Morita Baylis-Hillman (MBH) reaction a carbon-carbon bond forming reaction between an α,β-unsaturated carbonyl and aldehydes or activated ketones in the presence of a nucleophilic catalyst. The MBH reaction is an atom-economical method of rapid increase of molecular complexity. The development of this process has received considerable attention in recent years. This dissertation presents the development of a new catalytic system for the symmetric and asymmetric MBH reaction. The new system for the racemic version of this reaction was accomplished employing a 1:1:1 ratio of catalytic amounts (10 mol%) of MgI2, TMEDA and DMAP and proved to be highly effective. For the asymmetric version was developed a highly enantio-selective system based on Fu’s planar chiral DMAP derivative (II) with ee´s up to 98%. Abnormal MBH adducts are obtained employing either ethyl 2,3-butadienoate or ethyl propiolate in good yields, in the presence if MgI2 and either a tertiary amine or phosphine as the nucleophile. The α,β-unsaturated carbonyls where prepared by a modified direct α- methylenation using paraformaldehyde, diisopropylammonium trifluoroacetate, and catalytic acid or base with excellent yields for several carbonyls compounds. The Negishi cross-coupling reaction is the Pd or Ni-catalyzed stereoselective cross-coupling or organozincs and aryl-, alkenyl-, or alkynyl halides. Enantioselective Negishi cross-coupling of aryl zincs and α-bromo ketones was accomplished employing a NCN Pincer complex as the catalyst with ee´s up 99%. The required pincer complexes have been prepared by the oxidative addition of pincer ligands with palladium or nickel. Additionally, It has been developed a direct and highly active, (NCN)-Pd catalytic system for the α-arylation of ketones with a variety of aryl bromides using the air and moisture stable [t-BuPheBox-Me2]PdBr (XVI) as the catalyst. The adducts are obtained in excellent yields (92% average for 20 examples) in only 1 hour using 1 mol% of catalyst loading. Perhaps more importantly, the work described here shows that XVI is highly reactive, highly selective, even on substrates bearing challenging functional groups such alkenes.

Stroke is the 3rd leading cause of death in the United States. For this reason, it has become our goal to find a drug that is capable of reestablishing intracellular and extracellular Ca+2 flux upon direct binding to the sigma receptor, which can be delivered easily and efficiently. Our active research focuses the development of guanidine analogues that can serve as therapeutic drugs which target sigma 1 and sigma 2 receptors having a direct effect on Ca+2 levels on the cell. The use of symmetrical guanidine analogues such as N,N'-di-o-tolyl guanidine (o-DTG) as therapeutic drugs for ischemic stroke, is promising due to the fact that neuronal cells can restore the proper blood flow and block Ca+2 flux into the cell. Our main objective is to be able to develop a cost efficient, mild reaction methodology that affords access to guanidine analogues. The synthetic design of the guanidine analogues has been accomplished using copper-catalyzed cross-coupling diarylation reaction. This methodology employs a non-expensive guanidine salt and substituted aryl iodides along with N,N'-diethylsalicylamides as the key ligand in this strategy. Similar methodology was employed for the synthesis of monoarylated amidines employing ligand-free conditions for the copper-catalyzed cross-coupling reaction. Moreover, efforts to find alternative methodologies to access other sigma receptor ligands were accomplished. A new method to create N,N'-disubstituted carbamides employed HATU as a peptide coupling agent allowing for the formation of carbamides using the inexpensive guanidine nitrate and carboxylic acids as starting materials. Studies on the sigma response of the cortical neuron cell were conducted upon completion of the analogue design. Moreover, it was discovered that N,N'-di-p-bromophenyl guanidine (p-BrDPhG) gave a higher Ca+2 inhibition than N,N'-di-o-tolyl guanidine (o-DTG). Experimental studies, such as the middle cerebral occlusion were conducted on rats and subsequent injections of the p-BrDPhG at 24, 48, and 72 hours' time marks. When compared to o-DTG, it was found that p-BrDPhG is better at reducing the ischemic volume on the brain size

Domino catalysis is an ideal strategy in the synthesis of heterocyclic scaffolds, as multiple bonds can be formed under a single set of reaction conditions. In this work, we present the development of two novel domino processes which afford access to aza-analogues of the dihydrodibenzoxepine motif. Careful optimisation revealed that the Rh catalysed hydroarylation proceeds under mild conditions as compared to the C-O coupling. Furthermore, Pd was not required for the C-O bond formation when using alkenyl pyrazines as substrates. Variation of the substituents on both the heterocycle and on the boronic ester provided insight into the structural features required for successful domino reaction, and a stepwise protocol was developed for incompatible substrates. We have also developed the first multi-metal, multi-ligand domino reaction featuring both a chiral and achiral ligand in the same pot, still leading to an enantioenriched product.

Domino catalysis is an ideal strategy in the synthesis of heterocyclic scaffolds, as multiple bonds can be formed under a single set of reaction conditions. In this work, we present the development of two novel domino processes which afford access to aza-analogues of the dihydrodibenzoxepine motif. Careful optimisation revealed that the Rh catalysed hydroarylation proceeds under mild conditions as compared to the C-O coupling. Furthermore, Pd was not required for the C-O bond formation when using alkenyl pyrazines as substrates. Variation of the substituents on both the heterocycle and on the boronic ester provided insight into the structural features required for successful domino reaction, and a stepwise protocol was developed for incompatible substrates. We have also developed the first multi-metal, multi-ligand domino reaction featuring both a chiral and achiral ligand in the same pot, still leading to an enantioenriched product.

Face à l'apparition alarmante et continue de résistance massive des bactéries à l'arsenal actuel d'antibiotiques, la recherche de nouveaux agents antibactériens est actuellement un enjeu sociétal de tout premier ordre. Bien que connus depuis plus de 50 ans, les thiopeptides antibiotiques suscitent actuellement un très fort regain d'intérêt de la communauté scientifique internationale en raison de leurs propriétés antibactériennes remarquables, notamment contre les staphylococcus areus résistants à la méthiciline et les enterococci résistants à la vancomycine, impliquées dans de nombreuses infections qui engagent la vie des patients, et qui s'exercent de façon très intéressante selon deux modes d'action d'inhibition de la synthèse protéique originaux et encore inexploités en thérapie antibiotique humaine. Le travail développé s'inscrit dans ce programme international de valorisation pharmacologique qui repose pour une grande part sur le développement d'approches synthétiques rapides et modulables. Le projet a été centré en particulier sur la conception et la mise en oeuvre de nouveaux plans de synthèse des unités centrales di- ou trithiazolylpyridines, appelées coeurs hétérocycliques, communs à de nombreux thiopeptides de la série d et qui représentent les principaux défis synthétiques. Dans le cadre d'un programme de recherche du laboratoire ciblé sur l'étude de nouvelles méthodes de fonctionnalisation directe d'aromatiques et d'hétérocyclique, un premier travail méthodologique d'étude de la fonctionnalisation directe dans deux séries structurellement représentatives, thiazole-4-carboxylate et 2-cétothiazole, a été réalisé. Ainsi, une nouvelle méthodologie originale d'hétéroarylation directe pallado-catalysée régioselective du thiazole-4-carboxylate de tert-butyle avec une large gamme d'halogéno(hétéro)aromatiques a été développée avec succès. Une seconde méthodologie originale d'hétéroarylation directe de 4-bromo-2-cétothiazoles selon une séquence réactionnelle de boroylation pallado-catalysée suivie d'un couplage de Suzuki-Miyaura (BSC) a également été développée. Un second travail a porté sur l'exploitation des deux méthodologies de fonctionnalisation directe en série thiazolique développées et associées à la méthodologie de construction thiazolique de Hantzsch pour proposer et mettre en oeuvre un nouveau plan de synthèse expéditif et général d'accès aux coeurs hétérocycliques communs à une grande majorité des thiopeptides de la série d basé sur la fonctionnalisation séquencée d'un précurseur pyridinique aisément accessible. En particulier, la stratégie envisagée a permis, à partir des esters 5-bromopicolinates, la préparation tout d'abord d'un analogue thiazolique du coeur hétérocyclique des sulfomycines puis celle des coeurs hétérocycliques des micrococcines et des amithiamicynes.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

Made available in DSpace on 2014-06-11T19:30:18Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-07-27Bitstream added on 2014-06-13T18:06:41Z : No. of bitstreams: 1 goncalves_rs_me_bauru.pdf: 4669388 bytes, checksum: b30004cd2539c06798b6a06a2acbec15 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Amino ésteres lactâmicos derivados do PABA e que podem ser potencialmente bioativos, por exemplo, como anestésicos locais, foram sintetizados com bons rendimentos por uma reação seletiva de SnAr de ácidos benzóicos com n-(3-aminopropil)-lactamas seguida por esterificação com aminoálcoois terciários. Produtos da N-arilação do N, N-dimetilformamida foram também obtidos através da esterificação direta do ácido 4-cloro-3-nitrobenzóico / Lactamic amino esters PABA-related, and can potentially bioactive, for exemple, as local anesthetics were synthesized in good yields by a selective 'S IND. n'Ar reactions of benzoic acids with N-(3-aminopropyl)lactams followed by esteterification with tertiary aminoalcohols. Products of the N-arylation with N,N-dimethylformamide are also obtained through of direct esterification of 4-chloro3-nitrobenzoic acid

Orientador: Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-16T12:54:31Z (GMT). No. of bitstreams: 1 Moro_AngelicaVenturini_D.pdf: 11686142 bytes, checksum: b58d89c20ca896f67ba31310774b3fb0 (MD5) Previous issue date: 2010 / Resumo: O presente trabalho foi centrado na arilação de Heck de diferentes olefinas com sais de diazônio e a aplicação dos produtos arilados na síntese de ligantes quirais, produtos naturais e análogos. Nos estudos envolvendo arilação de Heck de estirenos com sais de diazônio foi desenvolvida uma metodologia eficiente, curta, régio- e estereosseletiva para a síntese do resveratrol, do DMU-212 e de análogos. Na reação de Heck de ésteres alílicos com sais de diazônio uma alta quimio-, regio- e estereosseletividade foi obtida. Os ésteres alílicos arilados foram sintetizados em altos rendimentos e com retenção do tradicional grupo de saída. Também foi possível a arilação de ésteres alílicos cíclicos, que foram utilizados na síntese total de kavalactonas naturais. A síntese total da (-)-isoaltolactona foi realizada com sucesso em 12 etapas com 13 % de rendimento global. A etapa-chave envolveu uma reação de Heck altamente estereosseletiva entre o sal de fenildiazônio e diidrofurano quiral. O grupo fenila introduzido diastereosseletivamente teve papel crucial no direcionamento dos demais centros estereogênicos da molécula. Nos estudos visando a síntese da aza-altolactona, dificuldades inesperadas foram encontrados em algumas etapas, em especial na oxidação de álcoois a aldeídos pelo uso de protocolos tradicionais. Esses problemas foram contornados pela alteração da rota sintética, entretanto novos problemas na etapa de lactonização impediram a obtenção da aza-altolactona, até o momento. Novos aminoálcoois quirais foram sintetizados pela arilação de enecarbamatos com sais de diazônio. Esses compostos foram empregados como ligantes quirais na arilação catalítica assimétrica de aldeídos e levaram aos diarilmetanóis em altos rendimentos e excessos enantioméricos. / Abstract: The present work was centered in the Heck arylation of several olefins with diazonium salts and application of the arylated products in the syntheses of chiral ligands, natural products and analogues. In studies involving the Heck arylation of styrenes with diazonium salts an efficient, short, regio- and stereoselective synthesis of resveratrol, DMU-212 and analogues was developed. In the Heck reaction of allylic esters with diazonium salts high chemo-, regio- and stereoselectivity was obtained. The arylated allylic esters were synthesized in high yields and with retention of the traditional leaving group. Moreover, the arylation of cyclic allylic esters was developed, and the products were used in the total synthesis of natural kavalactones. The total synthesis of (-)-isoaltholactone was successfully accomplished in 12 steps in 13 % overall yield. The key-step involved highly stereoselective Heck arylation between the phenyldiazonium salt and chiral dihydrofuran. The phenyl group was introduced with high diastereoselectivity and had a crucial role in directing the formation of the remaining stereocenters of the molecule. In the studies towards the synthesis of aza-altholactone, unexpected difficulties were found in some steps, particularly in the oxidation of alcohols to aldehydes by traditional protocols. These problems were circumvented by changing the synthetic route, but additional problems were found in the lactonization and hampered the obtention of the aza-altholactone, until the present moment. New chiral amino alcohols were synthesized by arylation of enecarbamates with diazonium salts. These compounds were used as chiral ligands in the catalytic asymmetric arylation of aldehydes and the diarylmethanols were prepared in high yields and enantiomeric excesses. / Doutorado / Quimica Organica / Doutor em Ciências

Orientador: Carlos Roque Duarte Correia / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-15T20:34:49Z (GMT). No. of bitstreams: 1 Azambuja_Franciscode_M.pdf: 6423668 bytes, checksum: 29069e3111714888aee628002e55cf0c (MD5) Previous issue date: 2010 / Resumo: A arilação de acrilatos 2-acetóxi ou acetamido substituídos foi estudada utilizando a reação de Heck com sais de arenodiazônio. Após avaliação do catalisador, solvente, temperatura e acidez do meio reacional na arilação do 2-acetoxiacrilato de metila com o sal tetrafluoroborato de p-metoxifenildiazônio, a melhor condição encontrada emprega Pd2dba3 e 2,6-di-terc-butil-4-metilpiridina em benzonitrila a 110 °C por 3 horas, fornecendo o produto em 59 % de rendimento. A utilização de outros sais de diazônio não foi eficiente e os produtos não foram obtidos. A arilação do 2-acetamidoacrilato de metila ocorreu em metanol a 65 °C, utilizando acetato de paladio (II) e 2,6-di-terc-butil-4-metilpiridina. Os rendimentos ficaram entre 24-73 % utilizando sais de arenodiazônio substituídos com iodo, fluor, metoxi ou nitro, além do 2-naftildiazônio e do benzenodiazônio. Os rendimentos insatisfatórios foram contornados com variando-se o grupo protetor da função amina de acetoxi para trifluoracetoxi. A arilação da olefina 2-trifluoroacetamido acrilato de metila, feita nas mesmas condições, ocorreu em rendimentos de 65-86 % para os mesmos sais. Os adutos nitrogenados 2-metoxilados obtidos foram submetidos a um protocolo eliminação/redução ou alquilação com o uso de BF3.OEt2 e nucleófilos de silano. Os derivados de fenilalanina protegidos foram obtidos em rendimentos variados e constituem uma alternativa para a obtenção de aminoácidos arilados não-naturais, a-substituídos ou não. Uma versão one-pot desta redução foi brevemente estudada mediante adição de hidreto de trietilsilano à reação de Heck. A eficiência desta reação em uma etapa foi comparável ao protocolo em duas etapas / Abstract: The arylation of 2-acetoxy or acetamido substituted acrylates was studied through the Heck reaction with arenediazonium salts. After evaluation of the catalyst, solvent, temperature and acidity of the reaction medium, methyl 2-acetoxyacrylate was arylated with p-methoxyphenyldiazonium tetrafluoroborate under Pd2dba3 catalysis, with 2,6-di-terc-butyl-4-methylpyridine as base in benzonitrile at 110 °C for 3 hours. The Heck adduct was obtained in 59 % of yield. Other diazonium salts did not furnished the expected adducts in good yields. Methyl 2-acetamidoacrylate arylation occurred in methanol at 65 °C, using Pd(OAc)2 as catalyst and 2,6-di-terc-butyl-4-methylpyridine as base. Yields between 24-73 % were observed using diazonium salts substituted with iodine, fluoro, methoxy or nitro groups, besides 2-naphthyl or benzenediazonium tetrafluoroborate. The lower yields were by-passed through methyl 2-trifluoroacetamidoacrylate arylation, under the same conditions, resulting in yields between 65-86 % for the same electrophiles. The aza-2-methoxylated adducts obtained were submitted to an elimination/reduction or alkylation protocol using BF3.OEt2 and silane nucleophiles. The protected phenylalanine derivatives were obtained in low to good yields and represent an alternative to prepare unnatural amino acids, a-substituted or not. A one-pot version of this reduction was briefly studied through triethylsilane hydride addition in the Heck reaction. The efficiency of this reaction was comparable with the two-step protocol / Mestrado / Quimica Organica / Mestre em Química

Orientador: Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-25T07:38:41Z (GMT). No. of bitstreams: 1 Schwalm_CristianeStorck_D.pdf: 13409001 bytes, checksum: 641c6de21f40f4ad79f3a11d0a95ad9d (MD5) Previous issue date: 2014 / Resumo: O presente trabalho teve como objetivo geral o estudo da reação de Heck-Matsuda, tanto no âmbito de novas aplicações sintéticas como no seu desenvolvimento metodológico. Na primeira parte deste trabalho, uma metodologia para obtenção de derivados 2- e 3-arilpirrólicos utilizando a reação de Heck-Matsuda como etapa chave foi desenvolvida, sendo esta posteriormente aplicada na síntese total do produto natural pentabromopseudilina. Na segunda parte do trabalho, esta metodologia foi estendida para a obtenção de uma pirroloanilina utilizada como intermediário chave na síntese total das marinoquinolinas, a qual foi completada pela reação de Pictet-Spengler com diferentes aldeídos. A rota sintética utilizada permitiu a preparação de quatro membros desta família de produtos naturais (marinoquinolinas A, B, C e E), bem como nove análogos não naturais, os quais foram encaminhados para avaliação de atividade antichagásica e antimalarial. Na parte final deste trabalho, esforços foram direcionados para o desenvolvimento de uma metodologia para a arilação enantiosseletiva do 2,3-diidrofurano via reação de Heck-Matsuda. Os resultados obtidos demonstraram que a escolha do ligante apropriado permite a modulação da reação, sendo que ligantes do tipo PyBOX levam aos adutos de Heck primários de configuração S, enquanto ligantes do tipo BOX levam aos respectivos acetais cíclicos de configuração R, formados pela isomerização do aduto primário seguida de adição de metanol na ligação dupla. Os dois tipos de produto puderam ser obtidos com rendimentos de moderados a bons e razões enantioméricas moderadas, e uma racionalização para a estereoquímica observada é proposta para ambos os casos. Por fim, um dos adutos obtidos foi utilizado na síntese de um análogo do produto natural (-)-gloeosporiol / Abstract: The present work had as general objective the study of the Heck-Matsuda reaction, aiming at new synthetic applications and its methodological development. In the first part of this work, a method was developed for the synthesis of 2- and 3- arylpyrrole derivatives using the Heck-Matsuda reaction as the key step, which was then applied to the total synthesis of the natural product pentabromopseudilin. In the second part of this work, this methodology was extended to the preparation of a pyrroloaniline compound, which was used as a key intermediate in the total syntheses of marinoquinolines, that were completed by the Pictet-Spengler reaction with different aldehydes. This synthetic route enabled the preparation of four members from this family of natural products (marinoquinolines A, B, C and E) as well as nine non-natural analogues, which were submitted to antichagasic and antimalarial activities evaluation. In the final part of this study, efforts were directed towards developing a methodology for the enantioselective arylation of 2,3-dihydrofuran by the Heck-Matsuda reaction. The results have shown that the appropriate choice of ligands modulates the reaction. PyBOX-type ligands lead to the primary Heck adducts with S configuration, while BOX-type ligands lead to the respective cyclic acetals with R configuration, formed by isomerization of the primary adduct followed by addition of methanol across the double bond. The two types of products were obtained in moderate to good yields with moderate enantiomeric ratios, and a rationalization for the observed stereochemistry is proposed for both cases. Finally, one of the adducts was used in the synthesis of an analogue of the natural product (-)-gloeosporiol / Doutorado / Quimica Organica / Doutora em Ciências