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: 9326317
• 负责人: Ming-Yu Ngai
• 金额: $ 39.24万
• 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/9326317
• 关键词: Agrochemicals; Biocompatible Materials; Biological; Biological Assay; Bioprobe; Chemical Industry; 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.

项目概要/摘要 含氟分子具有理想的化学、结构、药理和生物学特性 特性，并在制药、农用化学品和材料领域发生了根本性的范式转变 过去几十年的科学研究。值得注意的是，大约 25% 的上市药物和三分之二的药物 2011 年十大最畅销药品以及三分之一表现最好的药品至少含有一种 其结构中含有氟原子。然而，容易引入氟原子或氟化基团，特别是 三氟甲氧基（OCF3）、多氟烷氧基（ORf）和五氟硫基（SF5）基团转化为有机分子 被认为是合成化学领域的一项艰巨挑战。大多数当前的方法要么受到影响 底物范围较差或需要使用剧毒、难以处理和/或热不稳定的试剂。 因此，化工医药行业的需求与国内市场存在较大差距。 当前将氟化基团安装到感兴趣的分子中的策略的效率。我们的长期 目标是通过发明实验室稳定且易于处理的试剂并建立可操作的方法来缩小差距 简单且可扩展的反应，有利于将氟化基团直接掺入复合物中 分子。 在拟议的资助期内，我们将开发一种通用的分子内多氟烷氧基化（ORf） 芳烃和杂芳烃的反应。由于它们普遍存在于具有生物活性的天然产物中， 药物、农用化学品、带有 ORf 基团的芳烃和杂芳烃（例如 OCF3、OCF2H 和 OCF2CF3）将作为从药物化学到所有分子筛选的宝贵构建模块 材料科学。此外，我们还将发明用于后期自由基的新型试剂和反应。 复杂药物和天然药物的三氟甲氧基化 (OCF3) 和五氟磺酰化 (SF5) 产品，这将允许快速测定三氟甲氧基化和五氟磺酰化的生物活性 类似物。这些试剂和合成方法可以最大限度地提高结构多样性，并为 未来理性的物业设计。为了补充这些以多样性为导向的合成方法，我们还将 建立过渡金属催化酚类多氟烷基化反应，实现位点选择性合成 多氟烷氧基化化合物。鉴于氟化基团表现出对生物有利的特性 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、生物探针和显像剂的发现和开发。