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Watson, Christine Anne Louise. "Total synthesis of bistheonellic acid B/ total synthesis of scytophycin C." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627216.
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Mitra, Soumya. "Total synthesis of gomisin O asymmetric total syntheses of eupomatilones 1, 2 and 5; and studies towards total synthesis of mayolide A /." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1189449580.
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Chan, Bryan Ka Ip. "Total synthesis of streptonigrone." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31581.
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This thesis describes the total synthesis of streptonigrone. The centerpiece of our route to the target molecule is a facile one-pot construction of 3-alkylpyridones developed in our laboratory. The quinoline segment of the target molecule, prepared through a Conrad-Limpach synthesis, was condensed with 2-benzyloxy-3,4-dimethoxybenzaldehyde to afford a chalcone intermediate suitable for our pyridine-forming reaction. The assembly of the central 3-methylpyridone ring of the natural product was then accomplished through the merger of the chalcone with 2-cyanopropanamide. Functionalization of the pyridone was then completed through an anionic sequence.Science, Faculty of
Chemistry, Department of
Graduate
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Shelton, Ruth E. "Total synthesis of peduncularine." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526451.
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Sparling, Brian Andrew. "Total Synthesis of Hyperforin." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11098.
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Hyperforin is the component of the medicinal herb St. John's Wort (Hypericum perforatum) responsible for its antidepressant activity. It works by blocking the reuptake of a variety of neurotransmitters through a unique mechanism of action and may be a critical lead for the treatment of depression and possibly other human diseases. However, the therapeutic potential of hyperforin is severely handicapped by its poor water solubility, facile oxidative degradation, and potent activation of pregnane X receptor, leading to increased expression of many genes involved in xenobiotic metabolism. Access to a wide variety of hyperforin analogs is critical for mitigating these shortcomings while maintaining therapeutic activity. While limited semisynthetic manipulation of isolated hyperforin is feasible, total synthesis is the only possible means of obtaining diverse hyperforin analogs.Chemistry and Chemical Biology
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Baldwin, Ian Robert. "Total synthesis of acetoxyodontoschismenol." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284653.
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Chen, Cheng Yi. "Total synthesis of (+)-stenine /." The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487684245465948.
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Li, Fang. "Total Synthesis of (-)-Acutumine." BYU ScholarsArchive, 2009. https://scholarsarchive.byu.edu/etd/2193.
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Acutumine is a tetracyclic alkaloid isolated from the Asian vine Menispermum dauricum with selective T-cell cytotoxicity and antiamnestic properties. We have developed a total synthetic route to this congested alkaloid, during which we also found a novel, stereoselective radical-crossover reaction that combines an intramolecular radical conjugate addition with a subsequent enolate hydroxylation. Key features of this synthesis also include a reagent-controlled diastereoselective ketone allylation, an anionic oxy-Cope rearrangement to form a congested quaternary sterocenter, a pyridine-mediated selective ozonolysis, and a Lewis acid promoted Michael-type cyclization.
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Phillips, Andrew. "Studies towards the total synthesis of patellazole B." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269364.
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The patellazoles are a family of marine polyketide natural products first isolated from Lissoclinum patella in 1988 by both the Moore and Ireland groups. They exhibit significant cytotoxicity against the HCT 116 human colon tumour cells. To date however, their full 3D stereostructure have yet to be elucidated, which has hindered their development as potential drugs, and hampered full investigation into their biological mechanism of action and has deterred total synthesis efforts. This thesis describes synthetic efforts towards Patellazole B, which exhibits the highest potency of the three main congeners. To fully elucidate the structure and renew interest in the patellazoles as anticancer compounds, we have developed a flexible and modular synthesis that aims to define the unknown stereocentres within the pertinent region and allow for rapid fragment union. Compound 36 has been chosen as an initial target for NMR comparison studies. The synthesis of all eight diastereomers of this macrocycle should aid determination of the four unknown stereocentres. Chapter 2 describes the synthesis of the C1–C12 fragment, focusing on the configuring of the C5 methyl stereocentre and the construction of the C7-C10 stereotetrad via a boron-mediated anti aldol with an in-situ reduction. In the third chapter, the synthesis of the C13-C19 fragment is outlined. A boron-mediated glycolate aldol has been used to install the C16-C17 anti stereochemistry and a substrate-controlled reduction at C15 delivered the hydroxyl with high diastereoselectivity. Studies into the C¬17¬ methylation are also described. Chapter 4 describes the synthesis of one possible diastereomer of the C20-C25 fragment, as a template for the preparation of the other 7 possible diastereomers. The route therefore employs only catalyst based control methods to install the three stereocentres, utilising a Sharpless asymmetric epoxidation and Evans aldol to construct the stereotriad. The 22R, 23S, 24S diastereomer has been initially chosen to investigate the later chemistry. Chapter 5 contains discussion of the ongoing work investigating fragment union and formation of the macrocycle. A Heck coupling reaction has been employed to construct the C19-C20 bond and a Suzuki coupling reaction has been developed to facilitate the C12-C13 bond formation. These two cross couplings have delivered the C1 - C25 fragment, 360, the final compound reported in this thesis, which is three steps away from the completed macrocycle and six from compound 36. The experimental procedures and spectroscopic characterisation of the synthesised intermediates can be found in Chapter 6 and the Appendix.
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Rivas, Fatima R. "Synthetic studies towards the total synthesis of norzoanthamine." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3221252.
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Thesis (Ph. D.)--University of California, San Diego, 2006.Title from first page of PDF file (viewed September 8, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Rahn, Volker Siegfried. "Synthetic studies towards the total synthesis of (-)-alstonerine." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401724.
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Viseux, Eddy Michel Elie. "Synthetic studies towards a total synthesis of roseophilin." Thesis, University of Sussex, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420509.
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Charles, Mark David. "Synthetic studies toward a total synthesis of morphine." Thesis, University of Sussex, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272077.
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Chen, Yong. "Synthetic Studies on Total Synthesis of Azaspiracid-3." The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385895424.
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Shamim, Khalida. "I. Total synthesis of stemonine. II. Studies towards the total synthesis of kendomycin." [Bloomington, Ind.] : Indiana University, 2006. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3243781.
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Thesis (Ph. D.)--Indiana University, Dept. of Chemistry, 2006.Title from PDF t.p. (viewed Nov. 18, 2008). Source: Dissertation Abstracts International, Volume: 67-12, Section: B, page: 7099. Adviser: David R. Williams.
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Goh, Simin Shermin. "Total synthesis of rubriflordilactone A." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:796adfdf-b4d5-474d-85a6-d2e19c1085db.
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Rubriflordilactones A and B are highly oxygenated nortriterpenoid natural products isolated from Schisandra rubriflora. The latter is of particular biological interest as it shows significant anti-HIV activity. Two transition metal-catalysed cascade cyclisation approaches for the formation of the CDE rings of the rubriflordilactones were developed. Palladium-catalysed cyclisation of bromoenediynes and cobalt-catalysed triyne cyclotrimerisation both transform acyclic precursors into 7,6,5-bisannelated arenes in a single step. Two enantioselective syntheses of the AB ring fragment common to both rubriflordilactones, with bromoene or alkyne functional groups required for the respective cyclisation methods, are described; along with the refinement of a route to the CDE diyne fragment of rubriflordilactone A. From these fully functionalised bromoenediyne and triyne substrates, both metal-catalysed cyclisation methods were successful; these strategies converged on a late-stage intermediate bearing the ABCDE ring system of rubriflordilactone A. Construction of the F ring, followed by attachment of the G ring by an intriguing oxo-carbenium ion addition reaction completed two enantioselective total syntheses of (+)-rubriflordilactone A.
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Shah, Rushabh Surendra. "Total syntheses of the nakinadine alkaloids." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:c022e538-9ff8-4914-8c17-dc0b3ed1fbae.
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This thesis is concerned with the development of methodology for the asymmetric syntheses of the nakinadine family of marine alkaloids and through these synthetic endeavours, seeks to confirm the structure and assign the relative and absolute configurations of these alkaloids for the first time.
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Hassan, Haitham. "Total synthesis of eucophylline : a free-radical approach towards total synthesis of cytotoxic leucophyllidine." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0153/document.
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La thèse décrit la première synthèse totale de l'Eucophylline, le fragment sud de l'alcaloïde Leucophyllidine récemment isolé à partir de Leuconotisgriffithii et L. eugenifolius. La synthèse en 10 étapes comprend une nouvelle méthode d’accès au squelette azabicyclo[3.3.1]nonane par un processus de carbooximation radicalaire d'oléfines à trois composants. Au cours de ces études, nous avons également isolé des énamines présentant des stabilités inhabituelles résultant de leur conformation bicyclique tendue. La synthèse de la partie éburnane, le fragment nord de la Leucophyllidine, a été réalisée grâce à une nouvelle réaction radicalaire de carbo-cyanation à trois composants. Cette réaction radicalaire s'est révélée efficace pour installer le groupement fonctionnel nitrile sur des oléfines, et éventuellement former des centres quaternaires, notamment dans des structures complexes, puisqu'une bonne tolérance aux différents groupes fonctionnels a été observée. Le couplage biomimétique entre le squelette éburnane et l'Eucophylline a finalement été étudié en utilisant des modèles de structure similaire. Les résultats préliminaires de cette étude ont montré que l'absence d'effet gem-diméthyle dans le modèle éburnane empêche probablement la formation de l'imine cyclique,intermédiaire-clé dans le couplage désiréThe thesis describes the first total synthesis of Eucophylline, the south fragment of the Leucophyllidine alkaloid recently isolated from Leuconotis griffithiiand L. eugenifolius. The 10-step synthesis encompasses a new straight forward method to access to the azabicyclo[3.3.1]nonane skeleton through a free-radical three-component olefinic carbo-oximation process. During these studies, we also isolated enamines exhibiting unusual stabilities resulting from their strained bicyclicconformation. The synthesis of the Eburnane part, the north fragment of Leucophyllidine, was developed relying on a new free-radical three-component Carbo-Cyanation reaction. This new reaction showed high tolerance toward different functional groups and provided an efficient mean to install the nitrile group in complex structures and to introduce quaternary centers. The biomimetic coupling between the Eburnane and Eucophylline fragments was finally studied using structurally similar models. Preliminary results of this model study showed that absence of a gemdimethyleffect in the Eburnane model probably prevents the formation of the cyclicimine, key intermediate for the desired coupling
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Morris, Joanne Charleen. "The total synthesis of chamuvarinin." Thesis, University of St Andrews, 2013. http://hdl.handle.net/10023/4114.
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In 2004, the polyketide natural product, chamuvarinin (72) was isolated by Laurens et al. from the roots of Uvaria chamae, a member of the Annonaceae plant family. This unique tetrahydropyran containing acetogenin displayed potent levels of cytotoxic activity against the KB 3-1 cell line with an ED50 value of 0.8 nM. Upon initial isolation the relative and absolute stereochemical assignment of chamuvarinin (72) was unable to be readily achieved through ¹H and ¹³C NMR analysis. The initial synthetic route described herein has enabled the relative and absolute stereochemical determination of chamuvarinin (72) through the first total synthesis completed in 20 longest linear steps in 1.5% overall yield. A revised synthetic strategy towards chamuvarinin (72) was completed in 17 longest linear steps in 2.2% overall yield. The revised route facilitated the assembly of non-natural chamuvarinin-like analogues and their trypanocidal and cytotoxic activities have been assessed. The synthesis of these analogues has formed the basis of a more focussed study through the design and synthesis of simplified triazole (295), isoxazole (325) and butenolide triazole (305) analogues as potential Trypanosoma brucei (causative agent in African Sleeping sickness) inhibitors.
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Lineswala, Jayana P. "Total synthesis of lavendamycin amides." Virtual Press, 1996. http://liblink.bsu.edu/uhtbin/catkey/1036197.
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The synthesis of 7-N-acetyldemethyllavendamycin butyl amide (47), 7-Nacetyldemethyllavendamycin isopropyl amide (48), 7-N-acetyldemethyllavendamycin amide of piperidine (49), 7-N-acetyldemethyllavendamycin amide of pyrrolidine (50), 7N-acetyldemethyllavendamycin amide of morpholine (51), demethyllavendamycin butyl amide (52), demethyllavendamycin amide of pyrrolidine (53), and demethyllavendamycin amide of morpholine (54) are described. Pictet Spengler condesation of 7-acetamido-2formylquinoline-5,8-dione (28) with tryptophan butyl amide (66), tryptophan isopropyl amide (67), tryptophan amide of piperidine (68), tryptophan amide of pyrrolidine (69), and tryptophan amide of morpholine (70) in an anisole - pyridine solution directly afforded the five lavendamycin amides 47-51. Compounds 52, 53, and 54 were obtained by hydrolysis of 47, 50, and 51 with 70% H2SO4-H20 solution.Aldehyde 28 was prepared according to the following general procedure.Nitration of 8-hydroxy-2-methylquinoline (30) yielded 8-hydroxy-2-methyl-5,7 dinitroquinoline (31). Compound 31 was then hydrogenated and acylated with acetic anhydride to yield 5,7-diacetamido-2-methyl-8-acetoxyquinoline (33). Compound 33 was oxidized by potassium dichromate to give 7-acetamido-2-methylquinoline-5,8-dione (27). Treatment of 27 with selenium dioxide in refluxing 1,4-dioxane afforded compound 28.Compounds 66, 67, 68, 69, and 70 were synthesized from compounds 61,62, 63, 64, and 65. These compounds were deprotected with ammonium formate in the presence of 10% Palladium on charcoal in methanol under an argon balloon at atmospheric pressure.Compounds 61, 62, 63, 64, and 65 were obtained from 58 with butylamine, isopropylamine, piperidine, pyrrolidine, and morpholine respectively in the presence of triethylamine under an argon balloon at atmospheric pressure.Compound 58 was synthesized by the reaction of N-carbobenzyloxytryptophan, with N-hydroxy succinimide, in the presence of N-dicyclohexylcarbodimide in dried and distilled dioxane under an argon balloon at atmospheric pressure.The structures of the novel compounds 58, 47, 48, 49, 50, 51, 52, 53, and 54 were confirmed by 1H NMR, IR, EIMS, and HRMS.The structures of protected and deprotected amides 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70 were also confirmed by 1 H NMR and IR spectroscopy.Department of Chemistry
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Karki, Rajesh. "Total synthesis of oxygenated lavendamycin analogs." Virtual Press, 1998. http://liblink.bsu.edu/uhtbin/catkey/1115420.
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The synthesis of 7-acetyl-11'-benzyloxylavendamycin methyl ester (47), 7acetyl-11'-hydroxylavendamycin methyl ester (48), 11'-hydroxylavendamycin methyl ester (49), 11'-benzyloxylavendamycin methyl ester (50), are described. Pictet-Spengler condensation of 7-N-acetyl-2-formylquinoline-5,8-dione (26) with 5-benzyloxytrytophan methyl ester (45) or 5-hydroxytryptophan methyl ester (46) in dry xylene or anisole directly afforded lavendamycin analogs 47 or 48. Compound 49 was obtained by hydrolysis of 48 with 70% H2SO4 - H2Osolution. Compound 50 was obtained by hydrolysis of 47 with sodium carbonate solution.Aldehyde 26 was prepared according to the following general procedure. Nitration of 8-hydroxy-2-methylquinoline (28) yielded 8-hydroxy-2-methyl5,7-dinitroquinoline (29). Compound 29 was then hydrogenated and acylated with acetic anhydride to yield 5,7-bis(diacetamido)-8-hydroxy-2methylquinoline (31). Compound 31 was oxidized to give 5,8- dione 25 by using potassium dichromate. Treatment of compound 25 with selenium dioxide in refluxing 1,4-dioxane yielded compound 26.3 (Isopropylaminoethylidene)-6,7-dimethoxyindole (39) was prepared via the following procedure. Acylation of vanillin (32) with acetic anhydride yielded acetylvanillin (33). Compound 33 was nitrated and hydrolyzed to give 2nitrovanillin (35). Compound 35 was then methylated using dimethyl sulfate to produce 2-nitroveratric aldehyde (36). Condensation of compound 36 with nitromethane yielded 3,4-dimethoxy-2-f3-nitrostyrene (37). Ammonium formate reductive cyclization of compound 37 in refluxing methanol in the presence of a catalytic amount of 10% palladium on charcoal yielded 6,7dimethoxyindole (38). Electrophilic substitution reaction of compound 38 with ethylideneisopropylamine (41) in dry toluene yielded compound 39.Methyl (2RS, 3SR)-2-amino-3-[3-(5-benzyloxyindolyl)]butanoate (45) and methyl (2RS, 3SR)-2-amino-3-[3-(5-hydroxyindolyl)]butanoate (46) were obtained following the procedure described below. Electrophilic substitutionreaction of 5-bezyloxyindole (40) with ethylideneisopropylamine (41) in dry toluene yielded 3-(isopropylaminoethylidene)-5-benzyloxyindole (42). Condensation of compound 42 with methyl nitroacetate (43) in dry toluene gave methyl 3-[3-(5-benzyloxyindolyl)]3-nitrobutanoate (44). Hydrogenation of compound 44 in the presence of Raney nickel and trifluoroacetic acid in ethanol yielded methyl (2RS, 3SR)-2-amino-3-[3-(5-benzyloxyindolyl)] butanoate (45). Hydrogenation of compound 44 in the presence of 10% palladium on charcoal and trifluoroacetic acid in ethanol yielded methyl (2RS, 3SR)-2-amino-3-[3-(5-hydroxyindolyl)] butanoate (46).The structures of the novel compounds were confirmed by 1H NMR, IR, and HRMS or elemental analysis.Department of Chemistry
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Liu, Qingsong. "Large scale total synthesis of apoptolidinone and progress towards the total synthesis of ammocidin." [College Station, Tex. : Texas A&M University, 2006. http://hdl.handle.net/1969.1/ETD-TAMU-1054.
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Zhang, Yan Crimmins Michael T. "Total synthesis of (-)-mucocin and studies toward the asymmetric total synthesis of brianthein A." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1414.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Apr. 25, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry." Discipline: Chemistry; Department/School: Chemistry.
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Lefranc, David. "Total synthesis of micrococcin P1." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/3626.
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This thesis describes the total synthesis of the thiopeptide antibiotic micrococcin P1.
It unambiguously elucidates its structure, which has been subject to controversy for over thirty years. The centerpiece of the route to the target molecule is a facile one-pot construction of the central thiazole/pyridine cluster developed in our laboratory. This highlyconvergent route entails a delicate Michael addition to yield a Hantzsch dihydropyridine intermediate, which undergoes further oxidation to the fully aromatised heterocycle. The synthesis was completed by the coupling of this core with a highly-modified sensitive peptide chain. The modular nature of the synthesis can also accommodate modifications for
SAR studies, contributing thereby to the fields of medicinal chemistry, pharmacology, and microbiology. At a purely chemical level, we remain confident that this work will serve as a valuable guide in the elaboration of other members of the thiopeptide family.
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Sreekumar, Sanil. "Synthetic studies towards the total synthesis of lancifodilactone G." Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569566.
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This thesis presents our studies towards the first total synthesis of the novel anti- HIV agent lancifodilactone G, which has a highly unusual aliphatic enol. The first chapter provides a survey of architecturally diverse nortriterpenoids that were isolated from the Schisandraceae family. A proposed biosynthetic pathway for lancifodilactone G and closely related natural products provides a rationale for the formation of the consecutive 7/8/5 fused carbo cycles that are unique to Schisandra nortriterpenoids. Chapter 1 goes on to outline the reported strategies to access the core of lancifodilactone G and concludes with a retrosynthetic analysis proposed by the Evans group, which includes a biosynthetically inspired single-pot polycyclisation reaction. Chapter 2 describes the highly stereocontrolled synthesis of the eastern fragment (F-G rings) using transition metal-mediated Pauson-Khand reaction. This chapter also reviews the metal-mediated diastereoselective Pauson-Khand reaction directed by the stereogenic centre at C2, with the ample illustration to total synthesis. Attempted strategies for the assembly of the bicyclic cyclopentanone motif via a dienyl Pauson-Khand reaction of silicon- and oxygen- tethered diene-enes are presented. The failure of these strategies at different stages of the synthesis resulted in the exploration of a classical Pauson-Khand approach, which successfully furnished the eastern fragment. Finally, a second-generation synthesis is described which provided the fully functionalised eastern fragment with improved efficiency and overall yield. Chapter 3 discusses the successful synthesis of the western fragment (B-C rings) using a diastereoselective [4+3] cycloaddition strategy. Attempted strategies for the synthesis of the key 2,3-disubstituted furan derivative are presented, which was achieved via a hetero Pauson- Khand reaction. This chapter includes a brief account of the classical [4+3] cycloaddition reactions of furans using an in situ generated oxyallyl cation and also employing vinyl carbenoids in the metal-catalysed version. The review also highlights the application of the [4+ 3] cycloaddition reaction in the expeditious assembly of functionalised 7-membered rings that occur in a number of important biologically active natural products. The third chapter goes on to describe the application of these cycloaddition reactions in the synthesis of the fully functionalised western fragment of Lancifodilactone G. Chapter 4 describes a model study aimed at expediting the synthesis of the western fragment using a rhodium-catalysed allylic substitution reaction. A brief mechanistic discussion on unique aspects of the allylic alkylation reaction is illustrated. Chapter 4 concludes by outlining the coupling strategy for eastern and western fragments and the end game studies for the completion of the synthesis of lancifodilactone G.
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Dunn, Stephen Henry. "Total synthesis of norsegoline : synthetic approaches to the cystodytins." Thesis, University of East Anglia, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238806.
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Crawford, Claire Frances. "Synthetic studies towards a total synthesis of hemibrevetoxin B." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435783.
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Pearson, David James. "Synthetic studies towards the total synthesis of popolohuanone E." Thesis, University of Sheffield, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.267117.
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Audic, Alexandre. "Synthetic studies towards the total synthesis of hexacyclinic acid." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7790/.
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In the first chapter of this thesis, published works found in the literature about hexacyclinic acid and FR182877 are reported and commented. A quick summary of the previous work done in the Prunet group is also described. In the second and third chapter, a more detailed account of the work undertaken during this PhD was given. Firstly, syntheses of two ABC tricycles incorporating tert-butyl and (trimethylsilyl)ethyl esters were undertaken. These syntheses include two key steps previously developed in the group, a diastereoselective Michael addition and a Snider cyclisation. Multiple conditions for the hydrolysis of the esters were attempted but none of them gave the desired product. The main part of this work is focused on the synthesis of a CDEF model and in particular about the development of the key step, the formation of a nine-membered ring. Several DEF fragments were synthesised in short synthetic sequences and as single isomers. Six different synthetic pathways were developed in total and a novel method, a Michael/elimination reaction, was found to be a very efficient way to close the desired medium-size ring. From the nine-membered ring, regioselective reduction and palladiumcatalysed allylic substitution led to the formation of the CDF tricycle. Final steps of the synthesis were fruitless and led only to decomposition. A synthesis of a chiral C-ring was also developed during this PhD. II Finally, another project was undertaken, not related to hexacyclinic acid. Methodology developed in the group for the diastereoselective formation of trisubstituted alkenes employing a temporary silicon-tethered ring-closing metathesis was extended to homoallylic alcohols. The first steps of the method were similar to the previous methodology but the end-game had to be modified in favour of an oxidation/reduction sequence to successfully obtain the desired products with the correct geometry. In the fourth chapter, procedures and analytical data for the synthesised compounds previously described are reported.
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Ballette, Roberto. "Total synthesis of (+)-Madangamine D." Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/145559.
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Madangamines are a small group of marine alkaloids isolated from sponges of the order Haplosclerida collected by hand using scuba on reefs off Madang, Papua New Guinea.
Madangamine A show significant in vitro cytotoxicity against murine leukemia (P388), human lung (A549), brain (U373) and breast (MCF-7). However, no bioactivity data have been reported for madangamines B-E, and further pharmacological research on this alkaloid group has been prevented by the minute amount of alkaloid samples. We present herein the enantioselective synthesis of (+)-madangamine D, which represents the first total synthesis of an alkaloid of the madangamine group.
Using a phenylglycinol-derived bicyclic lactam as the starting enantiomeric scaffold we were able to control the stereochemistry of all three contiguous stereogenic centers on the BC ring system, while A ring was formed through a stereocontrolled cascade aminohydroxylation reaction, in which an “in situ generated” amine attacks an epoxide ring. This strategy provides a direct route to the diazatricyclic ABC core common to all madangamines, with the appropriate functionalization to allow the subsequent building of the macrocyclic D and E rings of these alkaloids.
The saturated 14-membered D ring of madangamine D, leading to the tetracyclic ABCD system was efficiently constructed using a ring-closing metathesis reaction followed by a catalytic hydrogenation of the resulting double bond. The (Z,Z)-unsaturated 11-membered E ring, required to complete the synthesis of madangamine D was successfully assembled in a straightforward manner using a Z-stereoselective Wittig reaction followed by an intramolecular macrolactamization.
Madangamine D showed significant in vitro cytotoxic activity against human colon HT29 (GI50 4.4 µg/mL) and pancreas PSN1 (GI50 7.4 µg/mL) cancer cell lines, but was inactive against lung NSCLC A549 and breast MDA-MB-231 cancer cell lines at the highest assayed concentration (10 µg/mL).Las esponjas del orden Haplosclerida representan una importante fuente de alcaloides estructuralmente diversos pero biogenéticamente relacionados, siendo las madangaminas uno de los menos estudiados desde el punto de vista sintético. En 1994 fue aislada el primer alcaloide de este grupo, la Madangamina A de la esponja marina Xestospongia ingens1 y unos años más tarde se aislaron cuatro nuevos alcaloides, las madangaminas BE.2 Estructuralmente, las madangamines son alcaloides pentacíclicos y se caracterizan por presentar un núcleo diazatricíclico (anillos ABC) y dos puentes de carbonados. El anillo macrocíclico D es diferente en cada madangamina en tamaño, así como en el grado y la posición de insaturación, mientras que el anillo E es idéntico en todas ellas. En la presente Tesis Doctoral presentamos la síntesis enantioselectiva de ()-madangamine D,3 que ofrece por primera vez una muestra pura de este producto natural y constituye la primera síntesis total de un alcaloide de la grupo de las madangamines. Usando de una lactama bicíclica derivada del fenilglicinol como el scafold enantiomérico de partida, nuestro enfoque consiste en la construcción inicial del núcleo diazatricíclico ABC y la posterior construcción de los anillos macrocíclicos D y E. La lactama de partida 2 es fácilmente accesible por ciclocondensación de oxoester 1 con el (R)-fenilglicinol, en un proceso en donde se instala el primer estereocentro. El intermedio diazatríclico se prepara a partir de una lactama insaturada derivada de 2. En este proceso son claves una reacción de adición conjugada estereoselectiva, el cierre del anillo carbocíclico mediante metátesis, una alquilación estereoselectiva y finalmente cierre del anillo A por aminohidroxilación. La anulación de los anillos macrocíclicos se lleva a cabo mediante una reacción de cierre del anillo por metátesis (anillo D) y una olefinación de Wittig seguida de macrolactamización (anillo E). Los datos de RMN de 1H y 13C de nuestra madangamina sintética fueron coincidentes con los reportados para el producto natural. La madangamina D sintética muestra citotoxicidad in vitro contra las líneas celulares de cáncer HT29 de colon humano y PSN1 páncreas.
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Kleinbeck, Florian Karl. "Total synthesis of bafilomycin A₁ /." Zürich : ETH, 2008. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17777.
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Bosch, Caroline. "Total Synthesis of Phlegmarine Alkaloids." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/399380.
Full textAbstract:
This doctoral thesis consists in two main parts. The first part focus in the study of methodology development in order to bring modularity and diversification to compounds studied within the research group. It consists first in the development of an easy procedure to access enantiopure substituted octahydroindoles relevant for natural products synthesis, then in the diversification of a common building block used for the total synthesis of phlegmarine alkaloids allowing access to unprecedented heterocyclic tetrahydrocarbazoles compounds, but most importantly in the achievement of a methodology allowing access to any phlegmarine alkaloids from a simple common precursor i.e. using a unified methodology. A stereodivergent hydrogenation route is reported in each phlegmarine alkaloid series, allowing modulation of the diastereoselectivity in key intermediates of the synthetic approach.
The second part focuses on synthetic applications of the methodology developed to allow to perform the first total synthesis of various phlegmarine alkaloids and also shed light on missassigned structures. These structure reassignments gave birth to a revised classification of the phlegmarine alkaloids and were confirmed by total synthesis using the unified methodology developed in the first part.
All of the analytical data obtained during this project led us to the establishment of general rules to determine easily the stereochemistry of any phlegmarine type alkaloids.
In summary, the first total syntheses of (+)-serratezomine E, (-)-serralongamine, (-)-huperzine K, huperzine M and (-)-huperzine N have been achieved and the usefulness of the tandem intermolecular Michael reaction/intramolecular aldol reaction and in-situ intramolecular aza-Michael process has been extended to other series of azabicyclic compounds in enantiopure form.
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Chiba, Hiroaki. "Total Synthesis of Tetrahydroisoquinoline Alkaloids." 京都大学 (Kyoto University), 2013. http://hdl.handle.net/2433/174544.
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Xu, Sanjia. "Formal total synthesis of (±)-tetrodotoxin." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/59489.
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This dissertation details a formal total synthesis of (±)-tetrodotoxin, a potent sodium channel blocker, based on a transformation developed in these laboratories: the bimolecular oxidative amidation of phenols. The present route leads to the Du Bois intermediate in 27 steps from a commercial starting material. Because the Du Bois intermediate can be elaborated to tetrodotoxin in 4 steps, this work constitutes a formal synthesis of the natural product in 31 steps. This is competitive with the best known alternatives. A structural revision of the Sato tetrodotoxin intermediate is also provided. Finally, an even more concise avenue to a new bis-lactonic precursor of the natural product is described, and potential enantioselective routes to tetrodotoxin are discussed.Science, Faculty of
Chemistry, Department of
Graduate
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Aulakh, Virender Singh. "Total synthesis of thiocillin I." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/29493.
Full textAbstract:
This thesis describes the first total synthesis of Thiocillin I, a thiopeptide antibiotic that is structurally similar to Micrococcin P1. Our group has recently completed the first total synthesis of the latter natural product. In that connection, new methodology had to be devised for the assembly of the central pyridine-thiazole cluster of the molecule. The present work details the development of a considerably more efficient "second generation approach" to that crucial molecular subunit. The new technique relies upon a three-component condensation to form the pyridine core with the full complement of thiazoles already in place. This transformation is recognized as a variant of the Bohlmann-Rahtz reaction that has heretofore eluded the synthetic community. Minor modification of this chemistry is likely to facilitate the synthesis of several other thiopeptide antibiotics, naturally occurring or otherwise. This presages the advent of technology for the conduct of medicinal chemistry studies of thiopeptide substances and promises to lead to new generations of chemotherapeutic resources.
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Scutt, James Nicholas. "Total synthesis of (+)-belactosin A." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419852.
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Bebbington, David. "Total synthesis of hypoglycin A." Thesis, University of Oxford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306112.
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Hayes, Stewart. "The total synthesis of vigulariol." Thesis, University of Nottingham, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.495554.
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(+)-Vigulariol was isolated in 2005 by Sheu and coworkers off the coast of Taiwan and belongs to the cladiellin (eunicellin) class of the 2-11 cyclised cembranoid family of natural products. Vigulariol along with numerous other members of the cladiellin family have been shown to possess interesting biological properties including cytotoxicity against various cell lines. This thesis presents the total syntheses of (±)-vigulariol and (-)-vigulariol, that were completed in 20 steps respectively in an overall yield of 4.1% and 5.9%. The key steps in the synthesis are; a samarium diiodide reductive cyclisation to furnish a 2,6-syn-5,6-anti tetrahydropyranol, oxonium ylide formation and an intermolecular Diels-Alder cycloaddition to construct the cyclohexyl ring.
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Anderson, Regan J. "Total synthesis of variolin B." Thesis, University of Canterbury. Chemistry, 2002. http://hdl.handle.net/10092/6061.
Full textAbstract:
This thesis describes the development of methodology which has led to the total synthesis of variolin B, a marine alkaloid with potent antitumour properties. In Chapter One, a brief summary of the association of organic synthesis and marine natural products is provided. This is followed by an account of the variolin family of natural products and synthetic efforts that have been directed towards them. A new strategy is proposed that exploits the hidden symmetry in variolin B.
Chapter Two covers investigations into the synthesis of the variolin skeleton using a variety of reagent systems. A rapid entry into the core structure of the variolins was found, with the key step being a deoxygenation/cyclisation protocol, which was mediated by the combination of triethylsilane and trifluoroacetic acid. Evidence was obtained to suggest an unexpected mechanism for this reaction. Straightforward functional group manipulation led to a synthesis of deoxyvariolin B.
In Chapter Three, the previously established methodology was applied to an alternative starting material, appropriate for a synthesis of variolin B. However, the process was low-yielding and gave variable results. Some modifications to the methodology led to a reliable and efficient procedure for the synthesis of the variolin skeleton, which was subsequently transformed to variolin B. The synthesis proceeded in a total of eight linear steps, with an overall yield of 13%.
The methodology which has been developed lends itself to the production of analogues of the variolins. The synthesis and biological testing of some analogues are presented in Chapter Four, along with a discussion on the structural features which confer biological activity on variolin B.
A brief summary of the work described in this thesis and potential future studies is given in Chapter Five.
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Brooke, Darby Gerard. "Total synthesis of hydroxystrobilurin A." Thesis, University of Canterbury. Chemistry, 2002. http://hdl.handle.net/10092/6541.
Full textAbstract:
This thesis describes the first three total syntheses of hydroxystrobilurin A, a member of the strobilurin family of fungicidal natural products which are produced by a variety of fungal species worldwide. Chapter 1 provides an account of the discovery, structure, and biological activity of the strobilurins, describes the total syntheses of strobilurins reported to date, and covers the synthetic and spectroscopic work that has been conducted on the strobilurins by other workers in this department. An overview of the use of palladium-catalysed carbon-carbon bond forming methodologies in syntheses of several natural products and strobilurin analogues is given, followed by a retro synthetic analysis of hydroxystrobilurin A which delineates two possible strategies for the synthesis of this compound based on the utilisation of such palladium-based chemistry.
Chapter 2 details investigations of these two strategies, with the diene-based route proving more successful than the enyne-based approach. Efficient diene synthesis was achieved via Stille coupling, but direct access to hydroxystrobilurin A via Stille coupling between a diene alcohol and a β-methoxyacrylate unfortunately proved impossible. The use of hydroxyl-group protection enabled the formation of two triene analogues of hydroxystrobilurin A via Stille coupling, and although one of these was found to have isomerised into a non-natural strobilurin triene system, the other possessed the correct stereochemistry and was able to be deprotected to afford a low yield of the natural product. An efficient synthesis of the triene ester analogue of hydroxystrobilurin A was developed, and this compound was reduced to give a low yield of the natural product. Access to the corresponding triene aldehyde was also established, and its reduction to hydroxystrobilurin A was slightly higher yielding, although efforts to improve the efficiency of this process were not successful. A summary of the above results is given in Chapter 3, followed by a description of several pathways by which future workers may be able to achieve a more efficient synthesis of hydroxystrobilurin A.
Chapter 4 describes preliminary results from the application of the palladium-catalysed carbon-carbon bond-forming techniques described in Chapter 2 to synthetic approaches towards 9-methoxystrobilurins A and K & phomoidrides A and B.
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Beiger, Jason James. "Total Synthesis of Aflastatin A." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11040.
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The syntheses of aflastatin A and its C3-C48 degradation fragment are described. The syntheses feature several complex diastereoselective fragment couplings, including a C35-C36 anti-Felkin-selective boron-mediated oxygenated aldol reaction, a C15-C16 Felkin-selective trityl-catalyzed Mukaiyama aldol reaction, and a C26-C27 chelate-controlled aldol reaction involving soft enolization with magnesium. Careful comparison of the spectroscopic data for the synthetic aflastatin A C3–C48 degradation fragment (2) to that reported by the isolation group revealed a structural misassignment in the lactol region of the naturally derived degradation product. The cause of the mismatch was initially believed to be stereochemical in origin. Ultimately, the data reported for the naturally derived aflastatin A C3–C48 degradation lactol (2, R = H) was attributed to its derivative lactol trideuteriomethyl ether \((R = CD_3)\). Further, the absolute configurations of six stereogenic centers (C8, C9 and C28–C31) in aflastatin A (1) were formally revised by the isolation group prior to completion of its total synthesis. The synthesis of the aflastatin A C3–C48 lactol trideuteriomethyl ether and its spectroscopic match to the naturally derived C3–C48 degradation fragment confirm the stereochemical revision. The synthesis of a degradation product containing the tetramic acid and two overlapping stereocenters (C4 and C6) was also achieved. Its spectroscopic match to the corresponding naturally derived degradation fragment verified the absolute configuration of the aflastatin A C5' stereocenter. When combined with previous degradation fragment syntheses, and eventually the total synthesis of aflastatin A, the revised stereochemical assignment of aflastatin A was fully affirmed.Chemistry and Chemical Biology
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George, Ian R. "The total synthesis of lodopyridone." Thesis, University of Nottingham, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.663246.
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Natural products are an important and diverse class of compounds; pyrones and pyridones, examples of their chemistry and natural products featuring these structures are discussed. Lodopyridone (75) is introduced as both a highly unusual natural product and a potential NQ02 inhibitor. A number of simple lodopyridone inspired analogues were prepared as potential NQ02 inhibitors and tested for binding to the enzyme. Synthetic studies toward lodopyridone featuring acetylation, rearrangement and cross coupling approaches to the key C-6 C-C bond formation were explored. Pyrone 175 was prepared by Suzuki coupling and oxidation studies towards amide 189, featuring a key modified Corey-Ganem-Gilman reaction were explored. The key pryone 189 was converted to the pyridone 196 and manipulation to complete the synthesis of lodopyridone (75) was achieved. Studies towards the related pyridone containing natural product antibiotic B 90063 were performed and a synthetic strategy presented. Conclusion in Chapter 3 and future work in Chapter 4 is presented followed by full experimental procedures in Chapter 5.
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Stocksdale, Mark G. "Total synthesis of lavendamycin analogs." Virtual Press, 1992. http://liblink.bsu.edu/uhtbin/catkey/834647.
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The syntheses of 7-N-chloroacetyllavendamycin methyl ester (55), 7-N-butyryllavendamycin methyl ester (56), 7-N-chloroacetyldemethyllavendamycin octyl ester (57), 7-N-butyryldemethyllavendamycin octyl ester (58), 7-N-chloroacetyldemethyllavendamycin isoamyl ester (59), and 7-N-butyryldemethyllavendamycin isoamyl ester (61) are described. Incorporation of the Pictet-Spengler condensation of 7-chloroacetamido-2-formylquinoline-5,8-dione (62) or 7butyramido-2-formylquinoline-5,8-dione (63) with B - methyltryptophan methyl ester (11), L-tryptophan octyl ester (64), or L-tryptophan isoamyl ester (65) in xylene directly afforded six lavendamycin analogs.The aldehydes 62 and 63 were prepared according to the following general procedure. Nitration of 8-hydroxy-2methylquinoline (66) yielded 8-hydroxy-2-methyl-5,772, and 73 are also included. 1H NMR and IR are provided compounds 67, and 71, and 1H NMR is provided for compound dinitroquinoline (67). Compound 67 was then hydrogenated and acylated with chloroacetic anhydride (or butyric anhydride) to yield 5,7-bis(chloroacet4mido)-8-hydroxy-2-methylquinoline (69) (or 5,7-dibutyramido-8-butyroxy-2 methylquinoline (71)).Compound 69 (and 71) was oxidized by potassium dichromate to give the corresponding 5,8-dione 70 (and 72). Treatment of 70 (and 72) with selenium dioxide in refluxing 1,4-dioxane afforded compound 62 (and 63). It was also noted that 71 would hydrolyze to its 8-hydroxy derivative 73 in hot methanol-water.Compound 64 was prepared through the neutralization of Ltryptophan octyl ester hydrochloride with a 14 % ammonium hydroxide solution followed by extraction. Compound 65 was synthesized via a Fischer esterification of L-tryptophan with isoamyl alcohol saturated with hydrogen chloride. The synthesis of H-methyltryptophan (44) was accomplished with the method of Snyder and Matteson.The structures of the novel compounds 55, 56, 57, 58, 59, 60, 62, 63, 69, 70, 72 and 73 were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of 62, 63, 69, 70,for 44.Department of Chemistry
44
Olang, Fatemeh. "Total synthesis of lavendamycin analogs." Virtual Press, 1995. http://liblink.bsu.edu/uhtbin/catkey/958797.
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The synthesis of 7-N -furoyllavendamycin methyl ester (35), 7-N -furoyl demethyllavendamycin methyl ester (36), 7-N -furoyldemethyllavendamycin ethyl ester (37), 7-N -furoyldemethyllavendamycin propyl ester (38), 7-N -furoyl demethyl lavendamycin butyl ester (39), 7-N -furoyldemethyllavendamycin isoamyl ester (40),7-N -furoyldemethyllavendamycin cyclohexyl ester (41), 7-N -furoyldemethyl lavendamycin octyl ester (42), 7-N -furoyldecarboxydemethyllavendamycin (43), and demethyl lavendamycin isoamyl ester (44) are described. Pictet-Spengler condensation of 7-furoylamino-2-formylquinoline-5, 8-dione (55) with (3-methyltryptophan methyl ester (4), Ltryptophan methyl ester (56), L-tryptophan ethyl ester (57), L-tryptophan propyl ester (58), L-tryptophan butyl ester (59), L-tryptophan isoamyl ester (60), L-tryptophan cyclohexyl ester (61), L-tryptophan octyl ester (62), L-tryptamine (63), in xylene, or anisole afforded ten lavendamycin analogs.Aldehyde 55 was prepared according to the following general procedure.Nitration of 8-hydroxy-2-methylquinoline (30) gave 8-hydroxy-2-methyl-5,7dinitroquinoline (31). Compound 31 was then hydrogenated and acylated with 2-furoyl chloride (or acetic anhydride ) to yield 5,7-difuroylamino-8-hydroxy-2-methylquinoline (53) or 5,7-diacetamino-8-acetoxy-2-methyl- quinoline (33). Compounds 53 and 33 were oxidized by potassium dichromate to give the corresponding 5,8-diones 54, and 27. Treatment of 53, and 27 with selenium dioxide in refluxing wet dioxane afforded compounds 55 and 28.Compound 4 was previously prepared by other members of our group, compounds 56, 57, 59, and 62 were obtained through the neutralization of the corresponding Ltryptophan ester hydrochlorides with a 14% ammonium hydroxide solution followed by extraction. Compounds 58, 60, 61 were synthesized via a Fischer esterification of Ltryptophan with : propyl alcohol, isoamyl alcohol, and cyclohexyl alcohol saturated with hydrogen chloride.The structures of compounds 53, 54, 55, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of 53, 54, and 55 are also included.The structures of esters 56, 57, 58, 59, 60, 61, 62, and 63 were confirmed by 1H NMR.Department of Chemistry
45
Stonehouse, Jeffrey Paul. "Total synthesis of (+)-rhizoxin D." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395458.
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Martin, Bruce John. "A total synthesis of myxothiazol." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283643.
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Sherlock, Alexandra. "A total synthesis of (+)-lactacystin." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.431860.
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Oehlrich, Daniel. "Total synthesis of luminacin D." Thesis, University of Warwick, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.412862.
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Tometzki, G. B. "d1-Progesterone : A total synthesis." Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374578.
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Kay, Claire-Louise. "The total synthesis of membrarollin." Thesis, University of Southampton, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438693.
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