A Novel Stereodivergent Approach to Amphidinolide N & the Total Synthesis

前沟藻N是从甲藻前沟藻中分离出来的，具有独特的碳骨架 其相对和绝对立体化学尚未确定。初步生物筛选 显示它是有史以来针对癌细胞系测试的最具细胞毒性的化合物之一;然而，其低 自然资源丰富，无法进行进一步的生物学研究。本文提出的是该化合物的第一全合成。 天然产物设计了一种立体分散剂途径以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，将对氨端内酯N进行结构解析 不需要综合所有的可能性。在许多情况下，在手性上的不对称诱导 中心将通过过渡金属催化反应来控制，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 一条简洁而收敛的路线。因此，26元大环内酯将被简化为五个关键片段 的同等复杂性和大环化的中心步骤将具有一种新的分子内钌催化 内炔和烯丙醇之间的烯烃-炔偶联。这一综合将使进一步 评估这种分子作为一种潜在的抗癌药物，并最终解决其未知的相对， 绝对立体化学

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.