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Synthesis of Substituted Ring- Fused 2-Pyridones and Applications in Chemical Biology

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Synthesis of Substituted Ring- Fused 2-Pyridones and Applications in Chemical Biology Synthesis of Substituted Ring- Fused 2-Pyridones and Applications in Chemical Biology Christoffer Bengtsson Doctoral thesis Department of Chemistry Umeå University Umeå, Sweden 2013 Copyright © Christoffer Bengtsson 2013 ISBN: 978-91-7459-552-9 Electronic version available at http://umu.diva-portal.org/ Printed by: VMC-KBC, Umeå University Umeå, Sweden 2013 Author Christoffer Bengtsson Title Synthesis of Substituted Ring-Fused 2-Pyridones and Applications in Chemical Biology Abstract Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections. Presented herein is a class of antibacterial ring-fused 2- pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent. The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring- fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed. Keywords Synthesis, 2-pyridone, 2-thiazoline, cross coupling, pili, curli, antibacterial i Table of Contents Table of Contents ii List of Papers iii Abbreviations v Introduction 1 History of organic synthesis: a Nobel Prize odyssey 1 Thiazolino ring-fused 2-pyridones 3 Biological target: the chaperone usher pathway 4 Biological target: curli inhibition 7 Biological testing for pilicide/curlicide activity 8 Synthetic development of the bicyclic 2-pyridones (Paper I + II) 9 Suzuki⎯Miyaura couplings onto bicyclic 2-pyridones (Paper I) 9 Synthesis of a bromomethyl substituted scaffold (Paper II) 14 Fluorescence: lighting up bacterial virulence (Paper III) 21 Synthesis of the coumarin analogues 21 Synthesis of the BODIPY analogues 26 Triazoles (Paper IV) 31 Functionalization of the 8-position 32 Functionalization of the 2-position 34 Acetylene spacer analogues (Paper V) 37 Asymmetric synthesis of Δ2-thiazolines (Paper VI) 43 2-Furanone or 2-pyrone ring-fused tricyclic scaffolds (Paper VII) 57 Concluding remarks 66 Acknowledgements 67 References 68 ii List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I. Bengtsson C., Almqvist F. Regioselective Halogenations and Subsequent Suzuki-Miyaura Coupling onto Bicyclic 2-Pyridones J. Org. Chem., 2010, 75, 972-975 II. Chorell E., Bengtsson C., Sainte-Luce Banchelin T., Das P., Uvell H., Sinha A. K., Pinkner J. S., Hultgren S. J., Almqvist F. Synthesis and Application of a Bromomethyl Substituted Scaffold to be Used for Efficient Optimization of Anti-Virulence Activity Eur. J. Med. Chem., 2011, 46, 1103-1116 III. Chorell E., Pinkner J. S., Bengtsson C., Edvinsson S., Cusumano C. K., Rosenbaum E., Johansson L. B. Å., Hultgren S. J., Almqvist F. Design and Synthesis of Fluorescent Pilicides and Curlicides: Bioactive Tools to Study Bacterial Virulence Mechanisms Chem. Eur. J. 2012, 18, 4522-4532 IV. Bengtsson C., Lindgren A. E. G., Uvell H., Almqvist F. Design, Synthesis and Evaluation of Triazole Functionalized Ring-Fused 2- Pyridones as Antibacterial Agents Eur. J. Med. Chem., 2012, 54, 637-646 V. Andersson E. K., Bengtsson C., Evans, M. L., Chorell E., Sellstedt M., Lindgren A. E. G., Hufnagel D. A., Bhattacharya M., Tessier P., Wittung-Stafshede P., Almqvist F., Chapman M. R. Modulation of Curli Assembly and Pellicle Biofilm by Chemical and Protein Chaperones 2013, Manuscript VI. Bengtsson C., Nelander H., Almqvist F. Asymmetric Synthesis of 2, 4, 5-Trisubstituted ∆2-Thiazolines Chem. Eur. J., 2013, DOI: 10.1002/chem.201301120 VII. Bengtsson C., Almqvist F. A Selective Intramolecular 5-exo-dig or 6-endo-dig Cyclization en Route to 2-Furanone or 2-Pyrone Containing Tricyclic Scaffolds J. Org. Chem., 2011, 76, 9817-9825 Reprints have been made with permission from the respective publisher. iii Other papers by the author not appended to this thesis Horvath I., Weise C. F., Andersson E. K., Chorell E., Sellstedt M., Bengtsson C., Olofsson A., Hultgren S. J., Chapman M. R., Wolf-Watz M., Almqvist F., Wittung-Stafshede P. E. L. Mechanisms of Protein Oligomerization: Inhibitor of Functional Amyloids Templates α-Synuclein Fibrillation J. Am. Chem. Soc., 2012, 134, 3439-3444 Chorell E., Pinkner J. S., Bengtsson C., Sainte-Luce Banchelin T., Edvinsson S., Linusson A., Hultgren S. J., Almqvist F. Mapping Pilicide Anti-Virulence Effect in Escherichia coli, a Comprehensive Structure-Activity Study Bioorg. Med. Chem., 2012, 20, 3128-3142 iv Abbreviations Aβ Amyloid β Ac Acetyl AD Asymmetric dihydroxylation aq Aqueous Arg Arginine Bn Benzyl Boc tert-butyloxycarbonyl BODIPY 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene Bu Butyl cat. Catalytic conc. Concentrated cPr Cyclopropyl CuAAC Copper(I) catalyzed azide alkyne cycloaddition CuTC Copper(I) thiophene-2-carboxylate DCC N,N´-dicyclohexyl carbodiimide DCE 1,2-dichloroethane DCM Dichloromethane DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMPK Drug metabolism and pharmacokinetics v DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO dimethylsulfoxide DPPF 1,1’-bis(diphenylphosphino)ferrocene DPPP 1,3-bis(diphenylphosphino)propane E. coli Escherichia coli e.g. Exempli gratia (Latin for ”for example”) EC50 Half maximal effective concentration ee Enantiomeric excess eq Equivalent Et Ethyl et al. et alia (Latin for ”with others”) FGI Functional group interconversion h hour N,N,N´,N´-tetramethyl-O-(1H-benzotriazol-1- HBTU yl)uranium hexafluorophosphate HMDS 1,1,1,3,3,3-hexamethyldisilazane i.e. id est (Latin for ”that is”) in vitro Latin for ”in glass” LDA Lithiumdiisopropylamide LiHMDS Lithiumhexamethyldisilazane LR Lawesson’s reagent Lys Lysine vi mCPBA meta-chloroperoxybenzoic acid Me Methyl MeCN Acetonitrile Meldrum’s acid 2,2-dimethyl-1,3-dioxane-4,6-dione MeOH Methanol MS Molecular sieves Ms Methanesulfonyl MWI Microwave irradiation NHC N-heterocyclic carbene NIS N-iodosuccinimide NMO N-Methyl morpholine N-oxide NMR Nuclear magnetic resonance Ns para-nitrobenzenesulfonyl Pd/C Palladium on charcoal Pd-NHC or Pd-IPr- [1,3-Bis(2,6-Diisopropylphenyl)imidazole-2- NHC ylidene](3-chloropyridyl)palladium(II) dichloride [1,3-Bis(2,6-diisopropylphenyl)imidazolidene](3- Pd-SIPr-NHC chloropyridyl) palladium(II) dichloride Ph Phenyl 5-Phenyl-2-[4-(5-phenyl-1,3-oxazol-2-yl)phenyl]-1,3- POPOP oxazole quant quantitative ref Reference vii rt Room temperature (s) Solid state TBAF Tetrabutylammonium fluoride N,N,N´,N´-tetramethyl-O-(1H-benzotriazol-1- TBTU yl)uronium tetrafluoroborate TEA Triethylamine Tf Trifluoromethanesulfonyl TFA Trifluoroacetic acid THF Tetrahydrofuran ThT Thioflavin T TMS Trimethylsilyl TMSA Trimethylsilylacetylene TMSE Trimethylsilylethyl UPEC Uropathogenic Escherichia coli WHO World health organization Å Ångström ≠ is not equal to viii Introduction History of organic synthesis: a Nobel Prize odyssey The word synthesis originates from the ancient Greek word σύνθεσις, which means “composition” that in this case, refers to the joining of one or more entities together to create something new. Friedrich Wöhler´s synthesis of urea in 1828,1 followed by Hermann Kolbe´s synthesis of acetic acid in 18492 can be considered as the beginning of organic synthesis (Figure 1). At the end of the 19th century, Adolf von Baeyer contributed to organic chemistry by his synthesis of the blue colored dye indigo (Figure 1). Adolf von Baeyer also discovered the oxidation procedure known as the Baeyer-Villiger oxidation, together with the Swiss chemist Victor Villiger at the end of the 19th century.3 In 1905, Adolf von Baeyer received the Nobel Prize in chemistry, partly for his work with indigo. During the 20th century, incredible development has occurred in organic synthesis. In 1900 the French chemist Victor Grignard made his breakthrough discovery of how to make carbon-carbon bonds from an organic halide, magnesium metal and a ketone,4 a very important discovery in organic synthesis indeed. Together with Paul Sabatier, he earned the Nobel Prize in chemistry in 1912 for his achievements in hydrogenations of organic compounds in the presence of finely disintergrated metals. In 1928 Otto P. H. Diels and Kurt Alder discovered their novel reaction for the construction of six membered rings, known as the Diels-Alder reaction.5 The Diels-Alder reaction is today widely used
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