Asymmetric total synthesis of a novel tumor promoter

从玫瑰毛霉中分离得到的新型毛霉烯类化合物--毛霉醇A、B和C具有很强的促癌作用。它们的促癌作用方式不同于其他已知的促癌因子，提示其致癌机制尚不清楚。为了研究毛霉烯类化合物的生物学性质，本项目开发了一条高效的三茂铁烯类化合物的合成路线。一种是在合成的早期阶段将甲基立体选择性地引入到由D-甘露醇衍生的手性丁烯内酯中。另一种是通过内酯γ位的立体反转构筑顺式A/B环。根据该合成方案，以手性丁烯内酯为原料，立体选择性地合成了第一个关键中间体，然后进行立体转化和环状烯烃歧化反应，得到了高产率的螺内酯。内酯部分的还原开环、保护、氧化和甲基化得到叔醇，它是环关闭到顺式A/B环之前的中间体。通过一次醇酸处理的烧瓶反应，以很高的产率得到了具有顺式A/B环所需的环连接的闭环产物。最后，以D-甘露醇为原料，高产率地完成了三氯乙烯的不对称全合成。螺内酯是合成路线中最重要的关键中间体之一，在合成螺内酯的过程中，闭环烯烃歧化反应是一种非常有用的方法。

Novel trichothecenes, trichothecinol A, B and C isolated from Trichothecium roseum, acts as strong tumor promoters. Their mode of action in tumor promotion is different from those of other known tumor promoters, suggesting the presence of unknown mechanisms on carcinogenesis. In this project, an efficient synthetic route of trichithecenes has been developed in order to investigate biological properties of trichothecinols.There are two important steps in the present synthetic strategy for trichothecenes. One is a stereoselective introduction of a methyl group into the chiral butenolide derived from D-mannitol in the early stage of the synthesis. The other is a construction of the cis A/B ring via the steric inversion at the γ-position of the lactone. According to the synthetic scheme, the first key intermediate was stereoselectively prepared from the chiral butenolide, followed by the steric inversion and ring closing olefin metathesis to afford the desired spirolactone in high chemical yield. Reductive opening of the lactone moiety, protection, oxidation and methylation gave the tertiary alcohol that is a intermediate before ring closing to the cis A/B ring. One flask reaction by acidic treatment of the alcohol yielded the ring closing product that has desired ring juncture for the cis A/B ring in good yield. Several steps led to an authentic compound reported by the Kraus group.In conclusion, a formal total synthesis of trichothecene was enantioselectively done in high yield using D-mannitol as the starting material. Ring closing olefin metathesiswas a very useful method for the construction of the spirolactone, one of the most important key intermediate in the synthetic route.