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New Aspect of Organic Reactions Induced by Novel Hypervalent Iodine Compounds and Its Application in the Development of New Drugs

新型高价碘化合物引发有机反应的新视角及其在新药开发中的应用

基本信息

批准号：
10470469
负责人：
KITA Yasuyuki
金额：
$ 6.66万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

In this research, we developed novel methods for preparing heterocyclic compounds using hypervalent iodine (III) -induced intramolecular nucleophilic substitution reactions on phenol ether derivatives. These heterocyclic compounds are important synthons for a variety of biologically active compounds. The newly developed methods are, (i) synthesis of quinone imine derivatives from phenol ethers having alkyl azido side-chain using PhI (OCOCFィイD23ィエD2)ィイD22ィエD2 (PIFA) -MeィイD23ィエD2 SiOTf, (ii) synthesis of sulfur-containing heterocycles from phenol ethers bearing benzylthioalkyl side-chain using PIFA-BFィイD23ィエD2 ・EtィイD22ィエD2 O, and (iii) intramolecular biaryl coupling reaction using PIFA-BFィイD23ィエD2 ・EtィイD22ィエD2 O. Utilizing these reactions we successfully completed the first total synthesis of marine natural product, (±) -makaluvamine F, which has both a unique N, S-acetal skeleton and potent biological activities. Furthermore, we exploited a versatile synthetic route, via oxidative phenolic coupling reaction, to galanthamine derivatives, which are anti-Alzheimer drug candidates. Our methodology has the following advantages for drug discovery; (i) the use of hypervalent iodine reagents with low toxicity, (ii) the use of fewer and higher yielding steps, and (iii) versatility to analogous natural products. Meanwhile, we developed a novel activation procedure for the nearly inactive iodine (III) reagents in a variety of solvents (from n-hexane to water) by the addition of a catalytic amount of cationic surfactant, cetyltrimethylammonium bromide (CTAB). Interestingly, by adding a catalytic amount of the diacyltartaric acid to the CTAB reversed micelles, we achieved the first example of catalytic asymmetric oxidation of sulfides to sulfoxides using iodine (V) reagent, PhIOィイD22ィエD2 with moderate optical yields (up to 72%ee). This method should become a new and powerful tool for the stereoselective synthesis of biologically active compounds.

在本研究中，我们开发了一种新的方法，利用高价碘（III）诱导的分子内亲核取代反应的酚醚衍生物制备杂环化合物。这些杂环化合物是多种生物活性化合物的重要配体。新开发的方法有：（i）用邻苯二甲酰亚胺（PhI）从含烷基叠氮基侧链的酚醚合成醌亚胺衍生物（OCOCF）-（OCOCF（iii）以PIFA-BF二芳基D23二芳基D2 ·Et二芳基D22二芳基D2 O为原料进行分子内联芳基偶联反应。利用这些反应，我们成功地完成了第一个海洋天然产物（±）-makaluvamine F的全合成，它既具有独特的N，S-缩醛骨架，又具有强大的生物活性。此外，我们开发了一种通用的合成路线，通过氧化酚偶联反应，加兰他敏衍生物，这是抗阿尔茨海默病的候选药物。我们的方法在药物发现方面具有以下优势：（i）使用低毒性的高价碘试剂，（ii）使用更少且产率更高的步骤，以及（iii）对类似天然产物的多功能性。同时，我们开发了一种新的活化程序的几乎无活性的碘（III）试剂在各种溶剂（从正己烷到水）通过添加催化量的阳离子表面活性剂，十六烷基三甲基溴化铵（CTAB）。有趣的是，通过将催化量的二酰基酒石酸加入到CTAB反胶束中，我们实现了使用碘（V）试剂PhIO二酰基D22二酰基D2催化不对称氧化硫化物为亚砜的第一个实例，具有中等的光学产率（高达72%ee）。该方法有望成为立体选择性合成生物活性化合物的一种新的有力工具。