O presente trabalho descreve 3 abordagens divergentes para obtenção do esqueleto bicíclico presente nos alcaloides indolizidínicos. A primeira abordagem consiste no desenvolvimento de um novo método de preparação de diazocetonas α,β-insaturadas a partir da reação de Horner-Wadsworth-Emmons (HWE) entre diazofosfonato e aldeídos. As dizocetonas α,β-insaturadas obtidas foram utilizadas como bloco de construção do esqueleto cabocíclico indolizidínico, onde o intermediário chave foi obtido através do rearranjo de Wolff. A segunda estratégia consiste no desenvolvimento do acoplamento redutivo entre derivados α-aminocarbonílicos e acrilato de metila mediado por SmI2, onde em apenas duas etapas foram obtidos os intermediários avançados da síntese da (-)-pumiliotoxina 251D e da (+/-)-epiquinamida. A terceira estratégia utiliza como etapa chave a reação de Wittig/HWE intramolecular para preparação do intermediário bicíclico contendo o sistema α,β-insaturado que pode ser utilizado na síntese divergente dessas substâncias. / Herein were described three diverted oriented approaches for the construction of the bicyclic scaffold of indolizidines alkaloids, that figures between one of the most important classes of natural products. In the first approach, a new method to prepare α,β - unsaturated diazoketones was described using the Horner-Wadsworth-Emmons (HWE) reaction between diazophosphonate and aldehydes. The unsaturated diazoketones were used as powerful plataforms to construct the indolizidine carbocyclic scaffold, enploying the Wolff rearrangement as the key step. The second approach was the development of a reductive coupling between α-aminocarbonyl derivatives and methyl acrylate, mediate by SmI2, from this approach, the well-known advanced intermediate for the synthesis of (-)-pumiliotoxin 251D e of the (+/-)-epiquinamide was obtained in only two steps. The third approach uses the intermolecular Wittig/HWE reaction as the key step in the construction of a bicyclic intermediate containing an α,β -unsaturated moiety that could be used for a diverted oriented approach in the indolizidine alkaloids synthesis.

Production of renewable fuels is of growing interest due to the ongoing concerns associated with combustion of fossil fuel contributing to global warming. Biomass-derived bio-oil is a potential alternative replacement for conventional fuels. But negative properties such as lower energy density, higher water content and acidity prevent the direct use of bio-oil as a fuel. It is universally agreed that for production of a viable fuel bio-oils must be significantly upgraded. Present upgrading techniques, such as hydrodeoxygenation and esterification consume high amounts of expensive hydrogen or large volumes of alcohols, respectively. Production of low yields continues to be a challenge for hydrodeoxygenation. Therefore, development of more efficient upgrading methods would be desirable. The current research was divided into two parts: in the first part the raw bio-oil was pretreated prior to upgrading to reduce coke formation and catalyst deactivation during upgrading. In the second part pretreated bio-oils were further upgraded by several techniques. The second chapter describes application of an olefination process to raw bio-oil to produce a boiler fuel. In the third chapter, raw bio-oil was pretreated by novel oxidation pretreatment to convert bio-oil aldehydes to carboxylic acids. Aldehydes lead to coke formation and their conversion to carboxylic acids circumvents this issue. Following oxidation pretreatment to raw bio-oil acid anhydride pretreatment was applied to reduce water content which leads to catalyst deactivation during upgrading. The fourth chapter tests esterification of pretreated bio-oil by oxidation to produce boiler fuel with relatively high HHV. The fifth chapter discusses hydrodeoxygenation of oxidized bio-oil produced by oxidation to increase hydrocarbons yield and reduced charring during hydrodeoxygenation. The sixth chapter describes application of catalytic deoxygenation of pretreated bio-oil by oxidation in the presence of pressurized syngas to produce a liquid hydrocarbon mixture. In the seventh chapter we tested direct hydrocracking of pretreated bi-oil by oxidation to produce a liquid hydrocarbon mixture. The end products were analyzed by following the ASTM methods for HHV, water content, viscosity, density, acid value, elemental analysis. Best performing fuels based on high HHV and low acid value were analyzed by FTIR, GC-MS, DHA, 1HNMR and simulated distillation.

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Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal.

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Orientador: Luiz Carlos Dias / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T11:13:03Z (GMT). No. of bitstreams: 1 Melgar_GliseidaZelayaran_D.pdf: 8992583 bytes, checksum: 4cacbcdc703a19bccdf5bea13368488a (MD5) Previous issue date: 2008 / Resumo: Em 1995 Miao e colaboradores relataram o isolamento da estavamicina (1), um novo produto natural, membro da família dos pirrolocetoindanos, a partir de uma cultura líquida de Streptomyses sp., isolada de uma amostra de terra coletada na Índia. A estavamicina contém uma interessante subestrutura hexahidroindeno de fusão de anel trans com 5 centros estereogênicos, uma cadeia lateral que contém outros 2 centros estereogênicos, um álcool dialílico, três duplas ligações e um resíduo de carboxilato de sódio. Apresenta atividade inibidora moderada contra a ligação do fator de transcrição EBV BZLF1 com o DNA com um valor de IC50 = 50 mM.O fragmento C11-C26 (206), contendo o grupo pirrol e 5 centros estereogênicos da estavamicina, foi preparado a partir do (R)-3-hidroxi-2-metilpropionato de metila, após uma sequência de reações, que envolveu 14 etapas (rota linear mais longa) e um rendimento global de 7%. As principais características incluem a preparação de uma imida a,b-insaturada utilizando a reação de Horner-Wadsworth-Emmons, a reação de olefinação de Takai, o acoplamento cruzado de Stille, seguido da cicloadição intramolecular de Diels-Alder que fornece dois adutos bicíclicos, sendo o majoritário correspondente ao produto desejado (para os casos de R = (R)-Bn e R = H). A última etapa foi a preparação da lactona tricíclica seguida da abertura utilizando o 2-lítio-N-MEM-pirrol.O fragmento C1-C6 (235) foi preparado a partir do 3-hidroxi-pentanodioato de dietila, após uma seqüência de reações, que envolveu 7 etapas e um rendimento global de 11,5%. As principais características incluem a elegante reação de transesterificação por quebra de simetria, redução do ácido com borana seguida por oxidação de swern e olefinação utilizando o procedimento modificado de Stork-Wittig.Em conseqüência, a rota de obtenção dos fragmentos C1-C6 e C11-C26 aqui descrita é, em princípio, prontamente aplicável para a preparação da estavamicina e análogos que eventualmente pudessem apresentar atividade farmacológica destacada. / Abstract: Epstein-Barr virus (EBV) is a human herpes virus that infects lymphocytes and epithelial cells. Is has been estimated that this virus infects a large part of the world¿s population. In 1995, stawamycin (1), a new natural product from the pyrroloketoindane family was isolated by Miao et. al from a liquid culture of Streptomyces sp, and displayed moderate inhibitory activity against the binding of the EBV BZLF1 transcription factor to DNA with IC50 = 50 mM in a DNA binding assay. Stawamycin has a trisubstituted trans-fused bicyclo[4.3.0]nonane substructure containing five stereogenic centres and a side chain that contains two stereogenic centres at C3 and C9 (absolute configuration not determined), a doubly allylic alcohol and a sodium carboxylate residue. To determine the relative configurations between C3 and C9, to establish the absolute configuration of stawamycin, and to provide material for further biological studies as well as access to novel analogues, we initiated a study towards the synthesis of this very interesting compound. We wish to describe here our successful efforts towards the preparation of the C1¿C6 as well as the C11¿C26 carbocyclic fragment of stawamycin. The bicyclo[4.3.0]nonane (C11¿C26) fragment of stawamycin has been prepared by a sequence involving 14 steps (7% overall yield) from methyl (R)-(-)-3-hydroxy-2- methylpropionate. Key steps are a Pd-catalysed Stille coupling reaction between a vinyl iodide and a vinyl stannane followed by an intramolecular Diels¿Alder cycloaddition reaction to give the desired adduct as the major isomer. The best result was obtained with the use of a triene bearing an achiral oxazolidinone in the presence of Et2AlCl to promote the IMDA cycloaddition reaction. The last step was an preparation of the tricyclic lactone followed by the opening by means of the 2-lítio-N-MEM-pirrol.The (C1¿C6) fragment of stawamycin has been prepared from diethyl-3- hydroxypentanedioate by a sequence which involved a symmetry breaking reaction of a cyclic anhydride, followed by the formation of a Z-vinyliodide employing a Stork-Wittig procedure. / Doutorado / Quimica Organica / Doutor em Ciências

Les antalgiques utilisés aujourd’hui sont des produits anciens et plusieurs d’entre eux datent du 19ème siècle. La morphine demeure l’antalgique de référence pour les douleurs dites par excès de nociception, mais elle est à l’origine d’effets indésirables gênants et graves. Il a été démontré que l’effet antalgique de la morphine passait par l’activation des canaux potassiques TREK-1. Les travaux de recherche ont donc comme objectif la recherche d’antalgiques originaux activateurs de TREK-1. Nous avons synthétisé des activateurs de TREK-1 décrits dans la littérature puis nous avons évalué leur activité antalgique in vivo (writhing test) ce qui nous a permis d’identifier le CDC comme molécule « lead ». Nous avons ensuite synthétisé 43 analogues du CDC que nous avons évalué pour leur effet antalgique ainsi que leur capacité à activer les canaux TREK-1 (électrophysiologie). Ces molécules ont été préparées en 3 à 12 étapes avec des rendements de 3 à 72 % en utilisant des réactions telles que : aldolisation, oléfination de Watsworth et Horner, Peterson, estérification …Des résultats très prometteurs ont émergé de cette étude de relation structure-activité avec 8 molécules qui se démarquent avec un très bon effet antalgique (>50% inhibition de la douleur) ainsi qu’une bonne activation des canaux TREK-1 (R>2). Enfin nous avons analysé les résultats de cette étude par modélisation moléculaire (QSAR) ce qui nous a permis d’identifier les caractéristiques structurales essentielles de ces molécules. / Analgesics used today are old products and several of them date from the 19th century. Morphine remains the analgesics of reference for pains called by excess of nociception, but it is at the origin of awkward and serious side effects. It was shown that the analgesic effect of morphine passed by the activation of potassium channels TREK-1. The objective of this work is thus to develop original analgesics, activators of TREK-1. We synthesized activators of TREK-1 described in the literature and we evaluated their analgesic activity in vivo (writhing test) which enabled us to identify CDC as a lead molecule. We then synthesized 43 analogues of CDC which we evaluated for their analgesic effect and their ability to activate TREK-1 channels (electrophysiology). These molecules were prepared in 3 to 12 steps with yields ranging from 3 to 72 % by using reactions such as : aldol reaction, Watsworth and Horner’s olefination, Peterson’s olefination, esterification … Very promising results emerged from this structure-activity relationship study with 8 molecules which display a very good analgesic effect (>50% inhibition of pain) as well as a good activation of TREK-1 channels (R> 2). Finally we analyzed the results of this study by molecular modeling (QSAR) which enabled us to identify the essential structural characteristics of these molecules.

<p>This thesis describes the use of copper and palladium to mediate transformations of carboranes, especially <i>p</i>-carborane.</p><p>1-(1-<i>p</i>-carboranyl)-<i>N</i>-methyl-<i>N</i>-(2-butyl)-3-isoquinolinecarboxamide, a carborane containing analogue of the peripheral benzodiazepine receptor (PBR) ligand PK11195, has been synthesised. A key step in the reaction is the copper (I) mediated coupling of p-carborane with ethyl 1-bromo-isoquinoline-3-carboxylate. </p><p><i>p</i>-Carborane has been arylated on the 2-<i>B</i>-atom in high yields, using the Suzuki–Miyaura reaction. Thus the reaction between 2-I-<i>p</i>-carborane and various arylboronic acids [1-naphthyl-, phenyl-, 4-MeO-C₆H₄-, 3-CH₃CONH-C₆H₄-, 4-NC-C₆H₄-, 3-NO₂-C₆H₄-], gave the corresponding 2-aryl-<i>p</i>-carboranes in DME solution when reacted in the presence of cesium fluoride and the catalytic Pd₂(dba)₃–dppb system. Under the same conditions, the boron-boron bond forming reaction of two <i>p</i>-carboranylboronic esters (2-[(pinacolato)boron]-<i>p</i>-carborane and 2-[(neopentyl glycolato)boron]-p-carborane) was also shown feasible.</p><p><i>p</i>-Carborane has been vinylated on the 2-<i>B</i>-atom in high yields by use of the Heck reaction. The coupling between 2-I-<i>p</i>-carborane and various styrenes [4-H-, 4-C₆H₄-, 4-Cl , 4-Br-, 4-NO₂-, 4-CH3O- and 4 CH₃ ] resulted in the formation of the corresponding<i>trans</i>-β-(2-<i>B</i>-<i>p</i>-carboranyl) styrene in DMF solution when reacted in the presence of silver phosphate and the palladacycle Herrmann´s catalyst. The reaction was shown to proceed at higher rate with electron rich than with electron deficient olefins.</p><p>The feasibility of palladium-catalysed isotopic exchange of an iodinated closo-carborane with a radioisotope of iodine has been studied. 2-I-<i>p</i>-carborane was selected as a model compound. It was shown, that such isotopic exchange is possible and provides a high yield (83 ± 4.2 %) during 40 min long reaction. The reaction conditions were optimised, and it was demonstrated that presence of the tetra n-butylammonium hydrogensulphate is important in order to stabilise catalyst and provide reproducibility of labelling. In this work we have modified the methodology and extended the application to a wider range of iodinated carboranes. By the use of Herrmann’s catalyst in toluene at 100 °C this [¹²⁵I]-iodide labelling could be improved and extended. 2-I-<i>p</i>- 9-I-<i>m</i>-, 9-I-<i>o</i>-, 3-I-<i>o</i>-carborane, 1-phenyl-3-I-<i>o</i>-carborane and 1,2-diphenyl-3-I-<i>o</i>-carborane could be [¹²⁵I]-iodide labelled in high to excellent yields within 5 minutes.This reported palladium catalyzed radio-iodination of the uncharged closo-carboranes might find use in pharmacokinetic studies of carborane derivatives.</p>

This thesis describes the use of copper and palladium to mediate transformations of carboranes, especially p-carborane. 1-(1-p-carboranyl)-N-methyl-N-(2-butyl)-3-isoquinolinecarboxamide, a carborane containing analogue of the peripheral benzodiazepine receptor (PBR) ligand PK11195, has been synthesised. A key step in the reaction is the copper (I) mediated coupling of p-carborane with ethyl 1-bromo-isoquinoline-3-carboxylate. p-Carborane has been arylated on the 2-B-atom in high yields, using the Suzuki–Miyaura reaction. Thus the reaction between 2-I-p-carborane and various arylboronic acids [1-naphthyl-, phenyl-, 4-MeO-C6H4-, 3-CH3CONH-C6H4-, 4-NC-C6H4-, 3-NO2-C6H4-], gave the corresponding 2-aryl-p-carboranes in DME solution when reacted in the presence of cesium fluoride and the catalytic Pd2(dba)3–dppb system. Under the same conditions, the boron-boron bond forming reaction of two p-carboranylboronic esters (2-[(pinacolato)boron]-p-carborane and 2-[(neopentyl glycolato)boron]-p-carborane) was also shown feasible. p-Carborane has been vinylated on the 2-B-atom in high yields by use of the Heck reaction. The coupling between 2-I-p-carborane and various styrenes [4-H-, 4-C6H4-, 4-Cl , 4-Br-, 4-NO2-, 4-CH3O- and 4 CH3 ] resulted in the formation of the correspondingtrans-β-(2-B-p-carboranyl) styrene in DMF solution when reacted in the presence of silver phosphate and the palladacycle Herrmann´s catalyst. The reaction was shown to proceed at higher rate with electron rich than with electron deficient olefins. The feasibility of palladium-catalysed isotopic exchange of an iodinated closo-carborane with a radioisotope of iodine has been studied. 2-I-p-carborane was selected as a model compound. It was shown, that such isotopic exchange is possible and provides a high yield (83 ± 4.2 %) during 40 min long reaction. The reaction conditions were optimised, and it was demonstrated that presence of the tetra n-butylammonium hydrogensulphate is important in order to stabilise catalyst and provide reproducibility of labelling. In this work we have modified the methodology and extended the application to a wider range of iodinated carboranes. By the use of Herrmann’s catalyst in toluene at 100 °C this [125I]-iodide labelling could be improved and extended. 2-I-p- 9-I-m-, 9-I-o-, 3-I-o-carborane, 1-phenyl-3-I-o-carborane and 1,2-diphenyl-3-I-o-carborane could be [125I]-iodide labelled in high to excellent yields within 5 minutes.This reported palladium catalyzed radio-iodination of the uncharged closo-carboranes might find use in pharmacokinetic studies of carborane derivatives.

This thesis deals with the development and application of methods for asymmetric olefinations, in particular Horner-Wadsworth-Emmons (HWE) reactions, in the synthesis of certain natural products. Relying on asymmetric HWE reactions to access key building blocks, two natu-ral products, pyranicin and pyragonicin, were synthesized from common late intermediates. The utility of the HWE reactions is highlighted through a desymmetrization of a meso-dialdehyde as well as a stereoconvergent reaction sequence employing the sequential use of a HWE parallel kinetic resolution fol-lowed by a Pd-catalyzed allylic substitution to convergently transform a race-mate to a single stereoisomer of the product. Methodological extensions of these syntheses include a divergent synthesis of 2,3,6-substituted tetrahydropyran derivatives and application of Zn-mediated asymmetric alkynylations to install key stereocenters. Synthetic studies directed towards a more complex target, mucocin, employing a triply convergent strategy, have also been performed. Expedient and reliable routes to three key fragments were developed, as well as methodology to access to all nine stereocenters. The fragment coupling to assemble the oligonuclear core still remains a challenge, however. Key features of the synthesis include the formation of two fragments from a common precursor derived from an asymmetric HWE desymmetrization, Zn-mediatedated asymmetric alkynylations, a stereoselective oxa-Michael cyclization dependent on a simultaneous protective group migration and a one-pot procedure for the synthesis of a TBS protected iodohydrin from a terminal epoxide. An investigation of the possibilities for developing a transition metal catalyzed asymmetric olefination using a chiral Re-complex is outlined. An enantioen-riched BINAP-Re complex was synthesized and characterized by X-ray. An efficient protocol for the olefination of functionalized aldehydes employing this catalyst was developed, but gave racemic products in two attempted kinetic resolutions of racemic substrates, most likely due to a reaction pathway proceeding via a non-metal associated phosphonium ylide. / QC 20100921