A Novel Stereodivergent Approach to Amphidinolide N & the Total Synthesis

Amphidinolide N 的新型立体发散方法

• 批准号: 7337128
• 负责人: AUDRIS HUANG
• 金额: $ 4.6万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-11-16 至 2009-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7337128
• 关键词: Alcohols; Alkenes; Alkynes; Antineoplastic Agents; Biological; Biological Factors; Cancer cell line; Carbon; Coupling; Dinophyceae; Evaluation; Exhibits; In Vitro; Macrolides; Malignant Neoplasms; Pliability; Reaction; Relative (related person); Route; Stereoisomer; Structure; Testing; Transition Elements; Ursidae Family; cytotoxic; design; novel; stereochemistry

Amphidinolide N was isolated from the dinoflagellate Amphidinium and bears a unique carbon framework of which the relative and absolute stereochemistry have not been determined. Initial biological screens revealed that it is one of the most cytotoxic compounds ever tested against cancer cell lines; however, its low natural abundance precludes further biological studies. Proposed herein is a first total synthesis of this natural product. A stereodivergent route has been designed to access all conceivable stereoisomers, however by using NMR shift analysis as a guide the structural elucidation of amphidinolide N will be achievable without having to synthesize every possibility. In many cases, asymmetric induction at chiral centers will be controlled by transition metal-catalyzed reactions to offer flexibility in obtaining either absolute configuration. The feasibility of synthesizing the correct stereoisomer of this natural product will also require a concise and convergent route. Hence, the 26-membered macrolide will be simplified to five key fragments of equal complexity and the central step for macrocyclization will feature a novel intramolecular Ru-catalyzed alkene-alkyne coupling between an internal alkyne and an allylic alcohol. This synthesis will enable further evaluation of this molecule as a potential anticancer drug and finally resolve its unknown relative and absolute stereochemistry.

Amphidinolide N是从双鞭毛虫中分离得到的，具有独特的碳结构 其中的相对和绝对立体化学尚未确定。初步生物筛查 显示它是对癌细胞株测试过的最具细胞毒性的化合物之一；然而，它的低 自然资源的丰富妨碍了进一步的生物学研究。在这里提出的是第一次完全合成这个 天然产物。已经设计了一条立体发散路线来获得所有可能的立体异构体， 然而，以核磁共振位移分析为指导，两性内酯N的结构将得到 不需要综合所有的可能性就可以实现。在许多情况下，手性不对称诱导 中心将由过渡金属催化的反应控制，以提供获得绝对 配置。合成这种天然产物的正确立体异构体的可行性还需要 一条简明而汇聚的路线。因此，26元大环内酯将被简化为五个关键片段 同样的复杂性，大环化的中心步骤将以新型分子内Ru催化的为特征 内部炔和烯丙醇之间的烯-炔偶联。这一合成将使进一步 评价该分子作为一种潜在的抗癌药物，并最终解决其未知的亲缘关系和 绝对的立体化学。