Keteneylidenetriphenylphosphorane as a Versatile C-2 Building Block Leading to Tetronic Acids with Potential Herbicidal and anti-HIV Activity by Gary John Gordon BSc. (Hons) Being a thesis submitted for the degree of Doctor of Natural Science (Dr. Rer. Nat.) to the Faculty of Biology, Chemistry and Geological Sciences of the University of Bayreuth Based on research carried out under the supervision of Prof. Rainer Schobert Organische Chemie I University of Bayreuth, (Germany) and The School of Chemistry The Queen’s University of Belfast, (UK) January 2004 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 19. Januar, 2004 Gary Gordon The following work was completed from February 2000 until September 2001 at The Queen’s University of Belfast (U.K.) and from October 2001 until January 2004 at the University of Bayreuth (Germany). This work was completed under the supervision of Prof. Schobert. I would like to thank Prof. Schobert for the interesting project and for all his encouragement and enthusiasm throughout the course of my research, for all his help and many hours of patience when I bombarded him with endless questions. I would also like to thank Prof. Schobert for the opportunity to come to Germany to complete my studies. Thanks are also due for his assistance in learning German (the language and the beer) and for encouraging us to travel and explore Germany. Acknowlegements I would like to thank Dr. Claus Hölzel for his help and assistance when we first arrived in Germany, for all the help with administration, computers and chemistry. Many thanks to all the staff of Bayreuth University in particular Rosie for administration assistance, sweets and cold remedies, Michael for MS analysis, Kerstin for NMR, Werner for chemicals and helping us get the labs sorted. Thanks also to Dr. Milius in inorganic chemistry for X-Ray measurements. Special thanks also to Carsten and Ralf for help with the German text translation. Also for trying to teach me some German and for all their help and assistence inside the lab and for all the fun times outside. Thanks also to Juan for his endless Columbian stories, jokes, general good humour and for all his help. To Carsten, Juan and Ralph, thanks for being good friends. Thanks also to Christoph for teaching me loads of German and for being a general source of entertainment while I should have been working. Thanks also to Thomas S., Andreas and Arno. I would also like to thank Marcus and Stefano and the entire group of Prof. Unverzagt who went out of their way to make us feel welcome when we first arrived in Bayreuth I would also like to acknowledge my undergraduate practical students Thomas Baumann, Bernhard, Julianna, Bigna and Daniel. Thanks for putting up with my endless demands for results for your friendliness and hard work. Thanks also to everyone in Germany who made us feel welcome when we landed in Bayreuth like three lost sheep. This work was begun in Belfast and naturally many people from Queens should be mentioned. Thanks to Prof. Boyd for introducing me to Prof. Schobert. To Dr. Stevenson and Dr. Vyle for all their help. Also thanks to the entire Queens staff, including Robert Boyd for MS measurements, to Richard for keeping the NMR’s running, Brian McKnight and Helen for administration. Thanks also to George and Phil fixing all my broken glassware for the tea and toast and all the laughs. To Clive and the two Johns in stores for endless hours of amusement and for eventually giving me what I called in for. Thanks also to Connor for all the chats and for stopping me from bleeding to death. Thanks also to Grant Smith and all the other characters around Queens. Thanks also to everyone who worked in LG48 including Daire, Andrew, Simone, Gavin, Dee and Stephanie. Working in LG48 could never be called dull and there was always plenty of craic. I would also like to say thanks to Hermann, Sven and Claire for all their help when I first arrived in the group. Thanks also to George Montgomery who had nothing to do with this thesis but who has been my best friend for ages and also for knowing next to nothing about chemistry. Special thanks must be reserved for Gillian for being a great friend from the first day we met. For giving me encouragement when everything went wrong (everyday), listening to me complain endlessly (everyday) and for keeping me sane (most of the time). For staying up late to help me finish this thesis, for all her advice and assistence. For making me take breaks and for showing me that there is indeed life outside the lab. This work is dedicated to my Mother, Donna, Debbie and Aimée Table of Contents 1 General section 1 1.1 Introduction and Objectives 1 1.2 Synthesis, structure and properties of keteneylidenetriphenylphosphorane 3 1.2.1 Synthesis of keteneylidenetriphenylphosphorane 3 1.2.2 Structure and properties of ketenylidenetriphenylphosphorane 5 1.2.3 Applications of keteneylidenetriphenylphosphorane 7 1.2.3.1 Reaction with halogen compounds 7 1.2.3.2 Reaction with acidic compounds 7 1.2.3.3 Reaction with Grignard compounds 8 1.2.3.4 Cycloadditions of keteneylidenetriphenylphosphorane 8 1.3 Synthesis and properties of tetronic acids 10 1.3.1 Properties of tetronic acids 10 1.3.2 Synthesis of tetronic acids 11 1.3.2.1 By Dieckmann condensation 11 1.3.2.2 By Blaise reaction 13 1.3.2.3 By tin chloride mediated cyclisation of α-hydroxy nitriles with β-dicarbonyl compounds 13 1.3.2.4 Tetronic acids from dioxolanones and α-lithioacetic acids 14 1.3.2.5 Tetronic acids by other cyclisation methods 14 1.4 Rearrangements in organic synthesis 17 1.4.1 Defintion of rearrangement reactions 17 1.4.2 Sigmatropic rearrangements 18 1.4.2.1 The Claisen rearrangement 18 1.4.3 The Conia rearrangement 20 1.5 Cyclopropanes in organic synthesis 22 1.5.1 Properties of cyclopropanes 22 1.5.2 Synthesis of cyclopropanes 22 1.5.2.1 By halomethylmetals 22 2.0 Disscusion 24 2.1 Synthesis of 3,5-dispirodihydrofuran-4,12-diones 24 2.1.1 Synthesis of 3,5-dispirodihydrofuran-4,12-dione 24 2.1.2 Investigations into the mechanism of 3,5-dispirodihydrofuran -4,12-dione formation 25 2.1.3 Optimisation of 3,5-dispirdihydrofuran-4,12-dione formation 28 2.1.4 Synthesis of Functionalised 3,5-dispirodihydrofuran-2,4-diones 30 2.1.4.1 Synthesis of functionalised cinnamyl alcohols 30 2.1.4.2 Synthesis of α-hydroxycarboxylic acids 32 2.1.4.3 Attempted synthesis of α-aminocyclohexane carboxylic acid 33 2.1.4.4 Esterification of α-hydroxycarboxylic acids using isoureas 33 2.1.4.5 Esterification of α-hydroxycarboxylic acids by other methods 36 2.1.4.6 Synthesis of 4-allyl-5-spirotetronates 37 2.1.4.7 Controllable synthesis of functionalised 3,5-dispirodihydro- furan-4,12-diones and 3-phenylallyl-5-spiro-tetronic acids. A comparison between thermal and microwave synthesis 38 2.1.5 Ring opening of 3,5-dispirodihydrofuran-4,12-dione with nucleophiles 40 2.1.5.1 Ring opening with oxygen nucleophiles 40 2.1.5.2 Ring opening with amine nucleophiles 44 2.1.5.3 Ring opening with thiols 47 2.1.5.4 Reaction with other carbon nucleophiles 47 2.1.5.5 Attempted ring opening with diazomethane 50 2.1.5.6 Attempted ring opening with enamines 51 2.1.5.7 Attempted ring opening with imines 52 2.1.5.8 Ring opening with phosphorous ylides 53 2.1.5.9 Hydrogenation of 3,5-dispirodihydrofuran-2,4-diones 55 2.1.6 Attempted reaction of 1-(2-chlorophenyl)-2-methyl-11oxadispiro [2.1.5.2]dodecane-4,12-dione with magnesium 56 2.1.7 Preliminary results from biological tests 57 2.2 Derivatives of 3-Allyl-tetronic Acids 58 2.2.1 Cyclopropanation of 5-spiro-(3-α-phenylallyl)-tetronic acids 58 2.2.2 Hydrogenation of 5-spiro-3-phenylallyl tetronic acid 60 2.2.3 Iodocyclisation of 3-allyl tetronic acids 60 2.3 Rearrangements of Tetronates Without a Cinnamyl Residue and Spirocyclopropane Trapping Reactions 63 2.3.1 Cyclisation of a pentadienyl tetronate 63 2.3.2 Attempted rearrangement of a 4-O-alkyne tetronate 64 2.3.3 Abnormal claisen rearrangements of tetronates 65 2.3.4 Trapping of spirocyclopropane intermediates 67 2.3.5 Attempts to dehydrate 3-(2’-alkoxy)tetronic acids 76 2.3.6 Attempts to react 3,4,5-trisubstituted butyrolactams with 1 77 2.3.7 Attempts to trap spirocyclopropanes with coumarin systems 79 2.3.7.1 O-Alkylation of 4-hydroxycoumarins 79 2.3.7.2 Rearrangments of 4-alkylcoumarins 79 2.3.7.3 Ring trapping of coumarin cyclopropanes 80 2.4 Investigations into the Baylis-Hillman alcohols 81 2.4.1 Attempts to synthesize Baylis-Hillman isoureas 82 2.4.2 Other attempts to esterify Baylis-Hillman alcohols with α-hydroxyacids 83 2.4.3 Formation of rearranged Baylis-Hillman α-hydroxy esters 84 2.4.4 Attempts to react rearranged Baylis-Hillman esters with 1 86 2.4.5 Attempts to alkylate tetronic acids with Baylis-Hillman alcohols 86 2.5 Three component synthesis of (E)-α,β-unsaturated amides 87 3.0 Experimental section 89 3.1 General 89 3.2 Synthesis of keteneylidenetriphenylphosphorane 1 89 3.3 Synthesis of 3, 5-dispirodihydrofuran-2,4-diones and tetronic acids 91 3.3.1 Synthesis of fuctionalised cinnamyl alcohols 91 3.3.2 Synthesis of α-hydroxy-carboxylic acids 92 3.3.3 Synthesis of O-allyl-isoureas 93 3.3.4 Synthesis of α-hydroxy-esters 97 3.3.5 Synthesis of tetronates using keteneylidenetriphenylphosphorane 1 112 3.3.6 Synthesis of Claisen rearranged tetronic acids 125 3.3.7 Synthesis of 3,5-dispirodihydrofuran-2,4-diones 137 3.4 Ring opening of 3,5-dispirodihydrofuran-4,12-diones 119 with nucleophiles 146 3.4.1 Ring opening of spirocyclopropyldihydrofuran-4,12-diones 119 with oxygen nucleophiles 146 3.4.2 Ring opening of spirocyclopropyldihydrofuran-4,12-diones 119 with nitrogen nucleophiles 156 3.4.3 Ring opening of spirocyclopropyldihydrofuran-4,12-diones 119 with thiols 161 3.4.4 Ring opening of spirocyclopropyldihydrofuran-4,12-diones 119 with Grignard reagents 163 3.4.5.