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

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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.