Les travaux décrits dans ce mémoire portent sur la synthèse du fragment C28-C46 de l'Hémicalide, un produit naturel extrait d'une éponge marine possédant une puissante activité antitumorale. Les étapes-clé de la synthèse sont : une addition conjuguée d'un boronate vinylique sur une lactone insaturée, une hydroxylation et une hydrogénation diastéréosélectives pour contrôler respectivement les centres C39, C40 et C42. La double liaison C34-C35 a été créée par une oléfination de Julia-Kocienski. Dans le cadre de ces travaux, une nouvelle méthode de synthèse diastéréosélective de delta-lactones alpha-hydroxylées a été mise au point mettant en jeu un réarrangement sigmatropique et une cyclisation catalysée par des complexes de métaux de transition. / The work described in this manuscript concerns the synthesis of the C28-C46 fragment of Hemicalide, a natural product extracted from a marine sponge exhibiting a highly potent antitumoral activity. The key steps of the synthesis are : a diastereoselective conjugate addition of a vinyl boroante on an unsaturated lactone, hydrogenation and hydrogenation to control the centers C39, C40 and C42, respectively. The C34-C35 double bond was created by a Julia-Kocienski olefination. During this work, a new method for the diastereoselective synthesis of delta-lactones was developed, involving a sigmatropic rearrangement and a cyclization catalyzed by transition metal complexes.

Wu Xiujuan. / "May 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (p. 294-314). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Baeyer-Villiger oxidation of 1,9-dibromopentacyclo[5.4.0.02,6.03,10.05,9]undecane-8,11-dione (1,9-dibromo-PCU-8,11-dione) was performed by using an excess amount of m-chloroperbenzoic acid (3 equivalents) and resulted in the formation of the corresponding monolactone. The reaction would not proceed to the dilactone stage. The structure of the reaction product was established unequivocally via single crystal X-ray diffraction. Baeyer-Villiger oxidation of 1,9-dibromo-PCU-8,11-dione using ceric ammonium nitrate (CAN) was also performed and afforded a mixture of lactones. Only one of these lactones, which also contained an alkene functionality, could be isolated and characterized. 1,7-dibromo-PCU-8,11-dione was also reacted with CAN, yielding the mono-lactone, which has also been characterized.

Esta tese de doutorado aborda alguns aspectos do estudo de plantas medicinais e de princípios ativos naturais. Os procedimentos experimentais incluíram o estudo fitoquímico de uma planta medicinal da família Asteraceae, o desenvolvimento de um método analítico com validação das análises empregadas e o estudo de atividades biológicas relativas ao processo inflamatório. A primeira etapa compreendeu o estudo fitoquímico da planta medicinal Smallanthus sonchifolius (Asteraceae), envolvendo o isolamento de metabólitos secundários da classe dos terpenóides. Do extrato de lavagem foliar foram isoladas as seguintes lactonas sesquiterpênicas (LSTs): enidrina, uvedalina, sonchifolina, fluctuanina, polimatina B, (1Z,4E)-8β-metacriloilóxi-9α-acetoilóxi-germacra-1(10),4,11(13)-trien-6α,12-olido-14-oato de metila, (1Z,4E)-8β-angeloilóxi-14-oxo-germacra-1(10),4,11(13)-trien-6α,12-olido, (1Z,4E)-8β-metacriloilóxi-germacra-1(10),4,11(13)-trien-6α,12-olido-14-oato de metila, ácido (1Z,4E)-8β-angeloilóxi-germacra-1(10),4,11(13)-trien-6α,12-olido-14-óico e (1Z)-3α,4β-epóxi-8β-[(1Z,4E)-(2S,3R)-2-hidróxi-3-óxi-(8β-angeloilóxi-germacra-1(10),4,11(13)-trien-6α,12-olido)]-9α-acetoilóxi-germacra-1(10),11(13)-dien-6α,12-olido-14-oato de metila. A segunda etapa tratou do desenvolvimento de método e validação das análises para controle de qualidade químico de S. sonchifolius em cromatografia líquida de alta eficiência (CLAE). Além disso, foi realizada a quantificação do principal metabólito secundário isolado nos extratos glandulares e de lavagem foliar, a LST enidrina. Esta substância compõe 0,97 % do peso seco das folhas de S. sonchifolius. A terceira etapa refere-se às atividades biológicas, as quais foram avaliadas empregando-se diversos ensaios. Também foi realizada a otimização de método para avaliação da secreção de elastase por neutrófilos humanos e o estudo da estimulação basal de neutrófilos. Ainda foram investigados os efeitos de produtos fitoterápicos, como gel de Arnica montana e extrato de Harpagophytum procumbens, e de metabólitos secundários, como LSTs e alcalóides, na atividade enzimática de elastase, na secreção de elastase por neutrófilos, na ativação do fator de transcrição NF-κB via EMSA, na produção de luciferase por meio de reporter gen assay e de interleucina-8 via ELISA. Com exceção de dois alcalóides, todas as substâncias e produtos testados apresentaram atividades de inibição dos processos inflamatórios investigados. / This Ph.D. thesis deals with some aspects of the study of medicinal plants and their biologically active natural compounds. The experimental procedures comprised the phytochemical study of a plant from the family Asteraceae, the development of an analytical method with validation of the employed analysis and the study of the biological activities related to the inflammatory process. The first step comprised the phytochemical study of the medicinal plant Smallanthus sonchifolius (Asteraceae) and the isolation of secondary metabolites. From the leaf rinse extract were isolated the sesquiterpene lactones (STLs) enhydrin, uvedalin, sonchifolin, fluctuanin, polymatin B, methyl (1Z,4E)-8β-metacryloyloxy-9α-acetoyloxy-germacra-1(10),4,11(13)-trien-6α,12-olide-14-ate, (1Z,4E)-8β-angeloyloxy-14-oxo-germacra-1(10),4,11(13)-trien-6α,12-olide, methyl (1Z,4E)-8β-metacryloyloxy-germacra-1(10),4,11(13)-trien-6α,12-olide-14-ate, (1Z,4E)-8β-angeloyloxy-germacra-1(10),4,11(13)-trien-6α,12-olide-14-oic acid, methyl (1Z)-3α,4β-epoxy-8β-[(1Z,4E)-(2S,3R)-2-hydroxy-3-oxy-(8β-angeloyloxy-germacra-1(10),4,11(13)-trien-6α,12-olide)]-9α-acetoyloxy-germacra-1(10),11(13)-dien-6α,12-olide-14-ate. The second part was related to the development and validation of a chromatographic method for the chemical quality control of S. sonchifolius using high performance liquid chromatography (HPLC). Furthermore, the quantification of the main secondary metabolite, the STL enhydrin on glandular and leaf rinse extracts was also performed. This compound comprises 0,97 % of dried leaves weight of the plant. The third part deals with biological activities, which were investigated through different assays. One method for the study of the elastase release from human neutrophils was evaluated and the basal stimulation of neutrophils was studied. The effects of phytoterapeutic agents, like Arnica montana gel and Harpagophytum procumbens extract, and of the secondary metabolites, like LSTs and alkaloids, on the enzymatic activity of elastase, on elastase release from neutrophils, on the activation of the transcription factor NF-κB through EMSA, on luciferase production through reporter gene assay and on interleucina-8 production through ELISA were also carried out. Both phytoterapeutic agents as well as the great majority of the tested compounds showed some inhibitory activity over the investigated inflammatory processes.

This thesis describes the development of chiral auxiliary based methodologies for the asymmetric synthesis of hydroxylated !-lactones and "-lactones containing multiple contiguous stereocentres. The first chapter introduces the concept of chirality and provides a general overview of the range of strategies available for the preparation of chiral molecules in enantiomerically pure forms. The second chapter critically reviews the range of synthetic methodology that is currently available for the asymmetric synthesis of chiral #-lactones that are either natural products or useful chiral building blocks for synthesis. The third chapter describes the development of novel methodology for the epoxidation/lactonisation of a range of $-vinyl-syn-aldols to directly afford !-lactones containing up to four contiguous stereocentres in high de. These reactions were shown to proceed via a mechanism whereby hydroxyl-directed diastereoselective epoxidation is followed by intramolecular attack of their !-acyl-oxazolidin-2- one fragment, to directly afford the desired chiral !-lactone. The ‘self-cleavage’ aspect of these reactions was exploited to enable this methodology to be transferred to polymer-support using an immobilised Evans’-oxazolidin-2-one for asymmetric synthesis. Chapter 4 describes the development of a complementary methodology for the asymmetric synthesis of this type of hydroxylated !-lactone based on a strategy involving dihydroxylation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols using catalytic amounts of osmium tetroxide. This methodology was developed as part of a reinvestigation of previously reported dihydroxylation reactions by Dias and coworkers, where we have clearly shown that the stereochemistry of thelactones reported in their paper have been incorrectly assigned. This diastereoselective dihydroxylation methodology has been successfully applied to the asymmetric synthesis of the natural product deoxyribonolactone. Finally, Chapter 5 describes the development of methodology for the asymmetric synthesis of chiral "-lactones containing four contiguous stereocentres of use as potential chiral building blocks for the synthesis of polyketide natural products. In this approach, cyclopropanation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols occurs under the sterodirecting effect of the $- hydroxyl group to afford cyclopropyl-aldols in very high de. These cyclopropyl-aldols are then ring opened in the presence of mercuric ions, with their N-acyl-oxazolidin-2-one fragment acting as an internal nucleophile, to afford highly functionalised alkyl-mercury species that may be subsequently reduced to afford their corresponding "-lactones in high de.

Orientador: Adolorata Aparecida Bianco Carvalho / Banca: Ana Maria Centola Vidal Martins / Banca: Estevam Guilherme Lux Hoppe / Banca: Paulo Sérgio Jorge / Banca: Fabio Fernando Ribeiro Manhoso / Resumo: As mudanças nos controles internacionais dos alimentos visando sua inocuidade se efetivaram com a mudança de século, tendo como base a Análise de Riscos e a Análise de Perigos e Pontos Críticos de Controle. Para os resíduos químicos, apesar de problema pré-existente, a situação só ganhou notoriedade a partir de 2010 com a detecção da presença de resíduos de avermectinas em produtos cárneos brasileiros exportados para os Estados Unidos e União Europeia. A partir de então, várias medidas de mitigação foram inseridas no conjunto rotineiro de autocontroles pelas empresas processadoras. Neste trabalho objetivou-se verificar a praticidade e eficácia dessas medidas para o controle efetivo dos processos, segregando animais abatidos que pudessem contribuir para níveis inaceitáveis do perigo, com base na monitoração de resíduos de avermectinas em duas matrizes amostrais, fígado e músculo de bovinos abatidos. Para a matriz músculo foram analisados 81.565 lotes de animais, com 1,41% desses ou 1.153 lotes que apresentaram resíduos de avermectinas superiores ao LMR de 10μg/kg durante os anos de 2010 e 2011. A partir de 2012 utilizou-se a matriz fígado, sendo analisadas 77.056 amostras. Dessas, 29.267 ou 37,98% apresentaram positividade para resíduos, sendo que 4.602 ou 5,97% foram superiores ao LMR de 100μg/kg. Os resultados analíticos demonstram, até agora, agravamento do problema no elo primário da produção de carne bovina brasileira / Abstract: Changes in international food controls aiming their safety occurred with the change of the century, based on the Risk Analysis and Hazard Analysis and Critical Control Points. For chemical residues, although a pre-existing problem, the situation only gained notoriety after 2010, with the presence of avermectin residues in Brazilian meat products exported to the United States and European Union. Since then, several mitigation measures were incorporated in the routine set of self-controls the processing companies.This work aimed to verify the practicality and effectiveness of these measures for effective control of processes, segregating slaughtered animals that could contribute to unacceptable levels of risk, based on monitoring of avermectins residues in two sample matrices, liver and muscle of cattle slaughtered. For the muscle matrix were analyzed 81,565 batches of animals, with 1,153 or 1.41% batches whose residues were above the avermectin MRL (Maximum Residue Level) of 10μg/kg during the years 2010 and 2011. from 2012 was used the liver matrix , with 77,056 samples being analyzed. Of these, 29,267 or 37.98% were positive for residues, with 4,602 or 5.97% above the MRL of 100μg/kg. The analytical results shown so far, the aggravation of problems at the primary link of the production chain of Brazilian beef / Doutor

In Pseudomonas aeruginosa, which causes severe secondary infections in immunocompromised patients, virulence factor expression is regulated by quorum sensing signal molecules known as acyl homoserine lactones (AHLs). One of the major AHLs produced by P. aeruginosa, N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), has also been shown to alter the function of a range of mammalian cells. The goals of experiments reported in this thesis were to use murine models to investigate the effects of in vivo exposure to OdDHL on TH responses, define the direct effects of OdDHL on TH cells and to explore the mechanism by which OdDHL alters the function of TH cells. It was found that in vivo exposure to OdDHL led to changes in cytokine and antibody subclass production indicative of a shift towards the underlying TH bias of the mouse strain studied. Such shifts may play a role in infections with P. aeruginosa, as strong TH1 or TH2 responses have been associated with worsening prognosis for the host, while more balanced responses have been associated with decreases in both infection and pathology. These results suggest that treatments targeting the immunomodulatory activities of OdDHL may be of benefit in the clinical setting in the future. Direct analysis of TH cells in defined in vitro systems revealed that exposure to OdDHL led to uniform decreases in cytokine production and proliferation. These decreases in cytokine production were found to be the result of OdDHL acting on both TH cells and the antigen presenting cells (APCs) that activate them, and only occurred when cells were exposed to OdDHL within 4 hours of stimulation. These findings suggest that OdDHL is acting on a molecular target common to several cells types, and that in TH cells and APCs, this target is involved in the early stages of TH cell activation. Experiments in which T cells were activated with mitogens that bypass the cell membrane revealed that OdDHL is not acting on the cell membrane or membrane-associated activation factors, suggesting that OdDHL is instead inhibiting TH cell function through interactions with one or more intracellular signalling molecules.

For the past years, our laboratory has been interested in the development of a specific class of functionalised orthoester derivatives and their application as annelating reagents. Previous work had demonstrated that these reagents could be used in a two-step procedure to generate interesting spirocyclic ketones. At the onset of our thesis, we devoted our efforts to the study and application of this methodology. This resulted in an improved and more efficient procedure for the spirohexannelation of â-ketoketals. During these initial studies, an intriguing and novel transannular cyclisation was discovered. The reactivity of these spirocycles was also briefly examined, laying the ground for an application to the total synthesis of Agarospirol, Hinesol and á-Vetispirene, three natural products belonging to the Spirovetivane family. The applicability of a CAN-catalysed deprotection of ketals and silyl ethers, in the presence of an enol triflate moiety, was also investigated. The potential of our functionalised orthoesters as annelating agents was then further evaluated in the context of other silyl enolethers. The heteroaromatic derivatives of furan proved to be excellent coupling partners for our functionalised orthoesters, and enabled the efficient preparation of a wide array of butenolides. These butenolides could then be elaborated, by an efficient and highly stereoselective radical-mediated cyclisation, into bicyclic lactones. Alternatively, treatment with base triggered an efficient spirocyclisation, delivering spirocyclic butenolides in good to excellent yields. The corresponding pyrrole derivative was also examinated, and preliminary work hints at the possibility of readily preparing azaspirocycles as well as indolizidine frameworks. Finally, the evaluation of silylated acyloins allowed an entry into the chemistry of cyclobutanones, and a simple procedure for the synthesis of spirocyclic ethers was developed. During these investigations, an unexpected fragmentation was serendipitously discovered upon application of the Beckmann rearrangement. We were able to use this reaction in a new procedure for the synthesis of interestingly substituted tetrahydropyrans.

The antioxidant and redox properties of L-ascorbic acid are closely associated with the electron rich 2, 3-enediol moiety of the molecule and therefore selective functionalization of the 2- and 3-OH groups is essential for the detailed structure-activity studies. Reactions of 5- and 6-OH protected ascorbic acid with electrophilic reagents exclusively produce the corresponding 3-O-alkylated products under mild basic conditions due to the high nucleophilicity of the C-3-OH. Based on the density functional theory (B3LYP) electron density calculations, a novel and general method was devised for the direct alkylation of the 2-OH group of ascorbic acid with complete regio- and chemo-selectivity. A complete spectroscopic analysis of two complementary series of 2- O -acetyl-3- O -alkyl and 2- O -alkyl-3- O -acetyl ascorbic acid derivatives was carried out to define their spectroscopic characteristics and to resolve common inconsistencies in the literature. The asymmetric approach to the synthesis of natural products or other biologically active compounds is impeded by low abundance of natural sources as well as a limited number of efficient synthetic methods. Nevertheless, carbohydrate-based systems such as the aldono-1,4-lactones (also known as aldono-γ-lactones) which generate a host of chiral compounds have been particularly rewarding in this respect. This study shows a practical approach using 5,6- O -isopropylidene-L-ascorbic acid (ketal of L-ascorbic acid) as a single common starting material for facile asymmetric synthesis of protected, optically pure and functionalized aldono-1,4-lactones derivatives, valuable in the synthesis of derivatives of various pharmacologically active agents for structure-activity studies. The practicality of this new approach is demonstrated by the convenient synthesis of a series of thermal Claisen-rearranged products of 5,6- O -isopropylidene-3- O -allyl-L-ascorbic acid and 5,6- O -isopropylidene-2- O -allyl-L-ascorbic acid as the corresponding 5,6- O -isopropylidene-2-allyl-3-keto-L-galactono-γ-lactone and 5,6- O -isopropylidene-3-allyl-2-keto-L-galactono-γ-lactone respectively. The synthetic routes are economical, efficient, diastereospecific, and proceed in high yields. / "August 2005." / Thesis (Ph.D.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry.

In recent years, N-hetereocyclic carbenes (NHCs) have received considerable attention as organocatalysts due to their unusual ability to induce a reversal of reactivity (Umpolung) in aldehydes. Indeed, NHCs unique properties have been applied to the efficient and metal-free synthesis of organic compounds that have proven elusive using traditional approaches.<p> My Masters research program has been focused on the use of NHCs as organocatalysts in ring expansion reactions and their applications to cascade reactions.<p> During my Masters studies, an NHC-catalyzed efficient ring expansion of 4-, 5-, and 6-membered oxacycloalkane-2-carboxaldehydes to generate the corresponding lactone derivatives was developed. This reaction provides access to a variety of lactones using readily available NHCs under mild conditions.<p> Then, the ring-expansion lactonization has been successfully extended to an efficient lactamization using azacycloalkane-carboxaldehydes, which could provide functionalized lactams in moderate yields under mild conditions.<p> In addition, intrigued by the possibility of effecting the Umpolung of electron-poor dienes using NHC catalysts, the ring-expansion lactonization was applied to an attempted Diels-Alder-ring expansion cascade reaction. Though no cascade reactions were observed, some very interesting results were obtained, and those results will guide future investigations in this area.