In efforts to search for tool compounds that are capable of probing normal and disease-associated biological processes, both quality and identity of the screening collection are very important. Towards this goal, diversity-oriented synthesis (DOS) has been explored for a decade, which aims to populate the chemical space with diverse sets of small molecules distinct from the traditional ones obtained via combinatorial chemistry. In the practice of DOS, macrocyclic ring-closing metathesis (RCM) reactions have been widely used. However, the prediction and control of stereoselectivity of the reaction is often challenging; chemical transformation of the olefin moiety within the product is in general limited. Chapter I of this thesis describes a methodology that addresses both problems simultaneously and thus extends the utility of the RCM reactions. By installing a silyl group at the internal position of one of the olefin termini, the RCM reaction could proceed with high stereoselectivity to afford the (E)-alkenylsiloxane regardless of the intrinsic selectivity of the substrate. The resulting alkenylsiloxane can be transformed to a variety of functionalities in a regiospecific fashion. The conversion of the (E)-alkenylsiloxanes to alkenyl bromides could proceed with inversion of stereochemistry for some substrates allowing the selective access of both the E- and Z-trisubstituted macrocyclic alkenes. It was also found that the silyl group could trap the desired mono-cyclized product by suppressing nonproductive pathways. Chapter II of this thesis describes the application of the concept of DOS in the area of fragment-based drug discovery. Most fragment libraries used to date have been limited to aromatic heterocycles with an underrepresentation of chiral, enantiopure, \(sp^3\)-rich compounds. In order to create a more diverse fragment collection, the build/couple/pair algorithm was adopted. Starting from proline derivatives, a series of bicyclic compounds were obtained with complete sets of stereoisomers and high \(sp^3\) ratio. Efforts are also described toward the generation of diverse fragments using methodology described in Chapter I. The glycogen synthase kinase \((GSK3\beta)\) was selected as the proof-of-concept target for screening the DOS fragments. / Chemistry and Chemical Biology

Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Doctor of Education / This case study looks at the impact of closing an urban secondary school. It considers the experiences of the students, the staff and the parents. It does not argue with the decision to close the school but concentrates on the experience for those most closely involved. The thesis is guided by the main research question which is: “What is the impact of school closure on the various elements of a school community and is there a way to close a school and minimise this impact?” Supplementary questions seek to describe how the closure was undertaken and what factors can be identified which helped ease the transition for those involved. While seeking to develop theory grounded in the research the findings have also been informed by theory associated with grief, place attachment, emotion in the workplace and change. Unpublished primary documents such as transcripts of group interviews, responses to written questionnaires and minutes of meetings are the basic sources of data for this thesis. The researcher was an active participant in the closure and well known to all respondents. The thesis concludes that although keeping the school open for the final year was of benefit to the morale and adjustment of staff it was probably less beneficial for the students involved. It suggests that with proper counselling support and identification of the closure as a critical incident, a quick closure would help student learning outcomes and prevent teacher de-skilling. It also confirms the importance of a school, or probably any institution, in the emotional life of those associated with it. Note: The students in this study range in age from 13 to 18 years of age in Years 7 through to 12.

O objetivo dessa dissertação é compreender como se dá a relação do trabalhador com atual contexto de acumulação capitalista em situações extremas como a de demissão iminente. Trata-se de um estudo de caso que tem como objeto uma multinacional do setor automotivo que encerrou suas atividades no Rio Grande do Sul em 2016. Objetivou-se discutir sobre como as relações de trabalho e a organização do trabalho foram historicamente construídas e aperfeiçoadas, de forma a tornar a exploração cada vez menos visível para os trabalhadores. Isso possibilita a exploração e consequentemente perpetua e maximiza a acumulação do capital. A análise das entrevistas, triangulada com notícias vinculadas na mídia, dados fornecidos pela empresa e boletins do sindicato, amparados na teoria sugerem que nesta era de financeirização e desterritorialização, alguns mecanismos facilitam a legitimação da exploração. São eles: o discurso do trabalho, a cooptação da subjetividade dos trabalhadores e a falácia da empregabilidade. À medida que a precarização do trabalho se propaga de formas cada vez mais complexas, potencializam-se também as contradições do capital e o trabalhador é colocado cada vez mais sob tensão. Percebe-se que a organização se apropria da subjetividade dos trabalhadores por meio de diferentes mecanismos de gestão e controle. Isso fragiliza os laços sociais, o que tem consequências nas formas de organização coletiva e mecanismos de resistência dos trabalhadores. Posteriormente, apresenta-se a questão da empregabilidade como uma falácia, em que cada vez mais o trabalhador vê-se responsável pelo seu próprio destino, bem como também pelo destino da empresa. Consequente a isso, percebe-se um sentimento de auto-culpabilização e responsabilização excessiva. Finaliza-se analisando os processos de resistência ao fechamento da fábrica. Verifica-se que o trabalhador já não tem mais amparo do seu sindicato, que se encontra enfraquecido politicamente. Outras formas de resistência coletiva articulada também não foram percebidas. Porém, algumas formas individualizadas de resistência foram encontradas, tais como o absenteísmo, boicote ao trabalho e até pequenas sabotagens. Conclui-se que as atuais formas de acumulação de capital, que se valem da desterritorialização, da financeirização e de mecanismos de legitimação da exploração, tornam a situação do trabalhador cada vez mais frágil. O caso da NX ilustra como a abstração do capital e as formas de controle cada vez mais sutis intensificam a precarização do trabalho e diminuem as possibilidades de resistência frente ao capital. As portas fecham porque no processo de reprodução capitalista a lógica das organizações é contribuir para o acúmulo de capital. A medida que essa lógica não atender mais à ética do capital - o lucro, a estratégia passa a ser o fechamento e a transferência para locais com menores custos. / The purpose of this dissertation is to understand how the relation of the worker with the current context of capitalist accumulation takes place in extreme situations like the one of imminent mass dismissal. It is a case study that has, as its object, an automotive multinational factory. Such factory closed its doors in Rio Grande do Sul in April 2016. It starts from this object to discuss how labor relations and the organization of work have historically been built and improved in order to make exploitation less visible to workers. Such invisibility enables exploitation and consequently perpetuates and maximizes the accumulation of capital. The analysis of the interviews triangulated with news in the media, data provided by the company and union bulletins, suggest that in this era of financialization and de-territorialization, some mechanisms enable the legitimation of exploitation. These are: the importance of work for the workers, the co-optation of workers’ subjectivity, and the fallacy of employability. As the precarization of work disseminate more and more, the contradictions of the capital are also potentiated and the worker is increasingly placed under tension. It is perceived that the organization appropriates itself from the subjectivity of workers through different management and control mechanisms. This weakens the social ties, which has consequences in the collective forms of organization and in the mechanisms of resistance of the workers. Subsequently, the issue of employability is presented as a fallacy, in which the worker is increasingly responsible for his own destiny, as well as for the fate of the company. As a result, there is a feeling of self-blame and excessive accountability over the worker. It ends by analyzing the processes of resistance before the closure of the factory. It was verified that the worker is no longer supported by his union, which is politically weakened. Other forms of organized resistance were not noticed. However, some individualized forms of resistance have been found, such as absenteeism, boycotting work and even minor sabotages. We conclude that the current forms of accumulation of capital, which use deterritorialization, financialization and mechanisms to legitimize exploitation, make the situation of the worker increasingly fragile. The doors close because in the process of capitalist reproduction the logic of organizations is to contribute to the accumulation of capital. As this logic no longer meets the ethics of capital - the profit, the strategy becomes closing or transfer to places with lower costs.

O objetivo dessa dissertação é compreender como se dá a relação do trabalhador com atual contexto de acumulação capitalista em situações extremas como a de demissão iminente. Trata-se de um estudo de caso que tem como objeto uma multinacional do setor automotivo que encerrou suas atividades no Rio Grande do Sul em 2016. Objetivou-se discutir sobre como as relações de trabalho e a organização do trabalho foram historicamente construídas e aperfeiçoadas, de forma a tornar a exploração cada vez menos visível para os trabalhadores. Isso possibilita a exploração e consequentemente perpetua e maximiza a acumulação do capital. A análise das entrevistas, triangulada com notícias vinculadas na mídia, dados fornecidos pela empresa e boletins do sindicato, amparados na teoria sugerem que nesta era de financeirização e desterritorialização, alguns mecanismos facilitam a legitimação da exploração. São eles: o discurso do trabalho, a cooptação da subjetividade dos trabalhadores e a falácia da empregabilidade. À medida que a precarização do trabalho se propaga de formas cada vez mais complexas, potencializam-se também as contradições do capital e o trabalhador é colocado cada vez mais sob tensão. Percebe-se que a organização se apropria da subjetividade dos trabalhadores por meio de diferentes mecanismos de gestão e controle. Isso fragiliza os laços sociais, o que tem consequências nas formas de organização coletiva e mecanismos de resistência dos trabalhadores. Posteriormente, apresenta-se a questão da empregabilidade como uma falácia, em que cada vez mais o trabalhador vê-se responsável pelo seu próprio destino, bem como também pelo destino da empresa. Consequente a isso, percebe-se um sentimento de auto-culpabilização e responsabilização excessiva. Finaliza-se analisando os processos de resistência ao fechamento da fábrica. Verifica-se que o trabalhador já não tem mais amparo do seu sindicato, que se encontra enfraquecido politicamente. Outras formas de resistência coletiva articulada também não foram percebidas. Porém, algumas formas individualizadas de resistência foram encontradas, tais como o absenteísmo, boicote ao trabalho e até pequenas sabotagens. Conclui-se que as atuais formas de acumulação de capital, que se valem da desterritorialização, da financeirização e de mecanismos de legitimação da exploração, tornam a situação do trabalhador cada vez mais frágil. O caso da NX ilustra como a abstração do capital e as formas de controle cada vez mais sutis intensificam a precarização do trabalho e diminuem as possibilidades de resistência frente ao capital. As portas fecham porque no processo de reprodução capitalista a lógica das organizações é contribuir para o acúmulo de capital. A medida que essa lógica não atender mais à ética do capital - o lucro, a estratégia passa a ser o fechamento e a transferência para locais com menores custos. / The purpose of this dissertation is to understand how the relation of the worker with the current context of capitalist accumulation takes place in extreme situations like the one of imminent mass dismissal. It is a case study that has, as its object, an automotive multinational factory. Such factory closed its doors in Rio Grande do Sul in April 2016. It starts from this object to discuss how labor relations and the organization of work have historically been built and improved in order to make exploitation less visible to workers. Such invisibility enables exploitation and consequently perpetuates and maximizes the accumulation of capital. The analysis of the interviews triangulated with news in the media, data provided by the company and union bulletins, suggest that in this era of financialization and de-territorialization, some mechanisms enable the legitimation of exploitation. These are: the importance of work for the workers, the co-optation of workers’ subjectivity, and the fallacy of employability. As the precarization of work disseminate more and more, the contradictions of the capital are also potentiated and the worker is increasingly placed under tension. It is perceived that the organization appropriates itself from the subjectivity of workers through different management and control mechanisms. This weakens the social ties, which has consequences in the collective forms of organization and in the mechanisms of resistance of the workers. Subsequently, the issue of employability is presented as a fallacy, in which the worker is increasingly responsible for his own destiny, as well as for the fate of the company. As a result, there is a feeling of self-blame and excessive accountability over the worker. It ends by analyzing the processes of resistance before the closure of the factory. It was verified that the worker is no longer supported by his union, which is politically weakened. Other forms of organized resistance were not noticed. However, some individualized forms of resistance have been found, such as absenteeism, boycotting work and even minor sabotages. We conclude that the current forms of accumulation of capital, which use deterritorialization, financialization and mechanisms to legitimize exploitation, make the situation of the worker increasingly fragile. The doors close because in the process of capitalist reproduction the logic of organizations is to contribute to the accumulation of capital. As this logic no longer meets the ethics of capital - the profit, the strategy becomes closing or transfer to places with lower costs.

O trabalho apresenta uma metodologia para a simulação de abertura e fechamento de trinca, durante o processo de propagação, utilizando um programa comercial de elementos finitos. Este programa é utilizado para determinar os fatores de intensidade de tensão de abertura e fechamento de trinca. É apresentado o modelo de Newman que serve de embasamento para o desenvolvimento da metodologia de liberação de nós na carga mínima, utilizada no trabalho para a propagação da trinca. São avaliados quatro tipos de corpos de prova SE-(B) (corpo de prova de três pontos de apoio submetido a flexão), SE-(T)(corpo de prova com trinca lateral submetido a tração), M-(T) (corpo de prova com trinca central submetido a tração) de uma liga de alumínio Al 2024-T351 e um aço bifásico ( ferrita + martensita). Um corpo de prova do tipo C-(T) (corpo de prova compacto submetido a tração) de aço bifásico também foi avaliado. Os corpos de prova SE-(B), SE-(T) e M-(T) da liga de alumínio Al 2024-T351 foram submetidos a carregamentos de amplitude constante, com razões de carga R = 0 e R = 0,5. Os resultados das análises são comparados com resultados do código FASTRAN, principal código numérico utilizado para simular abertura e fechamento de trinca por plasticidade induzida, através de uma normalização dos fatores de intensidade de tensão máxima e de abertura da trinca. Os resultados numéricos com o corpo de prova C-(T) submetido a carregamento de amplitude constante, com razão de carga R = 0,1 foram comparados com resultados de ensaio, objetivando validar o fator de intensidade de fechamento de trinca obtido através da análise numérica. Essa comparação é feita através de normalização numérica e experimental do fator de intensidade de tensão de fechamento de trinca com o fator de intensidade de tensão máxima. A metodologia de simulação de propagação de trincas, já aplicada na industria aeronáutica, pode ser aplicada em outras áreas como, por exemplo, na indústria automotiva, uma vez que o consumidor está cada vez mais exigente e o desenvolvimento de novos critérios de projeto se faz necessário. / The work introduces a methodology to simulate fatigue crack opening and closing during crack propagation, using a commercial finite element code. This code is used to determine the crack opening and closure stress intensity factors. The Newman model is used as a baseline to develop the methodology. The nodes are released at the minimum load, during the crack propagation process. Four kinds of specimens SE-(T) ( Single Edge Tension), SE-(B) ( Single Edge Bending), M-(T) ( Middle Tension) of the an aluminum alloy Al–2024-T351 and a dual phase steel (ferrite + martensite) were evaluated. A compact tension specimen C-(T) of a dual phase steel was evaluated. The aluminum alloy specimens, SE -(T), SE-(B) and M-(T), were evaluated under constant amplitude loading with load ratios R = 0 and R = 0.5. The results of these analyses are compared with the results of FASTRAN, principal numerical code used to simulate crack opening and closing plasticity induced by, normalizing the opening stress intensity factor. The numerical results from a C-(T) specimen, under constant amplitude loading and a load ratio R = 0.1, were compared with results from a test performed in the laboratory. The numerical and experimental closure stress intensity factors are normalized with the maximum stress intensity factor. Crack closure simulations are currently used in the aircraft industry. They are now being incorporated in same automotive and other ground vehicle fatigue analysis procedures.

O trabalho apresenta também um estudo de confiabilidade e estabelece uma faixa de valores para o esforço de fechamento de portas baseado na variação de algumas componentes chaves no cálculo. A curva característica que é um dos parâmetros de saída do modelo apresenta forma extremamente próxima da medição realizada em laboratório. No Brasil, a indústria automotiva é conhecida por sua grande influência e peso na economia do país, assim como em diversos outros países. O conjunto porta na concepção do veículo é de extrema importância, visto que é região do veículo com que o consumidor trava contato primeiro. Um valor de esforço elevado para realizar a abertura e fechamento das mesmas pode levar a uma imagem indesejada pela montadora do veículo. O valor do esforço necessário para fechar a porta é um item de extrema importância, pois além de influenciar a imagem do veículo e da marca, é um item do pacote de conforto e ergonomia do veículo. O evento fechamento da porta parte do instante em que a porta está na condição aberta e seus componentes se encontram em descanso. O evento é modelado matematicamente e em planilha dinâmica admitindo como parâmetros de entrada dados específicos do veículo e seus componentes, como saída têm-se o valor da energia de fechamento de portas e a parcela de cada componente envolvido. São apresentados resultados experimentais para que o modelo seja considerado válido. Com a conclusão do modelo é possível estimar a queda de energia em função da vida de alguns componentes como a fechadura e o pacote de guarnições, bem como a influência do uso de sobreinjetados autolubrificantes na fechadura. Este trabalho contribui com os profissionais de Engenharia de Produto nas áreas de Carroceria, Mecanismos e Partes Móveis com a elaboração de uma ferramenta de cálculo para uso em qualquer fase de projeto, principalmente para estimar o valor da energia de fechamento de porta no momento de sua conceituação e até na validação de veículos protótipo. / The Brazilian automotive industry is known by its great influence on the country economy, similar to several other countries. It is important to highlight the door assembly importance on the vehicle concept, as it is the first contact made to the customer. The vehicle ingress is through the side access area, established by the doors and a high door closing effort may lead to a wrong impression. The door closing effort or also known as door closing energy is an extreme importance asset, as well as influencing the image of the vehicle and the brand, it is an item of ergonomics and vehicle comfort. The automotive door closing event starts at the moment door is open and pushed to close itself. This event is math modeled and implemented as an excel dynamic calculation plan, considering as input the vehicle and components specific data, its output is the door closing effort and each components portion. It is presented a series of values so the model is considered valid. This work also presents a reliability study defining a range of experimental values for the door closing effort based on tolerances of components used in the model calculations. The characteristic curve which is one of the parameters of the model output is extremely close to the measurement performed in the laboratory. With the completion of the model is possible to estimate the energy loss due to the life of certain components such as latches and weatherstrips, and the influence of using self-lubricating over molding in the latch. This study contributes to the Product Engineering professionals in the areas of Body, Mechanisms and Body Closures, with the elaboration of a calculation tool for use in any design phase, but mostly serving to estimate the door closing effort at the moment of conception until the validation of prototype vehicles.

Orientador: Luiz Carlos Dias / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-13T21:30:59Z (GMT). No. of bitstreams: 1 Finelli_FernandaGadini_D.pdf: 6560101 bytes, checksum: 5eb9e7f25248bb940dd29d8af3e505ed (MD5) Previous issue date: 2009 / Resumo: O capítulo 1 relata as sínteses da macrolactona da migrastatina 11 e da macrolactona análoga 62a. A macrolactona da migrastatina é o composto que apresenta a maior atividade de inibição de migração de células tumorais in vitro dentre os compostos da família da migrastatina até hoje sintetizados. A macrolactona 62a, ainda inédita na literatura, é epímero em C8 da macrolactona 62b sintetizada pelo grupo do Professor Danishefsky em 2004 e apresenta atividade de inibição semelhante à macrolactona 11. Além disso, foram realizados estudos visando à síntese da macrolactona 124, epímero da macrolactona 11. Paralelamente, em colaboração com a Farmoquímica Cristália e o grupo do Professor Adriano Andricopulo, do IF/USP de São Carlos, foram realizados testes de avaliação biológica de diversos compostos sintetizados neste trabalho com o intuito de gerar novas substâncias químicas bioativas candidatas a novos fármacos no tratamento do câncer de mama. O capítulo 2 relata a síntese e aplicação de alguns substratos contendo grupos funcionais que ainda não haviam sido testados frente à reação de metátese de alcinos utilizando um novo catalisador de molibdênio. Este projeto foi desenvolvido no laboratório do Professor Alois Fürstner, no Instituto Max-Planck, em Mülheim an der Ruhr ¿ Alemanha. Além disso, um precursor do fragmento B das Latrunculinas A e B foi sintetizado em grande escala, fornecendo material para subsequentes estudos químicos e biológicos / Abstract: Chapter 1 describes the syntheses of macrolactones 11 and 62a. Macrolactone 11 presents the best tumor cell migration inhibitory effect among the compounds of the migrastatin family synthesized so far. Macrolactone 62a, not described in the literature, is the C8-epimer of macrolactone 62b, which was synthesized by Professor Danishefsky¿s group in 2004 and shows similar antitumor activities when compared to macrolactone 11. Studies aiming at the synthesis of macrolactone 124, epimer of macrolactone 11, were also performed. Besides, in collaboration with Farmoquímica Cristália and Professor Andricopulo¿s group (IF/USP, São Carlos), biological assays of several compounds synthesized in this work were carried out, with the purpose of developing new bioactive chemical substances which may soon be employed in the manufacturing of novel drugs in the treatment of breast cancer.Chapter 2 describes the syntheses of new substrates for applications in Mo-catalyzed RCAM. This project was carried out in Professor Fürstner¿s laboratory, at Max-Planck Institute, in Mülheim an der Ruhr ¿ Germany. In this part of the work, a Latrunculin A and B fragment precursor was also synthesized in large scale to provide further material for new biological and chemical studies / Doutorado / Quimica Organica / Doutor em Ciências

Ring closing metathesis (RCM) is a chemical transformation that converts a bisalkene compound into a cycloalkene. It is catalyzed by transition metal complexes containing carbene ligands (that feature metal-carbon double bonds). The mechanism is well-understood, however, there are numerous details of the reaction that are less well understood, especially concerning catalyst activation and decomposition and formation of byproducts. This thesis takes a new approach to the study of RCM: analysis of the reaction using real-time mass spectrometric techniques. Electrospray ionization (ESI) mass spectrometry was employed in this study, and the real-time aspect was enabled by using pressurized sample infusion (PSI). Observation of the reactants and products was enabled using charge-tagged bis-alkenes of the general formula [Bu2N{(CH2)nCH=CH2}2]+ [PF6]–. These were synthesized in two steps using a generally applicable methodology to generate a wide range of ring sizes of the product, from 5- to 15-membered rings. Examination of their behavior under carefully optimized RCM conditions using Grubbs’ second-generation catalyst showed a wide variation in reaction rates and amount of byproducts, largely due to ring-strain effects (especially high for 5- and 9-membered rings). Byproducts always exhibited a 14 Da mass unit difference from starting materials or products, and Orbitrap MS analysis confirmed it was CH2. Isomerization was suspected to lead to byproducts. A pathway for byproducts via isomerization and cross metathesis was proposed. The source of actual isomerization catalyst was believed to be from the precatalyst itself as the evidence of precatalyst decomposition was observed. Finally, to prove our isomerization hypothesis, an authentic isomerization catalyst was deliberately added into a fast and clean reaction along with Grubbs’ second-generation catalyst, and it produced the expected byproducts. Only small amounts of oligomeric intermediates were observed, probably because of the low concentrations used. [ClPCy3]+ was a new short-lived decomposition product stemming from catalyst breakdown, along with already-known imidazolium and protonated phosphine decomposition products. Overall, the thesis provides deep new insights into the nature of RCM reactions, in particular revealing the importance of isomerization in RCM reactions that are slow due to ring strain effects and in uncovering a new decomposition pathway for important RCM catalysts. / Graduate

The relatively new concept of ambidextrous leadership in innovation with the opposing yet complementary opening and closing leader behaviors has been proven to be positively related to fostering explorative and exploitative behaviors respectively among subordinates. The initiators of this concept propose that leaders in innovation need a ‘temporal flexibility to switch’ between opening and closing leader behaviors, which implies a sequential alignment of these behaviors. This proposition has yet remained theoretically and empirically unexplored and is initially questioned in this thesis with respect to related theoretical concepts. Therefore, this thesis aims to explain how innovation leaders align the recently defined opening and closing leader behaviors throughout the innovation process. By following a qualitative and inductive research approach, a multiple case study of five innovation leaders in German manufacturing companies was conducted. The data were collected through in-depth semi-structured interviews. The empirical data reveal that the initiators’ proposition of a sequential alignment is not sufficient to explain the complex alignment of opening and closing leader behaviors. Accordingly, a model which illustrates a predominantly simultaneous alignment of the two leader behaviors was developed. However, this model also considers that urgent situations or specific project phases and times of the year require innovation leaders to sequentially demonstrate one behavior at a time.