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.

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

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.

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.

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.

Les peptides aldéhydes sont connus comme inhibiteurs de protéases et précurseurs de différentes classes de composés biologiquement actifs. Les méthodes pour leur synthèse impliquent classiquement la transformation d'un précurseur (amide de Weinreb, ester, alcool, acétal) en aldéhyde en étape finale pour éviter l'épimérisation du stéréocentre en position α de l'aldéhyde. En revanche, les β-peptides aldéhydes, plus stables à l’épimérisation, ont été relativement peu explorés. Ils sont généralement obtenus par homologation de l'acide aminé correspondant malgré les faibles rendements, les problèmes d’épimérisation et de nombreuses étapes. Par conséquent, un nouvel accès synthétique aux β-peptides aldéhydes reste toujours un challenge difficile. Sur la base des travaux antérieurs dans notre équipe en hétérocycloaddition diastéréosélective [4+2] et [3+2], nous avons développé au cours de ce doctorat de nouvelles stratégies pour l'accès asymétrique à ces dérivés de β-aminoacides par deux voies complémentaires :1) Une voie utilisant les hétérocycles à six chaînons de type 6-ATO (6-alcoxytétrahydrooxazinone) qui ont été préparés par une réaction d’hétérocycloaddition hautement stéréosélective avec de bons rendements et ed. Ces cycloadduits ont été transformés par transacétalisation vers les aminoacétals intermédiaires «mixtes» ou «symétriques». Ces nouveaux acétals sont des intermédiaires parfaits pour la N-élongation par couplage peptidique, conduisant finalement aux aldéhydes peptidiques β3-C-terminaux monosubstitués. 2) Sur une autre approche, les hétérocycles à cinq chaînons 5-AISO (3,3'-disubstitué 5-alcoxy-isoxazolidines) ont été obtenus par cycloaddition dipolaire-1,3 entre des cétonitrones esters et des éthers vinyliques. Ces composés ont été utilisés avec succès en tant que précurseurs d'aminoaldéhydes β3-disubstitués après l’étape de transprotection de l'atome d'azote, suivie par la copure de la liaison N-O. L’extension asymétrique de l'étape de cycloaddition a été étudiée par des voies énantiosélective et diastéréosélective, ouvrant ainsi l'entrée vers les peptides aldéhydiques β3-disubstitués-C-terminaux énantioenrichis. / Peptide aldehydes are known as protease inhibitors and precursors for many biologically active compounds. Methods for their synthesis involve classically the transformation of a precursor (Weinreb amide, ester, alcohol, acetal) into an aldehyde as one of the final steps to prevent epimerization of the carbon α to the aldehyde. By contrast, β-peptide aldehydes, more stable to epimerization, have been relatively unexplored. They are usually obtained by homologation of the corresponding amino acid despite low yielding steps, an epimerization problem and low number of accessible amino acids. Therefore, new synthetic access to β-peptide aldehydes is still a challenging problem. On the basis of previous work in our team concerning [4+2] and [3+2] diastereoselective cycloadditions, we have developed during this PhD thesis new strategies for the asymmetric access of β-amino acid derivatives by two complementary ways :1) Original six-membered heterocycles 6-ATO (6-alkoxy-tetrahydrooxazinone ) were prepared by a highly stereoselective heterocycloaddition reaction with good yields and de. These cycloadducts were transformed via transacetalisation into both «mixed» and «symmetrical» aminoacetals. Moreover, these new acetals are ideal intermediates for further peptide coupling, leading ultimately to monosubstituted β3-C-terminal peptide aldehydes. 2) By another approach five-membered heterocycles 5-AISO (3,3’-disubstituted 5-alkoxy-isoxazolidines) were obtained via 1,3-dipolar cycloaddition between α-keto ester nitrones and vinyl ether. These compounds were successfully used as precursors of disubstituted β-amino aldehydes after transprotection of the nitrogen atom and N-O cleavage of the isoxazolidine ring. Asymmetric extension of the cycloaddition step was studied by enantioselective and diastereoselective pathways, thus opening unprecedented entry to enantioenriched disubstituted β3,β3-C-terminal peptide aldehydes.

A la suite des nombreux travaux sur l’inhibition de la glycogène phosphorylase (GP) menés au laboratoire et au travers de diverses collaborations, cette thèse décrit en cinq chapitres suivis d’une partie expérimentale détaillée, les dernières avancées en termes de synthèse et d’évaluation biologique des inhibiteurs du site catalytique de la GP. La chapitre I de ce manuscrit est consacrée à la présentation des diabètes et plus particulièrement du diabète de type II dont le traitement, motivation première de ce projet, repose sur la connaissance des mécanismes complexes régulant la glycémie. Les différents inhibiteurs synthétisés sont classés par famille selon leur structure qui associe un aglycone hétérocyclique, susceptible d’affinité pour le canal β proche du site actif de l’enzyme, avec un motif glycopyranosidique, ou glycopyranosylidène dans le cas des motifs spiro. Le chapitre II est consacré aux inhibiteurs spiro-bicycliques tels que les glucopyranosylidène-spiro-1,4,2-oxathiazoles et les glucopyranosylidène-spiro-isoxazolines. Le chapitre III décrit la synthèse de C- et N-glycosyles hétérocycles, principalement des glycopyranosyl-1,2,3-triazoles. Enfin le chapitre IV décrit la fonctionnalisation de 5-halogéno-1,2,3-triazoles 4-substitués par couplages pallado-catalysés qui ont constitué un développement imprévu mais original des travaux. Pour terminer, le chapitre V décrit l’évaluation des molécules préparées en tant qu’inhibiteurs de la glycogène phosphorylase. Les expériences et résultats d’enzymologie, de cristallographie ainsi que les tests cellulaires in vitro et in vivo sur le rat sont présentés / Following many studies lead on the inhibition of glycogen phosphorylase (GP) in our laboratory an trough several collaborations, this thesis describes in five chapters and a detailed experimental section, the most recent advances in the areas of synthesis and biological evaluation of GP’s catalytic site inhibitors. Chapter I is dedicated to the description of diabetes and especially type 2 diabetes of which treatment, the main goal of this project, requires knowledge of the complex mechanisms that regulates glycemia. Synthesized inhibitors are broken down into families according to their structure which associates an heterocyclic aglycon, prone to binding in the β pocket lining the active site, with a glycopyranoside or glycopyranosylidene moiety in the case of spiro compounds. Chapter II focuses on spiro-bicyclic inhibitors such as glucopyranosilidene-spiro-1,4,2-oxathiazoles and glucopranosylidene-spiro-isoxazolines. Chapter III describes the synthesis of C- and N-glycosyl-heterocycles, mainly glycopyranosyl-1,2,3-triazoles. Finally, chapter IV studies the palladium-mediated cross coupling fonctionalization of 4-substituted-5-halogenated-1,2,3-triazoles that represents an unexpected but interesting development of the project. To conclude, chapter V gathers the evaluation of synthesized molecules as GP inhibitors. Enzymology and crystallography as well as in vitro and in vivo experiments are presented

Dans la première partie de ce travail, nous avons réalisé une étude préliminaire qui avait pour objectif d’étendre la série de complexes dinucléaires du fer [Fe2(CO)4(k2-P2N2)(μ-dithiolate)], comprenant des ligands diphosphine de type P2N2, à des complexes possédant un pont azadithiolate en vue d’étudier leur comportement en milieu acide et le rôle des différentes bases présentes dans la seconde sphère de coordination de ces composés. Les nouveaux complexes [Fe2(CO)6(k2-PPh2NR2)(μ-adtBn)] (R = Ph, Bn)) ont été obtenus par réaction entre le précurseur [Fe2(CO)6(μ-adtBn)] et les diphosphines cycliques PPh2NR2 (avec R = Ph, Bn). Ces complexes ont été caractérisés spectroscopiquement et structuralement. Nous avons aussi montré que les modes de coordination de l’anion (tcnsR)-, dans l’ensemble des complexes sont très différents et affectent, par conséquent, les réseaux cristallins d’une manière très importante. Ceci permet de dire que la longueur de la chaine alkyl de l’anion (tcnsR)- ne devrait pas être le seul paramètre structural affectant les températures de transition. Le type de groupement CN (N3, N4, N5 ou N6) intervenant dans la coordination devrait alors jouer un rôle important dans l’empilement des entités moléculaires dans le réseau cristallin et par conséquent, les interactions intermoléculaires qui sont à l’origine des caractéristiques de la transition de spin (température de transition, coopérativité,…), devraient être affectées par le mode de coordination de l’anion. Dans la seconde partie, nous avons réalisé la synthèse de notre dipolarophile à partir de la sérine et la préparation des dipôles (oxydes de nitriles). La condensation de ces derniers avec la dehydroalanine nous a permis l’obtention de nouveaux α-aminoesters isoxazoliniques. Ces nouveaux α-aminoesters isoxazoliniques ont été obtenus d’une façon très accessible, et dans des conditions douces par la réaction de cycloaddition 1,3-dipolaire. Les résultats obtenus confirment l’utilité de cette réaction comme étant une voie très efficace pour former des nouveaux isoxazolines avec des bons rendements. / In the first part of this work, we realised a preliminary study to extend the series of dinuclear iron complexes [ Fe2(CO)4 (k2-P2N2) (μ-dithiolate)], including diphosphine ligands type P2N2, to complexes having an azadithiolate bridge, in order to study their behavior in acid medium and the role of different bases present in the second coordination sphere of these compounds. The new complexes [Fe2 (CO) 6 (k2-PPh2NR2) (μ -adtBn)] (R = Ph, Bn)) were obtained by reaction between the precursor [Fe2(CO)6(μ -adtBn)] and the cyclic diphosphines PPh 2NR2 (with R = Ph, Bn). These complexes have been spectroscopically and structurally characterized. We have also showed that the anion coordination modes (tcnsR)– in all these complexes are very different and affect, consequently, crystal lattices in a very important way. This suggests that the length of the alkyl chain of the anion (tcnsR)- should not be the only structural parameter affecting transition temperatures. The type of CN grouping (N3, N4, N5 or N6) involved in the coordination should then play an important role in the stacking of molecular entities in the crystal lattice as a result the intermolecular interaction, which are the origin of the spin transition characteristics (transition temperature, cooperativeness, ...), should be affected by the coordination mode of the anion.In the second part, we have realized the synthesis of our dipolarophile from serine and the preparation of dipoles (nitrile oxides). Their condensations with dehydroalanine allowed us to newly obtain isoxazolinic α-aminoesters. These novel isoxazolinic α-aminoesters were obtained in an accessible method, and under mild conditions by the 1,3-dipolar cycloaddition reaction. The obtained results prove the usefulness of this reaction as being a very efficient way to form new isoxazolines with good yields.