No description available.

Phytosterols are major components of food and are structurally related to cholesterol, but differ from it by virtue of a carbon substituent at the C-24 position and in some cases, a double bond between C-22 and C-23 (Figure i). Furthermore, phytosterols are shown to have protective actions against colon, breast, and prostate cancer1; further investigation is required as their mode of action is unknown. Thus, reported herein is the design and synthetic implementation required to construct these naturally occurring compounds. Figure i : Cholesterol Construction towards a double bond flanked by two asymmetric carbon atoms, observed in the phytosterol side chain, will be synthesised using an asymmetric Horner-Wittig (H-W) reaction, involving a chiral α-substituted aldehyde and a chiral β-substituted phosphine oxide. In addition to the synthesis, the stereochemical outcomes of these H-W reactions were probed. The results demonstrated, that by varying the steric bulk, electronic nature, and aromatic properties of the groups β to the phosphorus and α to the aldehyde can control the cis/trans selectivity in alkene formation. Finally, to display the utility of this methodology, the phytosterol compounds will be synthesised and tested in MD-MBA-231 cancer cell lines, allowing further investigation into the phytosterol mechanism of action.

Alcaloides indolizidínicos, quinolizidínicos e piperidínicos poliidroxilados representam classes de compostos amplamente investigados atualmente. Este fato se deve às pronunciadas atividades biológicas como inibidores de glicosidases expressadas por estes heterociclos, o que significa um grande atrativo para que muitos grupos de pesquisas desenvolvam metodologias sintéticas para a sua obtenção de forma efetiva e em poucas etapas. Neste trabalho de dissertação é apresentada uma rota sintética para a preparação de alcaloides indolizidínicos e quinolizidínicos diidroxilados a partir de diazocetonas α,β-insaturadas. A estratégia para a síntese destes alcaloides baseia-se na mesma metodologia, tendo como etapas chaves: uma reação de olefinação de Horner-Wadsworth-Emmons (HWE) a partir de aminoaldeídos, seguida de um Rearranjo de Wolff. Como material de partida para o esqueleto indolizidínico foi empregado o Cbz-S-prolinal. Este aminoaldeído foi empregado como fonte do centro estereogênico e de um dos anéis presentes na estrutura final. O acoplamento (reação de HWE) entre o Cbz-S-prolinal e um diazofosfonato recentemente descrito por nosso grupo de pesquisa forneceu um composto diazocarbonílico α,β-insaturado (67%), que em seguida, foi submetido a um rearranjo de Wolff fornecendo um éster β,γ-insaturado (96%). Este intermediário avançado foi funcionalizado através de uma reação de diidroxilação, a qual forneceu uma lactona (66%). A síntese foi completada através de uma reação de ciclização intramolecular (94%) seguida de uma reação de redução para fornecer a indolizidina diidroxilada em 71% de rendimento. Para o esqueleto quinolizidínico, foi empregado o aminoaldeído racêmico Cbz-(±)-pipecolinal como material de partida. A partir da reação de olefinação, foi obtida uma diazocetona α,β-insaturada (91%), que após Rearranjo de Wolff (95%), diidroxilação (75%), ciclização (54-74%) e reação de redução (87-90%), forneceu duas novas quinolizidinas diidroxiladas. Estes alcaloides indolizidínicos e quinolizidínicos poderão ser avaliados como inibidores de glicosidases. / Polyhydroxylated Indolizidine, quinolizidine and piperidine alkaloids represent classes of compounds widely investigated in the chemical community. This fact is due to their pronounced biological activities as glycosidase inhibitors. Considering that, many research groups have been developing new synthetic methodologies to obtain these alkaloids and analogs effectively and in few steps. This work presents a synthetic route for the preparation of dihydroxylated indolizidine and quinolizidine alkaloids from α,β-unsaturated diazoketones. The strategy for the synthesis of these compounds is based on the same methodology to construct the indolizidine and quinolizidine skeleton. The key steps involve a Horner-Wadsworth-Emmons (HWE) olefination reaction from aminoaldehydes, followed by a Wolff Rearrangement. As the starting material to construct the indolizidine skeleton, Cbz-S-prolinal was employed. This aminoaldehyde is also the source of the stereogenic center and one of the rings present in the final structure. The coupling reaction (HWE reaction) between Cbz-S-prolinal and a diazophosphonate (methodology recently described by our research group) has provided an α,β-unsaturated diazoketone in 67% yield. This compound was then subjected to a Wolff Rearrangement, providing a β,γ-unsaturated ester in 96% yield. This advanced intermediate was functionalized through a high selective dihydroxylation reaction, furnishing a hydroxylated lactone in 66% yield. The synthesis was then completed employing an intramolecular cyclization reaction (94% yield), followed by lactam reduction to provide the dihydroxylated indolizidine (1,6-dideoxyepicastanospermine) in 71% yield. For the construction of the quinolizidine skeleton, was employed racemic Cbz-pipecolinal as the starting material. From the olefination reaction, the corresponding α,β-unsaturated diazoketone was obtained in 91% yield. After a Wolff Rearrangement (95%), dihydroxylation reaction (75%), cyclization (54-74%) and lactam reduction (87-90%), two novel dihydroxylated quinolizidines could be synthesized. These indolizidine and quinolizidine alkaloids may be evaluated as new inhibitors of glycosidases.

Alcaloides indolizidínicos, quinolizidínicos e piperidínicos poliidroxilados representam classes de compostos amplamente investigados atualmente. Este fato se deve às pronunciadas atividades biológicas como inibidores de glicosidases expressadas por estes heterociclos, o que significa um grande atrativo para que muitos grupos de pesquisas desenvolvam metodologias sintéticas para a sua obtenção de forma efetiva e em poucas etapas. Neste trabalho de dissertação é apresentada uma rota sintética para a preparação de alcaloides indolizidínicos e quinolizidínicos diidroxilados a partir de diazocetonas α,β-insaturadas. A estratégia para a síntese destes alcaloides baseia-se na mesma metodologia, tendo como etapas chaves: uma reação de olefinação de Horner-Wadsworth-Emmons (HWE) a partir de aminoaldeídos, seguida de um Rearranjo de Wolff. Como material de partida para o esqueleto indolizidínico foi empregado o Cbz-S-prolinal. Este aminoaldeído foi empregado como fonte do centro estereogênico e de um dos anéis presentes na estrutura final. O acoplamento (reação de HWE) entre o Cbz-S-prolinal e um diazofosfonato recentemente descrito por nosso grupo de pesquisa forneceu um composto diazocarbonílico α,β-insaturado (67%), que em seguida, foi submetido a um rearranjo de Wolff fornecendo um éster β,γ-insaturado (96%). Este intermediário avançado foi funcionalizado através de uma reação de diidroxilação, a qual forneceu uma lactona (66%). A síntese foi completada através de uma reação de ciclização intramolecular (94%) seguida de uma reação de redução para fornecer a indolizidina diidroxilada em 71% de rendimento. Para o esqueleto quinolizidínico, foi empregado o aminoaldeído racêmico Cbz-(±)-pipecolinal como material de partida. A partir da reação de olefinação, foi obtida uma diazocetona α,β-insaturada (91%), que após Rearranjo de Wolff (95%), diidroxilação (75%), ciclização (54-74%) e reação de redução (87-90%), forneceu duas novas quinolizidinas diidroxiladas. Estes alcaloides indolizidínicos e quinolizidínicos poderão ser avaliados como inibidores de glicosidases. / Polyhydroxylated Indolizidine, quinolizidine and piperidine alkaloids represent classes of compounds widely investigated in the chemical community. This fact is due to their pronounced biological activities as glycosidase inhibitors. Considering that, many research groups have been developing new synthetic methodologies to obtain these alkaloids and analogs effectively and in few steps. This work presents a synthetic route for the preparation of dihydroxylated indolizidine and quinolizidine alkaloids from α,β-unsaturated diazoketones. The strategy for the synthesis of these compounds is based on the same methodology to construct the indolizidine and quinolizidine skeleton. The key steps involve a Horner-Wadsworth-Emmons (HWE) olefination reaction from aminoaldehydes, followed by a Wolff Rearrangement. As the starting material to construct the indolizidine skeleton, Cbz-S-prolinal was employed. This aminoaldehyde is also the source of the stereogenic center and one of the rings present in the final structure. The coupling reaction (HWE reaction) between Cbz-S-prolinal and a diazophosphonate (methodology recently described by our research group) has provided an α,β-unsaturated diazoketone in 67% yield. This compound was then subjected to a Wolff Rearrangement, providing a β,γ-unsaturated ester in 96% yield. This advanced intermediate was functionalized through a high selective dihydroxylation reaction, furnishing a hydroxylated lactone in 66% yield. The synthesis was then completed employing an intramolecular cyclization reaction (94% yield), followed by lactam reduction to provide the dihydroxylated indolizidine (1,6-dideoxyepicastanospermine) in 71% yield. For the construction of the quinolizidine skeleton, was employed racemic Cbz-pipecolinal as the starting material. From the olefination reaction, the corresponding α,β-unsaturated diazoketone was obtained in 91% yield. After a Wolff Rearrangement (95%), dihydroxylation reaction (75%), cyclization (54-74%) and lactam reduction (87-90%), two novel dihydroxylated quinolizidines could be synthesized. These indolizidine and quinolizidine alkaloids may be evaluated as new inhibitors of glycosidases.

<p>In some applications polynomials should be evaluated, e.g., polynomial approximation of elementary function and Farrow filter for arbitrary re-sampling. For polynomial evaluation Horner’s scheme uses the minimum amount of hardware resources, but it is sequential. Many algorithms were developed to introduce parallelism in polynomial evaluation. This parallelism is achieved at the cost of hardware, but ensures evaluation in less time.</p><p>This work examines the trade-off between hardware cost and the critical path for different level of parallelism for polynomial evaluation. The trade-offs in generating powers in polynomial evaluation using different building blocks(squarers and multipliers) are also discussed. Wordlength requirements of the polynomial evaluation and the effect of power generating schemes on the timing of operations is also discussed. The area requirements are calculated by using Design Analyzer from Synopsys (tool for logic synthesis) and the GLPK (GNU Linear Programming Kit) is used to calculate the bit requirements.</p>

Fast development in all areas of life and science over the last 50 years demands versatile, energy efficient and cheap materials with specific but easily tuneable properties which can be used for example in organic light emitting diodes (OLEDs), thin-film transistors, photovoltaic cells, etc. This thesis is devoted to the development of novel synthetic approaches to molecules with potential applications in the field of molecular electronics.  The acquisition of a detailed mechanistic understanding of the newly developed reactions is central to the work presented in this thesis. The first chapter is dedicated to the development of a new procedure for the preparation of phospha-Wittig-Horner (pWH) reagents, i.e. a reagents that has been known to convert carbonyl compounds into compounds with P=C double bonds. Each step of the synthetic sequence, i.e. preparation of the starting P,P-dichlorophosphines, their phosphorylation using the Michaelis-Arbuzov protocol, coordination to the metal centre and final hydrolysis, are presented in detail. A possible route to uncoordinated pWH reagents is also discussed. The second chapter focuses on the reactivity of the pWH reagents with acetone under different reaction conditions. The results show how changes in the ratio of starting material vs. base as well as reaction time or structure of the pWH reagent can influence the reaction outcome and the stability of the obtained products. The possibility to prepare unusual phosphaalkenes with unsaturated P-substituents is presented. The third chapter of the thesis is dedicated to the reactivity of pWH reagents towards symmetric and asymmetric ketones which contain one or two acetylene units. The proposed mechanisms of the reactions are studied by means of in situ FTIR spectroscopy as well as theoretical calculations. Physical-chemical properties of oxaphospholes, cumulenes and bisphospholes are presented. The last chapter is dedicated to reactivity studies of pWH reagents towards ketenes, and the exploration of a reliable route to 1-phosphaallenes. Detailed mechanistic studies of the pWH reaction that are based on the isolation and crystallographic characterization of unique reaction intermediates are presented. The reactivity of phosphaallenes towards nucleophiles such as water and methanol are examined. In summary, this thesis presents synthetic routes to novel phosphorus-containing molecules, together with detailed studies of the reaction mechanisms of the observed transformations.

In some applications polynomials should be evaluated, e.g., polynomial approximation of elementary function and Farrow filter for arbitrary re-sampling. For polynomial evaluation Horner’s scheme uses the minimum amount of hardware resources, but it is sequential. Many algorithms were developed to introduce parallelism in polynomial evaluation. This parallelism is achieved at the cost of hardware, but ensures evaluation in less time. This work examines the trade-off between hardware cost and the critical path for different level of parallelism for polynomial evaluation. The trade-offs in generating powers in polynomial evaluation using different building blocks(squarers and multipliers) are also discussed. Wordlength requirements of the polynomial evaluation and the effect of power generating schemes on the timing of operations is also discussed. The area requirements are calculated by using Design Analyzer from Synopsys (tool for logic synthesis) and the GLPK (GNU Linear Programming Kit) is used to calculate the bit requirements.

Phytosterols are major components of food and are structurally related to cholesterol, but differ from it by virtue of a carbon substituent at the C-24 position and in some cases, a double bond between C-22 and C-23 (Figure i). Furthermore, phytosterols are shown to have protective actions against colon, breast, and prostate cancer1; further investigation is required as their mode of action is unknown. Thus, reported herein is the design and synthetic implementation required to construct these naturally occurring compounds. Figure i : Cholesterol Construction towards a double bond flanked by two asymmetric carbon atoms, observed in the phytosterol side chain, will be synthesised using an asymmetric Horner-Wittig (H-W) reaction, involving a chiral α-substituted aldehyde and a chiral β-substituted phosphine oxide. In addition to the synthesis, the stereochemical outcomes of these H-W reactions were probed. The results demonstrated, that by varying the steric bulk, electronic nature, and aromatic properties of the groups β to the phosphorus and α to the aldehyde can control the cis/trans selectivity in alkene formation. Finally, to display the utility of this methodology, the phytosterol compounds will be synthesised and tested in MD-MBA-231 cancer cell lines, allowing further investigation into the phytosterol mechanism of action.

Orientador: Luiz Carlos Dias / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-07T11:46:58Z (GMT). No. of bitstreams: 1 Castro_IltonBarrosDaltrode_M.pdf: 2931991 bytes, checksum: c8a53e4f8a0a6d154ec91cd575ee9936 (MD5) Previous issue date: 2005 / Resumo: A migrastatina é um policetídeo que foi isolado da cultura de Streptomyces sp. MK929-43F1 em 2000 por Imoto e colaboradores e, posteriormente, isolado também da cultura de Streptomyces platensis NRRL 18993 por pesquisadores da Kosan Biosciences. Migrastatina apresenta um extraordinário efeito inibitório na migração de células tumorais, importantíssimo para o tratamento de metástese tumoral. Sua estereoquímica relativa e a configuração absoluta foram determinadas por análise cristalográfica de raios-X de um derivado. Migrastatina é uma macrolactona de 14 membros com uma cadeia lateral contendo anel de glutarimida. A molécula contém 5 centros estereogênicos e 3 ligações duplas. Nesse trabalho descreveremos uma rota sintética viavél para obtenção do fragmento C1-C13 da migrastatina. As etapas chaves para construção do fragmento C1- C13 são: a esterificação do ácido carboxílico 65 (fragmento C1-C6) com o álcool alílico 66 (fragmento C8-C13) e a reação de Nozaki-Hiyama-Kishi intramolecular. Os fragmentos foram construídos utilizando principalmente reações aldol syn seletiva e reações de Horner-Wadsworth-Emmons, além da utilização adequada de grupos protetores / Abstract: Migrastatin was isolated from a cultured broth of Streptomyces sp. MK929-43F1 in 2000 by Imoto and co-workers, as well as from a cultured broth of Streptomyces platensis NRRL 18993 by researchers from Kosan Biosciences. Migrastatin has a remarkable inhibitory effect on the migration of human tumor cells, very important to the tumor metastasis treatment. Its relative stereochemistry and absolute configurations were determined by X-ray analysis of a derivative. Migrastatin is a 14-membered lactone with a glutarimide side chain, 5 stereogenic centers and 3 double bonds. We wish to describe here an approach to the C1-C13 fragment of migrastatin. The key steps for the construction of the C1-C13 fragment of migrastatin are: a syn-aldol reaction to set up the C9 and C10 stereogenic centers, followed by a (Z)-seletive Horner-Wadsworth-Emmons reaction and esterification of carboxilic acid 65 (fragment C1-C6) with allylic alcohol 66 (fragment C8-C13) / Mestrado / Quimica Organica / Mestre em Química

No description available.