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Chapter 1 Tropone and Tropolone

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Chapter 1 Tropone and Tropolone School of Molecular and Life Sciences New Routes to Troponoid Natural Products Jason Matthew Wells This thesis is presented for the Degree of Doctor of Philosophy of Curtin University November 2018 Declaration To the best of my knowledge and belief this thesis contains no material previously pub- lished by any other person except where due acknowledgement has been made. This thesis contains no material which has been accepted for the award of any other degree or diploma in any other university. Signature: Date: i Abstract Malaria is an infectious disease found in humans and other animals, it is caused by a single-cell parasite of the Plasmodium genus with many different substrains. Of these, P. falciparum is the most deadly to humans causing the majority of deaths. Although research into the area of antimalarial compounds is wide spread, few have been devel- oped with new structural features. Cordytropolone 37 is a natural product isolated in 2001 from the insect pathogenic fungus Cordyceps sp. BCC 1681 and has been shown to have antimalarial activity against P. falciparum. It has a structure unrelated to antimalarial com- pounds currently used in therapy. It does not contain a peroxide bridge as with artemisinin 25 or quinoline rings as with chloroquine 22. This unique structure indicates that it could possibly interact with the malaria parasite in a fashion unlike current treatments. In order for cordytropolone to be further developed as a potential treatment, it must first be synthe- sised in a laboratory environment. This study attempts to develop the first total synthesis of cordytropolone. H HO O N O O N O N H H H O O Cl HO O 22 25 37 Figure 0.0.1: Cordytropolone 37 has a unique structure compared to the current common malaria treatments The first method investigated towards the total synthesis of cordytropolone involved an intramolecular Buchner ring expansion. One of the key features of cordytropolone is its bicyclic structure containing a 7 and 5-membered ring. Using diazo compounds such as 163 with a copper catalyst, bicyclic cycloheptatrienes such as 208 were able to be produced. The tropylium ion 210 was then formed via hydride abstraction, followed by nucleophillic aromatic substitution to give tropone 211. Although the approach worked for tropolone 211 , it was unsuccessful in forming sufficiently substituted tropolones. ii O O N2 Cu(acac)2 O DCM O O O Reflux 163 208 Ph3CPF6 O + O H /H2O 44% O O O O (3 steps) 211 210 Scheme 1: Buchner ring expansion followed by oxidation via hydride abstraction to pro- duce tropone 211 The other method investigated involved a Diels-Alder reaction between a thiophene-1,1- dioxide and a cyclopropene to produce a cycloheptatriene. In this reaction the diene, 3,4- dichlorothiophene-1,1-dioxide 244 goes through a [4 + 2] cycloaddition with the dienophile cyclopropene. This produces the intermediate 356 which spontaneously eliminates sulfur dioxide to form cycloheptatriene 247. The tropylium ion 357 was then formed which un- dergoes nucleophillic aromatic substitution to produce chlorotropone 54. Chlorotropone 54 was then converted to tropolone 3 by acetolysis followed by hydrolysis. This is the first instance of tropolone synthesis via a Diels-Alder reaction and was expanded to produce several cycloheptatrienes, tropones and tropolones. iii Cl O2 Cl S Cl -SO2 SO2 Cl DCM/THF 42% Cl RT Cl 244 356 247 AcOH DDQ, Reflux 61% HO Cl Cl O 1. AcOH/ATA 100 °CO Cl 2. AcOH/H2O 100 °C 35% 3 (2 Steps) 54 357 Scheme 2: Diels-Alder reaction between a thiophene dioxide and a cyclopropene produces a cycloheptatriene iv Acknowledgements I would like to thank my primary supervisor Dr Alan Payne. Thanks for taking me on as a student and for all your help over the past few years. Also thanks for taking my light hearted jibes as the jokes they were intended to be. Also thanks are deserved by my other two supervisors, Associate Professor Mauro Mocerino and Dr Hendra Gunosewoyo for all their help as well. Thanks should also go to the rest of the Curtin University Organic and Medicinal Research Group for their continued assistance over the years. There are some great people that I have worked with and I wish them all well. Thank you also to Dr Bruno Bašic for the fun times in the lab and the great conversations and all the advice you offered whilst you were here. You also deserve acknowledgement for convincing me to start a PhD, dubious advice, in hindsight. Also thank you to Dr Frankie Busetti of the Thermofisher Proof of Concept Lab, Edith Cowan University for performing the HRMS analysis. Thank you to my family, for support and laughs, and for puttingup with mebeing a student for a decade. Finally, to Lauren White, your contributions to my time at Curtin University has been immeasurable and so, in lieu of listing everything, I simply wish to thank you for being Lauren White. This research was supported by the contribution of an Australian Government Research Training Program Scholarship. v Contents 1 Tropone and Tropolone 1 1.1 MalariaandTropolones........................... 8 1.2 Synthesis of Cycloheptatrienes, Tropones and Tropolones......... 12 1.3 ProposedSynthesisofCordytropolone . .... 32 2 Intramolecular Buchner Ring Expansion via in situ Generated Diazo Com- pounds 34 3 Intramolecular Buchner Ring Expansion via Diazoesters 43 4 Diels-Alder Reaction of 3,4-Dichlorothiophene-1,1-dioxide and Substituted Cyclopropenes 72 5 General Conclusions 123 6 Experimental 127 Bibliography 171 A NMR Spectra 189 vi List of Abbreviations acac Acetyl acetone ACHN 1,1´-Azobis(cyclohexanecarbonitrile) AIBN Azobisisobutyronitrile Aq. Aqueous Ar Aryl ATA Acetyl Trifluoroacetate Boc tert-Butyloxycarbonyl CAN Ceric ammonium nitrate cat. Catalytic/catalyst CDCl3 Deuterated chloroform Conc. Concentrated COSY Correlation Spectroscopy d Doublet DCE Dichloroethane DCM Dichloromethane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DIAD Diisopropyl azodicarboxylate DIBAL Diisobutylaluminum hydride DMF Dimethylformamide DMSO Dimethylsulfoxide eq. Equivalents ESI Electron spray ionisation FTIR-ATR Fourier transform infrared - attenuated total reflectance HRMS High resolution mass spectrometry hrs Hours hv Photochemical reaction IBX 2-Iodoxybenzoic acid IR Infrared m Multiplet MP Melting point NR No reaction observed NBS N-Bromosuccinimide NMR Nuclear magnetic resonance PCC Pyridinium chlorochromate ppm Parts per million q Quartet RT Room temperature vii s Singlet sat. Saturated t Triplet TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography δ Chemical shift in ppm Δ Heating viii Chapter 1 Tropone and Tropolone Nonbenzenoid aromatic compounds are compounds which exibit aromatic character, but do not contain a benzene ring. While benzene contains a six membered ring, there are several seven membered ring containing compounds that exibit aromatic character. Tro- pone (1) is one such example. Tropone (1) consists of a seven membered ring containing three alkene groups and a carbonyl. The aromatic character of tropone and its derivatives comes from their ability to form the tropylium cation 2, a seven membered ring system with an aromatic 6π electron system, meeting Huckel’s Rule. The tropylium cation allows tropone and derivatives to undergo reactions such as nucleophilic aromatic substitution.1 O O 1 2 Tropone Tropyllium Cation Figure 1.0.1: The two main resonance contributors of tropone (1) 2-Hydroxytropone was first postulated by Dewar in 1945 as a substructure of the mould metabolite stipitatic acid 4. Dewar named this particular substructure (3), tropolone.2 Later that year, Dewar also postulated that tropolone made up one of the rings of colchicine 5, a natural product of great interest at the time (Figure 1.0.2),2 Although Dewar’s asserta- tion regarding the structure of colchicine was debated by Cook,3 Dewar was later proven 1 to be correct with the stucture of stipitatic acid confirmed by Corbett et al.4 and the struc- ture of colchicine later confirmed by King et al.5 O HO HO O O O O O O O OH HN HO O 3 4 5 Tropolone Stipitatic Acid Colchicine Figure 1.0.2: The compounds stipitatic acid 4 and colchicine 5 both contain the tropolone 3 structure In 1948, Erdtman and Gripenberg isolated several tropolone compounds from the heart wood of Thuja plicata.6 These compounds were named thujaplicins and indentified as an isopropyl tropolone 6, leading credence to Dewar’s claims, although, β-thujaplicin 6 (hi- nokitiol) was originaly isolated by Nozoe from Taiwanese hinoki in 1936.7 Later, Haworth et al. presented evidence that the compound purpurogallin 7 contained a benztropolone structure.8 These discoveries, along with Dewar’s assertations, stimulated interest into tropolone chemistry. Following this, some of the first tropolone derivatives to be synthe- sised in the lab were 3,4-benztropolone 8 by Cook et al.9, 4,5-benztropolone 9 by Tarbell et al.10 and purpurogallin 7 by Caunt and Hayworth et al.11 (Figure 1.0.3). HO OH HO HO HO O O OH O O HO 6 7 8 9 ß-Thujaplicin Purpurogallin 3,4-benzotropolone 4,5-benzotropolone Figure 1.0.3: More compounds were determined to contain the tropolone structure with both 8 and 9 among the first to be synthesised Tropolone 3 has shown activity as an insecticide, antifungal, metalloprotease inhibitor,12 2 grape polyphenol oxidase inhibitor,13 and mushroom tyrosinase inhibitor.14,15 Many sub- stituted tropolones and tropolone containing structures also exhibit biological activity.16 For example, β-dolabrin 10 (Figure 1.0.4) is another natural product found in western red cedar trees (Thuja plicata)17 and has been shown to display phytogrowth inhibition18 and antifungal activity.19 HO O 10 ß-dolabrin Figure 1.0.4 The thujaplicins (isopropyltropolones) are also found in Thuja plicata and are one of the more widely researched tropolone familes (Figure 1.0.5).
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