Taming Fluorine: Metal-Organic Frameworks for the Heterogeneous Delivery of Fluorinated Building Blocks

驯服氟:用于氟化构件异质输送的金属有机框架

基本信息

  • 批准号:
    10225599
  • 负责人:
  • 金额:
    $ 38.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary Despite decades of reaction development, medicinal chemists still frequently face synthetic barriers when preparing molecules with potential therapeutic value. For example, the substitution of C–H bonds for C–F bonds in a target molecule can improve its metabolic stability, membrane permeability, and biological activity, but this substitution is often impossible to realize in the laboratory. This obstacle arises because the fluorination of otherwise simple building blocks or reagents generally renders them gaseous, toxic, corrosive, or unstable. While this “reagent problem” is not limited to organofluorine chemistry, it has prevented significant advances in this area. Therefore, the overall objective of the proposed research is to “tame” the reactivity of fluorinated building blocks and enable their use for the construction of complex fluorinated molecules. Specifically, the proposed multidisciplinary program aims to employ insoluble porous nanomaterials, which commonly serve as “hosts” for “guest” molecules in materials science, to control the reactivity of fluorinating agents. The resulting heterogeneous species will function as “nanovessels” capable of controllably releasing the stored reagents or as “nanoreactors” that facilitate new transformations within their pores. The central hypothesis of this proposal is that metal–organic frameworks, a relatively new class of porous, crystalline materials constructed from organic “linkers” and inorganic “secondary building units,” are the ideal platform to achieve this objective due to their unparalleled structural tunability. This research aim is part of the PI’s broader research program to unlock the potential of metal–organic frameworks for applications in organic synthesis, medicine, and structural biology. The proposed research is composed of three comprehensive projects that target specific challenges of working with fluorinated reagents, all of which can be translated to applications involving non-fluorinated building blocks as well. First, fluorination depresses the boiling point of molecules, rendering most simple building blocks (such as trifluoromethyl iodide, CF3I) gases at room temperature. By using metal–organic frameworks to reversibly sequester these gases into the solid state, medicinal chemists will be able to safely handle them as powders. Second, fluorinated anions such as trifluoromethoxide (CF3O–) are typically unstable, and one of the most promising avenues to utilize them in organic synthesis – stabilization in stoichiometric late transition metal complexes – is hindered by purification, cost, and reliability concerns. This proposal aims to overcome these challenges by moving these complexes to the solid state as recyclable metal–organic framework ”nanoreactors.” Last, radical and electrophilic fluorinated building blocks can be tricky to prepare and often have undesirable reactivity patterns. This proposal aims to overcome these limitations by building on known reactivity in molecular complexes and metal–organic frameworks to generate these species in controlled fashion at high-valent metal centers. Overall, the proposed research program is significant because over the next five years it will enable the preparation of previously inaccessible fluorinated compounds and their evaluation as next-generation medicines.
项目摘要 尽管反应发展了几十年,药物化学家仍然经常面临合成障碍, 制备具有潜在治疗价值的分子。例如,C-H键取代C-F键 可以改善其代谢稳定性、膜渗透性和生物活性,但这 在实验室中通常不可能实现替代。这一障碍的出现是因为 否则简单的结构单元或试剂通常使它们变成气态、有毒、腐蚀性或不稳定。而 这种“试剂问题”并不局限于有机氟化学, 区因此,拟议研究的总体目标是“驯服”含氟建筑的反应性 嵌段,并使它们能够用于构建复杂的氟化分子。具体而言,建议 一个多学科的计划旨在采用不溶性多孔纳米材料,通常作为“主机”, 材料科学中的“客体”分子,用于控制氟化剂的反应性。所得 异质物质将起到“纳米容器”的作用,其能够可控地释放储存的试剂, 作为“纳米反应器”,促进其孔隙内的新转化。这项提议的核心假设是 是金属有机框架,一种相对较新的多孔晶体材料,由有机 “连接物”和无机“二级结构单元”是实现这一目标的理想平台, 无与伦比的结构可调性。这项研究目标是PI更广泛的研究计划的一部分, 金属有机框架在有机合成、医学和结构生物学中的应用潜力。 拟议的研究由三个综合项目组成,这些项目针对以下方面的具体挑战: 使用氟化试剂,所有这些都可以转化为涉及非氟化建筑的应用 块也是。第一,苯并咪唑降低了分子的沸点, (such作为三氟甲基碘,CF 3 I)气体。通过使用金属有机框架, 可逆地将这些气体隔离成固态,药物化学家将能够安全地处理它们, 粉末.第二,氟化阴离子如三氟甲氧基(CF 3 O-)通常是不稳定的,并且氟化阴离子中的一种是不稳定的。 在有机合成中利用它们的最有前途的途径--在化学计量的后过渡金属中的稳定化 复合物-受到纯化、成本和可靠性问题的阻碍。该提案旨在克服这些 通过将这些复合物作为可回收的金属有机框架“纳米反应器”转移到固态, 最后,自由基和亲电子氟化结构单元可能难以制备,并且通常具有不期望的性能。 反应模式该提议旨在通过建立在分子生物学中已知的反应性来克服这些限制。 络合物和金属-有机框架以在高价金属下以受控方式产生这些物质 中心.总的来说,拟议的研究计划是重要的,因为在未来五年内,它将使 制备以前无法获得的氟化化合物,并将其作为下一代药物进行评估。

项目成果

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Phillip John Milner其他文献

Phillip John Milner的其他文献

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{{ truncateString('Phillip John Milner', 18)}}的其他基金

Taming Fluorine: Metal-Organic Frameworks for the Heterogeneous Delivery of Fluorinated Building Blocks
驯服氟:用于氟化构件异质输送的金属有机框架
  • 批准号:
    10798398
  • 财政年份:
    2020
  • 资助金额:
    $ 38.07万
  • 项目类别:
Taming Fluorine: Metal-Organic Frameworks for the Heterogeneous Delivery of Fluorinated Building Blocks
驯服氟:用于氟化构件异质输送的金属有机框架
  • 批准号:
    10671605
  • 财政年份:
    2020
  • 资助金额:
    $ 38.07万
  • 项目类别:
Taming Fluorine: Metal-Organic Frameworks for the Heterogeneous Delivery of Fluorinated Building Blocks
驯服氟:用于氟化构件异质输送的金属有机框架
  • 批准号:
    10451724
  • 财政年份:
    2020
  • 资助金额:
    $ 38.07万
  • 项目类别:
Taming Fluorine: Metal-Organic Frameworks for the Heterogeneous Delivery of Fluorinated Building Blocks
驯服氟:用于氟化构件异质输送的金属有机框架
  • 批准号:
    10029224
  • 财政年份:
    2020
  • 资助金额:
    $ 38.07万
  • 项目类别:

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