In this thesis, different cycloaddition reactions, such as the enantioselective 1,3-dipolar-cycloaddition, which takes place between in situ generated stabilized azomethine ylides, and electrophilic alkenes, and the diastereoselective multicomponent reactions Amine-Aldehyde-Dienophile (AAD) or Phosphoramidate-Aldehyde-Dienophile (PAD) are described. In Chapter 1, an asymmetric 1,3-dipolar cycloaddition reaction involving an imino ester with tert-butyl acrylate was carried out using a silver(I) complex with double chirality, formed from a chiral phosphoramidite and chiral silver binolphosphate(I). The goal of this reaction is to synthesize key enantiomerically enriched structures to access the GSK-third generation of HCV inhibitors. In Chapter 2, the synthesis of polysubstituted cyclohex-2-enylamines using the multicomponent Amine-Aldehyde-Dienophile reaction involving benzyl or 4-methoxybenzylamine, is described. The study the diastereoselective version, employing commercially available chiral benzylic amines, or even a maleimide with the chiral information at the nitrogen atom, are also reported. In Chapter 3, the synthesis of polysubstituted cyclohex-2-enylamines derivatives using the multicomponent Phosphoramidate-Aldehyde-Dienophile (PAD), is described. Several series of N-substituted phosphoramidates reacted with α,β-unsaturated aldehydes, bearing hydrogen atoms at the γ-position, in good yields.

No description available.

[pt] Diante da importância terapêutica dos 1,2,3-triazóis e da versatilidade da reação de cicloadição 1,3-dipolar de Huisgen catalisada por cobre (reação CuAAC), o presente trabalho propõe a síntese de novos 1,2,3-triazóis-1,4-dissubstituídos abordando-se o conceito de hibridização molecular que associa ao núcleo triazólico outros grupos farmacofóricos privilegiados. Os compostos sintetizados foram divididos em duas séries e avaliados quanto ao potencial anticâncer, antileishmanial e distúrbios do sistema do nervoso central. Para obtenção da primeira série de triazóis utilizou-se como precursores aril azidas preparadas a partir de anilinas e éter propargílicos obtidos a partir de fenóis. A etapa chave da reação de CuAAC levou a obtenção dos 1,2,3-triazóis-1,4-dissubstituídos com rendimentos entre 50 e 85 porcento. Os compostos obtidos foram avaliados em diferentes linhagens celulares de glioblastoma (GBM, U87), incluindo linhagens celulares humanas altamente resistentes como a GBM02, GBM95, onde os compostos 2,2- (4,4-((1,3-phenilenebis(oxi))bis(methileno))bis(1H-1,2,3-triazol-4,1diyl))dibenzaldeído e (E)-4-metil-N-(2-(4-(fenoximetil)-1H-1,2,3triazolil)benzilideno)benzenosulfonohidrazida foram os mais ativos, com IC50 de 28,7 e 30,3 uM, respectivamente. Também foram avaliados nas linhagens de câncer de pulmão e próstata (A549, 22Rv1), entretanto, os compostos analisados não apresentaram atividade frente a estas linhagens celulares. Para a síntese da segunda série de compostos híbridos, tais quais os a-hidroxi-1,2,3-triazóis e benzocromenostriazóis, utilizou-se como materiais de partida aril azidas, preparadas através de ácidos aril borônicos e álcoois propargílicos, preparados a partir de benzaldeídos comerciais. A reação CuAAC na presença de metóxido de sódio levou a obtenção dos novos a-hidroxi-1,2,3-triazóis com rendimentos entre 35 e 75 porcento. A partir dos a-hidroxi-1,2,3-triazóis obtidos, realizou-se a reação de ativação C-H catalisada por paládio para obtenção benzocromenos-triazóis com rendimentos entre 35 e 40 porcento. Esses compostos foram avaliados como inibidores do transportador de glicina (Gly T1), transportadores relacionados a distúrbios neurológicos, e o composto (2-bromofenil)(1-(4-bromofenil)-1H-1,2,3-triazol-4-il)metanol apresentou 42porcento de inibição e IC50 de 13 uM, sendo este o melhor resultado de toda a série. Os compostos obtidos foram avaliados quanto a atividade antileishmanial (L. amazonenses), sendo que os compostos 2,2-(4,4-((1,3- phenilenebis(oxi))bis(methileno))bis(1H-1,2,3-triazol-4,1diyl)) dibenzaldeído e (E)-4-metil-N-(2-(4-(fenoximetil)-1H-1,2,3triazolil)benzilideno) benzenosulfonohidrazida apresentaram os melhores resultados, com IC50 de 8,85 e 8,81 uM, respectivamente. Todos os compostos sintetizados foram caracterizados por técnicas de espectroscopia de ressonância magnética nuclear (RMN), infravermelho (IV) e espectrometria de massas (CG-MS). / [en] In view of the therapeutic importance of 1,2,3-triazoles and the versatility of the copper-catalyzed Huisgen 1,3-dipolar cycloaddition (CuAAC), the present work proposes the synthesis of new compounds containing 1,2,3-triazoles-1,4-disubstituted derivatives by addressing the concept of molecular hybridization to obtain various triazole-containing compounds associated with other privileged pharmacophoric groups. The compounds synthesized were divided into two series and evaluated for their anticancer potential, as antileishmanial and central nervous system disorders. In order to the first series of triazoles, aryl azides were prepared from commercial anilines and propargylic ethers were obtained from commercial phenols. The key step of the CuAAC reaction afforded of 1,2,3-triazoles-1,4-disubstituted 50 - 85 percent in yields. All compounds were evaluated in different glioblastoma cell lines (GBM), including highly resistant human cell lines such as GBM02, GBM95, in which compounds 2,2-(4,4-((1,3 henylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))dibenzaldehyde and (E)-4-methyl-N-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)benzylidene)benzenesulfonohydrazide were the most active, with IC50 of 28.7 and 30.3 uM, respectively. The triazole derivatives were also evaluated for the lung and prostate cancer strains (A549, 22Rv1), however, the compounds analyzed did not show activity in these cell lines. For the synthesis of the second series of hybrid compounds such as a-hydroxy-1,2,3-triazoles and benzochromenes-triazoles, aryl azides were prepared from aryl boronic acids and the propargylic alcohols from commercial benzaldehydes. The CuAAC reaction in the presence of sodium methoxide provided the novel a-hydroxy-1,2,3-triazoles in 35 and 75 percents yields. The a-hydroxy-1,2,3-triazoles, were aplied palladium-catalyzed intermolecular (C-O) cyclization reaction and provided benzocromenes-triazoles in 35-40 percent yields. These compounds were evaluated as inhibitors of glycine transporter (Gly T1), which are related to neurological disorders. Therefore, compound (2-bromophenyl) (1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)methanol showed the best result with 42 percent of inhibition and IC50 of 13 uM. All compounds were avaluated for antileishmanial activity (L. amazonenses), compounds 2,2-(4,4-((1,3-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1-diyl))dibenzaldehyde and (E)-4-methyl-N-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl)benzylidene)benzenesulfonohydrazide presented the best results, with IC50 de 8,85 e 8,81 uM, respectively. All the compounds synthesized were characterized by nuclear magnetic resonance (NMR), infrared (FTIR) spectroscopy and mass spectrometry (GC-MS) techniques.

Ce mémoire est subdivise en deux parties. La première partie concerne la synthèse de pyrazoles présentant un intérêt sur le plan agrochimique. En effet, le noyau pyrazole est présent dans de nombreux composes ayant des activités biologiques diverses et en particulier antifongique. Au cours de ce travail, nous avons développé diverses approches convergentes de pyrazoles diversement substitués au moyen de réactions de couplages croisés pallado-catalyses sélectifs et séquentiels à partir de pyrazoles possédant différents points d’encrages. Dans la deuxième partie, nous nous sommes intéressés à la synthèse de diverses furopyridones en tant qu’analogues de produits naturels possédant une activité antifongique, et notamment le Cladobotryal. Dans ce but, diverses alcynylpyridones ont été synthétisées et mises en jeu dans divers processus de cyclisation pour atteindre de manière divergente une série de furo[3,2-c]pyridin-4-ones, furo[3,2-c]pyridin-6-ones et furo[2,3-b]pyridin-4-ones / This thesis is subdivided into two principal parts. The first part is focussed on the synthesis of pyrazole derivatives of agrochemical relevance. Indeed, the pyrazole nucleus is found in numerous compounds possessing interesting biological properties, and notably antifungal activities. Various convergent approaches to diversely substituted pyrazoles have therefore been developed by means of site-selective palladium-catalyzed cross-coupling reactions conducted sequentially on pyrazole scaffolds. In the second part, we have been involved in the synthesis of furopyridones as simplified analogues of natural compounds possessing antifungal activities such as Cladobotryal. Toward this end, various alkynylpyridones have been synthesizes and involved in diverse cyclization processes to access a series of furo[3,2-c]pyridin-4-ones, furo[3,2-c]pyridin-6-ones, and furo[2,3-b]pyridin-4-ones

This thesis is divided into four separate parts with amino alcohols as the common feature. The first part of the thesis describes the development of an efficient three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters are formed in high yields and excellent diastereoselectivities. An asymmetric version was also developed by employing chiral α-methylbenzyl imines as dipolarophiles yielding enantiomerically pure syn-α-hydroxy-β-amino esters. This methodology was also applied on a short asymmetric synthesis of the paclitaxel side-chain as well as in an asymmetric synthetic approach towards the proteasome inhibitor omuralide. Furthermore, the use of chiral Rh(II) carboxylates furnishes the syn-α-hydroxy-β-amino esters in moderate enantioselectivity (er up to 82:18), which indicates that the reaction proceeds via a metal-associated carbonyl ylide. The second part describes the development of a 1,3-dipolar cycloaddition reaction of azomethine ylides to aldehydes for the synthesis of α-amino-β-hydroxy esters. Different methods for the generation of the ylides, including Vedejs’ oxazole methology and an Ag(I)/phosphine-catalyzed approach have been evaluated. The best results were obtained with the Ag(I)/phosphine approach, which yielded the desired α-amino-β-hydroxy ester in 68% yield and 3.4:1 syn:anti-selectivity. The last two parts deals with the total synthesis of the amino alcohol-containing natural products D-erythro-sphingosine and (−)-stemoamide. The key transformation in the sphingosine synthesis is a cross-metathesis reaction for the assembly of the polar head group and the aliphatic chain. In the stemoamide synthesis, the key feature is an iodoboration/Negishi/RCM-sequence for the construction of the β,γ-unsaturated azepine core of stemoamide followed by a stereoselective bromolactonization/1,4-reduction strategy for the installation of the requisite C8-C9 trans-stereochemistry. / QC 20100820

<p>This thesis is divided into three separate parts with amino alcohols as the common feature. The first part describes the development of a novel three-component approach to the synthesis of α-hydroxy-β-amino esters. Utilizing a highly diastereoselective Rh(II)-catalyzed 1,3-dipolar cycloaddition of carbonyl ylides to various aldimines, syn-α-hydroxy-β-amino esters formed in high yields and excellent diastereoselectivities. This methodology was also applied in a short enantioselective synthesis of the C-13 side-chain of Taxol.</p><p>The second part of the thesis describes a total synthesis of D-erythro- Sphingosine based on a cross-metathesis approach to assemble the polar head group and the aliphatic chain.</p><p>The last part deals with the application of amino alcohols as scaffolds in a diversity-oriented protocol for the development of libraries of small polycyclic molecules. The design of the libraries is based on the iterative use of two powerful ring-forming reactions; a ring-closing metathesis and an intramolecular Diels-Alder reaction, to simultaneously introduce structural complexity and diversity.</p>

The work centersaround perfluoroaryl azides (PFAAs), and theirability to undergo certain fast and robusttransformations. The chemistry was furtherappliedfor biomedical applications. The first section focuses on the azide-aldehyde-amine cycloaddition using PFAAs. Experimental and computational investigations uncovered a fast azide-enamine cycloaddition to form triazolines, which spontaneously rearrange into stable amidine products. In addition, this transformation was explored in the formulation of pure nanodrugs. Because this reaction can introduce a phenyl and a perfluoroaryl moiety enabling supramolecular interactions near the antibiotic drug, the resulting ciprofloxacin derivatives formed nano-sized aggregates by precipitation, which displayed aggregation-induced emission for bacterial imaging as well as enhanced size-dependent antibacterial efficacy. In the second section, the high electrophilicity of PFAAs was explored to transform azides to aryl amides. The reactivity of PFAAs in the thioacid/azide reaction was studied. In addition, PFAAs were discovered to react with phenylacetaldehyde to form aryl amidesviaan azide-enol cycloaddition, similar tothe perfluoroaryl azide-aldehyde-amine reaction.This strategyof amide synthesiswas furthermoregeneralized through a combination of base-catalyzed azide-enolate cycloaddition reaction and acid-or heat-promoted rearrangement of triazolines. The last section describes a type of azide fluorogens whose fluorescence can be switched on by alight-initiated intramolecular nitrene insertion intoa C-H bond in the neighboring aromaticring. These fluorogenic structures were efficiently accessed via the direct nucleophilic aromatic substitution of PFAAs. / <p>QC 20150903</p>

Ce travail de thèse décrit la synthèse d’iminosucres bicycliques comportant un carbone quaternaire en jonction de cycle à partir de cétonitrones polyalcoxylées. Dans un premier temps, nous nous sommes intéressés à l’étude de l’addition nucléophile d’a-diazoesters sur des nitrones. Des β-N-hydroxyamino α-diazoesters ont ainsi été obtenus avec succès en employant le bis(triméthylsilyl)amidure de lithium comme base dans le THF à -78 °C. Le traitement de ces hydroxylamines par différents catalyseurs métalliques a conduit à la formation de cétonitrones inédites par migration 1,2 d’hydrure. Le triflate d’argent et le tétrakis acétonitrile hexafluorophosphate de cuivre ont été les catalyseurs les plus performants et ont permis de préparer dix nouvelles cétonitrones cycliques α-alcoxyméthylcarbonylées. Leur réactivité vis-à-vis de divers dipolarophiles a été explorée. Les cycloadduits résultant de la réaction de ces cétonitrones avec l’alcool allylique et l’alcool homoallylique ont été convertis en pyrrolizidines et en indolizidines par réduction de la liaison N-O en employant le molybdène hexacarbonyle. Des modifications fonctionnelles (réduction de la fonction ester et hydrogénolyse des éthers benzyliques) ont permis d’accéder à six nouveaux iminosucres bicycliques comportant un carbone quaternaire en jonction de cycle. L’évaluation biologique de ces molécules en tant qu’inhibiteurs de glycosidases a révélé que parmi elles, deux indolizidines étaient des inhibiteurs puissants et sélectifs d’α-glucosidases. / This manuscript reports the synthesis of bicyclic iminosugars bearing a quaternary carbon at their ring junction from polyalkoxylated ketonitrones. Firstly we have studied the nucleophilic addition of α-diazoesters to nitrones. The expected β-N-hydroxyamino α-diazoesters were successfully obtained by using lithium bis(trimethylsilyl)amide as base in THF at -78 °C. Treatment of these hydroxylamines with different metal catalyst induced 1,2-hydride shift and lead to unprecedented ketonitrones. To promote this transformation, silver triflate and tetrakis acetonitrile copper hexafluorophosphate were the most effective catalyst and ten new α-alkoxymethylcarbonyl cyclic ketonitrones were prepared. Their reactivity as 1,3-dipoles in cycloaddition reactions with various dipolarophiles was investigated. Cycloadducts obtained from the reaction between these ketonitrones and allyl alcohol or homoallyl alcohol were coverted into the corresponding pyrrolizidines or indolizidines by a molybdenum-catalyzed N-O bond cleavage. Subsequent modifications (ester reduction and benzylic ethers hydrogenolysis) gave acess to six new bicyclic iminosugars which are substituted at their ring junction. Among these molecules, the inhibitory activity evaluation revealed two potent and selective inhibitors of α-glucosidases.

A presente tese descreve a síntese e caracterização de 10 novas séries de moléculas na forma de banana contendo os anéis isoxazolina e isoxazol como reais candidatos na preparação de cristais líquidos polares. Foram avaliados parâmetros estruturais tais como o tipo de função conectora do centro curvado com os braços mesogênicos, a natureza do heterociclo e a sua posição relativa ao núcleo. A síntese dos compostos contou com a metodologia de preparação do anel isoxazolina, a cicloadição [3+2] 1,3-dipolar entre alcenos e óxidos de nitrila, os quais foram gerados pelas oximas preparadas a partir de aldeídos alifáticos e aromáticos. Todas as isoxazolinas foram oxidadas aos seus respectivos isoxazóis utilizando dióxido de manganês. Foram utilizadas ainda reações de alquilação, redução, desproteção, hidrogenólise, olefinação, adição de aminas à aldeídos e esterificação. Todas as moléculas sintetizadas foram caracterizadas por RMN de 1H e 13C, além de serem observadas por MOLP para determinação dos seus pontos de fusão. As moléculas que apresentaram comportamento mesomórfico foram ainda caracterizadas por DSC, XRD e voltagem triangular. No capítulo 3 é descrita a síntese dos isoftalatos 19a-b, 20a-b, 26a-b e 27a-b. No subgrupo dos Isoftalatos derivados de isoxazóis e isoxazolinas 3,5-diarilsubstituídos foi possível a síntese apenas do composto 11d que não apresentou comportamento líquido cristalino No subgrupo dos isoftalatos derivados de isoxazóis e isoxazolinas 3-alquil-5-arilsubstituídos as isoxazolinas 19a-b não apresentaram comportamento líquido-cristalino. Foram encontradas mesofases para os compostos 20a-b que ainda não foram determinadas com as técnicas disponíveis. Os isoxazóis 20a-b apresentaram uma provável Blue Phase logo após o resfriamento do isotrópico, que rapidamente se converte em uma provável mesofase monotrópica ferroelétrica com texturas e padrão de XRD peculiares até então não observada na literatura. No subgrupo dos isoftalatos derivados de isoxazóis e isoxazolinas 3-aril-5-alquilsubstituídos 26a-b e 27a-b não foi observado comportamento líquido-cristalino. O capítulo 4 descreve a síntese das isoftaliminas 35, 36, 44, 45, 50a-b, 51a-b, 56a-d, 57a-d, 63a-b e 64a-b. No subgrupo dos isoxazóis e isoxazolinas 3,5-diarilsubstituídos 35, 36, 44 e 45 foram observadas as mesofases B7 e B1 apenas com a inversão da orientação do anel isoxazol como braçomesogênicos dos compostos finais, enquanto que as isoxazolinas não apresentaram mesofases. A mesofase B7 do composto 36 apresentou comportamento antiferroelétrico enquanto que a mesofase B1 do composto 45 não mostrou resposta frente ao campo elétrico aplicado, além disso, o XRD mostrou que tal mesofase colunar B1 pode ser uma fase 3D modulada. No subgrupo das isoxazolinas e isoxazóis 3-alquil-5-arilsubstituídos 50a-b e 51a-b foram observadas fases do tipo DC para as isoxazolinas 50a-b, a qual deve ser confirmada por FFTEM. No subgrupo dos materiais 3-aril-5-alquilsubstituídos 56a-d, 57a-d, 63a-b e 64a-b foram observadas mesofases SmXPF para os compostos 56b-d. Os isoxazóis 57a-d apresentaram texturas similares, porém não apresentaram mesofase, mas os mesmos seguem o mesmo padrão de difração das isoxazolinas do capítulo 3. Apenas a isoxazolina 63b dos compostos perfluorados apresentou mesofase No capítulo 5 é descrita a síntese de ésteres não-simétricos contendo os heterociclos isoxazol e isoxazolinas como núcleo central 71a-f, 82, 83, 84 e 85. No primeiro subgrupo todos os ésteres cinâmicos 71a-f apresentaram comportamento mesomórfico com grandes faixas de temperaturas nas mesofases. No segundo subgrupo as isoxazolinas 82 e 83 apresentaram comportamento completamente distinto, onde só foi observada a formação de uma mesofase SmB para o composto que tem a posição éster localizada na direção do nitrogênio do heterociclo. Já os isoxazóis 84 e 85 deste subgrupo apresentaram as mesofases N e SmC em temperaturas bastante similares, porém, a observação desses materiais em uma cela alinhada revelou o crescimento de filamentos na transição N-SmC apenas para o composto 85, o qual também possui a porção éster na direção do nitrogênio do anel isoxazol. O capítulo 6 traz a síntese dos ésteres e iminas simétricos 88, 89, 94 e 95 utilizando os heterociclos como núcleo central, os quais apresentaram mesofases SmC e N. Além disso, o diéster 89 derivado de isoxazol apresentou a mesma característica que o composto 85 do capítulo 5, apresentando uma transição N-SmC com crescimento de filamentos perpendiculares à direção de alinhamento da amostra dentro da cela, podendo estar relacionada à uma mesofase NTB. / This thesis describe the synthesis and characterization of 10 new series of banana shaped molecules containing the isoxazoline and isoxazole rings as real players for preparation of polar liquid crystals. It was evaluate structural parameters such as the type of connecting function of the bent core with the mesogenic arms, the heterocycle nature and its position relative to the central core. The synthesis of the compounds included the methodology of preparation of the isoxazoline ring, the [3 + 2] 1,3-dipolar cycloaddition between alkenes and nitrile oxides, which were generated by the oximes prepared from aliphatic and aromatic aldehydes. Furthermore, all isoxazolines were oxidized to its respective isoxazoles using manganese dioxide. Besides the described methodologies, alkylation, reduction, deprotection, hydrogenolysis, olefination, addition of amines to the aldehydes and esterification reactions were used. All the synthesized molecules were characterized by 1H NMR and 13C NMR, and also observed by POM for determination of its melting points. The molecules previously analyzed by POM that showed mesomorphic behavior were characterized by DSC, XRD and triangular voltage still. Chapter 3 describes the synthesis of isophthalates 19a-b, 20a-b, 26a-b e 27a-b. In the subgroup of isophthalates derived from isoxazoles and isoxazolines 3,5-diarylsubstituted it was possible to synthesize only compound 11d which did not show liquid crystalline behavior In the subgroup of the isophthalates derived from isoxazoles and isoxazolines 3-alkyl-5-arylsubstituted the isoxazolines 19a-b did not show liquid crystalline behavior. It was found mesophases for compounds 20a-b that still could not be determined with the available techniques. The isoxazoles 20a-b presented a probable Blue Phase soon after cooling from the isotropic which quickly converts into a probable ferroelectric monotropic mesophase with peculiar textures and pattern of XRD until then not observed in the literature. In the subgroup of the isophthalates of isoxazoles and isoxazolines 3-aryl-5-alkylsubstituted 26a-b and 27a-b no liquid crystalline behavior was observed. Chapter 4 describes the synthesis of isophthalimines 35, 36, 44, 45, 50a-b, 51a-b, 56a-d, 57a-d, 63a-b and 64a-b. In the subgroup of the isoxazoles 3,5-diarylsubstituted 35, 36, 44 and 45 the B7 and B1 mesophases were observed only with the inversion of the isoxazole ring orientation as mesogenic arm of thefinal compounds whereas the isoxazolines did not present mesophases. The B7 mesophase of the compound 36 showed antiferroelectric switching while the B1 mesophase of the compound 45 showed no response to the applied electric field, in addition, the XRD showed that such B1 columnar mesophase could be a 3D modulated phase one. In the subgroup of 3-alkyl-5-arylsubstituted isoxazolines and isoxazoles 50a-b and 51a-b DC phases were observed for isoxazolines 50a-b which should be confirmed by FFTEM. The SmXPF mesophase were observed for componds 56b-d in the subgroup of 3-aryl-5-alkylsubstituted materials 56a-d, 57a-d, 63a-b e 64a-b. The isoxazoles 57a-d presented similar textures although did not showed mesophase, but they follow the same diffraction pattern of the chapter 3 isoxazolines. Only the isoxazoline 63b of the perfluorinated compounds showed mesophase In chapter 5 is described the synthesis of non-symmetric esters containing isoxazol and isoxazolines heterocycles as central core 71a-f, 82, 83, 84 e 85. In the first subgroup all the cinnamic esters 71a-f showed mesomorphic behavior with large mesophases temperature ranges. In the second subgroup the isoxazolines 82 and 83 showed completely different behavior which only was observed the SmB mesophase formation for compound having the ester position towards the heterocycle nitrogen. Furthermore, the isoxazoles 84 and 85 of this subgroup showed the N and SmC mesophases at very similar temperatures, however, the observation of these materials in an aligned cell revealed the filamentary growth in the N-SmC transition only for compound 85, which also has the ester moiety in the direction of the isoxazole ring nitrogen. Chapter 6 brings forward the synthesis of symmetrical esters and imines 88, 89, 94 and 95 using the heterocycles as the central cores, which showed SmC and N mesophases. Moreover, the isoxazole derived diester 89 showed the same feature as compound 85 of Chapter 5, exhibiting a N-SmC transition with filament growth perpendicular to the rubbing direction of the cell which may be related to a NTB mesophase.

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.