Development of Tandem Cyclization Reactions Catalyzed by Cu(II) Salts and Its Applications toward Biologically Active Compounds

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At first, the relationships between the substrate(s) structure and the copper(II) catalyst(s) were studied with the aim of developing general methods for indole syntheses. As a result, it was shown that this reaction could be applied to the any substrates on the acetylene terminal, even if that had an electron withdrawing nature and the any functional groups did not affect for the reactions. Three Kinds of copper salts, namely, Cu(OTf)_2, Cu(OAc)_2, and Cu(OCHO)_2・xH_2O were found to be excellent catalysts for sulfonamide substrates. However, good catalysts had not been found for the substrates having carbamate functional group, yet. On the other hand, copper(II) catalyzed cyclization reaction could be also applied toward unsubstituted aniline derivatives. For this compounds, Cu(OCOCF_3)_2・xH_2O was a best catalyst and it was found that this salt could catalyze the cyclization reaction for wide variety substrates. During the investigation described above, it was also clarified that the nature of the bond between copper atom and oxygen atom was important for the catalytic activities, e.g. Cu(OTs)_2 and Cu(OMs)_2, those Cu-O bond is somewhat covalent bond nature did not have any catalytic activities toward any substrates, whereas Cu(OTf)_2, which seems to be an ionic salt was a good catalyst.Next, tandem cyclization reactions were investigated. The tandem cyclization reactions could be realized by treating the substrates, which have the leaving group in the same molecules, first with KH, then heated with copper(II) salt.Finally, these reactions were applied to the syntheses of biologically active compounds. The formal synthesis of hippadine and duocarmycin SA were succeeded by using the indole synthesis as key steps. Asymmetric synthesis of arborescidine A is in progress.