Thursday, November 21, 2024
11/21/2024
SUMMARY Fluorination of an organic compound affects physicochemical properties, which in medicinal settings perturbs pharmacodynamic, pharmacokinetic, distribution, and/or metabolic profiles both in vitro and in vivo. Thus, the ability to selectively install fluorinated groups under mild conditions is essential for accessing new therapeutics and biological probes. However, the unique physical properties of fluorinated substrates and/or reagents typically perturb fundamental organic reactivities, which can complicate synthetic sequences to access fluorinated compounds. Thus, many routine organic reactions simply do not work in the presence of fluorinated reagents or with fluorinated substrates. Additionally, the unique properties of fluorinated substrates enable new reactivities that cannot be achieved by the respective non-fluorinated counterparts, which provides opportunities to develop innovative reactions and strategies for accessing medicinally relevant substructures With this R35 program, the Altman group has a long-term goal of developing innovative catalyst systems, reagents, and/or synthetic strategies for accessing medicinally relevant fluorinated substructures. In this area, we develop fluorination and fluoroalkylation methodologies using innovative strategies (e.g. electrochemistry, C– H functionalization, deoxyfluoroalkylation, transition metal catalyzed reactions) that enable synthetic chemists to convert simple and readily available functional groups (e.g. alcohols, carbonyls, fluorinated alkenes) into a broad spectrum of highly valuable fluorinated analogs. Additionally, we explore synthetic transformations in which fluorinated substructures react through distinct mechanisms and/or deliver products with distinct selectivities relative to analogous reactions of nonfluorinated substrates. Development of the proposed strategies will enable medicinal chemists to access new and unique biological probes and therapeutics. A second long-term goal is to explore physicochemical perturbations imparted by fluorinated substructures that might influence drug stability, distribution, metabolism, and/or ligand-protein interactions, and to apply such principles in the design of next- generation fluorinated therapeutic candidates with improved drug-like properties. In the next phase of our work, we will apply modern innovative synthetic reactions to deliver next-generation fluorinated analogs of natural products that will retain the therapeutically valuable pharmacodynamic action and also improve stability and distribution relative to the parent compounds.
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