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

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。业内消息人士估计，市场上多达30%-40%的农用化学品和20%的药品含有氟。氟被用来标记生化探针，用于研究各种生物过程，因为19F核的核磁共振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开发实用、选择性和高效的氟化分子合成方法密切相关，也与对其反应性的基本了解密切相关。在上一次筹资期间，我们取得了重大进展。我们打算在未来五年集中精力在三个主要研究领域。*含有SF5的分子的新合成方法*SF5-取代基也被称为“超级CF3”，因为它比CF3更吸引电子、更亲油、更稳定的化学和代谢，并产生比CF3更强的偶极矩。然而，它在这些领域的应用受到了与其引入有机分子相关的困难的阻碍。我们建议用两种方法来解决缺乏合成含SF5分子(特别是烷基分子)的通用方法：设计一种新的引入SF5的试剂，以及在金属催化的转化中使用含SF5的构件。*通过氢键激活和调制C-F键*C-F键的激活是一个深入研究的主题。我们最近发现氢键给体(HBD)分子可以用来实现这种激活。在这些有希望的结果之后，我们建议进一步研究这种变换(HBD的性质等)，特别是对于综合相关的变换。最后，我们还将研究在不取代C-F键的情况下通过氢键来调节有机氟化合物反应活性的可能性。*单氟烯的合成和二肽异构体的制备*单氟烯是一个重要的氟化基元，在许多领域都有应用。在过去的几年里，我们已经报道了从3，3-二氟丙烯(DFP)到这个基序的一些方法。我们希望进一步研究DFP(或相关衍生物)的反应性，长期目标是将它们用作制备单氟烯烃的简单和容易获得的底物。我们还想证明这种化学在合成与药物相关的二肽异构体方面的有效性，这些异构体最初将被用作固体核磁共振研究蛋白质-蛋白质相互作用的氟化分子探针。

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.