Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry

下一代有机合成C-H官能化方法及其在生物学研究中的应用

基本信息

  • 批准号:
    10625618
  • 负责人:
  • 金额:
    $ 5.84万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-05-01 至 2027-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Catalytic C-H bond functionalization has emerged as a powerful approach in synthetic organic chemistry for the discovery and production of new pharmaceuticals. The next generation C-H bond functionalization methods described in this proposal will enable the rapid assembly of pharmaceutically relevant compounds from simple and readily available inputs. In one program, we will access complex molecular architectures in a single step from simple precursors by the sequential three-component coupling of a C-H bond and two different types of coupling partners. Because many different coupling partners are effective for conventional C-H bond additions to one coupling partner, sequential three-component reactions utilitizing different combinations of coupling partners should provide access to an enormous diversity of motifs relevant to drug and natural product synthesis. Preliminary results obtained with MIRA funding have established the feasibility and utility of this approach. In a second program, we will apply reversible light-mediated C-H bond activation to obtain the most stable from the most accessible heterocycle stereoisomer. Saturated heterocycles such as piperidines, morpholines, piperazines, and lactams are prevalent in drugs and drug candidates but are often most efficiently prepared as the less stable stereoisomer. However, light-mediated processes can enable their highly stereoselective conversion to the more stable stereoisomer as we recently demonstrated for piperidines with MIRA funding. In a third program, we will broadly develop nitrogen heterocycle synthesis by imidoyl C-H functionalization. Imines derived from readily available aldehydes and primary amines are centrally important intermediates in organic synthesis. With MIRA funding, we developed a new approach for the efficient preparation of purine bioisosteres by imidoyl C-H activation of imines followed by in situ annulation with different coupling partners. Purine bioisosteres are found in large numbers of drugs and drug candidates, especially those that interact with biomolecular targets that have purine recognition motifs such as receptors, kinases, and mRNA. We will leverage our methods for the synthesis of purine bioisosteres to target the transcriptome and will apply imidoyl C-H activation and annulation to prepare other important heterocycles. With MIRA funding we advanced new enzyme inhibitor discovery approaches and potent and selective inhibitors to challenging enzyme targets. In proposed research, we will directly apply C-H functionalization to biological inquiry. For example, our methods for the synthesis and elaboration of dihydropyridines enable the rapid preparation of amine-containing structures with three-dimensional display of functionality and stereoselective introduction of multiple stereogenic centers, features increasingly sought after in medicinal chemistry endeavors. These approaches will be applied to the discovery of potent and selective ligands to challenging biomolecular targets relevant to the treatment of unmet medical conditions, including the identification of CNS penetrant, highly selective ligands to aminergic GPCRs.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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JONATHAN A ELLMAN其他文献

JONATHAN A ELLMAN的其他文献

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{{ truncateString('JONATHAN A ELLMAN', 18)}}的其他基金

Chemistry principles applied to the development of new catalytic C-H bond functionalization methods for amine and heterocycle preparation and to the design, synthesis and use of new enzyme inhibitors
化学原理应用于胺和杂环制备的新型催化C-H键功能化方法的开发以及新型酶抑制剂的设计、合成和使用
  • 批准号:
    9910428
  • 财政年份:
    2017
  • 资助金额:
    $ 5.84万
  • 项目类别:
Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry
下一代有机合成C-H官能化方法及其在生物学研究中的应用
  • 批准号:
    10797141
  • 财政年份:
    2017
  • 资助金额:
    $ 5.84万
  • 项目类别:
Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry
下一代有机合成C-H官能化方法及其在生物学研究中的应用
  • 批准号:
    10728428
  • 财政年份:
    2017
  • 资助金额:
    $ 5.84万
  • 项目类别:
Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry
下一代有机合成C-H官能化方法及其在生物学研究中的应用
  • 批准号:
    10602453
  • 财政年份:
    2017
  • 资助金额:
    $ 5.84万
  • 项目类别:
Next-generation C-H functionalization methods for organic synthesis and their applications to biological inquiry
下一代有机合成C-H官能化方法及其在生物学研究中的应用
  • 批准号:
    10406549
  • 财政年份:
    2017
  • 资助金额:
    $ 5.84万
  • 项目类别:
Substrate Activity Screening: A New Approach to Inhibitor Discovery
底物活性筛选:抑制剂发现的新方法
  • 批准号:
    7869641
  • 财政年份:
    2009
  • 资助金额:
    $ 5.84万
  • 项目类别:
600 MHz NMR Spectrometer for Solution-state NMR
用于溶液态 NMR 的 600 MHz NMR 波谱仪
  • 批准号:
    7214940
  • 财政年份:
    2007
  • 资助金额:
    $ 5.84万
  • 项目类别:
Carbon-Carbon Bond Forming Reactions in Via C-H Activation
通过 C-H 活化形成碳-碳键的反应
  • 批准号:
    8776717
  • 财政年份:
    2004
  • 资助金额:
    $ 5.84万
  • 项目类别:
Carbon-Carbon Bond-Forming Reactions Via C-H Activation
通过 C-H 活化形成碳-碳键的反应
  • 批准号:
    6841955
  • 财政年份:
    2004
  • 资助金额:
    $ 5.84万
  • 项目类别:
Carbon-Carbon Bond-Forming Reactions Via C-H Activation
通过 C-H 活化形成碳-碳键的反应
  • 批准号:
    6999333
  • 财政年份:
    2004
  • 资助金额:
    $ 5.84万
  • 项目类别:

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