Grâce à ses propriétés uniques, le groupement pentafluorosulfanyle (SF5) a récemment retenu beaucoup d'attention. Ce substituant encombrant, hautement lipophile et électro-attracteur est souvent considéré comme un "super groupement trifluorométhyl". Aujourd’hui, la chimie de groupement SF5 est un domaine de la chimie du fluor qui se développe rapidement, et les méthodologies de synthèse des nouveaux « building-blocks » pentafluorosulfanylés sont constamment développées. Néanmoins, les méthodes permettant l'introduction du groupement SF5 dans les hétérocycles restent encore assez limitées. L’objectif de cette thèse était de synthétiser des nouveaux « building-blocks » pentafluorosulfanylés, d’une part, et de développer des nouvelles approches synthétiques, conduisant à des hétérocycles azotés originaux, substitués par un groupement SF5, d’autre part. Dans la première partie de notre travail, nous avons développé une synthèse en 4 étapes, conduisant à de nouveaux esters et amides acryliques substitués par un groupement SF5, à partir des dérivés commerciaux de l’acetate allylique. En utilisant la même stratégie, quelques nouveaux allylsilanes pentafluorosulfanylés ont été synthétisés. Nous avons aussi développé une réaction d’allylation des aldéhydes, catalysée par indium, en utilisant le bromure SF5-allylique, conduisant aux alcools alpha- et gamma-homoallyliques correspondants.Dans la deuxième partie, deux stratégies différentes pour la synthèse de nouveaux hétérocycles SF5-substitués, ont été explorées. La première était la fluoration directe des thiols ou disulfures hétérocycliques, suivant la procédure de Umemoto. La deuxième approche était basée sur les réactions de cycloaddition de nos "building-blocks" pentafluorosulfanylés. Ainsi, nous avons développé avec succès la synthèse des premières pyrrolidines et isoxazolidines pentafluorosulfanylées. Enfin, des post-fonctionnalisations des SF5-pyrrolidines ont été effectuées, conduisant aux plusieurs "plateformes" pentafluorosulfanylées qui pourraient être facilement incorporées dans les molécules d’intérêt biologique. / Due to its unique properties, the pentafluorosulfanyl (SF5) group has recently reached much attention. This bulky, highly lipophilic and electron-withdrawing substituent is often called as a “super-trifluoromethyl group”. Currently, the SF5-chemistry is becoming a fast growing field of the fluorine chemistry and the new pentafluorosulfanylated building-blocks are under continuous development. Nevertheless, the methods for the introduction of the SF5-group into heterocycles remain still quite limited.The aim of this thesis was to synthesize new pentafluorosulfanylated building-blocks, on the one hand, and to develop new synthetic approaches leading to original pentafluorosulfanylated nitrogen-containing heterocyles, on the other hand.In the first part of our work, we have developed an efficient four-step synthesis of new SF5-acrylic esters and amides, starting from commercially available allyl acetate derivatives. Using the same strategy, several new pentafluorosulfanylated allylsilanes were synthesized. We have also developed an In-mediated allylation reaction of aldehydes, using the SF5-allyl bromide, leading to the corresponding pentafluorosulfanylated alpha- and gamma-homoallylic alcohols.In the second part, two different strategies for the synthesis of new SF5-substituted heterocycles were explored. The first one was the direct fluorination of heterocyclic thiols or disulfides, according to the Umemoto’s procedure. The second approach was based on the cycloaddition reactions of our pentafluorosulfanylated building-blocks. As a result, we have successfully developed the synthesis of the first SF5-substituted pyrrolidines and isoxazolidines. Finally, post-functionalizations of SF5-pyrrolidines were performed, leading to several pentafluorosulfanylated scaffolds which could be easily introduce into molecules of biological interest.

An introduction to nucleoside analogues containing heterocyclic sugar mimics and their synthesis is presented. This includes various ring sizes and different heteroatom combinations. concentrated on work between 1995-2000. The synthesis of novel nucleoside analogues from nitroimidazole precursors has been investigated. The regioisorners I-vinyl-4-nitroimidazole and I-vinyl-S-nitroimidazole have been synthesised from the readily available 4/S-nitroimidazole. Also synthesised from 4/S-nitroimidazoIe IS 3-vinyl-imidazo[ 4' ,S' :S,6]pyrido[2,3- d]pyrimidin-8-one, the pyridine stretched analogue of 3-vinylinosine. 1,3-Dipolar cycloaddition reactions of these three molecules are studied, with stabilised and unstabilised 1,3-dipolar compounds. to produce heterocyclic nucleoside analogues. Structures of these cycloadducts are investigated using nrnr studies to determine the regiochemistry of the reactions. This nrnr evidence is supported my MO calculations. Further studies have established synthetic routes to the pyridine stretched analogues of 2'-deoxyadenosine and 2'-deoxyinosine from deoxyribose and 4/5- nitroimidazole, involving directing the coupling of a chlorosugar to the sodium salt of 4-nitroimidazoIe to yield a maximum of the S-nitroimidazole isomer product

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.

Verdazyl radicals started receiving attention as substrates for organic synthesis only a few years ago. Since then, the chemistry of verdazyl radicals has advanced at a very fast rate. There are now a number of generations of novel molecular scaffolds derived from verdazyl radicals. Traditionally, verdazyl radicals have been synthesized from mono-substituted alkyl hydrazine and phosgene, which are extremely dangerous to handle. Alkyl hydrazines are restricted from being imported into certain countries, including Canada. A completely new alkyl hydrazine- and phosgene-free synthesis is reported in this thesis. The new synthesis, relative to previously reported syntheses of verdazyl radicals, is safer, more economical and provides the ability to derivatize verdazyl radicals to a larger extent. In addition, enantioselective 1,3-dipolar cycloaddition reactions with various metal- or organo-catalysts are reported. The project is still in progress with the highest e.e. of > 90%.

Made available in DSpace on 2014-06-12T16:24:59Z (GMT). No. of bitstreams: 2 arquivo1093_1.pdf: 3328003 bytes, checksum: 7ec0eb754a46ccba221bbd5d6ab76f03 (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2010 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / A Química Medicinal, uma interseção da Química e da Farmacologia, envolve a identificação, síntese e desenvolvimento de novas entidades químicas destinadas ao uso terapêutico. A conjugação de características estruturais de duas ou mais classes distintas de compostos em uma nova molécula, estratégia da Química Medicinal chamada hibridização molecular, é a essência da secção química deste trabalho. Nele, objetivou-se a síntese de novos compostos contendo três farmacóforos relatados na literatura como responsáveis por diversas atividades biológicas. Oxadiazolinas, compostos heterocíclicos extensamente relatados como responsáveis por atividades anti-inflamatória, antineoplásica, dentre outras, compuseram o novo scaffold desenvolvido neste estudo. Hidrazonas, classe de moléculas que apresentam várias atividades relatadas, tais como analgésica, anti-inflamatória, anticonvulsivante, antimicrobiana, entre outras. Semicarbazonas, que fazem parte de compostos com atividades antichagásica, anticonvulsivante e antinociceptiva, formam, junto das hidrazonas e oxadiazolinas, as partes que deram gênese aos híbridos almejados neste trabalho. Para tanto, foi planejada a obtenção de novos derivados oxadiazolil-aril-hidrazonas 83 e oxadiazolil-arilsemicarbazona 84, por meio, inicialmente, de uma cicloadição 1,3-dipolar, na qual se utilizou a 1-pirrolina 78 como dipolarófilo, e o óxido de carboetoxiformonitrila (CEFNO) 79 como dipolo do tipo alenila, sendo este formado in situ. Dessa cicloadição, originou-se um éster em C3 do novo biciclo pirrolidina[1,2-d][1,2,4]-2-oxadiazolina 80, com rendimento de 75%, que, em seguida, foi submetido à redução por meio de um redutor brando, o boroidreto de sódio, NaBH4, obtendo o respectivo álcool 81, com 95% de rendimento. A oxidação deste foi realizada por meio da oxidação de Swern, ou método do DMSO ativado, produzindo o aldeído 82 no mesmo sítio C3, com 72% de rendimento. Enfim, foram realizadas reações de condensação do aldeído oxadiazolínico 82 com fenil-hidrazinas p-substituídas e a fenilsemicarbazida, alcançando as desejadas oxadiazolil-aril-hidrazonas p-substituídas 83, em uma faixa de rendimento de 47-54%, bem como a oxadiazolil-aril-semicarbazona 84 com rendimento de 55%. Estas foram submetidas a testes biológicos, nos quais apresentaram percentual de proteção em um intervalo de 44-72% para atividade antinociceptiva, em concentração de 200μmol/kg, utilizando o método de contorção abdominal induzida por ácido acético. No método da formalina, proteção de 64-74% foi observada na primeira fase e de 45- 78% na segunda fase, na dose de 10mg/kg, todos os testes empregando camundongos. No teste antichagásico, a semicarbazona 84 apresentou IC50 de 27,42 μg/mL, em testes na forma epimastigota do Trypanosoma cruzi, além de apresentar citotoxicidade muito inferior a dos fármacos de referência, o Benznidazol e o Nifurtimox

La presente tesis doctoral describe la investigación sobre reacciones de cicloadición 1,3-dipolares, concretamente, la síntesis de moléculas que presentan pirrolidinas, pirrolizidinas δ-lactamas y dicetopiperacinas en su estructura. La preparación de estos compuestos se debe, principalmente, a las actividades biológicas que presentan dichas estructuras heterocíclicas. Además, la tesis está constituida por una introducción general y tres capítulos, los cuales describen la síntesis de compuestos N-heterocíclicos de manera diastereoselectiva. La introducción general describe las reacciones de cicloadición 1,3-dipolares, su importancia y sus características. El capítulo 1 describe la síntesis diastereoselectiva de pirrolidinas espirocíclicas catalizada por acetato de plata. El capítulo 2 se basa en el estudio de reacciones multicomponente para la preparación de pirrolizidinas. En concreto, la reacción se lleva a cabo de manera diastereoselectiva y el proceso se rige por 1,2-prototropía en una reacción 1,3-dipolar via descarboxilativa. El capítulo 3 detalla la síntesis secuencial de derivados de exo-3,5-difenil-4-nitroprolinatos de metilo sustituidos mediante una cicloadición 1,3-dipolar enantioselectiva seguido de una adición de tipo Michael diastereoselectiva. / The present work has been possible thanks to funding from the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P, CTQ2016-80375-P, CTQ2017-82935-P and PID2019-107268GB-I00), Generalitat Valenciana (APOTIP/2020/002) and the University of Alicante.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The present dissertation describes a chemical methodology for the synthesis of three series containing fourteen new molecules of trifluoro(chloro)methyl substituted 1H-1,2,3-triazoles, which are structural analogues to the antiepileptic drug Rufinamide. The protocol used consisted in reactions of 1,3-dipolar cycloaddition of 2,6-difluorobenzyl azide and 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trifluoro(chloro)-3-alken-2-ones, where the 4-substituents are H, Me, Ph, 4-OMeC6H4, 4-NO2C6H4,4-FC6H4,2-Thienyle 4,4 -Biphenyl. The optimized reactios were carried-out in absense of solvente, in reaction times of 48 to 96 hours at 100-150°C and in yields of 30-75%. The reactions employing the 4-alkoxy-4-aryl(heteroaryl)-1,1,1-trifluoro-3-alken-2-ones 1and 2,6-difluorobenzyl azidedemonstrated a 4-substituent dependency of the enones precursors (above mentioned) and conducted to the formation of isomeric mixtures of 4-trifluoroacetyl substituted and/or 5-trifluoromethyl substituted triazoles in varying proportions, which were separated and purified by chromatographic columns. On the other hand, the reactions employing the 4-alkoxy-4-alkyl(aryl/heteroaryl)-1,1,1-trichloro-3-alken-2-ones and the same 2,6-difluorobenzyl azide produced exclusively a series of 4- trichloroacetyl substituted triazoles without the detection of the respective 5-trichloromethyl substituted regioisomer. The synthesized triazoles were characterized by 1H, 13C, uni- and two-dimensional NMR Spectroscopy techniques as HMQC, gas chromatography coupled to mass spectrometry (GC-MS), mono-crystal X-ray diffraction, high resolution mass spectrometry (HRMS) and their purity determined by CHN Elemental Analysis. / A presente dissertação descreve uma metodologia química para a síntese de três séries de 1H-1,2,3-triazóis trifluor(cloro)metil substituídos, totalizando quatorze moléculas inéditas, as quais são análogas estruturais do fármaco antiepiléptico Rufinamida. O protocolo consistiu na realização de reações de cicloadição 1,3-dipolares envolvendo 2,6-difluorbenzil azida e 4-alcóxi-4-alquil(aril/heteroaril)-1,1,1-trifluor(cloro)-3-alquen-2-onas, sendo os substituintes 4-alquila(arila/heteroarila) iguais a H, Me, Ph, 4-OMeC6H4, 4-NO2C6H4,4-FC6H4,2-Tienila e 4,4 -Bifenila. As reações otimizadas se processaram na ausência de solvente, em tempos reacionais de 48 a 96 horas a 100-150°C e levaram a rendimentos na faixa de 30-75%. As reações que utilizaram 4-alcóxi-4-aril(heteroaril)-1,1,1-triflúor-3-alquen-2-onase 2,6-difluorbenzil azida apresentaram uma dependência quanto a substituição da posição 4 das enonas precursoras (acima descritos) e conduziram à formação de misturas isoméricas de triazóis 4-trifluoracetil substituídos e/ou 5-trifluormetil substituídos em proporções variadas, as quais foram passíveis de separação e purificação por cromatografia em coluna. Por outro lado, as reações empregando 4-alcóxi-4-alquil(aril/heteroaril)-1,1,1-tricloro-3-alquen-2-onas e a mesma 2,6-difluorbenzil azida produziram, exclusivamente, uma série de triazóis 4-tricloroacetil substituídos sem a detecção dos respectivos regioisômeros 5-triclorometil substituídos. Os triazóis sintetizados foram caracterizados por espectroscopia de RMN de 1H, 13C por técnicas uni- e bidimensionais (HMQC), cromatografia a gás acoplada à espectrometria de massas (GC-MS), difração de raios-X em mono-cristal, espectrometria de massas de alta resolução (HRMS) e a sua pureza determinada através de análise elementar CHN.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / This work reports the synthesis of a series of 29 new 1-(3-aryl-4,5-dihydroisoxazol-5-yl)methyl-4-trihalomethylpyrimidin-2(1H)-ones which have high pharmacological interest, since they are similar to natural and synthetic nucleosides. These compounds were obtained from 1,3-dippolar cycloaddition reaction between the 1-allyl-(6-aryl)-4-trihalomethylpyrimidin-2(1H)-ones and different benzonitrile oxides, obtained from the selected oximes of general formula ArCH=NOH (where Ar = Ph, 4-FC6H4, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, styryl, 2-OHC6H4 e 4-OHC6H4). The reaction conditions employed were highly regioselective, because it was observed the formation of only 3,5-substituted isomer by both NMR spectral analysis and X-ray diffractometry. The compounds were obtained in good yields (58 99%) and were purified from recrystallization or by column chromatography on silica gel. Some the obtained compounds showed antineoplastic activity in vitro against different tumor cell lines. Additionally, three new N3-substituted pyrimidinic dideoxynucleoside analogues were prepared, which were obtained in good yields (88 97%) from the reaction of N-allyl-2-methylthiopyrimidin-4(3H)-one and some of the benzonitrile oxides mentioned above. The reactions for the formation of N3-substituted nucleoside still require optimization. This thesis also described the regiochemisty controled synthesis of two series of pyrazoles, named 5(3)-aryl-3(5)-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides, structural analogues of Celecoxib (14 examples), where aryl = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, furan-2-yl, from the cyclocondensation reaction between 4-aryl-1,1,1-trifluoromethyl-4-methoxy-3-buten-2-ones and 4-hydrazinobenzenosulfonamide hydrochloride. The isolation of either isomer depended on the initial pH medium, where the alkaline pH favored the isolation of the 1,5-substituted isomer at yields of 73 99% and the reaction conducted in acid pH favored the isolation of the 1,3-substituted isomer, with yields of 77 94%. This study also allowed the isolation and spectroscopic characterization of a novel series of 3-aryl(heteroaryl)-5-hydroxy-5-trifluoromethyl-(1H-pyrazol-1-yl)benzenesulfonamides (7 examples) in yields of 75 97% with interesting anti-inflammatory and antinociceptive activities in vivo. / Esta tese apresenta a síntese de uma série de 29 moléculas inéditas de 1-(3-aril-4,5-diidroisoxazol-5-il)metil-4-trialometilpirimidin-2(1H)-onas que possuem alto interesse farmacológico, visto que são análogos a nucleosídeos naturais e sintéticos. Esses compostos foram obtidos a partir de reação de cicloadição 1,3-dipolar entre as 1-alil-(6-aril)-4-trialometilpirimidin-2(1H)-onas e diferentes óxidos de benzonitrila, obtidos a partir das oximas selecionadas, de fórmula geral ArCH=NOH (onde Ar = Ph, 4-FC6H4, 2-MeC6H4, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, Estiril, 2-OHC6H4 e 4-OHC6H4). As condições reacionais empregadas mostraram-se altamente regiosseletivas, uma vez que, por análise dos espectros de RMN e por difratometria de raios-X, observou-se a formação apenas do isômero 3,5-substituído. Os compostos foram obtidos em bons rendimentos (58 99%) e puderam ser purificados a partir de recristalização ou através de coluna cromatográfica em sílica gel. Alguns dos compostos obtidos apresentaram atividade antineoplásica in vitro frente a diferentes linhagens de células tumorais. Também estão apresentados 3 novos análogos nucleosídeos pirimidínicos N3-substituídos, obtidos em bons rendimentos (88 97%) a partir da reação da N-alil-2-metiltiopirimidin-4(3H)-ona e de alguns óxidos de benzonitrila acima citados. As reações para a formação dos nucleosídeos N3-substituídos ainda necessitam de otimização. Nesta tese também está descrito o controle regioquímico para a síntese de duas séries de pirazóis, nomeados 5(3)-aril-3(5)-trifluormetil-(1H-pirazol-1-il)benzenosulfonamidas, análogos estruturais do Celecoxib (14 exemplos), onde aril = Ph, 4-FC6H4, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, fur-2-il, a partir da reação de ciclocondensação entre 4-aril-1,1,1-trifluormetil-4-metóxi-3-buten-2-onas e o cloridrato de 4-hidrazinilbenzenosulfonamida. O isolamento de um ou outro isômero dependeu do pH inicial do meio, onde o pH básico favoreceu o isolamento do isômero 1,5-substituido com rendimentos de 73 99% e a reação conduzida em pH ácido favoreceu o isolamento do isômero 1,3-substituído, com rendimentos de 77 94%. Este estudo também possibilitou o isolamento e caracterização espectroscópica de uma série inédita de 3-aril(heteroaril)-5-hidróxi-5-trifluormetil-(1H-pirazol-1-il)benzenosulfonamidas (7 exemplos) em rendimentos de 75 97%, com interessante atividade anti-inflamatória e antinociceptiva in vivo.

Made available in DSpace on 2015-05-14T13:21:13Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 2559856 bytes, checksum: 50fe82b4059b56d6e01eb8e3cf66ea70 (MD5) Previous issue date: 2012-10-20 / Financiadora de Estudos e Projetos - Finep / Mesoionic compounds are notable heterocyclic for having the most diverse biological properties, physical and chemical properties. Are defined as flat and non-aromatic heterocyclic Betaines stabilized by electron delocalization. Through an in situ cycloaddition/cicloreversion 1,3-dipolar were obtained two mesoionic, MI-1.1 and MI-1.2 through of the interconversion system 1,3-oxazólio-5-olato (Munchnonas) for 1,3-tiazólio-5-tiolato. A nucleophilic substitution reaction with excess methyl iodide, CH3I, promoted the first modification to the mesoionic system were changed of free base to iodates salts, S-methylated forming derivatives mesoionic, MI-2.1 e MI-2.2. These underwent a cyclodehydration reaction in the presence of acetic anhydride yielding two mesoionic system 1,3-diazolium-5-thiolate, MI-3.1 and MI-3.2, which in turn were alkylated again and originated two derived in the form of iodates salts S-methylated, MI-4.1 and MI-4.2. As the mesoionic and its derivatives: MI-2.1, MI-2.2, MI-3.1, MI-3.2, MI-4.1 and MI-4.2 and unpublished literature. Their structures were elucidated by spectroscopic techniques for RMN 1H and 13C and infrared light through a comparative analysis with existing structures. / Os compostos mesoiônicos são heterocíclicos notáveis por apresentar as mais diversas propriedades biológicas, físicas e químicas. São definidos como betaínas heterocíclicas planas e não aromáticas estabilizadas por deslocalização de elétrons. Através de uma reação in situ de cicloadição/cicloreversão 1,3-dipolar obtiveram-se dois mesoiônicos, MI-1.1 e MI-1.2, através da interconversão do sistema 1,3-oxazólio-5-olato (Munchnonas) para 1,3-tiazólio-5-tiolato. Uma reação de substituição nucleofílica com excesso de iodeto de metila, CH3I, promoveu a primeira modificação no sistema mesoiônico sendo transformados de base livre para sais iodatos S-metilados formando os derivados mesoiônicos, MI-2.1 e MI-2.2. Estes sofreram uma reação de ciclodesidratação na presença de anidrido acético obtendo-se dois mesoiônicos do sistema 1,3-diazólio-5-tiolato, MI-3.1 e MI-3.2, que por sua vez foram alquilados novamente e originaram dois derivados em forma de sais iodatos S-metilados, MI-4.1 e MI-4.2. Sendo os mesoiônicos e seus derivados: MI-2.1, MI-2.2, MI-3.1, MI-3.2, MI-4.1 e MI-4.2 inéditos na literatura. Suas estruturas foram elucidadas por meio de técnicas espectroscópicas de RMN 1H e 13C e infravermelho através de uma análise comparativa com estruturas já existentes.

Le sujet de thèse concerne l’immunothérapie induite par des glycolipides synthétiques dont le chef de file est le KRN7000. Ce composé montre une activité à stimuler le système immunitaire renforçant l’action antitumorale. Cependant, comme la plupart des principes actifs, le KRN 7000 n’est pas spécifique des cellules tumorales. Pour pallier ce manque de spécificité, nous avons envisagé de coupler des glycolipides à un agent ciblant des cellules tumorales selon deux approches. La première a consisté à lier de manière covalente l’agent ciblant au glycolipide via un espaceur, ce qui a permis d’évaluer si le greffage de cet immunostimulant sur l’agent ciblant ne perturberait pas la reconnaissance par le récepteur membranaire. Concernant la seconde approche, une étude préliminaire reposant sur le relargage du KRN7000 a été abordé en préparant une prodrogue du glycolipide. Un autre problème du KRN7000 est qu’il n’est pas sélectif vis-à-vis de deux voies d’activation du système immunitaire. Pour pallier ce problème, la synthèse de nouveaux analogues C-glycosidiques d’alpha-galactosylcéramides plus stables et plus sélectifs de la voie Th1 a été envisagée. La stratégie de synthèse met en œuvre une cycloaddition 1,3-dipolaire entre un C-vinyl glycoside et une nitrone. Dans un premier temps, une étude méthodologique de cette réaction a d’abord été réalisée. Dans un deuxième temps, la fonctionnalisation du cycle isoxazolidine puis son ouverture devrait permettre d’accéder aux analogues ciblés. / This PhD work concerns glycolipid-induced activation of immune system with KRN7000 as lead compound. This latter has shown its ability to stimulate NKT cells which are T cells of the immune system resulting in potent antitumor activity. However, like lots of drugs, KRN7000 is not specific for tumor cells. To tackle this lack of specificity, we plan to graft glycolipids to a targeting agent for tumor cells following two approaches. The aim of the first one was to bind covalently the glycolipid to the targeting agent in order to determine the effect of the glycolipid grafting onto the targeting agent on the recognition by the membrane receptor. Regarding the second approach, a preliminary study based on the KRN7000 release was performed by synthesizing a glycolipid prodrug. Another drawback of the KRN7000 is the lack of selectivity towards two ways of activation of the immune system. In order to favor the Th1 immune response, the synthesis of new C-glycosidic analogues of alpha-galactosylceramides was implemented. The synthetic strategy has involved a 1,3-dipolar cycloaddition between a C-vinyl glycoside and a nitrone. First, a methodologic study about this reaction was performed. Then functionalization of the obtained isoxazolidine ring and the N-O bond cleavage should lead to the expected original analogs.