New Building Blocks for the Catalytic Synthesis of Organofluorine Compounds

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Fluorinated molecules are highly desirable targets for drug discovery and development owing to their improved potency, selectivity, and pharmacokinetic profiles when compared to non-fluorinated analogues. In the medical imaging field, 18F is a widely used radioisotope for positron emission tomography (PET) imaging due to its long half-life. Although >50% of the leading blockbuster drugs contain a fluorine atom, an analysis of fluoro-pharmaceuticals introduced in the last three decades reveals that there are few chiral organofluorine drugs currently on the market. This low representation can be attributed to the increased structural complexity of chiral molecules, combined with limited industrially friendly methods to synthesize these targets. Many of the developed asymmetric fluorination methods rely on electrophilic fluorinating reagents, which present several disadvantages on scale, such as high costs, low atom-economy, powerful oxidizing capabilities, and poor functional group tolerance. The proposed research program seeks to develop new organic reactions that harness the synthetic potential of readily accessible fluorine-containing building blocks, which are cost-effective, safer, and selective in their reactivity. Our overarching goal is to design methodologies that can transform simple starting materials into structurally and chemically diverse libraries of organofluorine compounds for biological testing. My group will explore the chemistry of two main classes of compounds, acyl fluorides and difluoroacetate derivatives, as their preparation does not require electrophilic fluorine sources and their application in catalytic asymmetric transformations remains underdeveloped. I have identified three critical areas with unmet synthetic challenges: 1) the development of complexity-building, atom-economical insertion reactions of acyl fluorides; 2) the controlled generation of transition metal difluorocarbenes under conditions amenable to asymmetric catalysis; and 3) the efficient translation of developed methodologies to 18F-radiolabeling for PET imaging applications. Leveraging tools in synthetic organic and organometallic chemistry, my group will develop novel catalysts that can facilitate the activation of these building blocks towards diverse carbon-carbon and carbon-heteroatom bond-forming reactions. Our primary focus will be on the use of nickel and boron catalysts, due to the higher natural abundance of these elements in comparison to commonly used precious metals (Pd, Pt, Rh). The central hypothesis is that rational ligand, catalyst, and reagent design will lead to the reliable prediction of reaction pathway and the discovery of new reactivity. Overall, the synthetic methodologies developed in my lab will find direct applications in drug discovery, medical imaging, and disease diagnosis, creating opportunities for interdisciplinary collaborations.