PROJECT SUMMARY Fluoroalkyl ethers and thioethers are important for medicinal chemistry, serving as both active pharmaceutical ingredients and biological probes. Therefore, the ability to access these fluorinated substructures is critical for the development of new therapeutics. Despite recent synthetic improvements that improve access to many fluorinated substructures, the community has not generally addressed the preparation of fluoroalkyl (thio)ethers. Thus, mild, convergent, and practical procedures for accessing these substructures are still lacking, which restricts access to new biological probes and therapeutic candidates. The Altman group aims to overcome the aforementioned limitations by developing new methods and general strategies for accessing fluoroalkyl (thio)ethers directly from simple and ubiquitous alcohol- and thiol-based substrates. More specifically, the proposed work will employ base-catalyzed nucleophilic addition reactions to C?C bonds to access a variety of biomedically important fluoroalkylether substructures. Development of the proposed strategies will enable medicinal chemists to access new and unique biological probes and therapeutics. The recent surge in synthetic organofluorine chemistry has provided a plethora of new methods capable of generating many new fluorinated substructures. In many cases, the creativity of the synthetic chemists for generating these fluorinated substructures has exceeded the experimentally validated uses of these new fluorinated groups. In fact, some synthetic chemists have proposed replacing synthetically challenging fluoroalkyl ethers and metabolically instable non-fluorinated ether substructures with more readily accessible fluorinated ethermimetics. However, no in silico, in vitro and in vivo data supports these claims. The Altman group aims to experimentally characterize the physicochemical and biophysical perturbations imparted by the proposed fluorinated ethermimetics using a combination of computational, physicochemical, in vitro and in vivo methods. This experimental data will enable medicinal chemists to rationally integrate these emerging fluorinated substructures in therapeutic candidates.