A [3+2] Annulation Route to Annonaceous Acetogenins

描述（由申请人提供）：番荔枝内酯类天然产物的许多化合物对几种类型的人肿瘤细胞表现出高度有效和选择性的细胞毒性。具有中心双四氢呋喃核的这类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的作用，需要针对番荔枝内酯的有效的和立体化学上通用的合成路线。该研究将开发番荔枝内酯家族的三个成员：10-hydroxytrilobacin，bullatacin和rolimemetrin的全合成。这三种含双四氢呋喃的化合物都具有细胞毒性或抗肿瘤性质，其中两种化合物的全合成方法目前尚不清楚。一个关键的[3 + 2]成环反应的手性烯丙基硅烷将被用来构建双-四氢呋喃片段的每一个天然产物的立体控制的方式。完成所提出的全合成将证明[3 + 2]成环方法在番荔枝内酯及其类似物的构建中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.