Visible Light Promoted Fluorination for Application to PET Imaging

Princeton University, Princeton NJ

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Abstract

Project Summary The incorporation of fluorine into molecules has been widely demonstrated to alter the physical properties as well as bioactivity of chemical compounds. While a variety of practical catalytic fluorination methods have been established for late-stage 19F chemistry there are relatively few practical methods for 18F that enable access to a broad scope of substrates. Conventional methods for accessing C-F bonds in radiochemistry are highly specialized for aliphatic compounds and utilize organometallic reagents or stoichiometric oxidants for aryl compounds. Ideally, a fluorination strategy would occur at room temperature and rely on abundant and stable organic substrates such as benzoic acids and inexpensive fluoride salts. Although cross- coupling methods are capable of promoting this type of reaction in the presence of a transition metal catalyst, a long-standing challenge, especially in aryl fluorination, is the effective reductive elimination of carbon-fluorine bonds from a low-valent transition metal complex. In this research strategy, we propose accessing a reactive, high-valent metal fluoride species with a photocatalyst, while still relying on convenient aryl starting materials. In addition to acting as an oxidant for the transition metal, we propose that the photocatalyst in its reduced state can activate an aryl ester for capture by the main transition metal catalyst. This ester can be easily made in situ or pre-synthesized from the corresponding carboxylic acid, making the procedure amenable to a radiochemist. The unification of a photoredox catalyst with a transition metal catalyst has precedent, however, has not yet been applied to fluorination chemistry. This dual catalytic system is predicted to enable the fluorination of Lewis basic and protic molecules under mild conditions. And, if successful, this reaction would provide the first example of light-driven synthesis of radiopharmaceuticals. Due to the prevalence of fluorine in bioactive molecules, the success of this chemistry with even 19F would represent a valuable advance in the field. Specific aim 1 discusses the design and optimization of the light promoted fluorination of activated aryl esters. Specific aim 2 presents the fluorination of activated aliphatic esters. And, specific aim 3 discusses the application of this methodlogy to the development of radiopharmaceuticals.