A Total Synthesis of Gambierol Using an Epoxide-Opening Cascade Approach

描述(由申请人提供)：海洋阶梯聚醚，包括冈比亚醇，是许多有害藻华的有毒成分，称为赤潮事件。这些强效毒素只能从它们的自然来源中分离出少量，只有在实现它们的全合成之后，才能对它们的生物活性进行研究。与其他几种激活电压门控钠离子通道的海洋梯形聚醚不同，甘比色罗已被证明能抑制小鼠味觉细胞的电压门控钾离子通道(Kv通道)。KV通道阻滞剂在治疗心律失常、中枢神经系统疾病和作为免疫抑制剂方面具有潜在的治疗作用。此外，梯形聚醚及其衍生物已被用作分子探针来阐明电压门控离子通道的结构和功能，最终导致治疗药物的改进设计。拟议的海洋梯形聚醚冈比亚醇的全合成利用了无直接基团的模板化环氧化物级联反应，该反应有可能简化毒素的合成。Jamison小组最近在简化的体系中展示了这种方法的成功，但到目前为止，它还没有被用于海洋聚醚的全合成。改善对天然产物和合成衍生物的获取将使进一步的生物学研究成为可能，并使人们更好地了解离子通道的结构和功能。海洋梯形聚醚的标志性结构特征包括一系列在聚醚骨架中具有C-C-O(碳-碳-氧)连接性的SYN/TRAN/SYN稠合环醚，无论中间环大小如何。一种解释这些结构特征的生物合成假说涉及聚烯烃的环氧化，然后是环氧化物开级联，在一步中形成所有的梯环。在全合成的背景下，成功地展示了环氧化物开放级联反应，将为这一生物合成假说提供额外的实验支持。与公众健康相关：海洋阶梯聚醚毒素是红潮事件期间食用鱼类和贝类造成的神经毒性影响的原因。其中一种毒素，冈比亚醇，已被证明能抑制某些离子通道。简明的全合成冈比亚红色素将提供足够数量的天然毒素及其合成衍生物，以便进行进一步的生物学研究。加深对离子通道结构和功能的了解可能会导致心律失常和中枢神经系统疾病的治疗。

DESCRIPTION (provided by applicant): Marine ladder polyethers, including gambierol, are the toxic constituents in many harmful algal blooms known as red tide events. These potent toxins can only be isolated in small quantities from their natural sources and the study of their biological activity could only be undertaken once their total synthesis was achieved. Unlike several other marine ladder polyethers which activate voltage-gated sodium ion channels, gambierol has been shown to inhibit voltage-gated potassium ion channels (Kv channels) in mouse taste cells. Kv channel blockers are potential therapeutic agents in the treatment of arrhythmia, diseases of the central nervous system, and as immunosuppressants. In addition, ladder polyethers and their derivatives have found use as molecular probes to elucidate the structure and function of voltage-gated ion channels, which ultimately leads to the improved design of therapeutic agents. The proposed total synthesis of the marine ladder polyether gambierol takes advantage of a directing group-free templated epoxide-opening cascade reaction that has the potential to streamline the synthesis of the toxin. The Jamison group has recently demonstrated the success of this method in simplified systems, but to date it has not been exploited in the total synthesis of a marine polyether. Improved access to the natural product and synthetic derivatives will enable further biological study and lead to a greater understanding of ion channel structure and function. The hallmark structural features of marine ladder polyethers include a series of syn/trans/syn fused cyclic ethers possessing C-C-O (carbon-carbon-oxygen) connectivity throughout the polyether framework, regardless of the intermediary ring size. One biosynthetic hypothesis that accounts for these structural features involves the epoxidation of a polyolefin, followed by an epoxide-opening cascade to form all of the ladder rings in a single step. The successful demonstration of an epoxide-opening cascade within the context of a total synthesis would additionally provide experimental support for this biosynthetic hypothesis. PUBLIC HEALTH RELEVANCE: Marine ladder polyether toxins are responsible for the neurotoxic effects resulting from the consumption of fish and shellfish during red tide events. One of these toxins, gambierol, has been shown to inhibit certain ion channels. A concise total synthesis of gambierol will provide sufficient quantities of the natural toxin and its synthetic derivatives to enable further biological study. An increased understanding of ion channel structure and function could lead to treatments for arrhythmia and disorders of the central nervous system.