Novel Strategies and Reagents for Introduction of Fluorinated Groups

引入氟化基团的新策略和试剂

• 批准号: 9893169
• 负责人: Ming-Yu Ngai
• 金额: $ 9.9万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893169
• 关键词: Agrochemicals; Biocompatible Materials; Biological; Biological Assay; Bioprobe; Chemical Industry; Chemical Structure; Chemicals; Complement; Complex; Development; Drug Industry; Dyes; Exhibits; Fluorine; Funding; Future; Goals; Inhalators; Life; Lubricants; Methodology; Methods; Molecular; Natural Products; Pesticides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenols; Polymers; Property; Reaction; Reagent; Research; Site; Structure; Synthesis Chemistry; Transition Elements; Work; analog; design; drug development; drug discovery; drug market; health care quality; imaging agent; improved; insight; interest; invention; materials science; novel; novel strategies; novel therapeutics; programs; propellant; tool

Project Summary/Abstract Fluorine-containing molecules have desirable chemical, structural, pharmacological and biological properties and have made a fundamental paradigm shift in pharmaceutical, agrochemical, and materials science research over the last few decades. Notably, approximately 25% of marketed drugs and three out of the ten top-selling pharmaceuticals in 2011 as well as one-third of the top-performing drugs contain at least one fluorine atom in their structure. However, facile introduction of fluorine atom or fluorinated groups, especially trifluoromethoxy (OCF3), polyfluoroalkoxy (ORf) and pentafluorosulfanyl (SF5) groups, into organic molecules is recognized as a formidable challenge in synthetic chemistry. Most of the current methodologies either suffer from poor substrate scope or require use of highly toxic, difficult-to-handle, and/or thermally labile reagents. Therefore, there is a significant gap between the needs of the chemical and pharmaceutical industry and the efficiency of current strategies for installation of fluorinated groups into molecules of interest. Our long-term goal is to bridge the gap by inventing bench-stable and easy-to-handle reagents and establishing operationally simple, and scalable reactions to facilitate direct incorporation of the fluorinated groups into complex molecules. In the proposed funding period, we will develop a general intramolecular polyfluoroalkoxylation (ORf) reactions of arenes and heteroarenes. Due to their ubiquity in biologically active natural products, pharmaceuticals, and agrochemicals, arenes and heteroarenes bearing ORf groups (e.g. OCF3, OCF2H, and OCF2CF3) will serve as invaluable building blocks for all molecular screenings from medicinal chemistry to materials science. In addition, we will invent novel reagents and reactions for late-stage radical trifluoromethoxylation (OCF3) and pentafluorosulfanylation (SF5) of complex pharmaceuticals and natural products, which will allow rapid biological-activity assays of trifluoromethoxylated and pentafluorosulfanylated analogues. These reagents and synthetic methods could maximize structural diversity and provide insights for future rational property design. To complement these diversity-oriented synthetic approaches, we will also establish transition metal-catalyzed polyfluoroalkylation of phenols to achieve site-selective synthesis of polyfluoroalkoxylated compounds. Given that the fluorinated groups exhibit favorable properties for biological applications, our research program will allow access to and study of new fluorinated functional molecules to aid the discovery and development of new drugs, biocompatible materials, bioprobes, and imaging agents.

项目摘要/摘要 含氟的分子具有理想的化学，结构，药理和生物学 性质，并在药物，农业和材料的基本范式上转变 在过去的几十年中，科学研究。值得注意的是，大约25％的销售药物和三种药物 2011年的十种销量最高的药品以及三分之一的表现最佳药物至少包含一个 氟原子的结构。但是，轻松地引入了氟原子或氟化基团，尤其是 三氟甲氧基（OCF3），多氟烷氧基（ORF）和五氟磺烷基（SF5）组成有机分子 被认为是合成化学中的巨大挑战。当前的大多数方法要么遭受 从较差的底物范围或需要使用剧毒，难以处理和/或热不稳的试剂。 因此，化学和制药行业的需求与 将氟化基安装到感兴趣的分子中的当前策略的效率。我们的长期 目标是通过发明台式稳定且易于手柄的试剂并在操作上建立差距来弥合差距 简单而可扩展的反应，以促进将氟化基团直接掺入复合物中 分子。 在拟议的资金期间，我们将开发一般分子内多氟烷基化（ORF） 竞技场和杂产的反应。由于它们在生物活性天然产品中的普遍性， 药物和农业化学，体现和杂种携带ORF组（例如OCF3，OCF2H和 OCF2CF3）将作为所有分子筛选从药物化学到所有分子筛选的宝贵构件 材料科学。此外，我们将为后期激进的新型试剂和反应发明新颖的试剂和反应 复杂药物和天然 产品，将允许对三氟甲氧基和五氟磺烷基的快速生物活性测定 类似物。这些试剂和合成方法可以最大化结构多样性，并为 未来的理性财产设计。为了补充这些面向多样性的合成方法，我们还将 建立过渡金属催化的苯酚的多氟烷基化，以实现现场选择性的合成 多氟烷氧化化合物。鉴于氟化基团具有生物学的有利特性 应用程序，我们的研究计划将允许访问和研究新的氟化功能分子以帮助 新药，生物相容性材料，生物探测器和成像剂的发现和开发。