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Fused and Spiro Furanones from Tetronic Acid Synthons: Oxa and Azacycles Featuring the Butenolide Ring

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Fused and Spiro Furanones from Tetronic Acid Synthons: Oxa and Azacycles Featuring the Butenolide Ring Fused and spiro furanones from tetronic acid synthons: Oxa and azacycles featuring the butenolide ring Vorgelegt von Juan-Manuel URBINA-GONZALEZ Dissertation zur Erlangung des Doktorgrades der Fakultät für Biologie, Chemie und Geowissenschaften Universität Bayreuth Bayreuth, 2006 Fused and spiro furanones from tetronic acid synthons: Oxa and azacycles featuring the butenolide ring Vorgelegt von Juan-Manuel URBINA-GONZALEZ Dissertation zur Erlangung des Doktorgrades der Fakultät für Biologie, Chemie und Geowissenschaften Universität Bayreuth Bayreuth, 2006 Erklärung Hiermit erkläre ich, dass ich die vorliegende Arbeit selbst verfasst und keine anderen als die angegebenen Quellen und Hilfsmittel verwendet habe. Ich habe nicht versucht (mit oder ohne Erfolg), eine Dissertation einzureichen oder mich der Doktorprufung zu unterziehen. Bayreuth, den 25. April, 2006 Juan Manuel Urbina González Acknowledgements Thanks to Prof. Dr. Rainer Schobert for his help, support and patience as supervisor throughout my PhD. Thanks to my colleagues: Dr. Gary J. Gordon, Dr. Carsten Jagusch, Dr. Claire M. Melanophy, Gillian Mullen, Ralf Stehle, Andreas Stangl, Bernhard Biersack, Alexander Gmeiner, Georg Rapp and Sebastian Knauer (PhD colleagues). To my colleagues in the lab Dr. Thomas Schmalz, Arno Bieser, Thomas Baumann, Andrea Schlenk, Ellen Wiedemann and Antje Grotemeier. Also to my students in Hauptpraktikum: André Wicklein, Sigrun Polier, Andreas Spoerl (†), Martin Hoffmann and Michael Mueller for their work. Thanks to the staff of OC1: Werner Kern, Rosie and Michael Glaessner, Kerstin Hannemann and Dr. Claus Hoelzel for their friendliness and help. I would also like to acknowledge the kindness of the Unverzagt’s group members especially Daniel, Nelson, Markus and Stefano. And heartfelt thanks to each of my family members who support me through the distance and have always been there for me. Since I know this part of the thesis will be read by everybody, I want to apologize in advance if I forgot your name – Do not worry, sure you are in some part of my mind. “.....We must consider another element which can almost be considered the most essential part of chemistry itself, which chemists boastfully, no doubt with reason, prefer above all others, and because of which they triumphantly celebrate, and to which they attribute above all others the marvelous effects of their science. And this they call the solvent." Hermannus Boerhaave (1668-1738); De menstruis dictis in chemia in Elementa Chemiae (1733) “Chemical synthesis always has some element of planning in it. But, the planning should never be too rigid. Because, in fact, the specific objective which the synthetic chemist uses as the excuse for his activity is often not of special importance in the general sense; rather, the important things are those that he finds out in the course of attempting to reach his objective” Robert Burns Woodward (1917-1979) This research was carried out from December 2001 to September 2005 in the Department of Organic Chemistry I, University of Bayreuth (Germany), under the supervision of Prof. Dr. Rainer Schobert. Vollständiger Abdruck der von der Fakultät Biologie, Chemie und Geowissenschaften der Universität Bayreuth zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Promotionsgesuch eingereicht am : 24. April 2006 Tag der mündlichen Prüfung : 11. Juli 2006 Erstgutachter : Prof. Dr. Rainer Schobert Zweitgutachter : Prof. Dr. Karl-Heinz Seifert Prüfungsausschuss : Prof. Dr. Helmut Alt Prof. Dr. Gerhard Platz (Vorsitz) Abbreviations d NMR chemical shift (in ppm) n IR absorption frequency band (in cm-1) n Tension vibration absorption (in IR) Abund. Abundance AcOEt Ethyl acetate ADMET acyclic diene metathesis polymerisation ATR Attenuated Total Refraction (IR) Bn benzyl br broad br. s. broad singlet (NMR multiplicity) d doublet (NMR multiplicity) CM cross-metathesis CMS Conventional Microwave Synthesis DBU 1,8-Diazabicyclo[5.4.0]undec-3-ene DCC N,N’-dicyclohexylcarbodiimide DCE dichloroethane DCM dichloromethane DIAD diisopropyldiazadicarboxylate DMAP dimethylaminopyridine DMF N,N-dimethylformamide EMS Enhanced Microwave Synthesis GC Gas Chromatography h hours HSQC Heteronuclear Single Quantum Correlation (NMR experiment) IR Infrared spectroscopy nJ coupling constant (in Hertz) through n bonds (NMR) m multiplet (NMR multiplicity) M Medium (intensity in IR spectra) MS Mass Spectrometry MW Microwave NMR Nuclear Magnetic Resonance NOESY Nuclear Overhauser Enhancement Spectroscopy Ph phenyl q quadruplet (NMR multiplicity) qu quintet (NMR multiplicity) Rf ratio of fronts (TLC) RCM Ring Closing olefin Metathesis ROM ring-opening metathesis ROMP ring-opening metathesis polymerisation RT room temperature s singlet (NMR multiplicity) S Strong (intensity in IR spectra) t triplet (NMR multiplicity) TLC Thin Layer Chromatography TMS Tetramethylsilane Ts tosyl VS Very strong (intensity in IR spectra) VW Very weak (intensity in IR spectra) W Weak (intensity in IR spectra) W Watt Table of Contents CHAPTER 1 – GENERAL SECTION 1 1.1 Introduction and objectives 1 1.2 Microwave irradiation in organic synthesis 2 1.3 Palladium assisted allylic alkylation – The Tsuji-Trost reaction 4 1.4 Ring Closing Olefin Metathesis using Grubbs’ first and second generation catalysts 8 CHAPTER 2 – ORIGINAL WORK – RESULTS AND DISCUSSION 12 2.1 Synthesis of a-hydroxy acids and a-hydroxy esters: A comparison between Fischer and Steglich Esterification 13 2.2 Synthesis of tetronic acids 17 2.3 Preparation of 3-acetyl tetronic acid using Ph3PCCO as acetyl source: Synthesis of pesthetoxin. 24 2.4 Microwave assisted pericyclic rearrangement: Synthesis of 3-allyl tetronic acids and spiro cyclopropane furandiones 29 2.5 Functionalisation of spiro cyclopropane furandiones. The cascade Conia – Ring opening reaction 36 2.6 4-O-alkylation in 3-allyl tetronic acid: Isoureas for the 4-O-benzyl protection and Mitsunobu esterification 41 2.7 Chemistry of 3-allyl tetronic acid derivatives 51 2.8 Synthesis of novel oxa heterocycles via Ring Closing Olefin Metathesis 67 2.9 The aza analogue case - from 4-aminobutenolides to fused furoazepines 74 2.10 Contribution to the synthesis of bakkenolide synthons 84 2.11 Contribution to the synthesis of furo[3,4-b]furan-2,4- diones. A potential access to (±) Canadensolide and related natural compounds 89 CHAPTER 3 – EXPERIMENTAL SECTION 98 3.1 Synthesis of a-hydroxy acids 99 3.2 Synthesis of a-hydroxy esters 101 3.3 Synthesis of O-alkyl-N,N’-dicyclohexylisoureas 109 3.4 Synthesis of 4-O-allyl tetronates 113 3.5 Synthesis of 5-alkyl tetronic acid derivatives 123 3.6 Synthesis of 3-acetyl-5-alkyl tetronic acids 125 3.7 Synthesis of 3-allyl tetronic acids 128 3.8 Synthesis of 5-oxa-spiro[2.4]heptane-4,7-diones 134 3.9 Synthesis of 4-hydroxy-3-(2-alkyloxypropyl)-5H-furan-2-ones 142 3.10 Synthesis of 3-allyl-4-benzyloxy-5H-furan-2-ones 154 3.11 Synthesis of 3-allyl-3-benzyl -furan-2,4-diones 161 3.12 Synthesis of 3-allyl-4-O-allyl tetronates 167 3.13 Synthesis of 3,3-diallyl-furan-2,4-diones 170 3.14 Synthesis of 3-alkyl-furan-2-ones via catalytic hydrogenation 177 3.15 Synthesis of dihydro-2H-furo[3,4-b]oxepin-6-ones and oxa-spiro[4.4]non-7-ene-1,4- diones 179 3.16 Synthesis of 4-allyl(phenyl)amino-5H-furan-2-ones 185 3.17 Synthesis of N-BOC (EtOOC) 4-allylamino furan-2-ones 191 3.18 Synthesis of tetrahydrofuro[3,4-b]azepin-6-ones 194 3.19 Synthesis of dispiro derivatives of tetronic acid 197 3.20 Synthesis of (4-benzyloxy-2,5-dihydrofuran-3-yl)-acetaldehyde and dimethyl acetal derivatives 198 3.21 Synthesis of 3-(2,2-dimethoxy-ethyl)-4-hydroxy-5H-furan-2-ones 202 3.22 Synthesis of (4-benzyloxy-2,5-dihydrofuran-3-yl)-acetic acid derivatives 204 3.23 Synthesis of diverse tetronic acid derivatives 207 CHAPTER 4 - SUMMARY 215 CHAPTER 4B - ZUSAMMENFASSUNG 222 CHAPTER 5 - REFERENCES 229 Appendix A 245 1 Chapter 1 General Section 1.1 Introduction and objectives The synthesis of natural products is a challenge and chemists have acquired the power through new synthetic methods, reagents, conditions, synthetic strategies to recreate exciting molecules from the natural world. Natural products isolated from diverse sources have shown vast utility in pharmaceutical chemistry, showing great benefit as biological tools and playing an important role in general industry. The molecules produced by living systems have always fascinated and inspired synthetic organic chemists. Particularly bioactive natural products, which show enormous value in pharmaceutical as well as general chemistry and play an important role in biology, have stimulated their ambition. As the chemists’ skills and equipment have advanced - for example regarding new synthetic methods and strategies, reagents and/or conditions - the compounds chosen for synthesis have become ever more challenging. So it is no surprise that today’s targets are found among the most "diabolically complex" natural substances ever discovered - the various secondary metabolites produced by plants and micro organisms for self-defense. Among the different chemical methodologies applied during the evolution of this thesis, the ring closing olefin metathesis must be mentioned as one of the most important. Robert Grubbs, Richard Schrock and Yves Chauvin were awarded the 2005 Nobel Prize in Chemistry for their contribution to the metathesis catalysts technology and the consequent enrichment in diverse chemistry areas of drug discovery, flavour / fragrances and polymers, which help scientists to discover new disconnections-connections and paths in synthetic organic chemistry. The use of RCM in the construction of new oxa (aza) heterocycles is discussed in sections 2.8 and 2.9. This work is principally concerned with the use of allyl tetronic acids as synthons for diverse natural products featuring a g-lactone. The synthetic paths developed should be used for the synthesis of diverse biologically active compounds. The objectives of this work were: 1.2 Microwave irradiation in organic synthesis 2 § Application of the domino addition – Wittig reaction between a-hydroxy esters and cumulated ylides for preparation of complex tetronates.
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