A Novel Sterodivergent Approach to Amphidinolide N

Amphidinolide N 的一种新的立体发散方法

• 批准号: 7110449
• 负责人: AUDRIS HUANG
• 金额: $ 4.4万
• 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/7110449
• 关键词: alkenes; alkynes; biological products; chemical synthesis; crosslink; cyclization; drug discovery /isolation; lactones; neoplasm /cancer chemotherapy; nuclear magnetic resonance spectroscopy; plant extracts; postdoctoral investigator; ruthenium; stereochemistry; stereoisomer

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：Amphidinolide N是从双鞭毛虫中分离出来的，具有独特的碳骨架，其相对和绝对立体化学尚未确定。初步的生物筛选显示，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，它的低自然丰度阻碍了进一步的生物学研究。本文提出的是该天然产物的首次全合成。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，通过使用核磁共振位移分析作为指导，将可以在不需要合成所有可能性的情况下实现对两性内酯N的结构鉴定。在许多情况下，手性中心的不对称诱导将由过渡金属催化的反应控制，以提供获得这两种绝对构型的灵活性。合成这种天然产物的正确立体异构体的可行性也需要一条简明和收敛的路线。因此，26元大环内酯将被简化为5个同等复杂的关键片段，大环化的中心步骤将是分子内Ru催化的内炔和烯丙醇之间的烯烃-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相对和绝对立体化学。