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A fitoalexina trans-resveratrol foi quantificada em vinhos varietais tintos brasileiros elaborados no Rio Grande do Sul, tendo sido determinado o valor médio de 2,57 mg.L-1, com os varietais Merlot, Sangiovese e Tannat sendo aqueles com teores mais elevados deste produto natural. Foram analisados, também. sucos de uva comerciais de preparo convencional e ecológico, mostrando valores médios de 1,01 e 1,98 mg.L-1, respectivamente. Foram desenvolvidas estratégias para as sínteses catalíticas seletivas dos moduladores seletivos de receptores de estrogênio trans-resveratrol e (Z)-tamoxifeno. Duas rotas foram apresentadas para a síntese de resveratrol e três rotas em desenvolvimento para a preparação de triariletilenos e tamoxifeno. As rotas de síntese dos compostos triariletileno utilizaram substratos até o momento originais para a obtenção de tamoxifeno, apresentando potencial e versatilidade para virem a se constituir em alternativas viáveis para sua obtenção em larga escala. / The natural product trans-resveratrol was quantified in southern brazilian red wines. The analytical methodology developed for thoose analyses showed good linearity, reproductibility and short analysis time. The average value achieved for the transresveratrol concentratios in wines was 2.57 mg.L-1. Some grape juice samples were also analyzed, showing mean values of 1.01 mg.L-1 for conventional juices and 1.98 mg.L1 for ecological ones. New resveratrol and tamxoxifen synthesis protocol were explored. Some new contributions on this field was achieved on applying transition metal catalysis in order to perform thoose syntheses. Two methods for trans-resveratrol synthesis are about to be completed as well as, at least, two new synthesis for tamxifen and other triarylethylene compounds.

Ausgehend von den dilithiierten Verbindungen [Cr(C6H5Li)2]·(tmeda), [Cr(C5H4Li)(C7H6Li)]·(tmeda) und [Mn(C5H4Li)(C6H5Li)]·(tmeda) konnten durch Umsetzung mit Elementdihalogeniden der Gruppe 4 neue [1]Metalloarenophane synthetisiert werden. Aufgrund des großen Kovalenzradius von Zirkon weisen diese Spezies erwartungsgemäß nur sehr geringe Molekülspannungen auf, weshalb deren intensive Färbung nicht allein auf eine mit der Verbrückung einhergehende Verkleinerung des HOMO-LUMO-Abstandes zurückgeführt werden konnte. Die UV-Vis-spektroskopischen Untersuchungen zeigten ein nicht einheitliches Verhalten, so dass deren Hintergrund mittels zeitabhängiger DFT-Rechnungen (B3LYP/BP86) untersucht wurden. Den Rechnungen zufolge muss bei der niederenergetischsten Anregung dieser [1]Metalloarenophane ein starker elektronischer Einfluss der ansa-Brücke mit berücksichtigt werden. Die Übergänge finden demnach aus dem metallzentrierten HOMO in das LUMO statt, welches hauptsächlich an der Zr-Brücke lokalisiert ist. Des Weiteren ist es gelungen, heteroleptische 1,1 ́-Bis(phosphanyl)trochrocenderivate darzustellen. Neben NMR-spektroskopischen Experimenten belegen auch Kristallstrukturanalysen die Gegenwart nahezu ungespannter Systeme. Die Reaktivität dieser 1,1 ́-Bis(phosphane) in Hinblick auf deren Verwendung als Chelatliganden wurde durch deren Umsetzung mit Metallcarbonylen der Gruppe 6 sowie mit geeigneten Palladium- und Platinkomplexen untersucht. Auf diese Weise konnten bimetallische [3]Trochrocenophane erhalten werden. Durch Umsetzung mit MeLi bzw. M-C≡C-Ph (M = Li, Na) ist es in weiterführenden Experimenten gelungen, die disubstituierten Spezies darzustellen, welche eine deutlich erhöhte Löslichkeit als die entsprechenden MCl2-verbrückten Ausgangsverbindungen zeigten und konnten isoliert und in Lösung vollständig durch NMR-Spektroskopie charakterisiert werden. Die Ergebnisse dieser Studien stehen erwartungsgemäß im Einklang mit der Gegenwart ungespannter Systeme, was weiterhin durch Röntgenstrukturanalysen belegt werden konnte. Die Eignung der PdCl2-verbrückten 1,1´-Bis(phosphanyl)trochrocene als Katalysator für die Heck-Reaktion wurde weiterhin untersucht. Katalysestudien zur Umsetzung von Brombenzol mit Styrol zu trans- und cis-Stilben belegen eindeutig die katalytische Aktivität dieser Spezies. / Based on the reaction of the dilithiated species [Cr(C6H5Li)2]·(tmeda), [Cr(C5H4Li)(C7H6Li)]·(tmeda) and [Mn(C5H4Li)(C6H5Li)]·(tmeda) with group 4 metal dichlorides new [1]metalloarenophanes were obtained. Due to the large covalent radius of the zirconium atom all species exhibit, as expected, little molecular ring strain. Therefore their intense colouration can not arise merely by the reduction of the HOMO-LUMO gap due to tilting. UV-Vis spectroscopy show an irregular trend, for which reason time-dependent DFT calculations (B3LYP/BP86) were conducted. According to these, the ansa-bridge executes a strong electronic influence on the lowest-energy transition in these [1]metalloarenophanes. These transitions arise from metal-centered orbitals (HOMO) to acceptor orbitals, predominately located at the zirconium bridge (LUMO). Furthermore, heteroleptic 1,1 ́-bis(phosphanyl)trochrocene derivatives could be obtained. In addition to solution NMR spectroscopic characterisation, the nonstrained character was further validated by X-ray diffraction analysis. The suitability of these 1,1 ́-bis(phosphanyles) to act as chelating ligands was subsequently evaluated by reactivity studies toward group 6 metalcarbonyls and adequate palladium- and platinum complexes. By this way the bimetallic [3]trochrocenophanes could be obtained. By further reaction with MeLi or M-C≡C-Ph (M = Li, Na) the disubstituted species could be synthesised. In contrast to their MCl2-precursors they show an increased solubility were isolated and fully characterised by solution NMR spectroscopy. Results of these studies suggest, as expected, the non-strained character of these systems, which is further validated by X-ray diffraction analysis. The applicability of the PdCl2-bridged 1,1´-bis(phosphanyl)trochrocenes to act as catalysts in the Heck reaction was investigated. Catalytic studies on the reaction of bromobenzene with styrene to trans- and cis-stilbene demonstrate the activity of these species.

M. Tech. (Department of Chemical Engineering, Faculty of Engineering and Technology): Vaal University of Technology / The arylation and alkenylation of alkenes under the influence of a palladium catalyst, commonly referred to as the Heck reaction, has been extensively exploited by synthetic chemists since its debut in the late 1960’s. A traditional Heck coupling is based on an aryl iodide or bromide as the electrophilic partner and a terminal alkene as the nucleophilic partner. Academic and industrial interest in this reaction has increased in recent years, fueled by the development of more active catalyst systems, the discovery of waste-free versions, and the desire to put the vast empirical data on a sound mechanistic basis. In this study, we wish to report the use of commercially available substituted pyrazolones (1-(4-Sulfophenyl)-3-methyl-5-pyrazolone (L1), 1-(2,5-Dicloro-4-sulfophenyl)-3-methyl-5-pyrazolone (L2) and 5-oxo-1-phenyl-2-pyrazolin-3-carboxylic acid (L3)) and pyrazoles (α-[(2-Ethoxy-2-oxoethoxy)imino]-3-pyrazole acetic acid (L4) and 3.5 dimethyl pyrazole (L5)) as auxiliary ligands in the Heck coupling reaction. These ligands were used either with PdCl2 or Pd(OAc)2 to catalyze the Heck reaction of iodobenzene with ethyl acrylate or butyl acrylate. GC-MS was used to monitor the reaction, percentage (%) conversions were determined based on the consumption of iodobenzene. Different reaction parameters such as ligands, temperature, base, solvent and influence of time were investigated. It was observed that the lower conversion was obtained for ethyl acrylate and conversions above 80% were obtained for butyl acrylate. Ligand effect proved to be very crucial during the Heck coupling reactions of iodobenzene with butyl acrylate and ethyl acrylate. For instance in the absence of ligands with PdCl2, the conversions were 29 % and 44 % for butyl acrylate and ethyl acrylate, respectively. When Pd(OAc)2 was used in the absence of ligands the conversions were 25 % and 36 % for butyl acrylate and ethyl acrylate, respectively. In the study for the effect of temperature, 80 ◦C was observed as the best temperature since promising conversions were obtained with little or no sign of deactivation of the catalysts. On the other hand, increasing the temperature to 120 ◦C and above high percent conversions are observed; however deactivation of the catalysts occurs as observed from the precipitation of palladium black at the bottom of the vial. From the results obtained it is clear that pyrazolone and pyrazole ligands/palladium systems are important at very low catalyst loadings and mild temperatures. Based on the employed reaction conditions the influence of base suggested that the organic base triethylamine was the reagent of choice since better conversions were obtained compared to inorganic bases. The inhomogeneity of the inorganic base proved to be a disadvantage in the reaction of iodobenzene with butyl acrylate at employed reaction conditions. It was also found that parameters such as solvents and time effects were important in the Heck reaction. Polar aprotic solvents proved to be solvents of choice rather than non-polar solvents, from the investigated solvents DMF gave better conversions under the used reaction conditions giving average conversions of 78 % and 75 % for all the ligands in the presence of PdCl2 and Pd(OAc)2, respectively. During the investigation of time effect, it was noteworthy to observe that L4 had a slow initiation rate, for instance after 0.5 h conversions of 2 % and 10 % were obtained for catalytic systems, PdCl2 and Pd(OAc)2 respectively. Also it was observed that under the investigated parameters there was no need to run the reaction for 24 h because after 4 h not much of a difference in conversions was observed. In comparing the influence of these two different auxiliary ligands, pyrazolone based ligands were more efficient than pyrazole based ligands under the investigated parameters. The fully detailed information supporting this has been discussed in Chapter 4.

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 / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-16T16:31:07Z (GMT). No. of bitstreams: 1 Godoi_MarlaNarciso_D.pdf: 10035986 bytes, checksum: 6deb65c44c4239f0ee6985fb972c18b1 (MD5) Previous issue date: 2010 / Resumo: Este trabalho de tese visou desenvolver rotas sintéticas eficientes para síntese de prolinas ariladas utilizando como etapa-chave a reação de arilação de Heck-Matsuda. Além disso, os aminoácidos arilados tiveram seu potencial organocatalítico avaliado frente a reações aldólicas e Mannich multicomponente. No primeiro capítulo serão apresentados resultados referentes à síntese de 5-arilprolinas. A preparação estereosseletiva destes compostos teve como etapa-chave uma das reações de arilação de Heck-Matsuda e envolveu um enecarbamato derivado do ácido piroglutâmico. Após foi realizada a avaliação organocatalítica destes aminoácidos, e constatamos que seu desempenho não superou a L-prolina. Diante disso, partimos para síntese e investigação do desempenho organocatalítico de derivados da prolina arilados em C-4. Iniciamos o segundo capítulo com resultados sobre o desempenho organocatalítico do arilcainóide 61, arilado em C-4. Este aminoácido foi inicialmente testado em uma reação aldólica e apresentou um desempenho catalítico um pouco superior ao da L-prolina. Desta forma, partimos para síntese de 4-arilprolinas, explorando uma segunda reação de arilação de Heck- Matsuda que utiliza L-desidroprolinas como olefinas. Nesta etapa do trabalho, realizamos um estudo metodológico para obtenção de enecarbamatos monoarilados. O uso de microondas na reação de arilação proporcionou uma redução bastante significativa nos tempos reacionais. A partir da eliminação estereosseletiva com hidreto de silano e BF3.Et2O dos intermediários 2- metoxiprolinas 4-arilados foi possível a obtenção de cis-4-arilprolinas em apenas 3 etapas. / Abstract: This work aimed at the development of efficient routes for the synthesis of aryl prolines with the Heck-Matsuda reaction as key step. The potential of these arylated amino acids as organocatalysts was evaluated through aldol and multicomponent Mannich reactions. In the first chapter results will be presented concerning the synthesis of 5-aryl prolines. The stereoselective preparation of these compounds employed the Heck-Matsuda reaction as key step and involved an enecarbamate derived from piroglutamic acid. The organocatalytic behavior of these amino acids was evaluated and one noted that its performance was inferior to that of L-proline. Due to this observation, derivatives of prolines arylated in C-4 were synthesized and tested as organocatalysts. The second chapter begins with studies on the performance of the C-4- arylated aryl kainoid xx as organocatalyst. This amino acid was initially tested in aldol reactions and presented an organocatalytic performance slightly superior to that of L-proline itself. Hence, 4-arylprolines were synthesized, exploring the Heck-Matsuda reaction with L-dehydroprolines as olefins, and their potential as organocatalysts was also investigated. In this moment of the work, a methodologic study concerning the preparation of monoarylated enecarbamates was performed. Employ of microwaves-based heating on the arylation reactions allowed significant reduction of reaction times. From a stereoselective methanol elimination from 4-arylated 2-methoxy-prolines, employing silane hydrides and BF3.Et2O, one could obtain cis-4-aryl-prolines in only three steps. / Doutorado / Quimica Organica / Doutor em Ciências

Orientador: Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-17T04:40:41Z (GMT). No. of bitstreams: 1 Miranda_KarenFabianeCanto_D.pdf: 2096574 bytes, checksum: b7fd48d07ff428a29ed0b7b0b0c1ad8c (MD5) Previous issue date: 2010 / Resumo: O primeiro capítulo deste trabalho concentra-se no estudo metodológico da reação de Heck com anidrido maleico empregando diversos sais de arenodiazônio. A reação foi investigada em diversas condições e, num primeiro momento, foi possível, utilizando acetato de paládio como catalisador, preparar uma série de anidridos maleicos mono e diarilados através da reação com sais de diazônio contendo grupos doadores de elétrons. Também investigou-se a reação empregando sais de diazônio contendo grupos retiradores de elétrons, entretanto, com o sistema catalítico utilizado inicialmente, não foi possível obter os correspondentes anidridos maleicos substituídos. A utilização do catalisador POPd solucionou o problema do emprego de sais de diazônio contendo grupos retiradores de elétrons. Desse modo foi possível preparar uma série de anidridos maleicos mono e diarilados, com diferentes demandas eletrônicas e padrões de substituição, em rendimentos satisfatórios. Além disso, foi possível preparar também anidridos maleicos dissubstituídos simétricos e não simétricos. Vários dos anidridos maleicos preparados apresentaram fluorescência. O segundo capítulo mostra a aplicabilidade da metodologia desenvolvida. É apresentada a síntese do alcalóide de origem marinha Policitrina A através de uma rota sintética curta, que tem como etapas chaves duas reações de Heck consecutivas com anidrido maleico empregando sal de diazônio. Neste capítulo também são mostrados os esforços visando à síntese total do alcalóide Policitrina B e a síntese formal do mesmo / Abstract: Chapter one of this work deals with methodological studies of the Heck reaction with maleic anhydride using several arenediazonium salts. Several reaction conditions were investigated and at first, it was possible by the use of palladium acetate as catalyst, to prepare a series of mono and diarylated maleic anhydrides through reaction with diazonium salts bearing electron donating groups. The reactions using diazonium salts bearing electron withdrawing groups were also investigated although, with the previous catalytic system used, the correspondent substituted maleic anhydrides weren¿t obtained. The use of POPd catalyst solved the problematic use of diazonium salts bearing electron withdrawing groups. In this way, it was possible to prepare a series of mono and diarylated maleic anhydrides, with different electron demanding conditions and substitution patterns, with satisfactory yields. Besides this, it was possible to prepare symmetric and non-symmetric bi-substituted maleic anhydrides too. Several of this maleic anhydrides prepared displayed fluorescence. Chapter two presents applications of the methodology developed in chapter one. The synthesis of marine alkaloid Polycitrin A is presented through a short synthetic route which has as key steps two consecutive Heck reactions with maleic anhydride using diazonium salt. Efforts towards total synthesis of alkaloid Polycitrin B as well as its formal synthesis are also shown in this chapter / Doutorado / Quimica Organica / Doutor em Ciências

Orientador : Fernando Coelho / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-04T19:13:37Z (GMT). No. of bitstreams: 1 Pavam_CesarHenrique_M.pdf: 19020302 bytes, checksum: 85b94c6c9f4716381ac3aeceba977667 (MD5) Previous issue date: 2005 / Resumo: O presente trabalho pode ser dividido em duas partes, ambas abordando a química de adutos de Baylis-Hillman. A primeira parte trata da reatividade destas moléculas frente a complexos de paládio em condições catalíticas de reação. Assim, empregamos adutos de Baylis-Hillman aromáticos halogenados na posição orto como substratos em reações de Heck intramoleculares, em condições reacionais diversas, visando a construção de esqueletos indânicos. Contudo, não obtivemos os produtos esperados na maioria das condições estudadas. Muito provavelmente, o modelo de ciclização 5-endo-trig, cineticamente desfavorecido, tenha inviabilizado nossa abordagem. Em continuação a este trabalho, empregamos estes mesmos substratos em reações de cic!ocarbonilação catalisadas por complexos do tipo Pd-tri-terc-butilfosfina em meio básico, visando a síntese de lactonas enólicas densamente funcionalizadas. Com esta abordagem, obtivemos diversos ftalidos (de naturezas estéreas e eletrônicas variadas), uma cicloexanona, um álcool alílico e uma b-espiro-Iactona em rendimentos de bons a excelentes. Estas reações procedem segundo transformações seqüenciais distintas catalisadas por paládio (ciclocarbonilação/isomerização no caso dos ftalidos e dupla ciclocarbonilação quimiosseletiva no caso da b-espiro-Iactona). No que se refere à preparação dos ftalidos, o modelo de ciclização observado foi o 5-exo-trig, explicando assim a dicotomia na reatividade observada entre os complexos aril-paládio e acil-paládio derivados de adutos de Baylis-Hillman. A segunda parte da presente Dissertação de Mestrado trata do estudo mecanístico da reação de Baylis-Hillman empregando espectrometria de massas com ionização por eletrospray (ESI-MS) e ESI-MS/MS (MS tandem). Esta técnica nos permitiu comprovar pela primeira vez o mecanismo desta reação, com a detecção e caracterização estrutural de todos os intermediários zwitteriônicos transientes do ciclo catalítico da reação de Baylis-Hillman, em suas formas protonadas em solução metanólica. / Abstract: The present work can be separated in two distinct parts, both concerning the chemistry of Baylis-Hillman adducts. The first part deals wíth the reactivity of these molecules facing palladium complexes in catalytic reaction conditions. In this way, we have employed aromatic orto halogenated Baylis-Hillman adducts as substrates for intramolecular Heck reactions, in severaI reaction conditions, aiming the construction of indanic frameworks. However, the expected products were not obtained at all in most of the studied catalytic systems. Probably, the 5-endo-trig cyclization model, kinetically disfavored, has been disfavored our approach. In continuation of this work, we employed these same substrates in cyclocarbonylation reactions catalyzed by Pd-tri-tert-butylphosphine type complexes in basic media, owing the synthesis of highly functionalized enol lactones. With this approach, we were able to synthesize severaI phtalides (with different steric and electronic properties), a cyclohexanone derivative, a b-spiro-Iactone moiety, as well an allylic alcohol compound, in good to excellent yields. These reactions proceed accordingly essentially different tandem transformations catalyzed by palladium (cyclocarbonylation/isomerization in the case of phtalides and double chemoselective cyclocarbonylation in the case of the b-spiro-Iactone). In the specific case of the phtalides, the cyclization model 5-exo-trig was observed, explaining therefore the dichotomy in the reactivity between the aryl- and acyl palladium complexes derived from the same Baylis-Hillman adducts precursors. The second part of the present Dissertation deals with the mechanistic study of the Baylis-Hillman reaction employing mass spectrometry with electrospray ionization (ESI-MS), as well as tandem mass spectrometry (ESI-MS/MS). This approach allowed us to probe, for the first time, the mechanism of this reaction, through the detection and structural characterization of all the zwitterionic intermediates involved in the catalytic cycle of the Baylis-Hillman reaction, in their protonated forms in methanolic solution. / Mestrado / Quimica Organica / Mestre em Química

Orientador: Carlos Roque Duarte Correia / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-06T03:45:01Z (GMT). No. of bitstreams: 1 Silva_KeziaPeixotoda_D.pdf: 3885447 bytes, checksum: c1e76b6f7330c1ac6f030347c8be0e06 (MD5) Previous issue date: 2006 / Resumo: O estudo das reações de arilação de Heck utilizando como olefina, uma desidroprolina quiral, tendo como grupos de arilação vários sais de arenodiazônio, leva a formação de uma série de 4-aril-2-desidroprolinas de grande interesse biológico. A aplicação de sais de diazônio nesta reação oferece diversas vantagens sobre a Heck tradicional, tais como condições suaves de reação e livres de fosfinas, além do curto tempo de reação. Nosso interesse nessa reação deriva na aplicação sintética de análogos do ácido acromélico, que vem a ser um composto de origem natural fortemente neuroexcitatório. A reação de arilação de Heck da 3-desidroprolina quiral foi obtida em ótimos rendimentos usando vários sais de tetrafluoroboratos arildiazônios, tendo duas condições de reação com acetonitrila-água ou em metanol; os dois métodos usam condições suaves livres de fosfinas. Realizamos um estudo comparativo com as reações de Heck tradicionais que utilizam como agentes arilantes haletos ou triflatos de arila. Nas condições tradicionais testadas (Jeffery, Crisp e Fu), apenas a reação nas condições de Jeffery levou à formação do produto de Heck, porém em muito baixo rendimento. O composto o-anisilado, análogo do acido acromélico que apresentou maior atividade neuroexcitatória, pode ser obtido a partir do composto vindo da reação de arilação de Heck por uma seqüência de reações que envolvem uma reação conjugada de Michael, selenilação e posterior eliminação oxidativa. Em seguida as reações de hidrogenação, descarboxilação, epimerização do centro em C-2 levaram ao produto desejado protegido dos ácidos acromélicos após 13 etapas e com um rendimento global de 8% a partir da 4-trans-hidroxi-prolina. Comparação dos dados espectrais da literatura e do valor de [a]D dos análogos do ácido acromélico obtidos comprovaram a formação dos adutos da Heck, as 4-aril-2-desidroprolinas, de forma altamente régio e estereosseletiva / Abstract: The Heck arylation of chiral 3-dehydroprolines using various aryldiazonium salt resulted in the formation of a series of 4-aryl-dehydroprolines of potential biological interest. The application of aryldiazonium salt in this arylation reaction offers several advantages over traditional Heck reactions such as mild reactions conditions of phosphine-free conditions and shorter reaction times. The 4-aryl-dehydroprolines were envisioned as potential precursors for the synthesis of a number of acromelic acid analogues, a potent neuroexcitatory neurotransmitter. The Heck arylation reaction of chiral 3-dehydroprolines was obtained in high yields under two basic protocols using acetonitrile-water or methanol as solvent; both methods use mild and phosphine-free conditions. A comparative study was designed involving the Heck arylation of 3-dehydroprolines using traditional electrophiles, such as aryltriflates and arylhalides. Among the traditional conditions tested (Jeffery, Crisp and Fu) only the conditions of Jeffery resulted in the formation of the Heck adduct, in rather low yields. The o-methoxyphenyl acromelic acid analogue, which displays high neuroexcitatory activity, was obtained from a Heck adduct by a sequence of reations involving Michael addition, selenylation and oxidative deselenylation. Next, catalytic hydrogenation, decarboxylation, and epimerization resulted in the desired protected analogue of the acromelic acid after 13 steps and with an overall yield of 8% from 4-trans-hydroxyproline. Comparison of the spectral data obtained for the compound synthesized herein and those published in the literature confirmed the structure of the acromelic acid analogue, including its absolute stereochemistry / 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