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首页> 外文学位 >Recent advances in indole aryne cycloaddition chemistry. Part I: Total synthesis of (+/-)-cis-trikentrin B. Part II: Investigation into the regioselectivity of 6,7-indole aryne cycloadditions. Part III: Synthesis and reactions of novel tribromoindoles.
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Recent advances in indole aryne cycloaddition chemistry. Part I: Total synthesis of (+/-)-cis-trikentrin B. Part II: Investigation into the regioselectivity of 6,7-indole aryne cycloadditions. Part III: Synthesis and reactions of novel tribromoindoles.

机译：吲哚芳烃环加成化学的最新进展。第一部分：（+/-）-顺式trikentrin B的全合成。第二部分：6,7-吲哚亚芳基环加成反应的区域选择性研究。第三部分：新型三溴吲哚的合成与反应。

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摘要

Since their discovery in the Buszek laboratories in 2007, the indole arynes and their cycloaddition chemistry has demonstrated its significance in achieving the total synthesis of biologically active indole alkaloid natural products such as the trikentrins and herbindoles in a facile manner. The application of 6,7-indole aryne cycloaddition methodology towards the total synthesis of (+/-)-cis-trikentrin B, one of the representative members of the trikentrin family of natural products is described.;The 5,6,7-tribromoindole served as the 6,7-indole aryne precursor which was synthesized via an adapted Leimgruber-Batcho synthetic protocol. The success with achieving annulation at the 6,7-position of the indole nucleus in (+/-)- cis-trikentrin B relied heavily on one crucial question i.e., whether the key intermediate 5,6,7-tribromo-N-TBS-indole would undergo selective metal-halogen exchange at C-7. Gratifyingly the indole underwent selective metal-halogen exchange at C-7 and subsequent elimination to give exclusively the 6,7-indole aryne which underwent Diels-Alder cycloaddition with cyclopentadiene. To complete the synthesis, the remaining unreacted C-5 bromo position was subjected to Stille cross-coupling to install the trans-butenyl side chain at this site.;The original regiochemical observations in 6,7-indole aryne cycloadditions werewere made with N-Me-4-phenyl-6,7-dibromoindole resulting predominantly in the contrasteric regiosiomer.This phenomenon was observed by the virtue of the polarized nature of the 6,7-indole aryne as revealed by computational studies involving ab initio calculations.;In order to probe further into the regioselective cycloadditions of 6,7-indole arynes, a series of 6,7-dibromoindoles were synthesized to investigate the effect of 2-, 3-, 4- and 5-substitution on the regioselectivity of 6,7-indole aryne cycloadditions with 2-tert-butylfuran. The results of this investigation indicated that the degree of polarization of the 6,7-indole aryne bond depends on electronic nature and the positions of the various substituents on the pyrrole and benzene rings of the indole which in turn is responsible for imparting regioselectivity in the 6,7-indole aryne cycloadditions.;The Buszek laboratories have previously demonstrated the exclusive generation of 6,7-indole arynes from 4,6,7- and 5,6,7-tribromoindoles via a remarkable selective metal-halogen exchange at C-7 for use in natural products total synthesis and library development. In connection to these previous efforts, synthesis of the 4,5,6- and 4,5,7-tribromoindoles, the remaining two members of the tribromoindole series, is described. Treatment with n-BuLi followed by quenching with various electrophiles reveals a strong preference for initial metal-halogen exchange at the C-7 position in the case of 4,5,7-tribromoindoles, and at the C-4 position in the case of the 4,5,6-tribromoindole scaffold. Exclusive generation of the 4,5-indole aryne in either system followed by cycloaddition with 2-tert-butylfuran shows only a modest regiochemical preference in the cycloadducts. Finally, the 4,5-benzannulated scaffolds were subjected to Negishi cross-coupling with dimethyl and diethylzinc to demonstrate the proof-of-concept for library development.
机译：自从2007年在Buszek实验室发现它们以来，吲哚芳烃及其环加成化学已显示出其在以简便的方式完全合成具有生物活性的吲哚生物碱天然产物（如三环酮和除草吲哚）中的重要性。描述了6,7-吲哚芳烃环加成法在全合成（+/-）-顺式trikentrin B（天然产物的trikentrin家族的代表成员之一）中的应用。; 5,6,7-三溴吲哚是6,7-吲哚芳烃的前体，它是通过改编的Leimgruber-Batcho合成规程合成的。在（+/-）-顺式-trikentrin B中吲哚核的6,7-位实现成环的成功很大程度上取决于一个关键问题，即关键的中间体5,6,7-三溴-N-TBS -吲哚将在C-7处进行选择性的金属-卤素交换。令人满足的是，吲哚在C-7进行了选择性的金属-卤素交换，随后被消除，仅得到了6,7-吲哚芳烃，该芳烃与环戊二烯进行了狄尔斯-阿尔德环加成反应。为了完成合成，将剩余的未反应的C-5溴位置进行Stille交叉偶联，以在该位点安装反丁烯基侧链。;用N-进行了6,7-吲哚芳烃环加成反应的原始区域化学观察。 Me-4-苯基-6,7-二溴吲哚主要产生于对映体区域异构体中，这种现象是通过6,7-吲哚亚芳基的极化性质而观察到的，这是由涉及从头算的计算研究揭示的;为进一步研究6,7-吲哚芳烃的区域选择性环加成反应，合成了一系列6,7-二溴吲哚，以研究2-，3-，4-和5-取代对6,7-吲哚的区域选择性的影响。吲哚亚芳基与2-叔丁基呋喃的环加成反应。该研究的结果表明，6，7-吲哚芳基键的极化程度取决于电子性质以及吲哚的吡咯和苯环上的各种取代基的位置，这进而赋予了该区域内的区域选择性。 6,7-吲哚芳烃的环加成反应。Buszek实验室以前通过在C处进行显着的选择性金属-卤素交换，证明了由4,6,7-和5,6,7-三溴吲哚独家生产的6,7-吲哚芳烃。 -7用于天然产物的全合成和文库开发。结合这些先前的努力，描述了4，5，6-和4，5，7-三溴吲哚的合成，这是三溴吲哚系列的剩余两个成员。用n-BuLi处理，然后用各种亲电试剂淬火表明，对于4,5,7-三溴吲哚，在C-7位置，对于C-4，在C-4位置，强烈倾向于初始金属-卤素交换。 4,5,6-三溴吲哚支架。在这两个系统中独家生成4,5-吲哚芳烃，然后与2-叔丁基呋喃进行环加成反应，仅显示环加合物中适度的区域化学偏好。最后，将4,5-苯甲酸酯支架与二甲基锌和二乙基锌进行Negishi交叉偶联，以证明用于文库开发的概念证明。

著录项

  • 作者

    Nerurkar, Alok.;

  • 作者单位

    University of Missouri - Kansas City.;

  • 授予单位 University of Missouri - Kansas City.;
  • 学科 Analytical chemistry.;Pharmaceutical sciences.;Organic chemistry.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 313 p.
  • 总页数 313
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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