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Au cours de ce travail, nous avons synthétisé des lactones bicycliques par réactions de Diels-Alder à demande électronique inverse, de façon énantio- ou diastéréosélective. Pour cela, nous avons étudié, d'une part, un système catalytique à base de triflate d'ytterbium utilisant le binol comme source de chiralité. Nous avons également étudié les cycloadditions d'une 2-pyrone portant une copule chirale dérivée de la pantalactone. Nous avons également découvert et développé un réarrangement radicalaire original de bicyclo[2.2.2]lactones substituées par un groupe phénylséléniure. L'étude du mécanisme de ce réarrangement nous a conduit à la production des lactones pontées [3,2,1], intermédiaires instables qui se transforment rapidement, sous conditions acides, dans les produits fusionnés correspondants. Nous avons ensuite étendu ces conditions à divers substrats et avons démontré que ce réarrangement procédait avec une rétention totale de la stéréochimie relative et absolue de la lactone de départ. Nous avons ensuite utilisé cette séquence tandem de réarrangement dans une courte synthèse de la lactone de Corey, intermédiaire important dans la préparation des prostaglandines.

The thesis titled “Stereoselective synthesis of bio-active styryllactones” comprises an introduction about styryllactones and three sections delineating the results and discussion about the synthesis of styryllactones and experimental section. Trees of the genus Goniothalamus of the plant family Annonaceae in South East Asia has been known for a long time for their proven use in folk medicine. The research group of McLaughlin isolated and characterized a series of styryllactones, possessing significant to marginal cytotoxic activity against human tumor cell lines. The structures and relative configurations of these compounds were determined either by X-ray crystallography or by extensive NMR spectral analysis. Classification of these styryllactones is based on the structural characteristics of the six different skeletons as shown in Figure 1. It was proposed by Shing et al. that the bio-synthesis of styryllactones 1-7 occur via the shikimic acid pathway. This proceeds through the formation of cinnamic acid from phenylalanine, followed by the incorporation of two acetate–malonate units activated as co-enzyme A, generating the styryl-pyrone, goniothalamin 9 a key styryllactone, which on further hydroxylation/oxidation leads to the formation of other styryllactones Section 1: Stereoselective synthesis of styryllactones containing furanofurone, pyrano-pyrone and styryl-pyrone structural units. In this section of the thesis, stereoselective total synthesis of furano-furone, pyrano-pyrone and styryl-pyrone type styryllactones (+)-7-epi-goniofufurone 1, (+)-goniofufurone 2, (+)goniopypyrone 3, (+)-goniotriol 4, (+)-9-deoxygoniopypyrone 5 and (+)-goniodiol 6 is discussed. It is anticipated that the masked tetrol 13, comprising an alkene tether and four contiguous hydroxy groups installed with definite configuration would serve as the intermediate for the synthesis of styryllactones 1-6. It is relied on exploiting the hydroxy directed lactonization via the oxidation of alkene in 13, and subsequent elaboration to styryllactones 1-6. Bis-dimethylamide 10, derived from D-(−)-tartaric acid was identified as the suitable precursor for the synthesis of 13. Synthesis of masked tetrol 13 is accomplished from 10 involving a combination of selective Grignard additions and a stereoselective reduction (Scheme 2). Section 2: Stereoselective synthesis of styryllactones containing tetrahydrofuran and furano-pyrone structural units This section deals with stereoselective synthesis of natural antitumor tetrahydrofuran containing natural product (+)-goniothalesdiol 8. Key features of the synthesis include a FeCl3 mediated formation of THF 15 with very high selectivity (Scheme 3). THF 15 is further elaborated into the furano-pyrone type styryllactones (+)-altholactone 7 and (−)-etharvensin 16 in good yields (Scheme 3). Section 3: Stereoselective total synthesis of (+)-cardiobutanolide Recently, a new styryllactone cardiobutanolide 20 was isolated from the stem bark of Goniothalamus cardiopetalus, together with four known styryllactones by Hisham et al. Stereoselective total synthesis of this natural product from D-(−)-tartaric acid is described in this section. Key features of the synthesis include the elaboration of the γ-hydroxy butyramide 17 obtained from the bis-dimethylamide 10, involving a combination of the addition of 1,3-dithian-2-yllithium and stereoselective reduction (Scheme 4). (For structural formula pl see the pdf file)

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first part of this thesis deals with the syntheses of ovalicin and its analogues. Ovalicin inhibits the endothelial cell proliferation. Apart from being anti-angiogenic it also exhibits antibiotic, antitumor, and immunosuppressive properties. Unlike other syntheses, we started with an acyclic compound, ethyl propiolate (1.66). Our flexible route towards the synthesis used intramolecular Heck cyclization reaction to construct an appropriately functionalized 3-methylene-6-(tert-butyldimethylsilyloxy)cyclohexene (1.63) from 1.66 in four steps. A number of synthetic analogues were synthesized via this strategy. Upon selective epoxidation and dihydroxylation of 1.63, a mixture of diols (3S*,4R*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.107) and (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-1-oxaspiro[2.5]octane-4,5-diol (1.108) were obtained. Subsequent functional group transformations of diols 1.107 and 1.108 gave ketones (3S*,4S*,5R*,6R*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan-4-one (1.112) and (3S*,5S*,6S*)-6-(tert-butyldimethylsilyloxy)-5-methoxy-1-oxaspiro[2.5]octan -4-one (1.117). Addition of vinyl lithium to the ketones followed by functional group transformation gave ovalicin analogues. Several intermediates were subjected to biological activity test for inhibition of growth of T. brucei. Our synthetic efforts towards the synthesis of ovalicin are discussed. The second part of my thesis deals with the synthesis of different tricyclic pyrone (TP) analogues which inhibit the aggregation of Aβ peptides. Alzhemier’s disease (AD) is caused by accumulation of fibrillar amyloid deposits in the AD brain. We synthesized a series of tricyclic pyrone derivatives and evaluated their counteraction on amyloid toxicity. TP analogue, (5aS,7S)-7-[(1R) and (1S)-2-(N3-adenyl)-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3 -b] [1] benzopyran (CP2) is nontoxic, small and permeable molecule prevents the death of human neuroblastoma MC65 cells that conditionally expressed SβC gene. We further found that CP2 ameliorates the toxicity and inhibits the formation of Aβ oligomeric complexes. Binding studies using surface plasma resonance and atomic force microscopy studies suggest that CP2 permeates into the cells and interacts with Aβ peptides and inhibits the Aβ oligomerization. To understand the mechanism of Aβ aggregation and toxicity, CP2 and its derivatives are synthesized to evaluate their action. The key intermediate in the synthesis of CP2 is (5aS*,7S*)-7-[(1R*) and (1S*)-2-bromo-1-methylethyl]-3-methyl-1H,7H-5a,6,8,9-tetrahyro-1-oxopyranol[4,3-b][1] benzopyran (2.9), which in turn can be prepared from our previously reported method. Our aim is to synthesize a series of compounds and investigate the biological activities of different TP analogues.

Pleiomaltinine is an alkaloid-pyrone natural product that was the first of its kind to be isolated in nature. Synthesis of this compound from pleiocarpamine and a reactive quinone methide-like pyrone is described. Furthermore, model compounds have been made that will allow for full testing of this new heterocycle’s biological properties. This process has also been rendered enantioselective using asymmetric organocatalysis with thioureas. Additionally, work has been conducted towards the total synthesis of vinylallene-derived natural products. Progress towards the syntheses of chloropupukeananin, chloropestolide A, pestalofone C, iso-A82775c, and maldoxin isolated from Pestalotiopsis fici are described. All of these compounds are complex and possess biological activities including anti-cancer and anti-HIV. The strategies applied to develop a selective synthesis of reactive vinylallenes are discussed and plans designed to overcome this synthetic challenge are shown in detail. New methodologies are presented along with literature precedent in these areas of research.

Yes / An experimental and computational investigation is conducted into the role of substituents in retro Diels-Alder extrusion of CO2 from 2-oxa-bicyclo[2.2.2]oct-5-en-3-ones. We provide the first experimental evidence that loss of CO2 from the cycloadducts significantly depends on the nature and position of the substituents. For example, we show that whilst 5-carboethoxy-2-pyrone undergoes a more facile cycloaddition that 3-carboethoxy-2-pyrone, the cycloadduct from the latter pyrone undergoes a more facile loss of CO2 than the cycloadduct from the former pyrone. / EPSRC, Yorkshire Cancer Research, Yorkshire Enterprise Fellowships

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The objectives of this research project were to (i) synthesize different bicyclic and tricyclic pyrone and pyridinone compounds; (ii) study the mechanism of action of these compounds in solution as anti-Aβ (amyloid β) agents using different biophysical techniques; and (iii) study the biological activity of pyrone compounds for the counteraction of Aβ toxicity using MC65 cells, a human neuroblastoma cell line and 5X- familial Alzheimer’s disease (5X FAD, a transgenic mice with five different mutations) mice. A series of tricyclic pyrone and pyridinone compounds were investigated. The tricyclic pyrones and pyridinones were synthesized utilizing a condensation reaction between cyclohexenecarboxaldehye (25) and 4-hydroxy-6-methyl-2-pyone (24) or 4-hydroxy-6-methyl-2-pyridinone (51), respectively. A tricylic pyrone molecule CP2 (2, code name) was synthesized and has an adenine base unit attached to the pyrone core. For structure activity relationship (SAR) studies, the adenine group of CP2 was replaced with other DNA base units (thymine, cytosine and guanine) and various heterocyclic moieties. Since nitrogen containing compounds often exhibit increased bioactivity and brain-penetrating abilities, oxygen atom (O5’) was displaced with a nitrogen atom in the middle ring of the tricyclic pyrone. A condensation reaction of pyrone 51 and 25 was carried out to give the linear pyranoquinoline (52) and the L-shaped pyranoisoquinoline (53). The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer’s disease (AD). Recent studies suggest that soluble Aβ oligomers rather then protofibrils and fibrils may be the primary toxic species. Different biophysical techniques including atomic force microscopy (AFM), circular dichroism (CD), surface plasmon resonance (SPR) spectroscopy, and protein quantification assays were used to study the mechanism of aggregation of Alzheimer Aβ peptide in solution. In search of potentially bioactive compounds for AD therapies, MC65 cell line was used as a screening model. Different tricyclic pyrone and pyridinone compounds protect MC65 cells from death. We studied the efficacy of CP2 in vivo by treatment of 5X FAD mice, a robust Aβ42-producing animal model of AD, with a 2-week course of CP2, which resulted in 40% and 50% decreases in non-fibrillar and fibrillar Aβ species respectively.

Made available in DSpace on 2015-05-14T12:59:54Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2521222 bytes, checksum: cfc5f6c38f54dd1ac44a377a98ba266e (MD5) Previous issue date: 2012-08-14 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / The aim of this study was to evaluate the mechanism of vasorrelaxante 6 - [(E) - styryl] - 2 - pyrone (pyrone-198), a natural estirilpirona isolated from the fruit of Aniba panurensis (Meisn.) Mez (Lauraceae), with protocols in normotensive rats in vivo and in vitro on the superior mesenteric artery rings isolated from rats. In non-anesthetized normotensive rats, 198-pyrone (10, 20, 30 and 40 mg / kg; iv) induced bradycardia and hypotension. In the superior mesenteric artery rings isolated from rats pyrone-198 (1 nM - 1 mM) induced relaxation of contractions induced by phenylephrine (Phe, 10 mM) concentration dependent manner and this effect was significantly attenuated after removal of the vascular endothelium. A similar effect occurred in rings pre-contracted with 1 mM of Phe, an effect significantly attenuated after removal of the endothelium. In the presence of 100 mM of L-NAME, 10  M ODQ, 300 mM of PTIO, the relaxation was attenuated. The effect of blocking with L-NAME was completely reversed in preparations with 1 mM L-arginine. In the presence of atropine (1 nM) and indomethacin (10 M), the response induced by pyrone-198 was not changed. The pyrone-198 inhibited contractions induced by increasing concentrations of Phe (1 nM - 1 mM) as well as the relaxation induced contractions induced by U46619 (10 M). In rings pre-contracted with S (-) Bay K8644 (200 nM) caused a relaxation pyrone the like, in rings pre-contracted with Phe (1 and 10 mM) in the presence of nifedipine. The pyrone-198 also interfered in the release of Ca+2 from intracellular stores mediated by Phe (1 and 10 M). In preparations incubated with 3 mM TEA and pre-contracted with 1 M Phe, relaxation of pyrone-198 was not attenuated, unlike the rings incubated with 3 mM TEA and pre-contracted with FEN 10  M. In preparations without endothelium preincubated with 1 mM TEA, relaxation to pyrone-198 was significantly attenuated, however, in the ring without endothelium preincubation with BaCl2 (30 M), 4-AP (1 mM) or GLIB (10 M) did not alter the relaxation induced by pyrone-198. The results suggest the action of pyrone-198 on hemodynamic parameters, alémde vasorrelaxante present a potent effect, an effect mediated in part by endothelium-dependent mechanisms involving via eNOS / CGs. But also by mechanisms independent of the vascular endothelium and the ability to promote relaxation in vascular smooth muscle seems to act interfering with contractile mechanisms subsequent to the entry of calcium, prinicpalmente by inhibiting the release of Ca+2 from intracellular stores sensitive to IP3, and engagement channels sensitive potassium calcium, these effects with different presentation by submaximal and maximal concentrations of phenylephrine. / O objetivo deste estudo foi avaliar o mecanismo vasorrelaxante da 6 [(E) estiril] - 2 - pirona (pirona-198), uma estirilpirona natural isolada a partir dos frutos de Aniba panurensis (Meisn.) Mez (Lauraceae), com protocolos in vivo em ratos normotensos e in vitro sobre anéis de artéria mesentérica superior isolada de ratos. Em ratos normotensos não anestesiados, pirona-198 (10, 20, 30 e 40 mg/kg, i.v.) induziu hipotensão e bradicardia. Em anéis de artéria mesentérica superior isolada de rato, pirona-198 (1 nM - 1 μM) induziu relaxamento das contrações induzidas por fenilefrina (FEN, 10 μM) de maneira dependente de concentração e esse efeito foi significativamente atenuado após a remoção do endotélio vascular. Efeito semelhante ocorreu em anéis pré-contraidos com 1 μM de FEN 7, efeito significativamente atenuado após a remoção do endotélio. Na presença de 100 μM de L- NAME, 10 M de ODQ, 300 μM de PTIO, o relaxamento foi atenuado. O efeito do bloqueio com L-NAME foi completamente revertido em preparações com 1 mM de L-arginina. Na presença de atropina (1 nM) e indometacina (10 M), a resposta induzida pela pirona-198 não foi alterada. A pirona-198 inibiu contrações induzidas por concentrações crescentes de FEN (1 nM 1 mM), como também induziu relaxamento nas contrações induzidas por U46619 (10 M). Em anéis pré-contraídos com S(-) Bay K8644 (200 nM), a pirona promoveu relaxamento tal como, em anéis pré-contraidos com FEN (1 e 10 μM) na presença de nifedipino. A pirona-198 também interferiu na liberação do Ca+2 dos estoques intracelulares mediado por FEN (1 e 10 M). Em preparações incubadas com TEA 3 mM e pré-contraídas com 1 M FEN, o relaxamento da pirona-198 não foi atenuado, diferentemente dos anéis incubados com TEA 3 mM e pré-contraídos com FEN 10 M. Em preparações sem endotélio pré-incubadas com 1 mM de TEA, o relaxamento para pirona-198 foi significantemente atenuado, entretanto, nos anéis sem endotélio a pré-incubação com BaCl2 (30 M), 4-AP (1 mM) ou GLIB (10 M) não modificou o relaxamento induzido pela pirona-198. Os resultados sugerem a ação da pirona-198 sobre os parâmetros hemodinâmicos, alémde apresentar um potente efeito vasorrelaxante, efeito este mediado parcialmente por mecanismos dependentes do endotélio, envolvendo a via eNOS/CGs. Como também por mecanismos independentes do endotélio vascular e essa capacidade de promover relaxamento no músculo liso vascular parece atuar interferindo em mecanismos contratéis posteriores à entrada de cálcio, prinicpalmente pela inibição da liberação de Ca+2 dos estoques intracelulares sensíveis ao IP3, e envolvimento dos canais de potássio sensíveis ao cálcio, efeitos estes com apresentação diferente mediante as concentrações submáxima e máxima de fenilefrina.