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published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

This research focused on the synthesis of novel ogranoboron reagents in efforts to perform a variety of synthetic transformations, and additionally, the development of new methodologies to generate drug-like scaffolds. Initially, three novel tripod ligands were synthesized, and two were effectively chelated to boron to provide the desired organoborates. Such organoborates were employed in nucleophilic additions where they were found to be ineffective, whereas some activity was observed in Suzuki-Miyaura cross-coupling reactions. An additional project on organoboron compounds was conducted and focused on the development of organoboron frustrated Lewis pairs (FLPs) to facilitate the storage and transfer of hydrogen, nucleophilic addition reactions, and Claisen rearrangements. A new method for synthesizing a pyrrolidine diol unit was accomplished, and this intermediate was utilized to synthesize two FLPs. The reactivity of the FLPs with small molecules was assessed, and the pyrrolidine diol unit was subsequently evaluated for its ability to undergo a multicomponent reaction (MCR) to yield compounds possessing beneficial biological activity. Further research in this area was conducted, and a 5-aminoimidazole scaffold was synthesized employing a new MCR which is more efficient than previously reported methodologies. 5-Aminoimidazoles are frequently found in compounds which possess desirable biological activity, and this novel method was employed to generate a library of eleven 5-aminoimidazoles. Additionally, two post condensation modification reactions were developed. During initial studies, a side product was observed which was identified as a dihydrotriazine, which is another biologically appealing chemotype. Therefore, an enhanced method of synthesizing this product was developed, and a library of eleven dihydrotriazines was produced. In summary, novel organoboron reagents were synthesized, and their activity was evaluated. The pyrrolidine diol utilized to synthesize FLPs was applied towards an MCR. Furthermore, a novel MCR was developed for the synthesis of 5-aminoimidazoles, and an enhanced protocol for the synthesis of dihydrotriazines was found.

A close critical scrutiny of Anne Brontë’s The Tenant of Wildfell Hall, Thomas Hardy’s A Pair of Blue Eyes, and Lewis Carroll’s Through the Looking-Glass reveals that these texts are linked through their use of a chess metaphor, a device that symbolizes how the central female characters of these works become stalemated in their efforts to achieve autonomy. While the disparate but related paths these characters take can be likened to the predetermined progress of a pawn that travels the length of a chessboard to become a queen, what Brontë, Hardy, and Carroll all recognize is that this process of becoming is by no means a fulfilling one. Rather, it only serves to reveal how trapped Helen, Elfride, and Alice are within a game in which Victorian society designates them as players of only secondary importance. There is a general movement towards a more complex integration of the chess motif as we move from Brontë to Hardy and finally, to Carroll. Brontë’s incidental chess scene is reminiscent of Thomas Middleton’s use of a similar episode in Women Beware Women, and shows less sophistication than what Hardy or Carroll achieve because her moral realism lacks the creative touches found in either Hardy’s use of symbolic imagery or Carroll’s use of the fantastic and the unorthodox. However, Brontë juxtaposes her chess game with Helen’s discovery of Huntingdon’s infidelity to demonstrate how her heroine becomes trapped within a game that she is willingly coerced into playing. If Brontë suggests that relationships are like chess games played according to rules that seriously limit a woman’s ability to compete, Hardy goes to even greater lengths in using chess to show how his Wessex universe operates as its own evolving game environment, replete with obstacles and conflicts that prove catastrophic for a player as unprepared as Elfride. Indeed, Hardy’s allusion to Shakespeare’s The Tempest is critical in demonstrating how in matters of social game-playing, his heroine suffers from the unsatisfactory education she receives from her controlling father. Hardy shows greater sophistication than Brontë in using parallel chess episodes to comment on the progress of Elfride’s relationships, and he even refers to a specific opening system in chess, the Muzio Gambit, whose catalogue of moves prefigures Elfride’s romantic involvements with Stephen and Henry, as well as the unavoidable problems she encounters from the novel’s vengeful Black Queen, Mrs. Jethway. Unlike Brontë, Hardy recognizes that fate is not so careful about giving individuals what they deserve, and that a character like Elfride can pay a heavy price for her romantic misdemeanours. However, neither Brontë nor Hardy achieves what Carroll does in Through the Looking-Glass, a work that can be seen to follow in the tradition of Middleton’s A Game at Chess, and which not only incorporates the game but structures its plot on the solution to an unorthodox chess problem. If Brontë is to be celebrated for her honest portrayal of a woman who becomes trapped in a destructive marriage, and Hardy can be commended for showing how his heroine’s education in social game-playing undermines her relationships with men, Carroll’s genius rests in his ability to illustrate these kinds of experiences on a chess board through Alice’s dream of travelling across Looking-Glass land to become a queen. He does not simply give us the impression that a girl’s progress towards womanhood is like a pawn’s promotion in chess, but instead integrates these two concepts into a single experience. He also keeps the reader off guard by creating an unorthodox chess problem and a curious cast of characters, giving us a sense of being caught in a game of our own. The result of all of this is that we are drawn into Carroll’s games even as we view them as spectators, and the critical giddiness we experience in the process both helps us to share a sense of Alice’s predicament in her frustrated quest to find fulfilment, and allows us to appreciate the underlying thematic implications of the chess motif in the narrative. / Graduate

A remarkable thing about natural language is that we can use it to share our beliefs and thoughts about the world with other speakers of our language. In cases of successful communication, beliefs seem to be transferred from speakers to hearers by means of the hearer recovering the contents of the speaker’s utterances. This is so natural to us that we take it for granted in our everyday life, and rarely stop to think about how it's is possible. Nevertheless, it's a phenomenon that calls for explanation. It is natural to expect that natural language semantics has a key explanatory role to play here. In order to understand this role, we must relate the semantic values assigned to sentences by semantic theories with the contents of our speech acts. The simplest possible relation would be identity; the meaning of a sentence is simply the belief expressed by an assertion of the sentence in a given context of utterance. However, a number of problem cases in the literature suggest that this cannot be the case. This dissertation offers a critical assessment of the arguments for distinguishing the semantic value of a sentence from its so-called assertoric content, focusing on problems arising from the analysis of tense and temporal expressions. I conclude that they are indeed distinct, and offer a constructive account of how they must be related in order to allow for an explanation of communicative success.​

A cursory glance into the background of Sinclair Lewis reveals that he was an ardent nonconformist. In this study, however, it is pertinent to view more closely the conditions that caused his rebellious attitudes, not only those concerning social reform but also those concerning his personal quest for individuality.

The purpose of this study is to introduce the three posthumous narrative poems of C. S. Lewis. Chapter One is an introduction to Lewis's life and scholarship. The second chapter is concerned with "Launcelot," in which the central theme of the story explores the effect of the Quest for the Holy Grail on King Arthur's kingdom. Chapter Three studies "The Nameless Isle," in which Celtic and Greek mythic elements strongly influence both characterization and plot. The fourth chapter is an analysis of The Queen of Drum and its triangular plot structure in which the motivating impetus of the characters is the result of dreams. Chapter Five recapitulates Lewis's perspectives of life and reviews the impact of his Christianity on the poems. The study also shows how each poem illustrates a separate aspect of the cosmic quest.

Since 1920, Lewis has written only novels in which he has ridiculed the leading phases of American life. He has given an exact picture; he has left no faults uncovered. He loves America and he hates to see her in a state of degeneration. He has tried to appeal to the human side of his public in order to open the eyes of America to her own defects. He has been cynical, satirical, and humorous in his attempt to picture America as she really is. I have chosen the novels that Lewis has written since the year 1920 to show that he has satirized America in her various phases of life. I have not explored the fields of poetry and drama nor the earlier novels; for beginning with Main Street in 1920 and ending with the Prodigal Parents in 1938, Lewis has depicted the faults of a nation struggling for peace and security in a world of materialistic ideals.

This thesis describes investigations into the ability of isothioureas to act as organocatalysts in formal [4+2] cycloadditions between carboxylic acids and various Michael acceptors via C1-ammonium enolate intermediates. Initial research focused upon establishing optimal reaction conditions to affect the asymmetric intermolecular formal [4+2] cycloaddition between a range of arylacetic acids and α-keto-β,γ-unsaturated esters, giving anti-dihydropyranones in high yield (49-87%) and with excellent diastereo- and enantioselectivity (up to 98:2 dr, up to 99% ee). This represented the first time that carboxylic acid derived ammonium enolates have been successfully applied towards an intermolecular reaction process. Subsequent studies utilised trifluoromethyl enones as Michael acceptors, forming a range of C(6)-trifluoromethyl anti-dihydropyranones with good diastereoselectivity (up to 95:5 dr) and enantioselectivity (up to >99% ee). Detailed mechanistic studies were carried out, revealing that the process was stereospecific, with the diastereoisomer of product formed dependent upon the configuration of trifluoromethyl enone used. A variety of product derivatisations were demonstrated including those which introduce additional trifluoromethyl-bearing stereogenic centres with high diastereoselectivity. Kinetic studies indicated that this Michael addition-lactonisation process is first order with respect to both in situ formed anhydride and catalyst concentration, with a primary kinetic isotope effect observed using α,α-di-deuterio 4-fluorophenylacetic acid. DFT computational studies support a rate-determining formation of a reactive ammonium enolate prior to a stereochemistry-determining enone conjugate-addition step. The isothiourea-catalysed α-amination of carboxylic acids with low catalyst loadings (as low as 0.25 mol%) using N-aryl-N-aroyl Michael acceptors was demonstrated, forming a range of 1,3,4-oxadiazin-6(5H)-ones or hydrazide products with excellent enantiocontrol (typically >99% ee). Notably, the scope of this methodology was expanded to allow the direct functionalisation of carboxylic acids bearing α-heteroatom and alkyl substitution for the first time. The synthetic utility of the hydrazide products was demonstrated through their derivatisation into a range of bespoke functionalised N-aryl-α-arylglycine derivatives in high enantiopurity (up to 99% ee). Isothiourea-mediated functionalisation of 3-alkenoic acids was shown to occur regioselectively, giving products derived from α-functionalisation of an intermediate C1-ammonium dienolate in a range of formal [2+2] and [4+2] cycloadditions. Formal [4+2] cycloadditions with either trifluoromethyl enones of N-aryl-N-aroyl diazenes allow access to products in high diastereo- and enantiocontrol (up to 95:5 dr, up to 99% ee). The simple, two-step elaboration of stereodefined hydrazides into aza-sugar analogues without erosion of enantiopurity has also been demonstrated. 2-Arylacetic anhydrides were also demonstrated as useful precursors for the formation of C1-ammonium enolates in isothiourea-mediated Michael addition-lactonisation processes. Trifluoromethylenones,α-keto-β,γ-unsaturated esters and N-aryl-N-aroyldiazenes are reactive Michael accceptors in this process, with HBTM-2.1 (5 mol%) readily promoting heterocycle formation with high diastereo- and enantiocontrol (up to 95:5 dr, up to >99% ee). This protocol offered a useful and practical alternative to the in situ carboxylic acid activation method, in which by-product formation and the amount of sacrificial base used is minimised. DHPB was shown to promote the one-pot synthesis of 2,4,6-subsituted pyridines bearing a readily derivatised 2-sulfonate functionality from (phenylthio)acetic acid and a range of α,β-unsaturated ketimines in moderate yields (40-66%). Functionalisation of the 2-sulfonate group via various methodologies allowed the rapid assembly of both novel and biologically relevant pyridines.

Orientador: Mônica R. V. Amarante / Banca: Alexandrina Sartori / Banca: Paulo Eduardo Martins Ribolla / Banca: Katia Denise Saraiva Bresciani / Banca: Maria Elisabete Jorge Amaral / Resumo: No presente estudo foram analisadas a dinâmica da infecção primária por Strongyloides venezuelensis em ratos Lewis, a influência do sexo do hospedeiro e sua resposta imune. Também foi comparada a sensibilidade da PCR com as técnicas histológica e parasitológica na caracterização desta infecção utilizando amostras de tecidos e fezes, respectivamente. No primeiro artigo, o número de ovos por grama de fezes (OPG) foi determinado pela técnica de McMaster modificada e o DNA foi extraído para análise por PCR. Comparou-se a sensibilidade de ambos os métodos para o diagnóstico do parasita em fezes de ratos inoculados com 40, 400 e 4000 larvas infectantes (L3) e essas infecções foram consideradas leve, moderada e grave, respectivamente. Na PCR dois pares de primers foram empregados, um foi desenhado a partir da seqüência parcial de rDNA de S. venezuelensis e o outro, amplifica o rDNA de diversas espécies deste gênero. Nas amostras oriundas dos animais com infecção leve o primer específico não detectou DNA, já o primer gênero apresentou maior sensibilidade que a quantificação de OPG. No segundo artigo foi analisada a influência do sexo dos hospedeiros na suscetibilidade às infecções leve, moderada e pesada. Machos com infecção moderada e pesada apresentaram maior média de OPG e de número de parasitas recuperados do intestino delgado em comparação com as fêmeas, porém esse fenômeno não foi observado nas infecções leves. No terceiro artigo, os animais foram inoculados com 4000 L3 para a avaliação da dinâmica da infecção e caracterização da resposta imune durante as fases aguda e de recuperação. A dinâmica da infecção foi monitorada, diariamente, por OPG durante 32 dias. A infecção apresentou período pré-patente de seis dias e picos de eliminação de ovos no oitavo e no 11º dias. Ambos os anticorpos específicos IgG1 e IgG2b apresentar... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: In the present study the dynamics of Strongyloides venezuelensis primary infection in Lewis rats, the host sex influence and its immune response were analyzed. We also compared the sensitivity between PCR, parasitological and histological techniques to characterize this infection using feces and tissue samples. In the first paper the number of eggs per gram of feces (EPG) using a McMaster modified technique was enumerated and DNA was extracted to do PCR analysis. Sensitivity of both methods to diagnosis the parasite in feces of rats inoculated with 40, 400 or 4000 infective larvae (L3) was compared. These infections were considered light, moderate and heavy, respectively. Two PCR primer pairs were employed, a specific one was designed from a S. venezuelensis rDNA partial sequence and the other one amplifies several species within this genus. In light infection, the specific primer did not detect DNA in any sample, in the other hand the genus primer presented higher sensitivity than EPG. The host sex influence in susceptibility to light, moderate and heavy infection was evaluated in the second experiment. The FEC means and the mean parasite infection intensity were higher in males than in females in animals with moderate and heavy infection. But this phenomenon was not observed in light infection. In the third paper, animals were inoculated with 4000 L3 to determine the kinetics infection and to characterize the immune response during acute and recovery phases. The kinetics of infection was daily measured by FEC during 32 days after infection. Parasite eggs were detected in the feces for the first time at day 6 post-infection, but the maximal egg number was observed at days 8 and 11 post-infection. Both IgG1 and IgG2b specific antibodies were elevated at the acute phase and there was a significant increase of IgG1 concentration in the recovery one. IgE and IL-10 also presented a high... (Complete abstract click electronic access below) / Doutor