Total Synthesis of Calyciphylline A - A Potent Cytotoxic Alkaloid

强效细胞毒性生物碱 Calyciphylline A 的全合成

• 批准号: 8665448
• 负责人: Craig Evan Stivala
• 金额: $ 5.33万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-07 至 2015-06-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8665448
• 关键词: Address; Affect; Alkaloids; Alkenes; Alkylation; Alkynes; Antineoplastic Agents; Biocompatible Materials; Biological; Biological Availability; Biological Factors; Biological Process; Catalysis; Chemicals; Complex; Coupling; Development; Dinophyceae; Evaluation; Evolution; Family; Future; Laboratories; Macrolides; Malignant Neoplasms; Marketing; Methodology; Methods; Molecular; Organic Chemistry; Pharmaceutical Preparations; Process; Relative (related person); Research; Structure; Text; Therapeutic Agents; Transition Elements; biological systems; cancer therapy; chemical synthesis; coral; cytotoxic; design; drug discovery; innovation; member; novel; programs; stereochemistry; tetrahydrofuran

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.

AmphidiniumN是从甲藻Amphidinium中分离出的34种不同大环内酯之一 sp.从冲绳珊瑚礁，代表，到目前为止，最强大的成员， 天然产品家族。它具有一定的抗癌活性，可以与一些最重要的 目前可用于治疗癌症的有效治疗剂。而 在几种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， 药学上相关的amphidinolides，amphidinolide N的合成还没有 成功地接近，分子的完整结构解释仍然未知。 我们的方法，以全化学合成的amphidinobenzene N的设想，以功能， 独特的Pd催化的不对称烯丙基烷基化，以构建反式四氢呋喃环。 此外，关键的Ru催化的烯烃-炔偶联将连接两个大的亚片段， 靶分子在一起。这项研究计划旨在进一步刺激发展 在主族和过渡金属催化中已有的方法。收敛 战略，上述，来自新的方法，目前正在进行 在我们的实验室里。他们提供了一个独特的机会，进一步探讨和 利用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 2）建立两性霉素N的绝对和相对化学合成方法， 分子的立体化学，和3）为进一步的生物学研究提供材料， 研究该分子作为潜在的治疗剂。