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

氟原子的独特性质使其在医药、农化和材料科学中具有重要意义。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，但也与对其反应性的基本理解密切相关。在上一次融资期间，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sf5分子的新合成方法*** sf5取代基也被称为“超级CF3”，因为它更吸电子，更亲脂，更化学/代谢稳定，并诱导比CF3更强的偶极矩。然而，由于难以将其引入有机分子中，它在这些领域的应用一直受到阻碍。我们建议采用两种方法来解决合成含SF5分子（特别是烷基基分子）缺乏通用方法的问题：设计一种新的试剂来引入SF5，以及在金属催化转化中使用含SF5的构建块。******通过氢键激活和调节C-F键*** C-F键的激活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），特别是对综合相关的转化。最后，我们还将研究通过氢键而不取代C-F键来调节有机氟化合物反应性的可能性。******单氟烯烃的合成和二肽同位体的制备***单氟烯烃是一种重要的氟化基序，在许多领域都有应用。在过去几年中，我们已经报道了从3,3-二氟丙烯（DFP）中获得该基序的一些方法。我们希望进一步研究DFP（或相关衍生物）的反应性，以使其成为制备单氟烯烃的简单易得的底物。我们还想证明这种化学在合成与医学相关的二肽同位异构体方面的有用性，这将最初用作蛋白质-蛋白质相互作用的固态核磁共振研究的氟化分子探针。

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.