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）：五种最畅销的药物中有三种含有氟，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，由于缺乏合成方法，在药物支架的中心核上包含多氟化芳基基团是罕见的。目前的选择性单核苷酸方法无法解决这一问题。一个概念上有吸引力的替代方案是利用市售的全氟芳烃，并选择性地减少或取代不需要的氟。本研究的目标是开发合成方法，使全氟芳烃成为合成多氟代药物支架的关键。为了实现这一目标，我们 将通过电子（具体目标1）和亲核加成（具体目标2）活化坚固的全氟芳烃。我们将证明，全氟芳烃可以通过C-F官能化进行许多C-C形成反应。我们还将表明，全氟芳烃也很容易亲核加成，通过开发一些取代反应，导致生物相关的图案。最后，我们将开发新的催化剂，扩大C-F官能化策略。这三个目标相辅相成，协同解决上述问题。在完成这些目标后，预计药物化学家将能够比目前更容易和更多样地获得和利用多氟芳烃。这将通过显着扩大对多氟芳烃的获取并显着减少合成此类分子所需的时间以及因此发现新药所需的时间来积极影响新药的设计。