L'étude des molécules issues du milieu naturel a conduit les chercheurs à s'intéresser à la synthèse d'un motif structural commun à un grand nombre de molécules bioactives, les spirocétals. La mise au point au sein de notre laboratoire, d'une méthodologie de synthèse d'éthers d'énols exo-cycliques, précurseur de spirocétals, nous a conduits à nous intéresser au fragment spirocétal puis à la synthèse totale du bistramide A. Cette molécule naturelle, issue d'un animal marin présente d'importantes propriétés cytotoxiques la plaçant comme un agent anti-tumoral ou inflammatoire potentiel. Notre méthodologie de synthèse d'éthers d'énols consistant au couplage d'une lactone et d'une sulfone selon une réaction de type Julia, nous a permis d'obtenir l'éther d'énol cible qui par spirocyclisation intramoléculaire a conduit au motif spirocétal [6,6] du bistramide A. La molécule naturelle ainsi que deux analogues sont ensuite obtenus par fonctionnalisation des chaînes latérales du spirocétal, et couplage avec les fragments de type aminoacide et tétrahydropyrane fournis respectivement par le groupe du Pr. Yli-Kauhaluoma et celui du Pr. Piva. L'étude biologique des produits montre d'intéressantes propriétés de différenciation cellulaire, de déclenchement de l'apoptose et de blocage de la cytodiérèse. L'application de notre méthodologie, à la synthèse du SPIKET, ainsi qu'à l'obtention du spirocétal [5,6] de l'atténol A, permet d'étendre le domaine d'application de cette synthèse d'éthers d'énols exo-cycliques / Spiroketals are widely occurring substructures in natural products. The ever-increasing range of pharmacological activities displayed by products containing spiroketals has triggered an intense interest in their study, both from a synthetic and biological aspect. The development in our laboratory of an original enol ether synthesis motivated us to prepare the spiroketal fragment of bistramide A and, subsequently, to undertake its total synthesis. Bistramide A is a biologically active molecule isolated from the marine ascidian Lissoclinum bistratum that has emerged as a potential anti-inflammatory and anti-tumoral agent based on its high cytotoxicity and potent antiproliferative effect. The [6,6] spiroketal ring system of the natural product was accessed using a modification of the Julia olefination, extended to the reaction between a lactone and a heteroarylsulfone to prepare an exocyclic enol ether. The lactone and sulfone precursors were synthesized from a common starting material, dicyclohexylidene-D-mannitol. Bistramide A and two of its analogs were prepared by functionalization of the spiroketal side chains, followed by coupling reactions with the amino acid and tetrahydropyran subunits prepared by the groups of Pr. Yli-Kauhaluoma and Pr. Piva, respectively. An alternative approach to the precursor of the tetrahydropyran system from the chiral pool was developed. Biological studies revealed interesting effects on cellular differentiation, apoptosis, and cytokinesis. Application of our methodology to the synthesis of SPIKET and studies towards the [5,6] spiroketal of attenol A, gave us the opportunity to extend the scope of our exocyclic enol ether methodology

Earnest carbohydrate research was initiated in the nineteenth century by several talented organic chemists. Carbohydrates, now known to play essential roles in a range of fundamental biological processes, are presently studied by a throng of scientists from many fields, including: biochemistry, molecular biology, immunology, structural biology, medicine, agriculture, pharmacology and, of course, chemistry. Organic chemistry remains as relevant to carbohydrate research as it has ever been; its practitioners, with their skills in synthesis and fundamental understanding of molecules, are truly indispensable. This thesis details various synthetic endeavours within the field of carbohydrate chemistry. It describes four projects with goals as diverse as natural product synthesis, rational inhibitor design and the development of new reagents in organic synthesis. The first chapter provides an account of the synthesis of compound 1, a potent germination stimulant present in smoke, from D-xylose. Many analogues of 1 were prepared from carbohydrates and evaluated as germination stimulants, which permitted the dissemination of several structure-activity relationships. Subsequent chapters describe the design and preparation of inhibitors for various carbohydrate-processing enzymes. Compounds 55 and 56 were sought after as putative synergistic inhibitors of a Vitis vinifera (grape) uridine diphospho-glucose:flavonoid 3-O-glucosyltransferase (VvGT1). It was hoped that crystallographic investigations of VvGT1-UDP-2/3 complexes by a collaborator, structural biologist Professor Gideon Davies, would aid in clarifying mechanistic aspects of this enzyme.Compounds 114, 115 and 118 were prepared as putative arabinanase inhibitors. Once again, this work was undertaken to assist in crystallographic studies that might provide a better understanding of how these enzymes operate. The thesis concludes by describing the development of compound 152.HCl, a novel reagent for the diazotransfer reaction. Previously, this reaction utilised trifluoromethanesulfonyl azide (TfN3), an expensive and explosive liquid with a poor shelf-life, to convert a primary amine directly into an azide. Reagent 152.HCl was developed to replace TfN3 in this useful synthetic transformation. A one-pot procedure enabled the simple and inexpensive preparation of 152.HCl, which was demonstrated to be shelf-stable, crystalline and, crucially, effective in the diazotransfer reaction.

The development and application of unnatural amino alcohols,prepared via hetero-Diels-Alder reactions,in synthesis and catalysis is described.The studies are concerned with the [i]scope of the hetero-Diels-Alder reaction and preparation of important intermediates in the synthesis of antiviral agents,[ii ]application of amino alcohols in the ruthenium transfer hydrogenation of ketones,[iii ]use of similar precursors in the in situ generation of oxazaborolidines for reduction of ketones,and [iv] development and application of new chiral auxiliaries for dialkylzinc additions to activated imines, respectively. [i ]The use of chiral exo -2-azanorbornyl-3-carboxylates in the preparation of enantiopure cyclopentyl-amines is described.At the same time the scope of the hetero-Diels-Alder reaction,used in their preparation,is extended by manipulations of the dienophiles. [ii ]Application of 2-azanorbornyl-3-methanol as a very efficient ligand in the ruthenium-catalysed asymmetric transfer hydrogenation of aromatic ketones.This ligand (2 mol%)in combination with [RuCl2(p -cymene)]2 (0.25 mol%)gave rise to a very fast reaction (1.5 h)leading to the reduced products in excellent yields and enantioselectivities (up to 97%ee ). [iii ]Preparation of α-disubstituded 2-azanorbornyl-3-methanols,in situ generation of the corresponding oxazaborolidines,and use of the latter in reduction of aromatic ketones.Concentration, solvent,and temperature effects on the reaction outcome are described. [iv ]Development of two generations of chiral auxiliaries for the addition of dialkylzinc reagents to N - (diphenylphosphinoyl)imines.Studies using density functional computations allowed the rationalisation of the reaction mechanism and the development of a second generation of ligands that improved the previously reported results.Up to 98%ee could be obtained with these new ligands. Solvent effects on the outcome of the reaction and extension of the work to a larger variety of N - (diphenylphosphinoyl)imines are described.

Transition metal catalysis is a powerful tool for the construction of biologically active and pharmaceutically relevant architectures. With the challenge of continually depleting resources that this generation of scientists faces, it is becoming increasingly important to develop sustainable technologies for organic synthesis that utilize abundant and renewable feedstocks while minimizing byproduct formation and shortening the length of synthetic sequences by removing unnecessary protecting group manipulations and functionalizations. To this end, we have developed four new methods that transform inexpensive starting materials to valuable products. This dissertation covers the following key areas: 1) activation of CO2 for a mild and functional group tolerant synthesis of carboxylic acids, 2) oxidative twofold C–H bond activations as a strategy toward biaryls, 3) migratory O- to N-rearrangements in pyridines and related heterocycles for the preparation of N-alkylated heterocycles, and 4) asymmetric hydrogenations of cyclic imines and enamines en route to chiral 1,2- and 1,3-diamines and macrocyclic peptides.

Transition metal catalysis is a powerful tool for the construction of biologically active and pharmaceutically relevant architectures. With the challenge of continually depleting resources that this generation of scientists faces, it is becoming increasingly important to develop sustainable technologies for organic synthesis that utilize abundant and renewable feedstocks while minimizing byproduct formation and shortening the length of synthetic sequences by removing unnecessary protecting group manipulations and functionalizations. To this end, we have developed four new methods that transform inexpensive starting materials to valuable products. This dissertation covers the following key areas: 1) activation of CO2 for a mild and functional group tolerant synthesis of carboxylic acids, 2) oxidative twofold C–H bond activations as a strategy toward biaryls, 3) migratory O- to N-rearrangements in pyridines and related heterocycles for the preparation of N-alkylated heterocycles, and 4) asymmetric hydrogenations of cyclic imines and enamines en route to chiral 1,2- and 1,3-diamines and macrocyclic peptides.

This thesis deals with the development and application of new synthetic methodology in organic chemistry. The first part describes the development of a new protocol for the synthesis of 3-pyrrolines by means of a microwave-assisted ring-expansion reaction of 2-vinylaziridines. In addition, this methodology is implemented as a key-step in a formal total synthesis of the antibiotic (-)-anisomycin. In the second part, a new methodology for the synthesis of arylglycines from Weinreb amides is described. In this procedure, a Grignard reagent is added to the iminium ion formed from the Weinreb amide upon treatment with a base. When a chiral amide is used, the nucleophilic addition proceeds with high diastereoselectivity. Finally, an easy and straightforward synthesis of α-amino amides via a base-mediated rearrangement of modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenylation or alkynylation of this intermediate affords the corresponding α-amino amides in excellent yields. Furthermore, a more generalized protocol for the α-arylation of Weinreb amides lacking an α-amino moiety is also discussed. / QC 20100719

Made available in DSpace on 2014-10-09T12:41:34Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T13:56:02Z (GMT). No. of bitstreams: 0 / Dissertação (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP

Rupture of the anterior cruciate ligament (ACL) of the knee leads to chronic joint instability and reduced range of motion while the long term results are marred by a high prevalence of degenerative joint disease especially osteoarthritis. Bundles of collagen threads have been widely investigated for the repair of torn ACL, but are limited by insufficient tissue ingrowth to repopulate and completely regenerate these grafts. We have developed a novel in vitro method of characterizing fiber-based thread matrices by probing their ability to promote tissue ingrowth from a wound margin as a measure of their ability to promote repopulation and regeneration. This method is useful in the optimization of thread scaffolds, and is sensitive enough to distinguish between subtle variations in biopolymer chemistry and organization. Furthermore, this method was used to characterize the effects of crosslinking on the cell outgrowth and correlated the findings with the mechanical properties of collagen threads. The results suggest that crosslinking is required to achieve sufficient mechanical properties for high stress applications such as ACL replacement, but regardless of technique, crosslinking attenuated the cell outgrowth properties of the threads. To improve the regenerative capacity of these scaffolds, novel fibrin microthread matrices were developed with a similar morphology to collagen threads and sufficient mechanical strength to be incorporated in composite thread scaffold systems. These fibrin microthreads were loaded with FGF-2, a potent mitogen and chemotactic agent that works synergistically with fibrin in regulating cell signaling and gene expression. Increases in fibroblast migration and proliferation in FGF-2-loaded fibrin threads were successfully demonstrated with the concomitant promotion of oriented, aligned, spindle-like fibroblast morphology. These results suggest that fibrin-FGF-2 microthreads have distinct advantages as a biomaterial for the rapid regeneration of injured tissues such as the ACL.

Au cours de ce travail de nouvelles méthodes pour la formation de liaison C-N ont été développées. Dans la première partie de cette thèse une application de catalyse métal-ligand bifonctionnelle pour la réaction énantiosélective aza-Michael est démontrée. Dans la deuxième partie nous présentons le travail sur les cyclisations, en utilisant des alcaloïdes du quinquina facilement disponibles, comme catalyseurs des plus prometteurs, fournissant des β-amino-acides d’indoline avec jusqu'à 98% ee. Parmi eux, l’hydroquinidine ressort du lot comme étant le catalyseur donnant le meilleur excès énatiomérique. La troisième partie est liée à l'élaboration d'un nouveau processus intermoléculaires de diamination de styrènes, diènes et triènes, utilisant des bis-sulfonylimides comme source d'azote, en combinaison avec le diacétate de iodosobenzène, qui fournit une approche intéressante et efficace de diamines vicinales biologiquement et chimiquement important. La réaction peut être effectuée à température ambiante sans avoir besoin de protection par atmosphère inerte. / The concept of metal-ligand bifunctionality was successfully applied for an enantioselective aza-Michael reaction by employing well-defined ruthenium amido complexes. The catalyst was optimised and the corresponding chiral indoline β-amino acid derivatives were obtained with high enantioselectivities. Next, a straightforward enantioselective bifunctional organocatalytic approach was also developed. Employing hydroquinidine as catalyst the corresponding cyclic products were obtained in excellent enantioselectivities and quantitative yields. These compounds can be selectively deprotected and applied to peptide synthesis. Finally, we have developed unprecedented diamination reactions of styrenes, butadienes and hexatrienes employing easily accessible hypervalent iodine(III) reagents under robust reaction conditions. The first examples of the metal-free 1,2-diamination of butadienes were demonstrated and this oxidation methodology was further extended to the highly attractive 1,4 installation of two nitrogen atoms within a single step.

Submitted by Priscila Nascimento (pnascimento@icict.fiocruz.br) on 2012-11-23T17:06:52Z No. of bitstreams: 1 leonardo-paiva.pdf: 1961921 bytes, checksum: 594a95b8411eb96639599136812ba28b (MD5) / Made available in DSpace on 2012-11-23T17:06:52Z (GMT). No. of bitstreams: 1 leonardo-paiva.pdf: 1961921 bytes, checksum: 594a95b8411eb96639599136812ba28b (MD5) Previous issue date: 2009 / Fundação Oswaldo Cruz. Instituto de Tecnologia em Imunobiológicos. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Rio de Janeiro, RJ, Brasil. / Esta dissertação apresenta uma análise estratégica da indústria brasileira de reagentes para diagnóstico. Nesta análise são discutidos a dinâmica industrial, os fatores críticos de sucesso e as características deinovação do setor. A partir desta análise são identificadas oportunidades mercadológicas e tecnológicas e discutidas estratégias de inovação passíveis de utilização pelo Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), da Fundação Oswaldo Cruz, Ministério da Saúde. A estrutura analítica utilizada para atingir esses objetivos foi o Modelo para Análise Estratégica de Indústrias baseadas em Ciência de Países em Desenvolvimento (MAEI) e os elementos explorados neste estudo foram: o regime mercadológico, o regime tecnológico e papel do governo. A análise permitiu evidenciar oportunidades a partir das demandas atuais e futuras do Sistema Único de Saúde (SUS), em conformidade com os perfis demográficos e de carga de doença do país. Foram identificadas demandas por produtos que possam contribuir com a redução dos gastos em saúde, sejam novos produtos, novas formas de acesso e uso dos reagentes para diagnóstico. No que se refere às tecnologias, observou-se que o país vem acompanhando o processo de difusão das tecnologias. A capacitação tecnológica atual do país não segue o mesmo padrão do estágio de difusão, entretanto existem potencialidades para atender as demandas identificadas. As estratégias de inovação propostas para Bio-Manguinhos buscam, com oportunidades de curto e médio-longo prazo, contribuir para enfrentar os desafios do SUS. / This dissertation presents a strategic analysis of Brazilian industry for in vitro diagnostic assay. In this analysis it has been discussed the industrial dynamics, the critical success factors and the innovation characteristics of this sector. From this analysis, marketing and technological opportunitiesare identified and strategies are discussed for technological innovation in order to implement on Technology Immunobiologicals Institute (Bio-Manguinhos), Oswaldo Cruz Foundation from Ministry of Health. The analytical structure used to achieve these goals was the strategic analysis framework of science-based industries in evelopingcountries (SAF) and the elements explored in this study were: the marketingstructure, the technological regime and the role of government. The analysis allowed to highlight opportunities from current and future demands of the Brazilian Public Health System/Unified Health System (UHS), in accordance with the demographic profiles and burden disease of the country. It was identified demands for products that can contribute to reduct health costs, using new products, new ways to access and/or use in vitro diagnostic assays. About technologies is concerned it was observed that the country is following the process of diffusion. The current technological capabilities of the country does not follow the same pattern of stage of diffusion, however there is potential to meet the demands identified. The innovation strategies proposed to Bio-Manguinhos search, with opportunities for short and medium-long term, to face the challenges from UHS.