Jean-Pierre Bégué

Bioorganic and medicinal chemistry of fluorine

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 Mechanism-Based Inhibitors. 7.4.1 Inhibition of Pyridoxal Phosphate Enzymes. 7.4.2 Thymidylate Synthase. 7.4.3 Inhibition of Monoamine Oxidases. 7.4.4 D-Ala-D-Ala Dipeptidase (VanX). 7.4.5 Inhibition of Ribonucleotide Diphosphate Reductase. 7.4.6 Inhibition of S-Adenosylhomocysteine Hydrolase. 7.4.7 Inhibition of Cytidine-5 0 -diphosphate-D-Glucose. 4,6-Dehydratase (CDP D-Glucose 4,6-Dehydratase). 7.4.8 Other Irreversible Inhibitors. 7.5 Fluorinated Inhibitors Involving a Still Unknown Mechanism. 7.5.1 Inhibition of the Steroid C17(20)lyase. 7.5.2 Phosphatidylinositol Phospholipase C (PI-PLC). 7.5.3 Inhibition of the Protein of Transfer of Cholesteryl Esters. 7.5.4 -Fluoropolyamines as Inhibitors of the Biosynthesis of Polyamines. 7.5.5 Inhibition of the Biosynthesis of Cholesterol. References. 8 Fluorinated Drugs. 8.1 Antitumor and Antiviral Fluorinated Drugs. 8.1.1 Fluoronucleosides. 8.1.2 Other Antitumor and Antiviral Drugs. 8.2 Anti-infectious Drugs. 8.2.1 Fluorinated Antibiotic Drugs. 8.2.2 Antifungal Drugs. 8.2.3 Fluorinated Drugs for Parasitic Diseases. 8.3 Drugs for CNS Disorders. 8.3.1 Neuroleptics. 8.3.2 Drugs for Depressive Disorders. 8.3.3 Anxiolytics and Sedatives. 8.3.4 Other Drugs for CNS Disorders. 8.4 Drugs of Inflammatory and Immunity Disorders. 8.4.1 Fluorocorticosteroids. 8.4.2 H1 Antagonist Antiallergics. 8.4.3 Drugs for Asthma and Respiratory Disorders. 8.4.4 Analgesic and Antiarthritic Drugs. 8.5 Drugs for Cardiovascular Disorders. 8.5.1 Cholesterol Lowering Drugs. 8.5.2 Drugs for Hypertension. 8.5.3 Drugs for Arrhythmias. 8.5.4 Antithrombosis and Anticoagulant Fluorinated Agents. 8.6 Drugs for Gastrointestinal Disorders. 8.6.1 Prevention and Treatment of Ulcer. 8.6.2 Antiemetic Agents. 8.6.3 Drugs for Bowel Disorders. 8.7 Drugs for Endocrine and Metabolic Disorders. 8.7.1 Drugs Acting on Steroid Hormone Receptors. 8.7.2 Drugs for Benign Prostatic Hypertrophy (BPH). 8.7.3 Drugs for Other Urologic Disorders. 8.7.4 Drugs for Calcemia Disorders. 8.7.5 Drugs for Diabetes. 8.7.6 Drugs for Hepatic Disorders. 8.8 Miscellaneous. 8.8.1 Drugs for Ophthalmic Disorders. 8.8.2 Drugs for Genetic Disease. 8.8.3 Contrast and Diagnostic Agents. 8.9 Highly Fluorinated Compounds with Clinical Uses. 8.9.1 General Anesthetics. 8.9.2 Therapeutic Uses of Perfluorocarbons. 8.10 Fluorinated Functions and Motifs in Medicinal Chemistry. 8.10.1 Fluorinated Ethers. 8.10.2 Fluorinated Alcohols and Amines. 8.10.3 Fluorinated Ketones. 8.10.4 Fluoroalkyl Groups. Appendix: INN and Trademark Names. References. Index.

A selective conversion of sulfide to sulfoxide in hexafluoro-2-propanol

Abstract A facile, selective and efficient method for the oxidation of sulfides to sulfoxides by aqueous 30% H 2 O 2 in hexafluoro-2-propanol at room temperature is described. Specific role of the solvent in the selectivity is exhibited.

Fluoro alcohol as reaction medium: one-pot synthesis of β-hydroxy sulfoxides from epoxides

Abstract β-Hydroxy sulfoxides were obtained in one-pot synthesis by the ring opening of oxiranes with thiols in hexafluoroisopropanol (HFIP) without any catalyst, followed by in situ oxidation under neutral conditions. The reaction is anti -selective. β-Hydroxy sulfoxides were transformed by pyrolysis in the corresponding allylic alcohols.

Role of Hexafluoro-2-propanol in Selective Oxidation of Sulfide to Sulfoxide: Efficient Preparation of Glycosyl Sulfoxides

Aqueous 30% H2O2 in hexafluoro-2-propanol (HFIP) is described as a facile, selective and efficient oxidant for the conversion of sulfides to sulfoxides under neutral conditions. The nitrogen center of the pyridine molecule and the carbon–carbon double bond are shown to not be affected by the reagent system used. The oxidation of glycosyl sulfides to glycosyl sulfoxides was achieved in very high yield at room temperature.

Manganese (III) acetate dihydrate catalyzed aerobic epoxidation of unfunctionalized olefins in fluorous solvents

Abstract Manganese(III) acetate dihydrate is used as a catalyst for the epoxidation of various olefins with molecular oxygen/pivalaldehyde as an oxidant in perfluoro-2-butyltetrahydrofuran. Various types of olefins, including substituted styrenes, stilbenes and cyclic and acyclic alkenes were epoxidized in excellent yields at 25°C. The reaction is stereodependent. Regioselectivity is observed on epoxidation of limonene. Mono- and disubstituted olefins show interesting dichotomy in their reactivity in fluorous solvents such as perfluoro-2-butyltetrahydrofuran and 1,1,1,3,3,3-hexafluoro-2-propanol.

Aza-Diels–Alder reaction in fluorinated alcohols. A one-pot synthesis of tetrahydroquinolines

Hexafluoroisopropanol and trifluoroethanol are found to promote imino-Diels–Alder reactions of the N-aryl aldimine 1 with alkyl vinyl ethers to afford the corresponding tetrahydroquinolines in good yields without Lewis acid under mild and neutral conditions. The reaction is also efficient in a three component process from aldehyde, amine and vinyl ethers.

Synthesis and biological activity of novel 3′-trifluoromethyl taxoids

Second generation taxoids possessing a trifluoromethyl moiety in place of the 3′-phenyl group are synthesized by means of the β-Lactam Synthon Method. The in vitro cytotoxicities of these new taxoids are evaluated against several different human cancer cell lines and found to exhibit greatly enhanced activities as compared to those of paclitaxel and docetaxel. The activity enhancement is most remarkable against a drug-resistant breast cancer cell line, MCF7-R, expressing MDR phenotype.

Synthesis of tetrahydroquinoline derivatives from α-CF3-N-arylaldimine and vinyl ethers

BF3.Et2O or Yb(OTf)3 catalyzed [4+2] cycloaddition reaction of α-CF3-N-arylaldimines with nucleophilic olefins afforded CF3-substituted tetrahydroquinoline derivatives.

TRIFLUOROMETHYLALKENES IN CYCLOADDITION REACTIONS

Abstract CF3-Substituted alkenes have been described to be good partners in Diels-Alder reactions with the Danishefskys diene and in 1,3-dipolar cycloadditions with nitrones and non-stabilized azomethine ylides. The influence of the CF3-group on both the activation of the double bond and the stereochemistry of the cycloaddition has been evaluated. New CF3-substituted mono- and polycyclic compounds 4 and 7, highly functionalized isoxazolidines 18, 19, 22 and 23 and pyrrolidines 12, 13 and 16 have been prepared.

Addition of organolithium reagents to α-(trifluoromethyl)styrene: concise synthesis of functionalised gem-difluoroalkenes

The treatment of α-(trifluoromethyl)styrene with organolithium reagents results in the selective formation of gem-difluoroalkenes in good-to-excellent yields. This reaction has been applied to the synthesis of 3-gem-difluoro-2-phenylallylic amines and other functionalised gem-difluoroalkenes.