Environmentally benign reactions for large-scale syntheses of bioactive natural products and their application to drug discovery

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1) Study using hypervalent iodine reagents : Efficient synthetic method of spiro dienone skeletons from phenyl ethers has been developed. The method was applied to the total synthesis of galanthamine and its analogues, in which the compound as a candidate drug for Alzheimer disease was found. Anti-tumor marine natural products, discorhabdins A, E, F, O and prianosin B, were synthesized. Among the synthesized analogues, a stable oxa analogue having almost the same biological activity as unstable discorhabdin A was found. Various transformation reactions activated by KBr in water have been developed. New recyclable and environmentally benign hypervalent iodine reagents have been developed.2) Study using radical reactions : Radical cyclization and efficient synthetic method of thioesters or amides from aldehydes in water have been achieved by the combination of water-soluble radical initiator and surfactant. New radical reaction without toxic Sn compound has been developed.3) Study using … More lipase catalyst : Versatile synthetic methods for chiral quaternary carbons using a new acylating agent, ethoxyvinyl 2-furoate, and lipase. Anti-cancer antibiotics, fredericmycin A, was synthesized in optically active form by this method as a key reaction. This asymmetric synthetic method of chiral quaternary carbons was also applied to concise asymmetric syntheses of the key intermediates for the syntheses of biologically active indole alkaloids. Unprecedented and efficient domino reactions, first optical resolution of alcohol with our acyl reagent and successive intramolecular Diels-Alder reaction, have been developed. These domino reactions were expanded to dynamic kinetic optical resolutions by using originally developed ruthenium catalyst, which does not inhibit the activity of lipase.4) Study using cation species : Efficient and versatile syntheses of various 2,3-disubstituted indole alkaloids have been developed by aromatic Pummerer-type reaction. Aromatic Pummerer-type reaction was also effective for regioselective introduction of carbon nucleophiles to thiophens and furans. Stereoselective rearrangement of 2,3-epoxy-1-alcohol derivatives has been developed to give chiral spiro centers and chiral quaternary carbon centers. The reaction was applied to the asymmetric syntheses of (-)-herbertenediol and (-)-α-herbertenol. Concise asymmetric synthesis of scyphostatin, which is recognized as a lead compound for the treatment such as inflammation and autoimmune disease, has been achieved by the intramolecular haloetherification and deprotection of acetals with TESOTf-base combination developed by us as key reactions. Less