No description available.

1,1-Dimethyl-2-neopentylsilene reacted with the N-methylimine of benzophenone to give 1,2,2-trimethyl-3- neopentyl-4,4-diphenyl-l-aza-2-silacyclobutane, I, and 2,3,4,4a-tetrahydro-2,3,3-trimethyl-1-phenyl-4-neopentyl-2- aza-3-silanephthalene, II, in 35% and 20% yields, respectively. Compounds I and II did not serve as thermal silene precursors. Heating I and II to over 280°C did not yield 1,3-disilacyclobutanes. In the presence of 2,3- dimethyl-1,3-butadiene typical silene products were not obtained. However, I and II reacted rapidly with methanol at room temperature to give the ring-opened products (E)-2- methoxy-2,5,5-trimethyl-2-silahex-3-ene, III, 1,1- diphenyldimethylamine, IV, and 2-methoxy-2,5,5-trimethyl-3- (N-methylaminodiphenyl) methyl-2-silahexane, V.

No description available.

<p> To investigate the stereochemical requirements for bishomoaromaticity it was necessary to develop a synthetic scheme that would give suitable precursors in which the stereochemistry could be unambiguously assigned. Arguments are presented in this theses to suggest that, if bishomoaromaticity is to be detected when the two methylene bridges are trans with respect to each other, the 1,4-bishomotropylium system is more favourably oriented for cyclic delocalization than the 1,3-bishomotropylium system. </p> <p> By reacting benzotropone ethylene ketal with phenyl mercuric trichloromethane, followed by removal of the chlorines and protecting group, it is possible to synthesize the trans-4,5-benzo-2,3:6,7-bishomotropone. The cis-4,5-benzo-2,3:6,7-bishomotroponewas synthesized by the action of dimethyloxosulfonium methylide on benzotropone. The stereochemistry in the cis and trans isomers was unambiguously established by examining the nmr spectra of the derived alcohols. </p> <p> To determine the effect of the benzene ring in these homoaromatic systems it was necessary to synthesize 4,5-benzo-2,3-homotropone. By reacting benzotropone with dimethyloxosulfonium methylide it was possible to obtain a high yield of 4,5-benzo-2,3-homotropone. </p> <p> The low temperature nmr spectra of protonated 4,5-benzo-2,3-homotropone and derived alcohol clearly showed that the benzene ring did not decrease the homoaromatic nature of these systems. The hydroxy substituent, however, had a marked effect on the homoaromatic nature. </p> <p> The low temperature nmr spectra of the protonated cis and trans-4,5-benzo-2,3:6,7-bishomotropones showed that the trans hydroxy cation could be best interpreted as a cyclopropyl carbinyl delocalized system and the cis hydroxy cation as a bishomoaromatic species. </p> <P> The low temperature nmr spectra of the trans-4,5-benzo-2,3:6,7bishomotropylium cation also supported the cyclopropyl carbinyl delocalization in this system. In contrast to the hydroxy-substituted system, however, the unsubstituted system was not equilibrating between the two possible equivalent boat conformations. This was attributed to the hydroxy substituent effect on the transition state of the boat-boat equilibrium. </p> <p> In conclusion, arguments are presented that would suggest that the trans-1,3-bishomotropylium cation is not a bishomoaromatic cation as previously reported, but that is can be best represented as a cyclopropylcarbinyl delocalized system. </p> / Thesis / Doctor of Philosophy (PhD)

Withanolides are a class of ergostane natural products found in plants of family Solanaceae. Plants of this family are used in traditional medicine in Asia and South America. Recently, a series of 17β-hydroxy withanolides were identified from high-throughput screens as inhibitors of androgen-induced changes in gene expression of prostate cancer cells. Therefore, these compounds may have important applications as new therapies against prostate cancer. We have devised a synthetic route to members of this family and their analogues which allows stereoselective introduction of C14, C17 and C20 hydroxyl groups in separate steps. This will allow preparation of differentially hydroxylated analogues so as to identify which contributes to the potency and thus gain a better understanding of the SAR of this class of bioactive molecules. As part of this we have shown that the stereochemical outcome of the epoxidation of Δ 14-15 cholestanes with m-CPBA is controlled by the steric bulk of a C17 substituent. When the C17 is in the β configuration, the epoxide is formed on the α face, whereas if the C17 is trigonal (flat) or the substituent is in the α configuration, the epoxide is formed on the β face. The presence of a hydroxyl substituent at C20 does not influence the stereochemical outcome of the epoxidation. We have successfully introduced aldehyde functionality to the lateral side chain 14 hydroxyl compound. This aldehyde compound is a key intermediate from which many of the withanolides can be made. We have also investigated the introduction of a hydroxyl at the C18 as an entry into the physachenolides. Finally, we have carried out an assessment of the potency of the synthesised compounds against hormone-insensitive prostate cancer cell line, PC-3.

In 2004, the polyketide natural product, chamuvarinin (72) was isolated by Laurens et al. from the roots of Uvaria chamae, a member of the Annonaceae plant family. This unique tetrahydropyran containing acetogenin displayed potent levels of cytotoxic activity against the KB 3-1 cell line with an ED50 value of 0.8 nM. Upon initial isolation the relative and absolute stereochemical assignment of chamuvarinin (72) was unable to be readily achieved through ¹H and ¹³C NMR analysis. The initial synthetic route described herein has enabled the relative and absolute stereochemical determination of chamuvarinin (72) through the first total synthesis completed in 20 longest linear steps in 1.5% overall yield. A revised synthetic strategy towards chamuvarinin (72) was completed in 17 longest linear steps in 2.2% overall yield. The revised route facilitated the assembly of non-natural chamuvarinin-like analogues and their trypanocidal and cytotoxic activities have been assessed. The synthesis of these analogues has formed the basis of a more focussed study through the design and synthesis of simplified triazole (295), isoxazole (325) and butenolide triazole (305) analogues as potential Trypanosoma brucei (causative agent in African Sleeping sickness) inhibitors.

O presente trabalho teve, como cerne, o estudo do campo dos conceitos estereoquímicos, sob a luz da Teoria dos Campos Conceituais proposta por Gérard Vergnaud. Neste sentido, a investigação foi conduzida com vistas a identificar os invariantes operatórios empregados por sujeitos ao enfrentar situações que envolvam a representação química. Estudar o papel da habilidade espacial perante a resolução de tarefas no campo em questão, assim como o estudo dos fatores associados à conceituação em situações em sala de aula, também fizeram parte dos objetivos. Mediante a participação de alunos dos cursos de Química e de Farmácia e Bioquímica da Universidade de São Paulo em minicursos que versavam sobre conceitos estereoquímicos, oferecidos como fonte de coleta de dados, foram selecionados três episódios. A partir da transcrição dos registros em vídeo e da análise qualitativa efetuadas com o auxílio de um programa especializado foram inferidas informações sobre o conteúdo conceitual da argumentação oral e gestual utilizados pelos alunos. Quanto à habilidade espacial, foram empregados instrumentos psicométricos distintos, quais sejam um que avalia esta habilidade via processamento gestáltico, disponível na literatura, e outro que avalia via processamento analítico. O desenvolvimento e validação, deste último, foi efetuado mediante o uso de dispositivos estatístico-inferenciais sobre um população de 561 alunos. Como resultado, foram propostos os invariantes operatórios, identidade estrutural (I), equivalência (E) e livre movimentação no espaço (M) como elementos conceituais passíveis de associação durante a ação do sujeito. Esta associação, então, constituiria três esquemas distintos, ME, MEI e EI, responsáveis por diferenças significativas nas conclusões chegadas pelos alunos em pelo menos um dos episódios estudos. Além disso, foi encontrado que, quando confrontados os diferentes episódios, nem todos os alunos empregam regularmente os mesmos invariantes operatórios. Neste sentido, foi proposto que o uso de esquemas está vinculado à reflexao pelo indivíduo. Logo, atividades de natureza metacognitiva estariam vinculadas à conceituação promovendo uma tomada de consciência sobre a própria argumentação e sobre a do outro. Finalmente, também foi sugerido, mediante o cruzamento de dados psicométricos com a análise dos registros efetuados em vídeo, que a habilidade espacial não figura como único nem, tampouco, principal fator envolvido ao sucesso na resolução de problemas estereoquímicos. A associação adequada dos invariantes operatórios bem como a reflexão sobre os procedimentos empregados seriam, também, elementos fundamentais ao desenvolvimento neste campo conceitual / The main objective of the present work was to identify the cognitive requirements for an adequate learning of stereochemical concepts. Vergnaud\'s Theory on conceptualization inspired most experimental activities, aimed to access common operating invariants or strategies that allow for a better understanding of stereo formulae and chirality properties. In order to collect reliable information, a group of graduate students, enrolled in Chemistry or Pharmaceutical Sciences Courses, were invited to follow a specially designed series of lectures. In three different occasions, they were asked to answer questions on stereochemical issues, and their performance was recorded in audio and video, and subsequently fully analyzed. As for the ability of moving or superimposing images in space, two sets of questions , requiring either an unified or an analytical approach, were presented to 561 students from different syllabi. After collecting, the entire database was submitted to statistical analysis, in order to verify if all groups of students could be considered comparable, despite of baseline differences. Data analysis allowed for the identification of three operating invariants, i.e.: structure identity (I), equivalence (E) and free movement in space (M). On the basis of these findings, students were classified as ME, MEI or EI, according to the set of invariants composing their problem solving schemes. However, different cognitive scenarios could be observed when the same students were confronted to new problem solving sessions. In some cases, after presenting their results, students were asked to answer questions raised by their peers or by the instructor. Such process of further reasoning frequently allowed for a change, and was responsible for achieving awareness of their own learning process and learning difficulties. Finally, it should be mentioned that a critical analysis of all experimental data revealed that the ability to operate movements of images in space is not mandatory for conceptualization in Stereochemistry. Moreover, the cooperative construction of cognitive schemes, resulting form reporting back activities, plays an important role towards success

En aquesta Tesi: 1) S’ha estudiat la reacció de metàtesi creuada (CM) de diferents derivats metilenciclopentànics utilitzant el catalitzador d’Hoveyda-Grubbs de segona generació, observant la formació dels alquens tetrasubstituïts corresponents amb bons rendiments. En el cas d’un derivat bis(metilenciclopentànic) s’ha observat la formació de productes de doble i triple CM amb elevada estereoselectivitat anti, fet que en el cas del producte de doble CM s’ha establert per difracció de raigs X. 2) S’ha preparat un nou ciclopentadiè 1,1-disubstituit funcionalitzat, i s’han estudiat les reaccions de Diels-Alder amb diferents dienòfils [anhídrid maleic, cis-1,2-bis(fenilsulfonil)etilè i triflat de fenil(2-iodoetinil)iodoni]. L’adducte amb l’últim dienòfil s’ha transformat en un derivat 2,3-diiodat 7,7-disubstituït del norbornadiè. 3) S’ha estudiat la reacció del triflat de (2-iodoetinil)feniliodoni amb 1,3-difenilisobenzofuran que depenen de les condicions dóna l’adducte Diels-Alder corresponent o un triflat naftalènic format per reducció de l’adducte inicial per part del 1,3.difenilisobenzofuran emprat en excés. 4) S’ha desenvolupat una seqüència sintètica per a l’obtenció de derivats del 2,8-etanonoradamantà molt funcionalitzats, que té com a etapa clau una reacció Diels-Alder intramolecular. Durant la reducció d’una enona a alcohol al•lílic amb NaBH4 / CeCl3•7H2O (mètode de Luche), es va haver de protegir una funció maleimida transformant-la en una barreja diastereomèrica d’adductes amb furà, regenerant la maleimida després de la reducció de l’enona, per escalfament en el sí de toluè a reflux durant 4 dies (reacció retro-Diels-Alder). També s’ha posat a punt un procediment alternatiu per preparar un intermediari clau en la seqüència sintètica anterior, 5-{[(t-butildimetilsilil)oxi]metil}-2-metil-5,6-dihidrociclopenta[c]pirrol-1,3(2H,4H)-diona, a partir de la N-metilmaleimida amb un rendiment cinc vegades superior al desenvolupat inicialment. 5) L’estructura dels diferents compostos obtinguts en aquesta Tesi s’ha establert per mètodes espectroscòpics [1H-RMN, 13C-RMN, correlacions 1H/1H (COSY, NOESY), correlacions 1H/13C (gHSQC, gHMBC), MS, IR] i en diversos casos, també per difracció de raigs X. / "Synthesis and reactivity of polycyclic compounds: Applications of the olefin metathesis reaction to their synthesis" In this PhD Thesis: 1) The cross metathesis (CM) reaction of different methylenecyclopentane derivatives using Hoveyda-Grubbs second generation catalyst has been studied. In these reactions, tetrasubstituted alkenes have been formed in good yields. In the case of a bis(methylenecyclopentane) derivative, the formation of products from double and triple CM has been observed. In general, high anti-stereoselectivity has been observed. The assignment of the stereochemistry of the single CM products has been performed through the analysis of the NMR data for the epoxide derivatives and in the case of the double CM product by X-ray diffraction analysis. 2) A new 1,1-disubstituted cyclopentadiene has been prepared. Its reactions with different dienophiles [maleic anhydride, cis-1,2-bis(phenylsulfonyl)ethylene and phenyl(2-iodoethynyl)iodonium triflate] has been studied. The adduct with the last dienophile has been transformed into a 2,3-diiodo-7,7-disubstituted norbornadiene. 3) The reaction of phenyl(2-iodoethynyl)iodonium triflate with 1,3-diphenylisobenzofuran has been studied. Depending on the reaction conditions, the corresponding Diels-Alder adduct or a naphthalenic triflate, formed by reduction of the initial adduct with 1,3-diphenylisobenzofuran used in excess, has been observed. 4) A synthetic sequence for the preparation of highly functionalized 2,8-ethanonoradamantane derivatives has been developed. The key step consists of an intramolecular Diels-Alder reaction. On reduction of an enone function to an allylic alcohol using NaBH4 / CeCl3•7H2O (Luche procedure), a maleimide function should be protected by transformation into a stereoisomeric mixture of Diels-Alder adducts with furan. The maleimide function was recovered, after reduction of the enone, through a thermal retro-Diels-Alder reaction. Also, an alternative procedure to prepare a key intermediate of the above synthetic sequence, 5-{[(t-butyldimethylsilyl)oxy]methyl}-2-methyl-5,6-dihydrocyclopenta[c]pyrrole-1,3(2H,4H)-dione, from N-methylmaleimide with a yield five times higher, have been developed. 5) The structure of the different compounds prepared in this PhD Thesis has been established by spectroscopic methods [1H NMR, 13C NMR, 1H/1H correlations (COSY, NOESY), 1H/13C correlations (gHSQC, gHMBC), MS, IR] and, in several cases, also by X-ray diffraction analysis.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / The essential oil of the leaves of Calea clematidea, a plant of Asteraceae family used in the folk medicine in treatment of flu, stomachic disease and gastric ulcer, was extracted and of it was isolated the monoterpene caleol. This metabolite was submitted to structural modification reactions by the opening of its epoxide functional group. In the reactions catalyzed by anhydrous iron (III) chloride, the epoxide opening was selective when primary alcohols was used like nucleophile, giving like product the less substituted alcohol. In addition, the absolute stereochemistry of caleol was analyzed by NMR, where was verified that the carbon C4 configuration is R. The essential oil, the caleol and the obtained derivatives were submitted to a microbiological activity. The caleol showed best activity against bacteria and derivatives against yes. / O óleo essencial das folhas de Calea clematidea, um arbusto da família Asteraceae utilizado popularmente como antigripal, estomáquico e contra úlceras gástricas, foi extraído e dele foi isolado o monoterpeno caleol. Este metabólito foi submetido a reações de modificação em sua estrutura por meio da abertura de seu grupo funcional epóxido. A reação catalisada por cloreto férrico anidro proporcionou a abertura seletiva do epóxido quando utilizado como nucleófilos alcoóis primários, no sentido da formação do álcool menos substituído. A estereoquímica do caleol foi também avaliada dor RMN, da onde se verificou que a configuração do carbono C4 é R. O óleo essencial, o caleol e os derivados obtidos foram submetidos a análise microbiológica. O caleol apresentou melhor atividade contra bactérias e os derivados melhor contra fungos.

O presente trabalho teve, como cerne, o estudo do campo dos conceitos estereoquímicos, sob a luz da Teoria dos Campos Conceituais proposta por Gérard Vergnaud. Neste sentido, a investigação foi conduzida com vistas a identificar os invariantes operatórios empregados por sujeitos ao enfrentar situações que envolvam a representação química. Estudar o papel da habilidade espacial perante a resolução de tarefas no campo em questão, assim como o estudo dos fatores associados à conceituação em situações em sala de aula, também fizeram parte dos objetivos. Mediante a participação de alunos dos cursos de Química e de Farmácia e Bioquímica da Universidade de São Paulo em minicursos que versavam sobre conceitos estereoquímicos, oferecidos como fonte de coleta de dados, foram selecionados três episódios. A partir da transcrição dos registros em vídeo e da análise qualitativa efetuadas com o auxílio de um programa especializado foram inferidas informações sobre o conteúdo conceitual da argumentação oral e gestual utilizados pelos alunos. Quanto à habilidade espacial, foram empregados instrumentos psicométricos distintos, quais sejam um que avalia esta habilidade via processamento gestáltico, disponível na literatura, e outro que avalia via processamento analítico. O desenvolvimento e validação, deste último, foi efetuado mediante o uso de dispositivos estatístico-inferenciais sobre um população de 561 alunos. Como resultado, foram propostos os invariantes operatórios, identidade estrutural (I), equivalência (E) e livre movimentação no espaço (M) como elementos conceituais passíveis de associação durante a ação do sujeito. Esta associação, então, constituiria três esquemas distintos, ME, MEI e EI, responsáveis por diferenças significativas nas conclusões chegadas pelos alunos em pelo menos um dos episódios estudos. Além disso, foi encontrado que, quando confrontados os diferentes episódios, nem todos os alunos empregam regularmente os mesmos invariantes operatórios. Neste sentido, foi proposto que o uso de esquemas está vinculado à reflexao pelo indivíduo. Logo, atividades de natureza metacognitiva estariam vinculadas à conceituação promovendo uma tomada de consciência sobre a própria argumentação e sobre a do outro. Finalmente, também foi sugerido, mediante o cruzamento de dados psicométricos com a análise dos registros efetuados em vídeo, que a habilidade espacial não figura como único nem, tampouco, principal fator envolvido ao sucesso na resolução de problemas estereoquímicos. A associação adequada dos invariantes operatórios bem como a reflexão sobre os procedimentos empregados seriam, também, elementos fundamentais ao desenvolvimento neste campo conceitual / The main objective of the present work was to identify the cognitive requirements for an adequate learning of stereochemical concepts. Vergnaud\'s Theory on conceptualization inspired most experimental activities, aimed to access common operating invariants or strategies that allow for a better understanding of stereo formulae and chirality properties. In order to collect reliable information, a group of graduate students, enrolled in Chemistry or Pharmaceutical Sciences Courses, were invited to follow a specially designed series of lectures. In three different occasions, they were asked to answer questions on stereochemical issues, and their performance was recorded in audio and video, and subsequently fully analyzed. As for the ability of moving or superimposing images in space, two sets of questions , requiring either an unified or an analytical approach, were presented to 561 students from different syllabi. After collecting, the entire database was submitted to statistical analysis, in order to verify if all groups of students could be considered comparable, despite of baseline differences. Data analysis allowed for the identification of three operating invariants, i.e.: structure identity (I), equivalence (E) and free movement in space (M). On the basis of these findings, students were classified as ME, MEI or EI, according to the set of invariants composing their problem solving schemes. However, different cognitive scenarios could be observed when the same students were confronted to new problem solving sessions. In some cases, after presenting their results, students were asked to answer questions raised by their peers or by the instructor. Such process of further reasoning frequently allowed for a change, and was responsible for achieving awareness of their own learning process and learning difficulties. Finally, it should be mentioned that a critical analysis of all experimental data revealed that the ability to operate movements of images in space is not mandatory for conceptualization in Stereochemistry. Moreover, the cooperative construction of cognitive schemes, resulting form reporting back activities, plays an important role towards success