INTRAMOLECULAR REDUCTIVE COUPLING REACTIONS

本提案的主要主题是发展碘化钐（SmI2）作为有机合成的选择性还原偶联剂。该提案的组织反映了三个当前的兴趣：SmI2可以促进个体反应的发展；从简单底物高效构建复杂分子的顺序过程；并将这些方法应用于生物相关分子的合成。由于文献中很少有这种反应的例子，并且手性、非外消旋底物的可用性有可能为高功能化、对映体富集的环烷醇提供有用的入口，因此将探讨酮-烯偶联反应。我们将对可以环化形成七元环、八元环甚至九元环的底物进行全面的研究。最后，对sm2生成的环氧酰基和氮基酰基自由基（或相应的阴离子）及其在有机转化中的应用进行了研究。一系列的级联过程已经成为研究的目标，这些过程将提供从相对简单的底物到相当复杂的产品的有用和有趣的转化。因此，提出了多种简单的还原偶联/裂解过程，这些过程将导致构建中元碳环和杂环。提出了两种对映选择性全合成，将利用smi2促进反应作为关键步骤。第一个是生物活性抗高血压药变菌素的有效合成。第二种是合成一种抑制糖基磷脂酰肌醇（GPI）在纳摩尔浓度下锚定的四环酯萜。gpi锚定抑制剂的作用机制的研究可能会导致寄生虫原虫感染的治疗。

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.