Nucleophillic Fluorination

An expansive array of medicines, agrochemicals, and materials possess fluorinated scaffolds due to the unique chemical properties conferred by fluorine substitution. One of the chief obstacles in the discovery and production of these compounds is the availability of synthetic methods for carbon–fluorine (C–F) bond formation. For example, the most abundant and inexpensive fluorine sources, nucleophilic fluoride salts, typically suffer from low solubility, high hygroscopicity, and strong Brønsted basicity, rendering them recalcitrant reagents in chemical synthesis.

An ongoing program of research in the Doyle laboratory is focused on the invention of novel reagents and catalytic strategies to address limitations in nucleophilic fluorination.

Our laboratory developed the first asymmetric catalytic aliphatic fluorination reactions using nucleophilic fluoride reagents. For example, we disclosed (salen)Co-catalyzed enantioselective fluoride ring-opening reactions of epoxides and aziridines, as well as Pd-catalyzed asymmetric allylic fluorinations of allylic chlorides. Recently, we have exploited visible light photoredox catalysis to develop redox-neutral methods for SN1-type nucleophilic fluorination.

We have also invented new reagents to accomplish nucleophilic fluorination. One recent example is PyFluor, a stable and low-cost deoxyfluorination reagent that fluorinates a broad range of alcohols without substantial formation of elimination side products.

Positron emission tomography (PET) is a nuclear imaging modality that enables visualization of dynamic biological processes at the molecular or cellular level. Molecular imaging has become an indispensable tool in research and the clinic. However, a roadblock for PET is the chemical “tagging” of small-molecule tracers with a radioisotope, such as 18F, to mediate the imaging studies. Due to the poor reactivity of fluoride salts such as KF, rates of fluoride incorporation into radiotracers are often not competitive with decay of the radioisotope. An additional challenge is that most methods for 18F incorporation fail in the presence of complex functionality found in bioactive molecules; yet 18F incorporation prior to functional group installation is not viable due to the radioisotope’s short half-life.

A goal of the Doyle laboratory is to develop mild, general, robust, and rapid methods for late-stage incorporation of 18F into small molecules.

We have translated our methods for Co-catalyzed fluoride ring-opening of epoxides, Cu-catalyzed insertion of HF into a-diazo carbonyl derivatives, and decarboxylative fluorination of N-hydroxyphthalimide esters into mild and robust protocols for radiofluorination. These methods deliver access to clinically validated and experimental PET tracers with fluoride incorporation in the final step. Furthermore, building upon our discovery of the deoxyfluorinating agent PyFluor, we have identified the first no-carrier-added deoxy-radiofluorination.

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