Synthesis of Multiply Fluorinated Aromatics

多氟芳烃的合成

• 批准号: 9346628
• 负责人: Jimmie Dean Weaver
• 金额: $ 28.37万
• 依托单位: OKLAHOMA STATE UNIVERSITY STILLWATER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346628
• 关键词: Address; Alkylation; Amino Acids; Attention; Biological; Bromides; Chlorides; Coupling; Drug Industry; Electron Transport; Electrons; FDA approved; Fluorine; Future; Goals; Health; Human; Lead; Left; Libraries; Ligands; Metals; Methods; Mono-S; Oxidation-Reduction; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Reaction; Reagent; Route; Structure; Therapeutic Uses; Time; catalyst; design; functional group; improved; novel; novel therapeutics; nucleophilic addition; public health relevance; scaffold; small molecule

 DESCRIPTION (provided by applicant): Three of the five top-selling drugs contain fluorine and in 2013, 9 of 27 new small molecules approved by the FDA for therapeutic use contained fluorine. Currently, due to a lack of synthetic methods inclusion of multiply fluorinated aryl groups on the central core of a drug scaffold is rare. Ongoing, selective mono- fluorination methods cannot address this issue. A conceptually attractive alternative is to utilize commercially available perfluoroarenes and selectively reduce or substitute the undesired fluorines. The goal of this proposal is develop synthetic methods will allow the perfluoroarenes to serve as linchpins for synthesis of multiply fluorinated drug scaffolds. To realize this goal we will activate the robust perfluoroarenes with an electron (Specific Aim 1) and via nucleophilic addition (Specific Aim 2). We will show that perfluoroarenes can undergo a number of C-C forming reactions that take place via C-F functionalization. We will also show that perfluoroarenes are also quite susceptible to nucleophilic addition by developing a number of substitution reactions that lead to biologically relevant motifs. Finally, we will develop novel catalysts that expand C-F functionalization strategies. The three aims are complimentary and synergistically approach the aforementioned problem. Upon completion of these aims, it is expected that medicinal chemists will be able to access and utilize polyfluorinated arenes with far greater ease and diversity than currently possible. This will positively influence the design o new pharmaceuticals by significantly expanding access to multiply-fluorinated arenes and significantly reducing the time needed to synthesize such molecules and, consequently, the time needed to discover new drugs.

 描述（由申请人提供）：五种最畅销药物中的三种含有氟，2013 年 FDA 批准用于治疗用途的 27 种新小分子中有 9 种含有氟，目前，由于缺乏包含多重氟化的合成方法。药物支架中央的芳基很少见，目前的选择性单氟化方法无法解决这个问题，一种概念上有吸引力的替代方案是利用市售的全氟芳烃和。该提案的目标是开发合成方法，使全氟芳烃能够用作合成多氟化药物支架的林替平。 将通过电子（具体目标 1）和亲核加成（具体目标 2）激活强全氟芳烃。我们将证明全氟芳烃可以通过 C-F 官能化发生许多 C-C 形成反应。通过开发许多导致生物学相关基序的取代反应，也很容易发生亲核加成。最后，我们将开发扩展 C-F 的新型催化剂。这三个目标是互补的并协同解决上述问题，预计药物化学家将能够比目前更容易和更多样化地获取和利用多氟化芳烃。通过显着扩大多氟化芳烃的获取范围并显着减少合成此类分子所需的时间以及因此减少发现新药所需的时间来设计新药物。