Organofluorine Chemistry: New Synthetic Methods, New Reactivity and Novel Applications

有机氟化学：新合成方法、新反应性和新应用

• 批准号: RGPIN-2015-04664
• 负责人: Paquin, JeanFrançois
• 金额: $ 4.3万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613095
• 关键词: Organofluorine; Chemistry; New; Synthetic; Methods

The unique properties of the fluorine atom make it significant in medicinal, agrochemical, and material sciences. Industry sources estimate that as many as 30-40% of agrochemicals and 20% of pharmaceuticals on the market contain fluorine. Fluorine is used to tag biochemical probes for the study of various biological processes, as the NMR activity of the 19F nuclei enables in vivo magnetic resonance imaging. Also,18F-positron-emitting tomography is used daily for diagnosing, staging, and detecting the recurrence or progression of various diseases. Further development in these fields are closely related to the development of practical, selective, and efficient methodologies for the synthesis of fluorinated molecules, but also on fundamental understanding on their reactivity. During the last funding period, we accomplished significant advances. We intend to concentrate our efforts in the next five years in three major research areas. Novel Synthetic Approaches to SF5-Containing Molecules The SF5-substituent is also known as "super CF3" as it is more electron-withdrawing, more lipophilic, more chemically/metabolically stable, and induces a stronger dipole moment than CF3. However, its use in these fields has been hindered by the difficulty associated with its introduction into organic molecules. We propose to address the lack of a general method for the synthesis of SF5-containing molecules (especially alkyl-based ones) using two approaches: the design of a new reagent for the introduction of SF5, and the use of SF5-containing building blocks in metal-catalyzed transformations. Activation and Modulation of C–F Bonds through Hydrogen Bonding The activation of C–F bonds is a topic of intensive research. We have recently discovered that hydrogen-bond donor (HBD) molecules could be used to achieve such activation. Following these promising results, we propose to further investigate this transformation (nature of the HBD, etc.), especially for synthetically relevant transformations. Finally, we will also investigate the possibility of modulating the reactivity of organofluorine compounds through hydrogen bonding without replacing the C–F bond. Synthesis of Monofluoroalkenes and Preparation of Dipeptide Isosteres The monofluoroalkene is an important fluorinated motif that has applications in a number of fields. Over the past few years, we have reported a number of approaches to this motif from 3,3-difluoropropenes (DFP). We want to further study the reactivity of DFP (or related derivatives) with the long-term goal of using them as simple and readily accessible substrates for the preparation of monofluoroalkenes. We also want to demonstrate the usefulness of this chemistry for the synthesis of medicinally-relevant dipeptide isosteres, which will be initially used as fluorinated molecular probes for solid-state NMR study of protein-protein interactions.

氟原子的独特性质使其在医学、农业化学和材料科学中具有重要意义。据业内人士估计，市场上多达30-40%的农用化学品和20%的药品含有氟。氟被用于标记生物化学探针，用于研究各种生物过程，因为19 F核的NMR活性使体内磁共振成像成为可能。此外，18F-正电子发射断层扫描每天用于诊断，分期和检测各种疾病的复发或进展。这些领域的进一步发展与合成氟化分子的实用、选择性和有效方法的发展密切相关，但也与对其反应性的基本理解密切相关。在上一个融资期间，我们取得了重大进展。我们打算在未来五年集中力量在三个主要研究领域。 含SF 5分子的合成新方法 SF 5-取代基也被称为“超级CF 3”，因为它比CF 3更吸电子、更亲脂、更化学/代谢稳定，并且诱导更强的偶极矩。然而，其在这些领域的应用受到与其引入有机分子相关的困难的阻碍。我们建议使用两种方法来解决缺乏合成含SF 5分子（特别是烷基分子）的通用方法：设计一种新的引入SF 5的试剂，以及在金属催化转化中使用含SF 5的结构单元。 氢键作用下C-F键的活化与调控 C-F键的活化是一个深入研究的课题。我们最近发现，氢键供体（HBD）分子可以用来实现这种激活。根据这些有希望的结果，我们建议进一步研究这种转化（HBD的性质等），特别是对于综合相关的变换。最后，我们也将探讨在不取代C-F键的情况下通过氢键调节有机氟化合物反应性的可能性。 单氟烯烃的合成及二肽电子等排体的制备 单氟烯烃是一种重要的氟化基序，其在许多领域中具有应用。在过去的几年里，我们已经报道了一些方法，从3，3-二氟丙烯（DFP）这个主题。我们希望进一步研究DFP（或相关衍生物）的反应性，长期目标是将其用作制备单氟烯烃的简单且易于获得的底物。我们还希望证明这种化学方法在合成医学相关的二肽电子等排体方面的有用性，这些电子等排体最初将用作蛋白质-蛋白质相互作用的固态NMR研究的氟化分子探针。