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Synthetic Strategies to Access Biologically Important Fluorinated Motifs: Fluoroalkenes and Difluoroketones
Yang, Ming-Hsiu
Yang, Ming-Hsiu
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Abstract
Fluorine plays an important role in drug design, because of some unique features imparted by fluorine. The incorporation of fluorine into small molecules can modulate molecular physicochemical properties, metabolic stability, lipophilicity, and binding affinity to the target proteins. However, few fluorinated molecules are biosynthesized by enzymes. This means incorporating fluorine into the molecules relies on synthetic methods. Thus, efficient synthetic strategies to access the molecules bearing a variety of privileged fluorinated moieties are important for drug discovery. Fluoroalkenes are an isopolar and isosteric mimic of an amide bond with distinct biophysical properties, including decreased H-bond donating and accepting abilities, increased lipophilicity, and metabolic stability. Moreover, fluoroalkenes can also serve as probes for conducting conformational analyses of amides. These potential applications require the development of efficient methods to access fluoroalkenes. In chapter 2, a Shapiro fluorination strategy to access peptidomimetic fluoroalkenes is demonstrated. The Shapiro fluorination reactions convert a ketone into a fluoroalkene in one or two steps. Moreover, this method uses inexpensive and readily available reagents, and no transition metals are involved in the reactions. Thus, it provides an operation-simple alternative to access fluoroalkenes in medicinal chemistry. a,a-difluoroketones represent a privileged substructure in medicinal chemistry, and serves as inhibitors to many hydrolytic enzymes, such as serine and aspartyl proteases. From chapters 3 to 5, palladium-catalyzed decarboxylative methods are developed for accessing a-alkyl- and a-aryl-a,a-difluoroketones. This decarboxylative strategy overcomes two major challenges associated with alkylation reactions of a,a-difluoroketone enolates. Chapter 3 demonstrates that decarboxylation regioselectively generates a,a-difluoroketone enolates, which are difficult to access by base deprotonation. Moreover, palladium catalysis enables the coupling of the a,a-difluoroketone enolate with benzylic electrophiles to form a key C(a)–C(sp3) bond. In chapter 4, an orthogonal catalytic system is developed for accessing linear and branched a-allyl-a,a-difluoroketones. Two distinct mechanisms are involved in the formation of the regioisomers. Chapter 5 describes a base-mediated selective para-C–H difluoroalkylation of arenes, which represents a different strategy for para-C–H functionalization of arenes compared to the known methods. These decarboxylative coupling reactions provide structurally diverse a,a-difluoroketone derivatives, and should be useful for accessing potential biological probes and therapeutics.
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Date
2017-05-31
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University of Kansas
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Organic chemistry, Chemistry