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.

在这项研究中，我们开发了利用高价碘 (III) 诱导的苯酚醚衍生物分子内亲核取代反应制备杂环化合物的新方法，这些杂环化合物是多种生物活性化合物的重要合成子。 i) 使用PhI从具有烷基叠氮基侧链的苯酚醚合成醌亚胺衍生物(OCOCF D23 D2) D22 D2 (PIFA) -Me D23 D2 SiOTf、(ii) 使用 PIFA-BF D23D2 ・EtD22D2 O 从带有苄基硫烷基侧链的苯酚醚合成含硫杂环、以及 (iii) 分子内联芳基利用PIFA-BF D23 D2 ・Et D22 D2 O进行偶联反应。利用这些反应，我们成功完成了第一个海洋天然产物(±)-makaluvamine F的全合成，它具有独特的N，S-缩醛骨架和有效的生物活性。此外，我们还开发了一种通过氧化酚偶联反应合成加兰他敏衍生物的通用合成路线，该衍生物是抗阿尔茨海默病的候选药物。该方法对于药物发现具有以下优点：（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。通过添加催化量的阳离子表面活性剂十六烷基三甲基铵，对各种溶剂（从正己烷到水）中几乎不活泼的碘 (III) 试剂进行活化暗示，通过在 CTAB 反相胶束中添加催化量的二酰基酒石酸，我们实现了使用碘 (V) 试剂 PhIO-D22-D2 催化不对称氧化为亚砜的第一个例子，具有中等光学性能。该方法应该成为立体选择性合成的新的强大工具。生物活性化合物。