A Novel Sterodivergent Approach to Amphidinolide N

描述（由申请人提供）：Amphidinolide N是从双鞭毛藻Amphidinium中分离出来的，具有独特的碳框架，其相对和绝对立体化学尚未确定。最初的生物筛选显示，它是迄今为止针对癌细胞系测试过的最具细胞毒性的化合物之一；然而，其天然丰度较低，阻碍了进一步的生物学研究。本文首次提出了这种天然产物的全合成。已经设计了一种立体发散的途径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，可以实现两萜内酯N的结构解析，而不必合成每一种可能性。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还需要一条简洁和收敛的路线。因此，26元大环内酯将被简化为5个同样复杂的关键片段，而大环化的核心步骤将是在分子内钌催化的内炔和烯丙醇之间的烯-炔偶联。该合成将有助于进一步评价该分子作为潜在的抗癌药物，并最终解决其未知的相对和绝对立体化学。

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.