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

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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.