RING FRAGMENTATION ROUTES TO BIOACTIVE NATURAL PRODUCTS

这份提案是最初提交的提案的修订版 在“一等奖”计划下。这项研究的总体目标是 探索应变环化合物的基本化学反应能力， 特别是自由基诱导的环氧化物的裂解，并利用 合成几种重要天然产物的化学。这个 建议描述了许多新的和综合有用的发展 基于这种轻而易举的碎裂而形成环的反应。 通过“试点研究”，我们已经证明了这一过程可以 发挥优势构筑有用的双环 化合物。在项目的第一部分，这些化合物的基本化学 将对裂解反应进行研究，以期开发出更好的 对化学的范围和局限性有基本的理解。 将研究基本过程的几个有趣的变化， 包括(A)制备对映体纯化合物的方法， (B)氮杂环丙烷和环丙烷体系的反应性；(C)新方法 和(D)官能化方法 最初的激进站点。 研究工作的重点将放在密钥的应用上 在生物重要化合物的全合成中的反应。在……里面 特别是，我们将利用这个反应序列作为 心脏类固醇洋地黄苷元的高效合成 洋地黄毒素是治疗糖尿病最广泛使用的药物之一 充血性心脏病。然而，这类化合物表现出严重的 毒性，因此非常需要更有效的治疗剂。在……里面 我们的策略是，大部分类固醇骨架将被构建在 通过分子内Diels-Alder反应获得对映体纯品 易得天然产物R-(-)-香芹酮的衍生物。我们的 研究应该引导出一条通向这类化合物的短而一般的路线， 适用于各种潜在活性类似物的合成。我们会 还利用环氧化物裂解化学全合成了 三喹烷天然产物，(-)-Delta9(12)-Capnellene和(+)- 毛状烯，以及含有三环呋喃的萜烯， 从战术上讲，这些合成方法与 而且，除了高效之外，还被设计成 每一个都将提供关于化学反应的洞察力。

This proposal is a revised version of one that was originally submitted under the "FIRST Award" program. The overall objective of this study is to explore the fundamental chemical reactivity of strained ring compounds, particularly the radical-induced fragmentation of epoxides, and to utilize the chemistry for the synthesis of several important natural products. The proposal describes the development of many new and synthetically useful ring-forming reactions that are based on of this facile fragmentation. Through "pilot studies" we have already demonstrated that the process can be exploited to advantage for the construction of useful bicyclic compounds. In the first part of the project, the basic chemistry of these fragmentation reactions will be studied with the aim to develop a better fundamental understanding of the scope and limitation of the chemistry. Several interesting variations of the basic process will be studied, including (a) methods for preparation of enantiomerically pure compounds, (b) the reactivity of aziridine and cyclopropane systems, (c) new methods for generating omicron-quinodimethanes, and (d) methods for functionalizing the initial radical site. The thrust of the research effort will be on the application of the key reaction in the total synthesis of biologically important compounds. In particular, we will utilize this reaction sequence as the key step in an efficient synthesis of the cardiac steroid digitoxigenin, the aglycone of digitoxin, one of the most widely used drugs for the treatment of congestive heart disease. Compounds in this class, however, exhibit severe toxicity, so the need for more effective therapeutic agents is great. In our strategy, the bulk of the steroid skeleton will be constructed in enantiomerically pure form by an intramolecular Diels-Alder reaction of a derivative of the readily available natural product R-(-)-carvone. Our studies should lead to a short, general route to this class of compounds, suitable for the synthesis of various potentially active analogs. We will also utilize the epoxide fragmentation chemistry in a total synthesis of the triquinane natural products, (-)-delta9(12)-capnellene and (+)- hirsutene, as well as the tricyclic furan-containing terpene, furoscrobiculin D. Tactically, these syntheses differ significantly from one another and, in addition to being highly efficient, are designed so that each will provide insight on chemical reactivity.