Novel Strategies and Reagents for Introduction of Fluorinated Groups

项目概要/摘要 含氟分子具有理想的化学、结构、药理学和生物学性质， 在制药、农用化学品和材料领域， 科学研究在过去的几十年里。值得注意的是，大约25%的上市药物和三分之一的 2011年10种最畅销的药物以及三分之一的表现最好的药物至少含有一种 氟原子在其结构中。然而，容易引入氟原子或氟化基团，特别是 三氟甲氧基（OCF 3）、多氟烷氧基（ORf）和五氟硫烷基（SF 5）基团，转化为有机分子 被认为是合成化学中的一个巨大挑战。目前的大多数方法要么受到 或需要使用高毒性、难以处理和/或热不稳定的试剂。 因此，在化学和制药工业的需求与 将氟化基团安装到感兴趣的分子中的当前策略的效率。我们的长期 我们的目标是通过发明实验室稳定和易于操作的试剂， 简单的和可扩展的反应，以促进氟化基团直接结合到络合物中， 分子。 在建议的资助期内，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物中的普遍存在， 药物和农用化学品、带有ORf基团的芳烃和杂芳烃（例如OCF 3、OCF 2 H和 OCF 2CF 3）将作为从药物化学到 材料科学此外，我们将发明新的试剂和反应，为后期自由基 三氟甲氧基化（OCF 3）和五氟硫烷基化（SF 5）的复杂药物和天然 产品，这将允许快速生物活性测定三氟甲氧基和五氟硫烷基 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，并提供见解， 未来的理性设计为了补充这些面向多样性的综合方法，我们还将 建立了过渡金属催化酚类多氟烷基化反应， 多氟烷氧基化化合物。考虑到氟化基团表现出有利的生物特性， 应用，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、生物探针和成像剂的发现和开发。

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.