Asymmetric total synthesis of a novel tumor promoter

从玫瑰曲霉菌中分离到的新型曲霉菌酚A、B和C是强肿瘤促进剂。它们促进肿瘤的作用方式不同于其他已知的肿瘤启动子，提示存在未知的致癌机制。本课题为研究毛霉酚类化合物的生物学特性，探索了一种高效的毛霉烯类化合物的合成途径。在目前的合成策略中，有两个重要的步骤。一是在合成的早期阶段将甲基立体选择性地引入d -甘露醇衍生的手性丁烯内酯。另一种是通过内酯的γ位位位反位构造顺式a /B环。根据合成方案，首先以手性丁烯内酯为原料，进行立体选择性合成第一个关键中间体，然后进行立体反相和闭环烯烃复分解，以高收率合成所需的旋内酯。内酯部分的还原打开、保护、氧化和甲基化产生了叔醇，叔醇是顺式a /B环闭合前的中间体。在一个烧瓶反应中，对醇进行酸性处理，制得的闭合环产物具有顺式A/B环所需的闭合环，收率高。走了几步，就到了克劳斯小组报告的一个真正的院落。综上所述，以d -甘露醇为原料，对映选择性地高收率合成了三角木烯。闭环烯烃反应是合成螺旋内酯的一种非常有用的方法，螺旋内酯是合成路线中最重要的关键中间体之一。

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.