Le cancer constitue l’une des principales causes de mortalité, plus particulièrement dans l’ensemble des pays développés, et représente, de ce fait aujourd’hui un problème de santé publique majeur.Depuis quelques années, les alcaloïdes marins représentent une source d’inspiration importante pour les chimistes en vue d’obtenir de nouveaux médicaments anticancéreux.Dans cette optique, des recherches effectuées au sein de notre laboratoire ont fait état de la synthèse d’analogues de ces alcaloïdes possédant une structure tris aromatique.Nous avons développé une approche synthétique originale de ces composés disposant d’un hétérocycle central sur lequel sont greffés deux noyaux phényles ou indoles substitués avec des groupes hydroxy ou hydrophiles. Ils sont reliés entre eux par une liaison carbone-carbone ou carbone-amine ce qui a généré une bibliothèque de près de 150 molécules originales.Différentes évaluations pharmacologiques ont été réalisées. L’inhibition des kinases (DYRK1A, CDK5, GSK3) par nos produits et l’évaluation de leur cytotoxicité sur diverses lignées cellulaires cancéreuses humaines ont été réalisées.L’obtention de ces composés a été également l’occasion de nous intéresser à la synthèse et la réactivité du 2-indolyltrifluoroborate de potassium dans les réactions de Suzuki-Miyaura. Un travail méthodologique a été réalisé dans ce sens. / Cancer, one of the leading causes of death, particularly in the developed countries, represents today a major public health problem.Over the last few years, marine alkaloids represent a source of inspiration for chemists in order to obtain new anticancer drogs.For this purpose, as a part of our laboratory researches, analogues of marine alkaloids were synthesized possessing a tris-aromatic structure.We developed an original approach to synthesize these compounds formed by a central heterocycle core on wich is graft two arylic or indoles patterns with hydroxylic or hydrophilic side chains. They are related by a carbon-carbon or carbon-amine bond that generated a library of 150 original molecules.Various pharmacological analyses were carried out. The inhibition of kinases (DYRK1A, CDK5, GSK3) by our products and the evaluation of their cytotoxicity on various human cancer cell lines have been performed.Obtaining these compounds was also an opportunity to be interested in the synthesis and reactivity of potassium 2-indolyl trifluoroborate towards Suzuki-Miyaura reaction. A new methodology was developed.

Esta tese descreve, em dois diferentes capítulos, a síntese assimétrica da Malevamida D e a aplicação de compostos organotelúrio em reações de Suzuki-Miyaura. O primeiro capítulo refere-se ao estudo da síntese assimétrica da Malevamida D, um depsipeptídeo natural pertencente à família das dolastatinas, compostos estes com grande atividade citotóxica. As unidades DAP e MMMAH foram alcançadas em ótimos redimentos e estereosseletividades, utilizando-se reações de adição de crotil ou aliltrifluoroborato de potássio à aldeídos derivados da L-prolina e L-isoleucina, respectivamente. A elongação da cadeia da malevamida D se fez a partir de reações de esterificação e amidação; infelizmente não foi possível completar a síntese devido a problemas na última reação de acoplamento peptídico. O segundo capítulo descreve as reações entre teluretos aromáticos ou vinílicos e sais de organotrifluoroborato de potássio, mediadas por um catalisador de paládio. A partir destas reações de acoplamento cruzado tipo Suzuki-Miyaura foi possível obter-se 1,3-eninos, sistemas biarílicos, (E)- ou (Z)-estilbenos e 1,3-dienos. Todas as reações mostraram serem tolerantes a uma grande variedade de grupos funcionais e altamente estereoconservativas, nos casos envolvendo substratos vinílicos. / This thesis describes, in two different chapters, the asymmetric synthesis of malevamide D and the application of organotellurium compounds in Suzuki-Miyaura reaction. The first chapter refers to the asymmetric synthesis of malevamide D, a natural depsipeptide which belongs to the dolastatins family, and these compounds have a great interest due to theirs citotoxic activities. The DAP and MMMAH units were reached in excellent yields and stereoselectivities from 1,2-addition reaction of potassium crotyl or allyltrifluoroborate to aldehydes derivate from L-proline and L-isoleucine, respectively. The malevamide D elongation was made from reaction of esterification and amidation, unfortunately it was not possible finish the synthesis due to some problems in the last step of the total synthesis. The second chapter describes the reaction between aryl or vinyl tellurides and potassium organotrifluoroborate salts, mediated by a palladium catalyst. From this cross-coupling reaction type Suzuki-Miyaura was possible obtain 1,3-dienes, biarylic systems, (E)- or (Z)-stylbenes and 1,3-dienes. Al reactions showed to be tolerant to a wide range of functional groups and highly stereoconservative, in the cases involving vinylic substrates.

Made available in DSpace on 2015-07-22T20:49:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-06-24. Added 1 bitstream(s) on 2015-08-11T03:25:29Z : No. of bitstreams: 1 Publico-00299a.pdf: 807068 bytes, checksum: e4fb701e403dec161fff1eb2278518d5 (MD5). Added 1 bitstream(s) on 2015-08-11T03:25:29Z : No. of bitstreams: 2 Publico-00299a.pdf: 807068 bytes, checksum: e4fb701e403dec161fff1eb2278518d5 (MD5) Publico-00299b.pdf: 1749779 bytes, checksum: d8cc731e3f8410ce7bdb335a435143ec (MD5) / Neste trabalho, desenvolvemos uma nova metodologia para a obtencao estereosseletiva de pirrolidin-2-onas substituidas na posicao 5 atraves de adicao de sais de potassio de organotrifluoroboratos a cations N-aciliminio ciclicos. As reacoes de ƒ¿- amidoalquilacao envolvem lactamas derivadas do acido tartarico . (3R,4R)-3,4,5-tris- (acetoxi)-1-benzil-2-oxopirrolidin-3-il, (3R,4R,5R)-3,4-bis-(acetoxi)-5-hidroxi-1-benzil-2- pirrolidinona e sais de potassio de organotrifluoroboratos alquilicos, arilicos, heteroarilicos, alilicos e alquinilicos, fornecendo pirrolidin-2-onas substituidas na posicao ƒ¿ de 1 a-b, com rendimentos que variam de 63% a 87% e com diastereosseletividade de moderadas a boas, onde o diastereoisomero syn foi obtido preferencialmente nos casos onde o carbono nucleofilico tem hibridizacao sp e sp2 e ocorrendo a inversao da diastereosseletividade, isto e, preferencialmente o diastereoisomero anti nos casos de carbonos hibridizados sp3. A estereoquimica relativa syn/anti dos produtos majoritarios foi inferida atraves dos dados espectroscopicos de RMN de 1H e 13C. Os sais de heteroaril, aril, alquil e acetilênicos foram obtidos através da geração dos respectivos ânions organomagnésio e organolítio seguido pela adição de trimetilborato à baixa temperatura e posterior reação com KHF2 aquoso. / In this work, we developed a new methodology for the stereoselective acquisition of substituted pyrrolydin-2-ones in the 5 position through the addition of potassium organotrifluoroborate salts to cyclic N-acyliminium cations. The á-amidoalkylation reactions involve lactams derivative tartaric acid – (3R, 4R, 5R)-3,4-bis-(acetoxy)-5- hidroxy-1-benzyl-2-pyrrolydinone and alkyl, aryl, heteroaryl, allyl and alkynyl potassium organotrifluoroborate salts, providing substituted pyrrolydin-2-ones in the á position of 1 ab, with yield variable of 63% to 87% and diastereoselectivity of moderate to good, where the diastereoisomer syn were obtained preferentially in the cases where of the nucleophilic carbon have sp and sp2 hybridization and occurring the inversion of the diastereoselectivity, that is, preferentially the diastereoisomer anti in the case of carbon hybridization sp3. The relative stereochemistry syn/anti of the majority products were deduce through of the spectroscopic data of 1H and 13C NMR. The salts of heteroaryl, aryl, alkyl and acetylenes compounds were obtained through the generation of the respective organomagnesium and organolitium anions followed by the addition of trimethylborate at low temperature and further reaction with aqueous KHF2. / TEDE / BV UNIFESP: Teses e dissertações

Esta tese descreve, em dois diferentes capítulos, a síntese assimétrica da Malevamida D e a aplicação de compostos organotelúrio em reações de Suzuki-Miyaura. O primeiro capítulo refere-se ao estudo da síntese assimétrica da Malevamida D, um depsipeptídeo natural pertencente à família das dolastatinas, compostos estes com grande atividade citotóxica. As unidades DAP e MMMAH foram alcançadas em ótimos redimentos e estereosseletividades, utilizando-se reações de adição de crotil ou aliltrifluoroborato de potássio à aldeídos derivados da L-prolina e L-isoleucina, respectivamente. A elongação da cadeia da malevamida D se fez a partir de reações de esterificação e amidação; infelizmente não foi possível completar a síntese devido a problemas na última reação de acoplamento peptídico. O segundo capítulo descreve as reações entre teluretos aromáticos ou vinílicos e sais de organotrifluoroborato de potássio, mediadas por um catalisador de paládio. A partir destas reações de acoplamento cruzado tipo Suzuki-Miyaura foi possível obter-se 1,3-eninos, sistemas biarílicos, (E)- ou (Z)-estilbenos e 1,3-dienos. Todas as reações mostraram serem tolerantes a uma grande variedade de grupos funcionais e altamente estereoconservativas, nos casos envolvendo substratos vinílicos. / This thesis describes, in two different chapters, the asymmetric synthesis of malevamide D and the application of organotellurium compounds in Suzuki-Miyaura reaction. The first chapter refers to the asymmetric synthesis of malevamide D, a natural depsipeptide which belongs to the dolastatins family, and these compounds have a great interest due to theirs citotoxic activities. The DAP and MMMAH units were reached in excellent yields and stereoselectivities from 1,2-addition reaction of potassium crotyl or allyltrifluoroborate to aldehydes derivate from L-proline and L-isoleucine, respectively. The malevamide D elongation was made from reaction of esterification and amidation, unfortunately it was not possible finish the synthesis due to some problems in the last step of the total synthesis. The second chapter describes the reaction between aryl or vinyl tellurides and potassium organotrifluoroborate salts, mediated by a palladium catalyst. From this cross-coupling reaction type Suzuki-Miyaura was possible obtain 1,3-dienes, biarylic systems, (E)- or (Z)-stylbenes and 1,3-dienes. Al reactions showed to be tolerant to a wide range of functional groups and highly stereoconservative, in the cases involving vinylic substrates.