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Enantioselective Synthesis of Tetrahydrofuran- Imidazole Based Human Histamine H 3 and H 4 Receptor Agonists

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Enantioselective synthesis of tetrahydrofuran- imidazole based human histamine H 3 and H 4 receptor agonists Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften Dr. rer. nat. an der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von Chinna Ashalu Kashamalla aus Warangal (Indien) Regensburg 2009 Die Arbeit wurde angeleitet von: Prof. Dr. O. Reiser Promotionsgesuch eingereicht am: 14 September, 2009 Promotionskolloquium am: 02 Oktober, 2009 Prüfungsausschuss: Vorsitz: Prof. Dr. Armin Buschauer 1. Gutachter: Prof. Dr. Oliver Reiser 2. Gutachter: Prof. Dr. Burkhard König 3. Prüfer: Prof. Dr. Sigurd Elz Der experimentelle Teil der vorliegenden Arbeit wurde unter der Leitung von Herrn Prof. Dr. Oliver Reiser in der Zeit von August 2005 bis Mai 2009 am Institut für Organische Chemie der Universität Regensburg, Regensburg, Germany. Herrn Prof. Dr. Oliver Reiser möchte ich herzlich für die Überlassung des äußerst interessanten Themas, die anregenden Diskussionen und seine stete Unterstützung während der Durchführung dieser Arbeit danken. Dedicated to my family. Contents 1. Introduction 1.1 Medicinal Chemistry 1 1.2 Drug action at receptors 3 1.2.1 The receptor role 3 1.2.2 Neurotransmitters 4 1.3 Receptors 5 1.3.1 Receptor families 6 1.4 G-protein coupled receptors 7 1.4.1 Molecular structure of GPCRs 8 1.4.2 G-Proteins and their role 8 1.4.3 G-Protein cycle and Classification of G-Proteins 9 1.4.4 Types of G proteins 9 1.4.5 G-protein cycle 9 1.5 Two state activation model of GPCRs and ligand classification 10 1.6 Histamine 12 1.6.1 Metabolism of histamine 12 1.6.2 Synthesis and storage 13 1.6.3 Release 14 1.6.4 Actions 14 1.6.5 Gastric secretion 14 1.6.6 Smooth muscle effects 14 1.6.7 Cardiovascular effects 15 1.7 Histamine Receptors 15 1.7.1 The histamine H 1 receptor 16 1.7.2 The histamine H 2 receptor 19 1.7.3 The histamine H 3 receptor 21 1.7.4 The histamine H 4 receptor 24 References 30 Aim of the work 2. Enantioselective synthesis of histamine H 3 and H 4 receptor potential agonists based on γ-butyrolactones 2.1. Stereoselective Synthesis of γ-Butyrolactones (GBLs) 38 2.2 Synthesis of chiral bisoxazoline ligands 42 2.3 Cyclopropanation 45 2.4 Ozonolysis 47 2.4.1 Ozonolysis of alkenes 47 2.4.2 Mechanism of Ozonolysis 47 2.5 Sakurai Allylation 48 2.5.1 Determination of Stereochemistry 49 2.6 Retroaldol Reaction 50 2.6.1 Formation of the anti-substituted lactones 51 2.7 Introduction to tetrahydrofuran-imidazole based histamine H3 and H 4 receptor agonists 2.7.1 Synthesis of histamine H 3 and H 4 agonists by Kurihara and coworkers 55 2.8 Enantioselective Synthesis of histamine H 3 and H 4 receptor potential agonists using γ- butyrolactone (GBL)-55 58 2.8.1 Results and discussion 60 2.8.2 Synthesis of lactol 60 2.8.3 Synthesis of bisprotected imidazole 60 2.8.4 Synthesis of imidazole diols 60 2.8.5 The Mitsunobu reaction 61 2.8.6 Hydroboration 73 2.8.7 Hydroboration of cyclic buiding blocks 74 2.8.8 Phthalimidation 76 2.8.9 Synthesis of amines 77 2.9.0 Deprotection of TBDMS and Sulfonamide groups 77 Summary 2.9.2 Synthesis of cyclic building blocks for the human histamine H 3 and H 4 receptor potential agonists 79 2.9.3 Towards the synthesis of human histamine H 3 and H 4 receptor potential agonists 80 2.9.4 Synthesis of OUP-13 analogues from γ-butyrolactone GBL-64 82 2.9.5 Synthesis of cyclic building blocks for the human histamine H 3 and H 4 receptor potential agonists from GBL-64 83 2.9.6 Towards the synthesis of human histamine H 3 and H 4 receptor potential agonists from GBL-64 cyclic building blocks 84 2.9.7 Final steps towards the synthesis of histamine H 3 and H 4 receptor potential agonists 85 2.9.8 Conclusion 86 References 87 Aim of the work 3. Synthesis of histamine H 3 and H 4 receptor potential agonists by NBS mediated cyclopropane ring opening methodology 3.1.1 Introduction to cyclopropane ring opening methodology 94 3.1.2 Enantioselective synthesis of histamine H 3 and H 4 receptor potential agonists by furan cyclopropane ring opening methodology 97 3.1.3 Retrosynthetic analysis based on cyclopropanation of furan 97 3.1.4 Asymmetric cyclopropanation and hydrogenation 98 3.1.5 NBS mediated cyclopropane ring opening reactions 98 3.1.6 Protection of amine and selective hydrolysis of methyl ester 100 3.1.7 Synthesis of neuraminidase (NA) NA B inhibitor by Wang et al 101 3.1.8 Synthesis of key intermediate bromomethyl ketone by Arndt-Eistert elongation 101 3.1.9 Synthesis of histamine H 3 and H 4 receptor agonists by increasing the spacer length between imidazole and THF ring 102 3.2 Enantioselective synthesis of histamine H 3 and H 4 receptor potential agonists by imidazole-furan cyclopropane ring opening methodology. 3.2.1 Retrosynthetic analysis for the Histamine H 3 and H 4 receptor agonists based on Imidazole-Furan 103 3.2.2 Preparation of furan-imidazole 103 3.2.3 Synthesis of cyclopropane dihydrofuran-imidazole 104 3.2.4 Proposed synthesis of histamine H 3 and H 4 receptor potential agonists 104 3.3 Synthesis of Imifuramine and OUP-16 an alternative route to Kurihara synthesis 3.3.1 NH protection and Grignard reaction of imidazole aldehyde 106 3.3.2 Sharpless asymmetric dihydroxylation 106 3.3.3 Epoxidation and racemic dihydroxylation 108 Conclusion 108 References 108 4. Pharmacology 4.1 Determination of histamine receptor agonism and antagonism in GTPase assays 4.1.1 Generation of recombinant baculoviruses, cell culture and membrane preparation 110 4.1.2 Synthesis of [ γ-32 P]GTP 111 4.1.3 Steady-state GTPase activity assay with Sf9 insect cell membranes expressing histamine H 3 and H 4 receptors 111 4.1.4 Pharmacology activity for human histamine H 3 and H 4 receptor agonists 112 4.1.5 Graphs 112 References 117 Experimental part Synthesis of bis(oxazolines) 119 Synthesis of γ-butyrolactones 121 Synthesis of histamine H 3 and H 4 receptor potential agonists based on γ-butyrolactones 123 Synthesis of histamine H 3 and H 4 receptor potential agonists by furan cyclopropane ring opening methodology 128 Synthesis of histamine H 3 and H 4 receptor potential agonists by imidazole-furan cyclopropane ring opening methodology 132 Synthesis of histamine H 3 and H 4 receptor potential agonists based on imidazole aldehyde 134 Appendix 1 13 1 H and C NMR spectra 136 Acknowledgement 153 Curriculum vitae 156 Abbreviations AC adenylyl cyclase AChE acetylcholinesterase AD asymmetric dihydroxylation ADDP 1,1-(azodicarbonyl)dipiperidine AMP Adenosine Monophosphate 9-BBN 9-Borabicyclo[3.3.1]nonane Boc tert -butoxycarbonyl BOX bis(oxazoline) BuLi n-butyl lithium cAMP cyclic 3 ′, 5 ′-adenosine monophosphate Cbz benzyloxycarbonyl cDNA Complementary Deoxyribonucleic Acid CI chemical ionization CNS central nerves system COSY Correlation spectroscopy CREB cAMP response element binding protein DA Donar-Acceptor DAG Diacylglycerol DAO diamine oxidase DCM dichloro methane DEAD diethyl azodicarboxylate DHDT 4,7-dimethyl-3,5,7-hexahydro-1,2,4,7-tetrazocin-3,8-dione DIAD diisopropyl azodicarboxylate DIBAL-H diisobutylaluminium hydride DMF dimethyl formamide DMS dimethyl sulfide EA ethyl acetate EC 50 half maximal effective concentration ECL extracellular loops EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EDTA ethylendiaminetetraacetic acid EI electronic impact ionization Ent enantiomer GABA γ-aminobutyric acid GBL γ-butyrolactone GDP guanosine diphosphate GPCRs G-protein couple receptors GTP guanosine triphosphate h hour hH 1R human histamine H 1 receptor hH 2R human histamine H 2 receptor hH 3R human histamine H 3 receptor hH 4R human histamine H 4 receptor HMBC heteronulcear multiple bond correlation HNMT histamine N-methyltransferase HOBT Hydroxybenzotriazole HPLC high performance (pressure) liquid chromatography HRMS high resolution mass spectrometry HSQC heteronuclear single quantum coherence ICL intracellular loops IC 50 half maximal inhibitory concentration IgE immunoglobuline E IPC 2BH diisopinocampheylborane IP 3 inositol-1,4,5-trisphosphate IR infra red LA Lewis Acid LDA lithium diisopropyl amine mAChR muscarinic acetylcholine receptor MAO monoamine oxidase MAPK mitogen-activated protein kinase m-CPBA m-chloroperbenzoic acid MS molecular sieve NA neuraminidase NBS N-bromosuccinimide NIS N-iodosuccinimide NMO N-Methylmorpholine-N-Oxide NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY nuclear overhauser enhancement spectroscopy PKA protein kinase A PLC β phospholipase C β PNS peripheral nervous system PPARs Peroxisome proliferator-activated receptors R inactive state of a GPCR R* active state of a GPCR rac racemic ROM ring opening metathesis rpm revolutions per minute RT room temperature S.E.M. standard error of the mean SEMCl 2-(Trimethylsilyl)ethoxymethyl chloride Sf9 Spodoptera frugiperda insect cell line SM starting material Sp Sparteine TBAF tetrabutylammonium fluoride TBDMS tert-butyldimethylsilyl TEAD N, N, N', N'-tetraethyl azodicarboxylate TFA trifluoroacetic acid TIPA N,N,N',N'-tetraisopropylazodicarboxamide THF tetrahydrofuran TLC thin layer chromatography TMAD N, N, N', N'-tetramethylazodicarboxamide TMS trimethylsilyl TMSI trimethylsilyl iodide or iodo(trimethyl)silane Tris tris(hydroxymethyl)aminomethane Ts tosyl Chapter 1 1. Introduction 1.1 Medicinal Chemistry Medicinal chemistry is a scientific discipline at the intersection of chemistry and pharmacology, involved with designing, synthesizing and developing pharmaceutical drugs.1 It is a highly interdisciplinary science combining organic chemistry with biochemistry, pharmacology, molecular biology and molecular modeling. 2 The medicinal chemist attempts to design and synthesize a medicine or a pharmaceutically active compound, which has to satisfy the following criteria.
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  • Programme and Abstracts Book

    Programme and Abstracts Book

    0 33. Annual Meeting European Histamine Research Society 28. April – 2. May 2004 Düsseldorf / Köln, Germany 1 Dear Histaminologists 28. April 2004 Welcome to the 33rd Annual Meeting of the European Histamine Research Society at the Kardinal Schulte Haus near Cologne. Many of you have seen Cologne at the occasion of the 1993 meeting. The host institution is now located 30 km to the north: Department of Neurophysiology, Heinrich-Heine-University, Düsseldorf. Heinrich Heine, the patron of our University and one of our major poets, was born in Düsseldorf in 1797, he died in Paris in 1856. He wrote romantic poems often with a unique and unusual ironic or disillusioning twist at the end. He was the founder of the modern feuilleton and wrote a bit caustic about his birthplace. Nevertheless, Düsseldorf is worth a visit, there is interesting recent architecture (e.g. O’Gehry) a fine art collection (20th century) and a jewel in the south: Benrath castle and park (1777). We meet at the south end of “Bergisches Land” that we will explore during our excursion. The chemical industry founded by Bayer and Leverkus is around us: Leverkusen and Wuppertal. Düsseldorf is a village (1/2 Mio inhabitants) located at the mouth of the river Düssel into the Rhine. A formerly romantic part of the Düssel-valley has been praised by the 17th century pastor Neander and is consequently called the Neanderthal, the valley where the first bones of the Neandertal-man were found in 1856. Schloss Burg is a mediaeval castle, its 12th century appearance has been restored and a museum recalls the long bygone times.