Total Synthesis of Calyciphylline A - A Potent Cytotoxic Alkaloid

Amphidinolide N是从甲藻中分离得到的34种不同的大环内酯类化合物之一 SP.来自冲绳珊瑚礁，代表着到目前为止这个大型 天然产品系列。它的抗癌活性水平可以与一些最强的 目前可用于癌症治疗的有效治疗药物。而当 在几个化合物的合成和生物学评价方面已经取得了相当大的进展 与药物相关的两性内酯类化合物N的合成尚未得到报道 方法成功，但对该分子的完整结构解释仍不清楚。 我们对两性内酯N的全化学合成的方法被设想为具有一个 独特的钯催化的不对称烯丙基烷基化反应构建了一个反式四氢呋喃环。 此外，一个关键的Ru催化的烯烃-烯烃偶联将连接两个大的亚片段 靶向分子聚集在一起。这项研究计划旨在进一步刺激发展 主族和过渡金属催化两种已有方法的比较。汇聚者 战略，如上所述，源自目前在 我们实验室的发展。他们提供了一个独特的机会，进一步探索和 开发它们在复杂分子环境中的潜在用途。 成功完成拟议项目将实现以下目标：1)完成 全化学合成两性内酯N，2)建立绝对和相对 分子的立体化学，以及3)为进一步的生物学研究提供材料，以便 将该分子作为潜在的治疗剂进行研究。

Amphidinolide N is one of 34 distinct macrolides isolated from the dinoflagellate Amphidinium sp. from the Okinawan coral reefs and represents, by far, the most potent member of this large family of natural products. It possesses a level of anti cancer activity that rivals some of the most potent therapeutics agents that are currently available for the treatment of cancer. While considerable progress has been made in the synthesis and biological evaluation of several pharmaceutically relevant amphidinolides, a synthesis of amphidinolide N has not been approached successfully and the full structural elucidation of the molecule still remains unknown. Our approach to the total chemical synthesis of amphidinolide N is envisioned to feature a unique Pd-catalyzed asymmetric allylic alkylation to construct a trans-tetrahydrofuran ring. Additionally, a key Ru-catalyzed alkene-alkyne coupling will join two large sub fragments of the target molecule together. This research program is designed to further stimulate the development of preexisting methods in both main group and transition metal catalysis. The convergent strategy, described above, emanated from the novel methodologies that are currently under development in our laboratory. They have provided a unique opportunity to further explore and exploit their potential use in complex molecular settings. Successful completion of the proposed project would achieve the following: 1) Complete the total chemical synthesis of amphidinolide N, 2) Establish the absolute and relative stereochemistry of the molecule, and 3) Provide material for further biological studies in order to investigate the molecule as a potential therapeutic agent.