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 尽管经过几十年的反应发展,药物化学家仍然经常面临合成障碍,当 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、膜通透性和生物活性,但这 在实验室里,通常不可能实现替代。这一障碍的出现是因为氟化 否则,简单的积木或试剂通常会使它们变成气态、有毒、腐蚀性或不稳定。而当 这个“试剂问题”并不局限于有机氟化学,它阻碍了这方面的重大进展。 区域。因此,拟议研究的总体目标是“驯服”含氟建筑的反应性。 并使其能够用于构建复杂的氟化分子。具体地说,建议的 多学科计划的目标是使用不溶的多孔纳米材料,这种材料通常用作 材料科学中的“客体”分子,用于控制氟化剂的反应性。由此产生的 异质物种将充当能够可控地释放存储的试剂或 作为“纳米反应器”,促进其毛孔内的新转变。这项提议的核心假设是 金属-有机骨架,一种相对较新的由有机材料构成的多孔、结晶材料 “链接器”和无机“二次建筑单元”是实现这一目标的理想平台,因为它们 无与伦比的结构可调性。这项研究的目的是PI更广泛的研究计划的一部分,以解锁 金属有机骨架在有机合成、医学和结构生物学中的应用潜力。 拟议的研究由三个综合性项目组成,针对以下具体挑战 使用含氟试剂,所有这些都可以转化为涉及非含氟建筑的应用 街区也是如此。首先,氟化作用降低了分子的沸点,使大多数简单的积木 (如三氟甲基碘、CF3I)气体在室温下。通过使用金属有机骨架来 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。其次,氟化阴离子,如三氟甲基氧化物(CF3O-)通常是不稳定的,其中之一 有机合成中最有前途的途径--化学计量比后过渡金属的稳定化 复合体-由于净化、成本和可靠性方面的考虑而受到阻碍。这项建议旨在克服这些问题 通过将这些络合物转移到固态作为可回收的金属-有机骨架“纳米反应器”,这是一个挑战。 最后,基团和亲电的氟化积木的制备可能很棘手,而且经常会有不受欢迎的 反应模式。这一提议旨在通过建立在分子的已知反应性基础上来克服这些限制。 在高价金属中以受控方式生成这些物种的络合物和金属有机骨架 中锋。总体而言,拟议的研究计划意义重大,因为在未来五年内,它将使 以前难以获得的含氟化合物的制备及其作为下一代药物的评价。

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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