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Benzylic fluorides are attractive target molecules for medicinal chemistry, agrochemicals and materials chemistry. The enantioselective synthesis of benzylic fluorides is challenging and few general methods exist. This thesis describes several approaches to the synthesis of benzylic fluoride targets, including enantioselective processes. Chapter 1: Reviews the properties, uses and synthetic approaches to fluorinated molecules, with a particular focus on benzylic fluorides and enantioselective syntheses. Chapter 2: Describes the fluorination cyclisation of prochiral indole precursors. The use of catalytic amounts of a bis-cinchona alkaloid gave good enantioselectivities for the cyclisation. Alcohol, tosylamine, amide and carbamate pendant nucleophiles all cyclised successfully to give quaternary benzylic fluorides in moderate yields and with enantioselectivities up to 92%. The substrate scope of the reaction is described, as well as methodology for deprotection of cyclised nitrogen nucleophiles. Chapter 3: Details an investigation of the Pd catalysed substitution of polycyclic benzylic fluorides by a range of nucleophiles and their relative reactivity in comparison to oxygen leaving groups. Modification of the methodology to enable reaction of monocyclic substrate substitution was enabled by the use of a protic solvent. Chemoselective reaction conditions were identified for selective reaction of Bn-F or Ar-Cl bonds and comparative reactivity studies were undertaken. The feasibility of Pd(0)/(II) catalysed nucleophilic C-F bond formation was examined. Chapter 4: The development of the defluorination methodology from Chapter 3 for secondary substrates is described. The stereochemical course of defluorination was probed, showing that displacement of fluoride is mechanistically similar to that of oxygen leaving groups. A kinetic resolution with a low selectivity was developed for access to enantioenriched benzylic fluorides.

Made available in DSpace on 2015-07-22T20:50:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-11-25 / O melanoma é a forma mais agressiva de câncer de pele em virtude do elevado grau de proliferação, invasão e metástase das células tumorais. Menos de 10% dos pacientes com melanoma metastático sobrevivem por 5 anos. Quimioterapias com um único composto são bem toleradas, mas associadas a baixas taxas de resposta terapêutica. Associações de quimioterápicos já aprovados para uso humano também foram relacionadas a baixas taxas de resposta, sem redução da toxicidade. Logo, a identificação de novos agentes antitumorais é crítica para o tratamento do melanoma, e este trabalho buscou avaliar a atividade antitumoral de novos quimioterápicos derivados de paládio e rutênio no modelo pré-clínico de melanoma murino B16F10-Nex2. Um composto ciclopaladado, [Pd2(S(-)C2, N-dmpa)2 (μ-dppe)Cl2], denominado C7A, avaliado anteriormente pelo nosso grupo, demonstrou elevada atividade antitumoral e baixa toxicidade in vivo, porém, seu mecanismo de ação ainda não estava determinado. Neste trabalho demonstramos que este composto interage com grupos tiol presentes em proteínas da membrana mitocondrial, induzindo uma abrupta redução na acidificação extracelular, colapso do potencial de membrana mitocondrial e translocação da proteína Bax para o interior dessa organela. Evidenciamos também um aumento nas concentrações intracelulares de cálcio, proveniente de organelas celulares e do meio extracelular. Estes efeitos iniciais causaram ativação de caspases efetoras, condensação nuclear, degradação do DNA e dramáticas alterações morfológicas nessas células. Esses dados sugerem que C7A provoca uma morte celular por apoptose induzindo a via intrínseca em células de melanoma murino B16F10-Nex2. Observou-se que células tumorais humanas são sensíveis ao C7A, e o mecanismo de ação do composto nessas células parece ser idêntico ao observado em células murinas. O ciclopaladado 7A reduziu significativamente o número de nódulos pulmonares sem toxicidade aparente, indicando sua eficiência também contra tumores metastáticos. A atividade antitumoral de diversos compostos nitrosil-tetraamina-rutênio (trans-[RuII(NH3)4(L)NO+], onde L corresponde a diferentes ligantes de estabilização, e que são doadores de óxido nítrico (NO) em meios biológicos foi avaliada. Todos os compostos testados foram citotóxicos in vitro para células tumorais murinas e humanas. Alguns compostos foram selecionados e avaliados in vivo, mostrando uma elevada toxicidade em paralelo a uma atividade antitumoral. No entanto, observou-se que os compostos onde o NO havia sido substituído por um radical sulfato, utilizados como controles dos compostos doadores de NO, apresentaram elevada atividade antitumoral e baixa toxicidade in vivo, retardando o desenvolvimento do tumor subcutâneo e prolongando a sobrevida dos animais tratados. Os compostos sulfatados também apresentaram baixa toxicidade ao reduzir o número de nódulos metastáticos dos animais tratados. Esses compostos também foram citotóxicos in vitro para células tumorais humanas, e as alterações morfológicas, externalização de fosfatidilserina, condensação nuclear e degradação de DNA observados sugerem que os compostos tetraamina rutênio sulfatados levam a célula tumoral à morte por apoptose. Ambos os quimioterápicos testados abrem novas possibilidades para o tratamento do melanoma maligno. / Melanoma is the most aggressive form of skin cancer mainly because of the high degree of tumor cell proliferation, invasion and metastasis. Less than 10% of metastatic melanoma patients show 5 years survival. Single drug chemotherapy is well tolerated but associated with low response rates. Associations of chemotherapeutic agents approved for human use are related to low response rates, without improvement on side effects. Therefore, the identification of new antitumor agents is critical to melanoma treatment, and this study aimed to evaluate the antitumor effect of novel palladium and rutheniun derived chemotherapeutic drugs in the preclinical model of murine melanoma B16F10-Nex2. A cyclopalladated compound, [Pd2(S(-)C2, N-dmpa)2 (μ-dppe)Cl2], named C7A was previously evaluated by our group. The complex showed high antitumor and low toxicity in vivo, however, the targets for this compound in tumor cells were not determined yet. In this work we demonstrated that C7A interacts with thiol proteins present in the mitochondrial membrane, leading to an abrupt reduction of extracellular acidification, collapse of mitochondrial membrane potential and Bax translocation to the interior of this organelle. It was also observed an increase in intracellular calcium concentrations, originated from cellular organelles as well as from extracellular medium. These initial effects caused activation of effector caspases, nuclear condensation, DNA degradation and dramatic morphological changes in these cells. All these data suggests that the cyclopalladated 7A induces the intrinsic pathway apoptotic cell death on B16F10-Nex2 murine melanoma cells. Human tumor cells are sensitive to this compound and mitochondria also seem to be the target for C7A on these cells. Cyclopalladated 7A significantly reduced the number of pulmonary nodules with no apparent toxicity, indicating that this compound is also active against metastatic melanoma lesions. Antitumor activity of several nitrosyl tetraammine ruthenium compounds with general formula (trans-[RuII(NH3)4(L)NO+], where L corresponds to different stabilization ligands, were evaluated. These compounds are nitric oxide (NO) donors in biological media. All tested compounds were cytotoxic in vitro to human and murine tumor cells. Some compounds were selected and evaluated in vivo, showing numerous side effects in association with the antitumor effect. However, it was found that the compounds where the NO was replaced by a sulfate group, used regularly as a negative control for NO-donor ruthenium complexes, showed a pronounced antitumor activity and low toxicity in vivo, delaying subcutaneous tumor development and extending survival of treated animals. Sulfate compounds also reduced the number of metastatic lung nodules with no apparent toxicity. These compounds were also cytotoxic for human tumor cells in vitro, and the morphological alterations, phosphatidylserine externalization, nuclear condensation and DNA degradation observed after cell treatment suggested that sulfate tetraamine compounds induced an apoptotic cell death. Both evaluated chemotherapeutic drugs open new possibilities for malignant melanoma treatment. / TEDE / BV UNIFESP: Teses e dissertações