A [3+2] Annulation Route to Annonaceous Acetogenins

说明书(申请人提供)：番荔枝内酯类天然产物中的许多化合物对几种类型的人类肿瘤细胞表现出高度有效和选择性的细胞毒性。这类带有中心双四氢呋喃核心的成员作为抗癌药物特别令人感兴趣。实现这一目标的一个障碍是缺乏关于天然产品生物活性机制的准确信息。为了便于理解这些化合物在促进肿瘤死亡中所起的作用，需要有效的和立体化学上通用的合成路线来合成番荔枝内酯。这项拟议的研究将开发番荔枝内酯家族的三个成员的全合成：10-羟基三菌素、布拉丁酸和罗林姆膜。这三种双四氢呋喃化合物均具有细胞毒性或抗肿瘤活性，其中两种化合物的全合成目前尚不清楚。手性烯丙基硅烷的关键的[3+2]环化反应将被用来以立体控制的方式构建每个天然产物的双四氢呋喃片段。完成拟议的全合成将展示[3+2]环法在构建番荔枝内酯及其类似物方面提供的立体化学和功能多样性。

DESCRIPTION (provided by applicant): Many compounds from the annonaceous acetogenin class of natural products exhibit highly potent and selective cytotoxicities against several types of human tumor cells. Members of this class bearing central bistetrahydrofuran cores are of particular interest as anti-cancer drugs. One obstacle towards this goal is the lack of precise information regarding the mechanism of the natural products' biological activity. To facilitate understanding the role these compounds have in promoting tumor death, there is a need for efficient and stereochemically general synthetic routes towards the annonaceous acetogenins. The proposed research will develop total syntheses of three members of the annonaceous acetogenin family: 10-hydroxytrilobacin, bullatacin, and rollimembrin. These three bis-tetrahydrofuran containing compounds all have cytotoxic or anti-tumor properties, and the total syntheses of two are currently unknown. A key [3+2] annulation reaction of chiral allylsilanes will be employed to construct the bis-tetrahydrofuran fragment of each natural product in a stereocontrolled fashion. Completion of the proposed total syntheses will demonstrate the stereochemical and functional diversity that the [3+2] annulation approach provides in the construction of annonaceous acetogenins and their analogs.