A Cascade Reaction to Synthesize Ladder Polyethers with 1,3 Diaxial Methyl Groups

描述（由申请人提供）：虽然船用梯状聚醚是剧毒化合物，但它们也具有抗真菌和抗癌特性。这些化合物的生物合成被认为是通过环氧化物打开级联反应进行的，并且已经开发了一些仿生反应来合成这些分子的部分。一般来说，级联反应是一系列连续的化学反应，通过活性中间体进行，并在一个连续的过程中产生多个新键。这些反应允许快速创建分子复杂性，并提供比以迭代方式构建分子更有效的合成路线。特别是，本提案中描述的级联反应将使具有1,3-二轴甲基的熔融聚醚环体系得以合成，这是许多阶梯聚醚中存在的基序。尽管这种基序在这些化合物中普遍存在，但没有报道级联反应产生含有这种取代模式的环。本提案还描述了该级联反应在合成部分短链F和其他几种海洋阶梯聚醚中的应用。Brevisulcenal F是一种海洋阶梯聚醚天然产物，1998年在新西兰海岸被确定为有害藻华（HAB）的组成部分。它是已分离的最大和最有毒的海洋聚醚之一。因此，它的合成将为研究其独特的生物活性和确定其治疗疾病的可能应用提供材料。重要的是，甘比罗是一种相关的阶梯聚醚，已被用作化学探针来研究与阿尔茨海默病分子基础相关的受体。本文提出了一种短链F- d环和F- i环的合成策略

DESCRIPTION (provided by applicant): Although marine ladder polyethers are extremely toxic compounds, they are also known to have antifungal and anticancer properties. The biosynthesis of these compounds is proposed to occur via an epoxide-opening cascade reaction, and several biomimetic reactions have been developed to synthesize portions of these molecules. In general, a cascade reaction is a consecutive series of chemical reactions that proceed via reactive intermediates and create multiple new bonds in one sequential process. These reactions allow for the rapid creation of molecular complexity and provide a more efficient synthetic route than building a molecule in an iterative fashion. In particular, the cascade reaction described in this proposal will enable the synthesis of fused polyether ring systems with 1,3-diaxial methyl groups, a motif that is present in many ladder polyethers. Despite the prevalence of this motif in these compounds, no cascade reactions have been reported that create rings containing this substitution pattern. This proposal also describes the application of this cascade reaction to the synthesis of a portion of brevisulcenal F and several other marine ladder polyethers. Brevisulcenal F is a marine ladder polyether natural product that was identified as a component of a harmful algal bloom (HAB) off the coast of New Zealand in 1998. It is one of the largest and most toxic marine polyethers that has been isolated. Therefore, its synthesis would provide material to study its unique bioactivity and determine possible applications for treating disease. Importantly, gambierol, a related ladder polyether, has been used as a chemical probe to study receptors implicated in the molecular basis of Alzheimer's disease. In this proposal, a strategy for the synthesis of the B-D and F-I rings of brevisulcenal F is outlined in which several rings are created iteratively, and the cascade process is then applied to the synthesis of the remaining rings. A similar strategy is presented for portions of maitotoxin, gambierol, gambieric acid A, and brevetoxin B. It is expected that the success of this proposal will set the stage for the total synthesis of these molecules and provide material to study their mechanisms of action.