Catalyst-Controlled, Site-Selective C-H Functionalization of Heterocycles

杂环化合物的催化剂控制、位点选择性 C-H 官能化

基本信息

  • 批准号:
    8341688
  • 负责人:
  • 金额:
    $ 36.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-05 至 2016-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Heterocyclic rings are ubiquitous motifs in drug molecules, and their functionalization primarily relies on ring formation from acyclic precursors or transition metal-catalyzed cross-coupling strategies. We propose to develop site-selective C-H functionalizations of readily available and simple heterocycles, such as pyridine, to access complex heterocycles for the preparation of pharmacologically important molecules. Despite recent developments, transition metal-catalyzed C-H functionalization reactions currently rely on chelating functional groups to direct selective metalation and subsequent functionalization. This directing group strategy is not suitable for pyridine-like heterocyclic substrates due to both the poor-electron nature of the aromatic ring and the strong ?-coordination of the nitrogen lone pair with the metal, which sequesters the catalyst away from target C-H bonds. We therefore propose to develop new and broadly applicable catalysts to answer these widely recognized challenges in the synthetic and medicinal chemical communities. Based on our recently discovered ligand scaffold for Pd-catalyzed C-3-selective C-H olefination of pyridine, we propose to develop more effective Pd- and Cu-based catalysts using two strategies to access a number of novel chemical transformations available for the selective functionalization of nitrogen heterocycles. At the onset of the research program, we will design ligands based on the phenanthroline scaffold to further weaken the ?-coordination of the pyridine nitrogen atom with the metal catalyst and promote the beneficial ?-coordination with the metal that is necessary for selective C-3 functionalization. Additionally, we propose to construct ligand scaffolds that contain a second binding site to recruit the pyridine substrate, thereby increasing the effective molarity of pyridine in the vicinity of the metal and allowing for use of the heterocycle as the limiting reagent. These methods will be applied to prepare diverse analogs of important heterocyclic pharmaceuticals, such as the cancer drug Gleevec, for extensive biological screening in order to develop new anti-cancer agents. PUBLIC HEALTH RELEVANCE: Catalyst-controlled, C-3 selective C-H functionalizations of pyridines and other heterocycles described in this proposal will provide broadly useful tools for the rapid synthesis of drug molecules. The expedient syntheses of diverse heterocyclic pharmaceuticals, including analogs of the cancer drug Gleevec, are outlined. Furthermore, the biological activities of these Gleevec analogs will be screened in a collaborative effort to identiy new anti-cancer drugs.
描述(由申请人提供):杂环是药物分子中普遍存在的基序,其功能化主要依赖于无环前体的成环或过渡金属催化的交叉偶联策略。我们建议开发位置选择性C-H官能化的容易获得的和简单的杂环,如吡啶,以获得复杂的杂环制备的重要分子。尽管最近的发展,过渡金属催化的C-H官能化反应目前依赖于螯合官能团直接选择性金属化和随后的官能化。这种导向基团的策略是不适合吡啶类杂环底物由于两个贫电子性质的芳环和强?-氮孤对电子与金属的配位,其使催化剂与目标C-H键隔离。因此,我们建议开发新的和广泛适用的催化剂,以应对合成和医药化学界广泛认识到的这些挑战。基于我们最近发现的用于Pd催化的吡啶的C3-选择性C-H烯化的配体骨架,我们提出使用两种策略来开发更有效的Pd和Cu基催化剂,以获得许多可用于氮杂环的选择性官能化的新颖化学转化。在研究计划开始时,我们将设计基于菲咯啉支架的配体,以进一步削弱?吡啶氮原子与金属催化剂的配位,并促进有益的?与选择性C-3官能化所必需的金属配位。此外,我们建议构建含有第二个结合位点的配体支架来招募吡啶底物,从而增加吡啶在金属附近的有效摩尔浓度,并允许使用杂环作为限制试剂。这些方法将被应用于制备重要的杂环药物的不同类似物,如抗癌药物格列卫,用于广泛的生物筛选,以开发新的抗癌药物。 公共卫生关系:在该提议中描述的吡啶和其他杂环的催化剂控制的C-3选择性C-H官能化将为药物分子的快速合成提供广泛有用的工具。各种杂环药物,包括类似物的抗癌药物格列卫的方便的合成,概述。此外,这些格列卫类似物的生物活性将被筛选,以确定新的抗癌药物。

项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Jin-Quan Yu其他文献

Jin-Quan Yu的其他文献

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{{ truncateString('Jin-Quan Yu', 18)}}的其他基金

Catalyst-Controlled Site-Selective C-H Functionalizations of Arenes and Heteroarenes
芳烃和杂芳烃的催化剂控制位点选择性 C-H 官能化
  • 批准号:
    10461954
  • 财政年份:
    2012
  • 资助金额:
    $ 36.01万
  • 项目类别:
Catalyst-Controlled Site-Selective C-H Functionalizations of Arenes and Heteroarenes
芳烃和杂芳烃的催化剂控制位点选择性 C-H 官能化
  • 批准号:
    10657626
  • 财政年份:
    2012
  • 资助金额:
    $ 36.01万
  • 项目类别:
Catalyst-Controlled, Site-Selective C-H Functionalization of Heterocycles
杂环化合物的催化剂控制、位点选择性 C-H 官能化
  • 批准号:
    8539807
  • 财政年份:
    2012
  • 资助金额:
    $ 36.01万
  • 项目类别:
Catalyst-Controlled Site-Selective C-H Functionalizations of Arenes and Heteroarenes
芳烃和杂芳烃的催化剂控制位点选择性 C-H 官能化
  • 批准号:
    10254416
  • 财政年份:
    2012
  • 资助金额:
    $ 36.01万
  • 项目类别:
Catalyst-Controlled, Site-Selective C-H Functionalization of Heterocycles
杂环化合物的催化剂控制、位点选择性 C-H 官能化
  • 批准号:
    8704957
  • 财政年份:
    2012
  • 资助金额:
    $ 36.01万
  • 项目类别:
Ligand-Promoted Enantioselective C-H Activation Reaction
配体促进的对映选择性 C-H 活化反应
  • 批准号:
    10439915
  • 财政年份:
    2008
  • 资助金额:
    $ 36.01万
  • 项目类别:
Ligand-Promoted Enantioselective C-H Activation Reaction
配体促进的对映选择性 C-H 活化反应
  • 批准号:
    10651648
  • 财政年份:
    2008
  • 资助金额:
    $ 36.01万
  • 项目类别:
Development of carboxyl- and amide-directed C-H activation/C-C coupling reactions
羧基和酰胺定向的 C-H 活化/C-C 偶联反应的开发
  • 批准号:
    8073652
  • 财政年份:
    2008
  • 资助金额:
    $ 36.01万
  • 项目类别:
Ligand-Promoted Enantioselective C-H Activation Reaction
配体促进的对映选择性 C-H 活化反应
  • 批准号:
    10299074
  • 财政年份:
    2008
  • 资助金额:
    $ 36.01万
  • 项目类别:
Ligand-promoted Enantioselective and Remote C-H Activation Reactions
配体促进的对映选择性和远程 C-H 激活反应
  • 批准号:
    8691885
  • 财政年份:
    2008
  • 资助金额:
    $ 36.01万
  • 项目类别:

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