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首页> 外文学位 >I. Catalysis of Intra- and Intermolecular Schmidt Reactions. II. Copper-Catalyzed Oxaziridine-Mediated C-H Bond Oxidation. III. Synthesis and Cytotoxic Evaluation of Withalongolide A Analogues.
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I. Catalysis of Intra- and Intermolecular Schmidt Reactions. II. Copper-Catalyzed Oxaziridine-Mediated C-H Bond Oxidation. III. Synthesis and Cytotoxic Evaluation of Withalongolide A Analogues.

机译：I.分子内和分子间施密特反应的催化。二。铜催化的恶唑烷介导的C-H键氧化。三， Withalongolide A类似物的合成和细胞毒性评估。

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The research presented herein describes four separate projects, focusing on synthetic methodology development, discovery of novel cytotoxic agents, and natural product isolation.;Catalysis of Intra- and Intermolecular Schmidt Reactions A method for carrying out the intramolecular Schmidt reaction of alkyl azides and ketones using a substoichiometric amount of catalyst is described. Following extensive screening, the use of the strong hydrogen-bond-donating solvent hexafluoro-2-propanol (HFIP) was found to be consistent with low catalyst loadings, which ranged from 2.5 mol % for favorable substrates to 25 mol % for more difficult cases. Reaction optimization, broad substrate scope, and preliminary mechanistic studies of this improved version of the reaction are discussed. The use of HFIP as the solvent also allowed for the extension of this methodology to intermolecular variants of Schmidt reaction favoring the development of mild, operationally simple, and more efficient protocols, requiring considerably less amounts of acid catalysts for these variants.;Copper-Catalyzed Oxaziridine-Mediated C-(--)H Bond Oxidation. The highly regioand chemoselective oxidation of an activated C-(--)H bond via a copper-catalyzed reaction of oxaziridine is described. The oxidation proceeded with a variety of substrates, primarily comprising of allylic and benzylic examples, as well as one example of an otherwise unactivated tertiary C-(--)H bond. The mechanism of the reaction is proposed to involve single-electron transfer (SET) to the oxaziridines to generate a copper-bound radical anion, followed by hydrogen atom abstraction and collapse to products, with regeneration of the catalyst by a final SET event. The involvement of allylic radical intermediates en route to the product was supported by a radical-trapping experiment with TEMPO.;Synthesis and Cytotoxic Evaluation of Withalongolide A Analogues. The natural product withaferin A exhibits potent antitumor activity and other diverse pharmacological activities. The recently discovered withalongolide A, a C-19 hydroxylated congener of withaferin A, was reported to possess cytotoxic activity against head and neck squamous cell carcinoma (HNSCC). Interestingly, semisynthetic acetylated analogues of withalongolide A were shown to be considerably more cytotoxic than the parent compound. To further explore the structure-(--)activity relationship (SAR), 20 new semisynthetic analogues of this highly oxygenated withalongolide A were designed, synthesized, and evaluated for cytotoxic activity against four different cancer cell lines. A number of derivatives were found to be more potent than the parent compound and withaferin A.;Isolation of Withalongolide O from Physalis longifolia. The SAR analysis of reported bioactive withanolides revealed certain crucial structural requisites for possessing a potent cytotoxic activity. The semisynthesis of a putative unnatural withanolide incorporating all the basic and essential structural features to boost the antiproliferative activity was contemplated. Withaferin A was considered as an appropriate starting material for this purpose. Although the semisynthetic efforts met with failure, it was during the isolation of withaferin A from the crude plant extract that we discovered a novel withanolide, withalongolide O. The structure of withalongolide O was determined using various spectroscopic techniques and subsequently confirmed by X-ray crystallographic analysis. Both withalongolide O and its diacetate exhibited potent cytotoxicity against four different cancer cell lines.
机译：本文介绍的研究描述了四个单独的项目，重点是合成方法学的发展，新型细胞毒剂的发现和天然产物的分离。分子内和分子间施密特反应的催化一种使用叠氮化物和酮进行分子内施密特反应的方法描述了亚化学计量的催化剂。经过广泛的筛选，发现使用强氢键供体溶剂六氟-2-丙醇（HFIP）与低催化剂负载量相一致，催化剂负载量从2.5摩尔％（适合的底物）到25摩尔％（更困难的情况） 。讨论了反应的优化，较宽的底物范围以及对该改进反应形式的初步机理研究。使用HFIP作为溶剂还允许将该方法扩展到Schmidt反应的分子间变体，从而有利于开发温和，操作简单和更有效的方案，这些变体所需的酸催化剂的量要少得多。恶唑烷介导的C-（-）H键氧化。描述了通过铜催化的恶唑烷反应的活化的C-（-）H键的高度区域和化学选择性氧化。氧化反应进行了多种底物的处理，主要包括烯丙基和苄基实例，以及未活化的叔C-（-）H键的一个实例。提出了反应机理，涉及到向恶唑烷的单电子转移（SET），以生成铜键合的自由基阴离子，然后夺取氢原子并坍塌为产物，最终的SET事件使催化剂再生。 TEMPO的自由基捕获实验支持了烯丙基自由基中间体在进入产品过程中的参与； Withalongolide A类似物的合成和细胞毒性评估。带有Aferin A的天然产物具有强大的抗肿瘤活性和其他多种药理活性。据报道，最近发现的withalongolide A（withaferin A的C-19羟基同类物）具有针对头颈部鳞状细胞癌（HNSCC）的细胞毒活性。有趣的是，与阿糖胞苷A的半合成乙酰化类似物显示出比母体化合物明显更高的细胞毒性。为了进一步探讨结构-（-）活性关系（SAR），设计，合成了20种新的高度氧化的阿糖胞苷A半合成类似物，并评估了其对四种不同癌细胞系的细胞毒活性。发现许多衍生物比母体化合物和枯草杆菌肽A更有效。从长叶酸中分离出冬虫草醚O。对已报道的生物活性withanolides的SAR分析显示出具有强大的细胞毒性活性的某些关键结构要求。设想了半合成掺入所有基本和必要结构特征以增强抗增殖活性的非天然withanolide。为此，Withaferin A被认为是合适的原料。尽管半合成的努力失败了，但是在从粗植物提取物中分离枯萎素A的过程中，我们发现了一种新型的枯参碱，即枯萎酚O。枯萎苷O的结构是通过各种光谱技术确定的，随后通过X射线晶体学证实分析。铝箔内酯O及其双乙酸盐均对四种不同的癌细胞系均表现出强大的细胞毒性。

著录项

  • 作者

    Motiwala, Hashim F.;

  • 作者单位

    University of Kansas.;

  • 授予单位 University of Kansas.;
  • 学科 Health Sciences Pharmacy.;Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 462 p.
  • 总页数 462
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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