A [3+2] Annulation Route to Annonaceous Acetogenins

描述（由申请人提供）：许多来自无机乙酰原素类天然产物的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。这类具有中心双四氢呋喃核的成员作为抗癌药物特别感兴趣。实现这一目标的一个障碍是缺乏关于天然产物生物活性机制的精确信息。为了更好地理解这些化合物在促进肿瘤死亡中的作用，需要一种高效的、立体化学的合成途径来合成这些无机乙酰原。该研究将开发全合成的三种氨基乙原蛋白家族成员：10-羟基三叶杆菌蛋白，布拉他星和罗利膜蛋白。这三种含双四氢呋喃的化合物都具有细胞毒性或抗肿瘤特性，目前尚不清楚其中两种化合物的总合成方法。手性烯丙基硅烷的关键[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。全合成的完成将证明[3+2]环化方法在构建annanneous acetogenins及其类似物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.