Synthesis of Multiply Fluorinated Aromatics

多氟芳烃的合成

• 批准号: 9116911
• 负责人: Jimmie Dean Weaver
• 金额: $ 28.39万
• 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/9116911
• 关键词: Address; Alkylation; Amino Acids; Attention; Bromides; Chloride Ion; Chlorides; Coupled; Coupling; Drug Industry; Electron Transport; Electrons; FDA approved; Figs - dietary; Fluorine; Future; Goals; Health; Human; Lead; Left; Libraries; Ligands; Metals; Methods; Mole the mammal; Mono-S; Oxidation-Reduction; Partner in relationship; Pattern; Pharmaceutical Preparations; Pharmacologic Substance; Protons; Reaction; Reagent; Route; Structure; Therapeutic Uses; Time; catalyst; design; improved; novel; novel therapeutics; nucleophilic addition; 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.