Novel Strategies and Reagents for Introduction of Fluorinated Groups

项目摘要/摘要 含氟分子具有理想的化学、结构、药理和生物特性 并在制药、农用化学品和材料方面进行了根本性的转变 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3%的 2011年最畅销的十种药物以及三分之一的表现最好的药物中至少含有一种 它们的结构中有氟原子。然而，氟原子或氟化基团的容易引入，特别是 三氟甲氧基(OCF3)、多氟烷氧基(ORF)和五氟硫(SF5)基团，形成有机分子 在合成化学中被认为是一个巨大的挑战。目前的大多数方法要么受到影响，要么 从较差的底物范围或需要使用剧毒、难以操作和/或热不稳定的试剂。 因此，化工和制药行业的需求与 当前将氟化基团安装到感兴趣的分子中的策略的效率。我们的长期合作 目标是通过发明工作台稳定和易于操作的试剂来弥补差距，并建立可操作的 简单且可扩展的反应，便于将氟化基团直接结合到络合物中 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。由于它们在生物活性天然产品中无处不在， 药物、农用化学品、芳烃和杂芳烃(例如OCF3、OCF2H和 OCF2CF3)将成为从药物化学到 材料科学。此外，我们还将发明用于晚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)和五氟磺化(SF5) 产品，这将允许快速测定三氟甲氧基化和五氟磺化的生物活性 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综合方法，我们还将 建立过渡金属催化的苯酚多氟烷基化反应实现中心选择性合成 多氟烷氧基化化合物。由于氟化基团表现出良好的生物性能 应用，我们的研究计划将允许访问和研究新的含氟功能分子以帮助 新药、生物相容材料、生物探针和显像剂的发现和发展。

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.