Bioorganic and Medicinal Chemistry of Fluorine

Abstract

Foreword. Preface to the English Edition 1 General Remarks on Structural, Physical, and Chemical Properties of Fluorinated Compounds. 1.1 Structural Effects. 1.2 Physical Properties. 1.2.1 Boiling Point. 1.2.2 Surface Tension and Activity. 1.2.3 Polarity-Solubility. 1.2.4 Lipophilicity. 1.3 Effects on Electronic Properties and Reactivity. 1.3.1 Effects of Fluorination on Bond Energies and Reactivity. 1.3.2 Effects of Fluorination on the Electronic Repartition of a Molecule. 1.3.3 Acidity, Basicity, and Hydrogen Bond. 1.3.4 Steric Effects. 1.3.5 Fluorination Effects on the Stability of Reaction Intermediates (Carbocations, Carbanions, and Radicals). References. 2 Overview on the Preparation of Fluorinated Compounds. 2.1 Preparation of Monofluorinated Compounds. 2.1.1 Nucleophilic Fluorination. 2.1.2 Electrophilic Fluorination. 2.1.3 Formation of Carbon-Carbon Bonds Starting from Monofluorinated Synthons. 2.2 Preparation of Difluorinated Compounds. 2.2.1 Nucleophilic Fluorination. 2.2.2 Electrophilic Fluorination. 2.2.3 Starting from Di- and Trifluoromethyl Compounds. 2.3 Preparation of Trifluoromethyl Compounds. 2.3.1 Fluorination. 2.3.2 Nucleophilic Trifluoromethylation. 2.3.3 Electrophilic Trifluoromethylation. 2.3.4 Radical Trifluoromethylation. 2.3.5 Metal-Catalyzed Trifluoromethylation. 2.3.6 Formation of Carbon-Carbon Bonds from Trifluoromethyl Compounds. 2.4 Synthesis of Perfluoroalkyl Compounds. References. 3 Effects of Fluorine Substitution on Biological Properties. 3.1 Affinity for the Macromolecule Target. 3.1.1 Steric Effects. 3.1.2 Conformational Changes. 3.1.3 Dipolar Interactions and Electric Field. 3.1.4 Hydrogen Bonds and Other Weak Interactions. 3.1.5 pKa of Amines. 3.1.6 Fluorous Interactions. 3.2 Absorption. 3.2.1 Lipophilicity. 3.2.2 pKa and Solubility. 3.3 Metabolism. 3.3.1 Oxidative Metabolism. 3.3.2 Hydrolytic Metabolism. 3.4 Modification of Chemical Reactivity: Enzyme Inhibitors. 3.4.1 Analogue of Substrates as Inhibitors. 3.4.2 Inhibition by Stabilization or Destabilization of Intermediates of Biological Processes. 3.4.3 Irreversible Inhibition with Mechanism-Based Inhibitors (Suicide Substrates). References. 4 Fluorinated Analogues of Natural Products. 4.1 Fluorinated Products in Nature. 4.2 Steroids. 4.2.1 Corticosteroids. 4.2.2 Steroids with Trifluoromethyl Groups in Angular Position. 4.2.3 Fluorinated Analogues of Metabolites of Vitamin D3. 4.2.4 Other Fluorinated Steroids. 4.3 Terpenes. 4.3.1 Artemisinin. 4.3.2 Taxol. 4.4 Pigments and Vitamins. 4.4.1 Retinoids. 4.4.2 Carotenoids. 4.4.3 Vitamin D. 4.4.4 Vitamins E and K. 4.4.5 Porphyrins. 4.5 Lipids and Prostanoids. 4.6 Pheromones and Toxins. 4.7 Alkaloids. 4.7.1 Vinca Alkaloids. 4.7.2 Cinchona Alkaloids. 4.7.3 Camptothecin. 4.7.4 Other Fluorinated Alkaloids. 4.8 Macrolides. 4.8.1 Epothilone. 4.8.2 Erythromycin. 4.8.3 Amphotericin B. 4.8.4 Avermectin. 4.9 Anthracyclines. References. 5 Fluorinated Derivatives of a -Amino Acids and Proteins. 5.1 Fluorinated Aliphatic Amino Acids. 5.1.1 Alanines. 5.1.2 Valines, Leucines, and Isoleucines. 5.1.3 Prolines. 5.2 Aromatic Amino Acids: Phenylalanine, Tyrosine, Histidine, and Tryptophan. 5.3 Functional Fluorinated Amino Acids. 5.3.1 Serines and Threonines. 5.3.2 Aspartic Acids and Arginines. 5.3.3 Glutamic Acids and Glutamines. 5.3.4 Lysine, Ornithine, and Arginine. 5.3.5 Cysteines and Methionines. 5.4 -Fluoroalkyl Amino Acids. 5.4.1 Mono- and Difluoromethyl Amino Acids. 5.4.2 -Trifluoromethyl Amino Acids. 5.5 Incorporation of Fluorinated Amino Acids into Peptides and Proteins. 5.5.1 Polypeptides. 5.5.2 Proteins. References. 6 Saccharidic Fluorinated Derivatives. 6.1 Glycosyl Fluorides. 6.2 Mono- and Difluorinated Analogues of Sugars. 6.2.1 Fluorinated Furanoses and Nucleosides. 6.2.2 Fluorinated Pyranoses. 6.3 Fluoromethyl Derivatives of Sugars. 6.3.1 Difluorovinyl Compounds. 6.3.2 Difluoromethylene-C-Glycosides. 6.3.3 C-Difluoromethyl Glycosides. 6.3.4 Trifluoromethylated Sugars. 6.4 Perfluoroalkylated Sugars. 6.4.1 Preparation of C-Perfluoroalkyl Sugars. 6.4.2 O- and S-Fluoroalkyl Glycosides. 6.4.3 Applications of Amphiphilic Fluoroalkyl Sugars. References. 7 Inhibition of Enzymes by Fluorinated Compounds. 7.1 Substrate Analogues. 7.1.1 Fluorine Replaces a Hydrogen Involved in the Catalytic Cycle. 7.1.2 Fluorine Replaces a Hydroxyl. 7.1.3 Fluorinated Analogues of Substrates in Which Fluorine is Not Directly Involved in the Inhibition. 7.2 Destabilization of Reaction Intermediates (or of Transition States) of Enzymatic Processes by Fluorinated Groups. 7.2.1 Prenyl Transfer. 7.2.2 Inhibition of Glycosidases and Glycosyltransferases. 7.2.3 Inhibition of UDP-GlcNAC Enolpyruvyltransferase (MurZ). 7.2.4 Enolpyruvate Shikimate Phosphate Synthase (EPSPS). 7.3 Inhibitors that are Analogues of the Transition State: Di- and Trifluoromethyl Ketones. 7.3.1 Serine Enzymes. 7.3.2 Inhibition of Aspartyl Enzymes. 7.3.3 Inhibition of Metalloproteases. 7.3.4 Cysteine Protease and Thiol Enzymes. 7.4 Mechan