BIORELEVANT TOTAL SYNTHESIS OF THE ELEUTHEROBIN CORE

本研究的主要目的是通过一种高效且具有生物学相关性的途径构建这种极有效的抗肿瘤海洋产物。伊柳红素和紫杉醇与迪德莫内酯和埃波霉素具有共同的作用机制和微管蛋白结合域，这一事实表明，尽管这些抗癌药物在结构上有很大的不同，但它们在结合位点上的形式相似。结构（键）重组可提供活性形式。这种重排是否发生在体内或可以证明是合成有用的是要提出的重要问题，并且包括所提议的合成的关键特征。这个想法设想的重组包括一种新的碎片化。准备施工的基材，适当的测试碎片也将从这个计划流动。其他有趣的化学问题探讨了相关的环内功能性rommp相互作用，包括氧化还原途径和烯酮的立体选择性异构化，以及在分子间相互作用中施加这种立体控制（例如，使用“baylis - hillman”反应），这些相互作用与上述仿生重排中活性位点的拟议作用有关。整个方法预计将在竞争性的15-20个步骤内完成，还应通过其中间体和容易衍生的类似物（特别是硫醚和氮杂醚）提供重要的SAR信息，提供快速获取briarellins和asbstinins（相关的生物活性二萜）的方法，并提供一种新的裂解方法来获得中环。

This total synthesis of the eleutherobin core proposes, as its main objective, to construct this extremely potent antitumor marine product by an efficient and biologically relevant route. The fact that eleutherobin and taxol share a common mechanism of action and tubulin binding domain with discodermolide and the epothilones suggests the possibility that, although structurally quite different, these anticancer agents each achieve similar forms at the binding site. Structural (bond) reorganization may furnish the active form. Whether such rearrangement occurs in vivo or can be shown to be synthetically useful are important questions to ask and comprise a key feature of the proposed synthesis. Reorganizations envisioned in this idea include a novel fragmentation. Ready construction of substrates appropriate to test the fragmentation will also flow from this plan. Other interesting chemical questions asked explore pertinent intraannular functional romp interactions, including redox pathways and stereoselective isomerization of enones, as well as exerting such stereocontrol in an intermolecular interaction (for example, using a "Bayliss-Hillman" reaction) related to a proposed role of the active site in the aforementioned biomimetic rearrangement. The overall approach, which projects completion in a competitive 15-20 steps, should also supply important SAR information by way of its intermediates and easily derived analogues (especially thio- and aza-ethers), afford rapid access to the briarellins and asbestinins (related, bioactive diterpenes), and provide a novel fragmentation methodology to afford medium rings.