INTRAMOLECULAR REDUCTIVE COUPLING REACTIONS

本提案的主要主题是碘化钐（II）（Sm I2）作为有机合成的选择性还原偶联剂的发展。 该提案已组织，以反映当前的三个利益：发展的个人反应，可以促进SmI 2的顺序过程，从简单的基板复杂的分子的有效建设;和应用开发的方法来合成生物相关的分子。酮联烯偶联反应将探讨，因为这个反应的例子很少存在于文献和手性，非外消旋底物的可用性有可能提供一个有用的进入高度官能化，对映体富集的环烷醇。 将对可以进行环化以形成七元环、八元环甚至九元环的底物进行全面检查。 最后，检查的环氧酰基和aziridinyl酰基自由基（或相应的阴离子）的生成由钐2和它们的使用在有机转化将进行。一系列的级联过程已成为研究的目标，这将提供一个有用的和有趣的转换，导致从相对简单的基板相当复杂的产品。因此，提出了各种简单的还原偶联/断裂过程，这将导致中员碳环和杂环的建设。两个对映选择性的全合成建议，将利用钐促进的反应作为一个关键步骤。 第一个是生物活性抗高血压剂变叶菌素的有效合成。 第二种是四环二萜类化合物的合成，其在纳摩尔浓度下抑制糖基磷脂酰肌醇（GPI）锚定。 GPI锚定抑制剂的作用机制的研究可能会导致寄生原生动物感染的治疗。

The primary theme of this proposal is the development of samarium(II) iodide (SmI2) as a selective reductive coupling agent for organic synthesis. The proposal has been organized to reflect three current interests: development of individual reactions that can be promoted by SmI2; sequential processes for the efficient construction of complex molecules from simple substrates; and application of the methods developed to the synthesis of biologically relevant molecules. Ketyl-allene coupling reactions will be explored because few examples of this reaction exist in the literature and the availability of chiral, nonracemic substrates has the potential to provide a useful entry to highly functionalized, enantiomerically enriched cycloalkanols. A comprehensive examination of substrates that can undergo cyclization to form seven-, eight-, and perhaps even nine-membered rings will be undertaken. Finally, an examination of the generation of epoxy acyl- and aziridinyl acyl radicals (or the corresponding anions) by SmI2 and their use in organic transformations will be undertaken. A series of cascade processes has been targeted for study that would provide a useful and interesting transformation leading from relatively simple substrates to reasonably complex products. Thus a variety of simple reductive coupling/fragmentation processes are proposed that would lead to the construction of medium-membered carbocycles and heterocycles. Two enantioselective total syntheses are proposed that will utilize a SmI2-promoted reaction as a key step. The first is an efficient synthesis of the biologically active antihypertensive agent variecolin. The second is a synthesis of a tetracyclic sesterterpenoid that inhibits glycosylphosphatidylinositol (GPI)- anchoring at nanomolar concentrations. The study of the mechanism of action of GPI-anchoring inhibitors may lead to therapies for parasitic protozoan infections.