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

Cu(II)盐催化串联环化反应的进展及其在生物活性化合物中的应用

基本信息

批准号：
13672206
负责人：
KOU Hiroya
金额：
$ 1.98万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672206/
关键词：
Indole Derivatives Lewis Acid Cu(II) Salts Biologically Active Compounds Cyclization Reactions Hippadine Duocarmycin SA Arborescidine A 2-ethynylaniline copper acetate copper trifluoroacetate copper triflate indole 閉環反応アルカロイド合

项目摘要

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.

首先，研究了基质结构与铜（II）催化剂之间的关系，旨在开发吲哚合成的通用方法。结果表明，该反应可以应用于乙炔末端上的任何底物，即使其具有吸电子性质并且任何官能团对反应没有影响。三种铜盐Cu（OTf）_2、Cu（OAc）_2和Cu（OCHO）_2·xH_2O对磺酰胺类化合物的催化性能较好。然而，对于具有氨基甲酸酯官能团的底物，尚未发现良好的催化剂。另一方面，铜（II）催化的环化反应也可以应用于未取代的苯胺衍生物。Cu（OCOCF_3）_2·xH_2O是该类化合物的最佳催化剂，并发现该盐对多种底物的环化反应都有较好的催化作用。在上述研究过程中，还阐明了铜原子和氧原子之间的键的性质对于催化活性是重要的，例如Cu（OTs）_2和Cu（OMs）_2，那些Cu-O键有点共价键性质，对任何底物都没有任何催化活性，而Cu（OTf）_2，其似乎是离子盐，是良好的催化剂。研究了串联环化反应。首先用KH处理同一分子中含有离去基团的底物，然后用铜盐加热，可以实现串联环化反应，最后将这些反应应用于生物活性化合物的合成。以吲哚合成为关键步骤，成功地合成了希帕定和倍癌霉素SA。Arborescidine A的不对称合成正在进行中。