in the first total synthesis of (±)-Nominine. This synthesis, however, is constituted of forty steps, and consequently requires tremendous energies and expert synthetic skills. So, we reviewed the synthetic route, and contrived to improve it and get a clue for the preparation of the optical active alkaloid.Attempted improvement of the synthetic route : Although transformation of 2-methoxybenzoic acid into 2-alkylenone derivative, applying the Taber's method, was investigated in detail in order to foreshorten the route toward the 2-phenethylcyclohexenone intermediate, only the undesired styrene derivative was obtained through dehydroiodination from the starting phenethyliodide derivative. On the other hand, a novel quantity synthetic method of the starting 2-bromo-5-methoxyphenethyliodide was efficiently devised.Attempted optical resolution of intermediates: Asymmetric addition of nitromethane to the cyclohexenone intermediate did not proceed at all under the all literature methods tried. The obtained product in a small amount under drastic conditions was found to be racemic. The acetal derived from ell-nitromethane adducts and dimethyl tartrate, meanwhile, became clear to be separable to four diastereoisomers by the HPLC analysis. But attempted separation by an open column chromatography failed under the same eluting solvent. It was concluded from the above results that the most practical method for the preparation of optical-active nominine would be chiral-HPLC separation of a benzoate derived from (±)-Nominine.