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

在这项研究中，我们开发了一种新颖的方法，用于用高水平碘制备异环化合物（III）--诱导对苯酚醚衍生物的内分子核反应。这些异环化合物对生物活性化合物的一种重要的合成物是一种重要的。新开发的方法是：（i）使用PhI使用苯酚醚使用烷基氮齐多侧链的奎诺酮衍生物的合成（OCOCF型D23型D2）型D22型D2 （PFA）-Me型D23型D2 SiOTf， （ii） synthesis of sulfur-containing heterocycles from phenol ethers bearing benzylthioalkyl side-chain using PIFA-BF型D23型D2 ·Et型D22型D2 O，and （iii） intramolecular biaryl coupling reaction using PIFA-BF-D23-D2 ·Et-D22-D2O。利用这些反应，我们成功地完成了海洋自然产品的第一个总合成， （±）-马卡鲁瓦明F，它有两种独特的N、S-醋酸酮和潜在的生物活性。Furthermore，我们利用了一条通用合成路线，通过氧化物苯偶联反应，达到了甲氨酰胺衍生物，是一种抗阿尔茨海默氏剂的药物。我们的方法在药物发现方面具有以下的优势; （i）毒性低的高水平碘蛋白试剂的用途;（ii）使用少量和更高的步骤;（iii）对模拟自然产品的可比较性。尽管如此，我们开发了一个用于接近非活性碘的新型激活程序（III）溶液中的各种试剂（从n-己烷到水），通过添加了一种催化剂数量、溴化六甲基三甲基铵（CTAB）。有趣的是，通过将二酰基酸添加到CTAB逆转的微细胞中的催化量，我们实现了使用碘（V）代理将硫氧化物的催化不对称氧化的第一个例子， PhIO D22与中等光学年（最高为72% ee）。这一方法应该成为生物活性化合物的立体声合成的一种新的和强大的工具。

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.