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
• 负责人: Phillip John Milner
• 金额: $ 38.07万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10451724
• 关键词: Anions; Area; Biological; Cell Membrane Permeability; Chemistry; Complex; Corrosives; Development; Elements; Evaluation; Face; Fluorine; Gases; Health; Human; Hydrogen Bonding; Iodides; Laboratories; Medicine; Metabolic; Metals; Molecular; Organic Synthesis; Pattern; Pharmacologic Substance; Porifera; Powder dose form; Preparation; Reaction; Reagent; Research; Temperature; Therapeutic; Transition Elements; Translating; cost; crystallinity; improved; interdisciplinary approach; materials science; metal complex; multidisciplinary; nanomaterials; next generation; prevent; programs; solid state; structural biology; success

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 尽管有数十年的反应发展，但当药物化学家在 制备具有潜在治疗价值的分子。例如，C – H键代替C – F键 在目标分子中可以改善其代谢稳定性，膜渗透性和生物活性，但这是 在实验室中通常无法实现替代。出现此障碍是因为 否则，简单的构件或试剂通常会使它们气体，有毒，腐蚀性或不稳定。尽管 这种“试剂问题”不仅限于有机氟化化学，因此阻止了这一点的重大进展 区域。因此，拟议的研究的总体目标是“驯服”氟化建筑的反应性 块并使它们用于构建复杂的氟化分子。具体而言，提议 多学科计划旨在使员工不溶性多孔纳米材料，通常用作“宿主” 材料科学中的“来宾”分子，以控制荧光剂的反应性。结果 异质物种将充当能够控制释放的储存试剂或 作为“纳米反应器”，促进了毛孔内的新转变。该提议的中心假设 是金属 - 有机框架，是一种相对新的多孔，结晶材料，由有机构建 “接头”和无机“二级建筑单元”是实现此目标的理想平台 无与伦比的结构可可匹配性。该研究目的是PI更广泛的研究计划的一部分，以解锁该计划 金属 - 有机框架在有机合成，医学和结构生物学中应用的潜力。 拟议的研究由三个针对特定挑战的综合项目组成 使用氟化试剂，所有这些试剂都可以转化为涉及非氟化建筑物的应用 块。首先，氟化会降低分子的沸点，使最简单的构件构成 （例如三氟甲基碘化物，CF3I）在室温下气体。通过使用金属有机框架 可逆地将这些气体隔离为固态，药物化学家将能够安全处理它们 粉末。其次，氟化阴离子（例如三氟甲氧化物（CF3O））通常不稳定，其中之一是 最有前途的途径可以在有机合成中利用它们 - 化学计量后期金属的稳定 复合物 - 受到净化，成本和可靠性问题的阻碍。该建议旨在克服这些建议 通过将这些复合物作为可回收金属有机框架“纳米反应器”移动到固态来挑战。 最后，自由基和亲电氟化的构件可能很棘手，并且通常有不希望的 反应性模式。该提案旨在通过建立已知反应性来克服这些局限性 复合物和金属有机框架以高价值以受控方式生成这些物种 中心。总体而言，拟议的研究计划很重要，因为在接下来的五年中 制备以前无法访问的氟化化合物及其作为下一代药物的评估。