Thesis advisor: Lawrence T. Scott / Thesis advisor: James P. Morken / Expeditious establishment of molecular complexity in a stereoselective manner is a prominent goal in organic synthesis. In this regard, multicomponent coupling reactions have received substantial attention due to their ability to access complex molecules from simple starting materials in a single step. Chapter 1 is a comprehensive review on catalytic bismetallative multicomponent reactions. The scope of this process in terms of both bismetallic reagents and the pi components are broad enough to be generally applied to more elaborate synthetic sequences. Particularly, contemporary applications of the bismetallative multicomponent coupling reactions, in which high enantio- and/or diastereoselectivities are displayed, have enabled the study of this area to make a significant step forward. Chapter 2 presents nickel-catalyzed coupling reactions of aldehyde, diene, and a diboron reagent in the presence of a trialkyl phosphine ligand. Compared to borylation reactions with one pi-component, these borylative multicomponent reactions (involving two pi components) lead to formation of a new C-C bond between the pi components as well as generation of highly functionalized, stereodefined products. Chapter 3 describes a remarkable turnover in regioselectivity of the borylative multicomponent coupling when PCy3 is replaced with P(SiMe3)3. In particular, the products from the reactions with P(SiMe3)3 feature three contiguous stereocenters and an alpha-chiral allylboronate. The effect of P(SiMe3)3 ligand on the product selectivity is intriguing. According to the experimental and computational results, it has an ability to act as an electron acceptor, which will facilitate reductive elimination from the intermediate nickel complex during the course of the reaction. In Chapter 4, we show that borylative ketone-diene coupling reactions can be accomplished in high yields and with excellent levels of diastereocontrol. This reaction occurs in a predictable fashion, yet with regioselection that is distinct from related aldehyde-diene coupling reactions. The reaction products from these coupling processes, which possess tertiary alcohol functionality and an allylic alcohol moiety, are particularly well suited for the preparation of polyketide natural products. Chapter 5 presents investigations on bowl-shaped geodesic polyarenes, which are the missing links between the "classic" planar polycyclic aromatic hydrocarbons (PAHs) and the spheroidal fullerenes. The present study has shown that open geodesic polyarenes can feature chemistry inherent to both classes of aromatics. The curved pi system induces unequal environments on the two faces of circumtrindene, significant strain energy to the molecule, and non-identical bond lengths. Along with the electronic effects, the stereoelectronic effect enabled the site-selective functionalization with fullerene-type chemistry. On the other hand, the edge carbons, which are not present in fullerenes, still possess reactivity of common planar PAHs. Chapter 6 describes the intermolecular oxidative cyclotrimerization reactions of alkenes and aromatic compounds with DDQ and trifluoromethanesulfonic acid. The Scholl-type oxidation reactions involving alkenes have never been demonstrated. Moreover, the DDQ/acid system has never been used for the intermolecular oxidative cyclization reactions. This convenient non-metallic reagent system (DDQ/TfOH) is advantageous over the metal-based Scholl-type oxidants because it eliminates the possibility of halogenation of aromatic compounds and the reduced oxidant can be reoxidized. In Chapter 7, the regioselective formation of cyclic trimers from substituted benzenes and heteroaromatic compounds is demonstrated. This DDQ/TfOH method provides a simple and convenient synthetic route toward star-shaped oligomers containing triphenylene or isotruxene cores. Furthermore, the experimental outcome suggests that this oxidative process proceeds by an electron transfer mechanism. This is the first experimental evidence for mechanistic details on the Scholl-type oxidation. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Section 1 of this thesis contains an introduction to method development in organic synthesis, multicomponent reactions, sulfonyl azides, tracer development in 11C chemistry and the biological target. Section 2 describes the use of sulfonyl azides in carbonylative chemistry. Paper I covers development of a diazotransfer protocol. In total, 30 arylsulfonyl azides were synthesised from primary sulfonamides (20–90% yield). 15N mechanistic studies were carried out and in Paper II, the products were converted into sulfonamides, sulfonylureas and sulfonyl carbamates (19–90% yield). For ureas and carbamates, a two-chamber protocol was employed to release CO from Mo(CO)6. 15N mechanistic studies showed that the sulfonamides were formed by direct displacement of azide. Section 3 covers imaging and biological studies of the angiotensin II receptor subtype 2 (AT2R). In Paper III, 12 11C-sulfonyl carbamates were prepared in isolated radiochemical yields of 3–51% via Rh(I)-mediated carbonylation. The first non-peptide AT2R agonist, C21, was labelled (isolated RCY 24±10%, SA 34–51 GBq/µmol). C21 was tested in a prostate cancer assay, followed by biodistribution and small-animal PET studies. In Paper IV, a 11C-labelled AT2R ligand prepared via Pd(0)-mediated aminocarbonylation was used for autoradiography, biodistribution and small-animal PET studies.   Section 4 describes the development of a multicomponent method for the synthesis of 3,4-dihydroquinazolinones (Paper V). 31 3,4-dihydroquinazolinones were synthesized via a cyclic iminium ion.

Submitted by Willian Henrique dos Santos null (willian_santos@fc.unesp.br) on 2017-03-02T13:42:56Z No. of bitstreams: 1 DEFESA-24-02-2017.pdf: 11727986 bytes, checksum: 5e700d656e3faf3c665363a77b6371b2 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-03-08T12:53:39Z (GMT) No. of bitstreams: 1 santos_wh_dr_bauru.pdf: 11727986 bytes, checksum: 5e700d656e3faf3c665363a77b6371b2 (MD5) / Made available in DSpace on 2017-03-08T12:53:39Z (GMT). No. of bitstreams: 1 santos_wh_dr_bauru.pdf: 11727986 bytes, checksum: 5e700d656e3faf3c665363a77b6371b2 (MD5) Previous issue date: 2017-02-24 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A demanda por fontes de energias renováveis já é uma necessidade mundial, pois, o crescimento populacional e industrial trouxe concomitantemente um aumento no consumo de energia. Infelizmente, a matriz energética dos países que estão em pleno desenvolvimento se baseia na queima de combustíveis fósseis, o que traz sérios problemas ambientais e para a saúde da população. Tendo em vista esta necessidade, este trabalho retrata o estudo sobre o uso do pentacloreto de nióbio (NbCl5) como ácido de Lewis em reações multicomponentes para a síntese de compostos derivados de cumarinas e xantenos, compostos com potencial aplicação como corantes sensibilizadores em dispositivos fotovoltaicos. Os compostos de interesse foram obtidos através dos reagentes de partida: 4-hidróxicumarina, derivados fenólicos 3,5-dimetóxifenol e 3,4,5-trimetóxifenol, aldeídos aromáticos e 1,3-ciclo-hexanodiona. Foram estudadas as condições reacionais (% NbCl5, solvente utilizado e tempo reacional) para se estabelecer protocólos de síntese para a formação dos produtos de interesse na presença do pentacloreto de nióbio. O pentacloreto de nióbio demonstrou ser capaz de promover as reações estudadas neste trabalho. Esta nova possibilidade de obtenção destes compostos é de fundamental importância, pois, estes compostos possuem um leque muito amplo de aplicações, das quais algumas foram citadas neste trabalho. / The demand for renewable energy sources is already a worldwide need, because, the population and industrial growth concurrently brought an increase in energy consumption. Unfortunately, the energy matrix of the countries that are in full development is based on burning fossil fuels, which causes serious environmental problems and the health of the population. In view of this need, this work shows that the study about the use of niobium pentachloride (NbCl5) as Lewis acid in multicomponent reactions for the synthesis of coumarin and xanthene derivatives of compounds with potential application as sensitizing dyes in photovoltaic devices. These compounds were obtained from the starting materials: 4-hydroxycoumarin, phenolic derivatives (3,5-dimethoxyphenol and 3,4,5-trimethoxyfenol, aromatic aldehydes and 1,3-cyclohexanedione. The reaction conditions (% NbCl5, solvent and reaction time) to establish protocols synthesis for the formation of the products in the presence of niobium pentachloride were studied.Niobium pentachloride has been shown to be capable of promoting the reactions studied in this work. This new method of obtaining these compounds is of fundamental importance, considering that these compounds have a wide range of applications, some of which have been cited in this work.

Orientador: Rosangela da Silva de Laurentiz / Resumo: As lignanas apresentam grande variedade estrutural e diversidade de propriedades biológicas, desta forma ocupam um papel de destaque na busca por moléculas bioativas. A introdução de nitrogênio no esqueleto químicos de lignanas ariltetralínicas e arilnaftalênicas fornece compostos azo-heterocíclicos que contém o núcleo quinolínico e o anel lactônico e, portanto, são lactonas dihidroquinolinicas e quinolínicas. Essas estruturas podem ser potenciais alvos na pesquisa por novas moléculas para o desenvolvimento de fármacos para uma série de enfermidades. Desta forma, o objetivo deste trabalho foi sintetizar azo-análogos de lignanas ariltetralínicas, de estruturas conhecidas e inéditas, a fim de determinar suas propriedades leishmanicida, esquistossomicida, antimicrobiana e citotóxica contra células tumorais. A síntese dos azo-ariltetralinicos foi realizada a partir da reação multicomponente assistida por micro-ondas entre ácido tetrônico, anilinas substituídas e aldeídos aromáticos. O uso de reação multicomponente assistida por micro-ondas tem a finalidade a obtenção desses compostos de uma forma mais rápida e eficiente em relação às metodologias tradicionais de síntese. Foram obtidos 39 derivados azo-ariltetralínicos, pela variação dos substituintes dos aldeídos e anilinas, em rendimentos que variaram de 70 a 94%. Dentre os ensaios biológicos aos quais esses compostos foram submetidos, deve-se destacar a atividade leishmanicida e atividade antimicrobiana com valores de CI50, par... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Lignans have a great variety of structure and diversity of biological properties, thus they play a prominent role in the search for new bioactive molecules. The introduction of nitrogen into the chemical skeleton of aryltetralin and arylnaphthalene lignans provides azo-heterocyclic compounds containing the quinolinic nucleus and the lactonic ring and thus are dihydroquinolinic and quinolinic lactones. These structures may be potential targets in the search for novel molecules for the development of drugs for a range of diseases. Thus, the aim of this work was to synthesize azo-analogues of aryltetralin lignans of known and novel structures in order to determine their leishmanicidal, schistosomicidal, antimicrobial and cytotoxic properties against tumor cells. The synthesis of azo-aryltetralinics was carried out from the microwave-assisted multicomponent reaction between tetronic acid, substituted anilines and aromatic aldehydes. The use of microwave-assisted multicomponent reaction has the purpose of obtaining these compounds more quickly and efficiently than traditional synthetic methodologies. Thirty-nine azo-aryltetralin derivatives were obtained by varying the aldehyde and aniline substituents in yields ranging from 70 to 94%. Among the biological assays to which these compounds were submitted, the leishmanicidal activity and antimicrobial activity with IC50 values varying of 1.07-3.57 μg/mL and 12.5-100 μg/mL, respectively, for the most active compounds, should be highli... (Complete abstract click electronic access below) / Doutor

Submitted by Livia Mello (liviacmello@yahoo.com.br) on 2016-10-05T19:33:10Z No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-10-20T18:49:34Z (GMT) No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Approved for entry into archive by Marina Freitas (marinapf@ufscar.br) on 2016-10-20T18:49:39Z (GMT) No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) / Made available in DSpace on 2016-10-20T18:49:47Z (GMT). No. of bitstreams: 1 DissGSS.pdf: 4312480 bytes, checksum: 8eef058f121a266e5a7c67e3b4613506 (MD5) Previous issue date: 2014-11-28 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / The derivatization of organocatalysts with functional appendages suitable to anchor onto solid supports is usually achieved by stepwise syntheses. As an alternative to such a strategy, this work describes a one-pot approach to silylated prolyl-peptide catalysts by a multicomponent reaction that enables the simultaneous incorporation of the catalytic and the heterogenizable (triethoxysilane) moieties. A microreactor with high catalytic efficacy and reproducibly in the conjugate addition of aldehydes to nitroolefins was obtained by grafting onto HPLC-grade silica (10 μm) and packing into a column with a selected catalyst. A 3 D continuous-flow system that includes the on-line monitoring of the reaction outcome was set up. For that, the microreactor was coupled to a chromatographic column for the separation of the remaining substrates from the Michael adduct in the second dimension, followed by a chiral polysaccharide column for the analysis of conversion and stereoselectivity. This approach represents a new instrumental setup that combines the advantages of multidimensional chromatography and flow catalysis. / A derivação de Organocatalisadores com apêndices funcionais adequados para ancorar em suportes sólidos é geralmente obtida por síntese “passo a passo”. Como uma alternativa para tal estratégia, este trabalho descreve uma abordagem de síntese one-pot de catalisadores prolil-peptio sililados através de uma reação multicomponentes, que permite a incorporação simultânea do sítio catalítico e o grupo funcional de ancoragem (trietoxisilano). Um micro-reactor foi obtido, tendo elevada eficácia catalítica e reprodutibilidade, na adição conjugada de aldeídos a nitro-olefinas, enxertando sobre sílica de grau HPLC (10 um) e preenchendo uma coluna com um catalisador escolhido. Um sistema de fluxo contínuo 3D que inclui a monitoração em linha do resultado da reação foi ajustado para cima. Para isso, o micro-reator foi acoplado a uma coluna cromatográfica para a separação dos substratos restantes do aduto de Michael na segunda dimensão, seguido por uma coluna de polissacarídeo quiral para a análise de conversão e estereosselectividade. Essa abordagem representa uma nova configuração do instrumento que combina as vantagens de cromatografia multidimensional e reações catálisadas em fluxo.

Les travaux de cette thèse ont porté sur le développement de nouvelles méthodes de synthèse autour de la chimie des réactions multicomposants et des réactions de Tsuji-Trost des dérivés nitrés et phosphorylés. Dans le chapitre I, nous avons développé une nouvelle voie d’accès aux indoles propargyliques impliquant des adduits A3 et une réaction d’élimination d’amine en présence du 1,2-dibromoethane. Dans le chapitre II, nous avons démontré la possibilité d’exploiter des réactions de Tsuji-Trost par la formation de produits O-allylés issus des α-hydroxyphosphonates. La méthatèse cyclisante appliquée sur une gamme d’α-hydroxyphosphonates O-allylés a permis de synthétiser des phosphono-oxahétérocycles. Par ailleurs nous avons aussi démontré l’intérêt des α-hydroxyphosphonates du cinnamaldehyde pour des tandems Tsuji-Trost/ Claisen par la formation de dérivés d’acides α allylés. Dans le chapitre III, nous avons décrit un couplage entre les acides boroniques et les nitronates silylés pour aboutir à des oximes α, β insaturés. Par la suite nous avons convertis les oximes α,β-insaturés obtenus en isoxazoles par une cyclisation oxydante . Finalement dans le chapitre IV, nous avons poursuivi sur les réactions de Tsuji-Trost en mettant au point une synthèse de diènes à partir de dérivés nitrés allyliques. Cette réaction a été élargie à la synthèse des naphatlènes substitués en position 1. / The work of this thesis focused on the development of new synthesis methods around the chemistry of multicomponent reactions and Tsuji-Trost reactions of nitro and phosphorylated derivatives. In Chapter I, we developed a new pathway to propargylic indoles involving A3 adducts and an amine removal reaction in the presence of 1,2-dibromoethane. In Chapter II, we demonstrated the possibility of exploiting Tsuji-Trost reactions by the formation of O-allyl products from α-hydroxyphosphonates. The ring closing metathesis applied to a range of O-allylated α-hydroxyphosphonates allowed phosphono-oxaheterocycles to be synthesized. Furthermore, we also demonstrated the interest of α-hydroxyphosphonates from cinnamaldehyde for Tsuji-Trost / Claisen tandems by the formation of α-allylated acid derivatives. In Chapter III, we described a coupling between boronic acids and silylated nitronates to produce α, β-unsaturated oximes. Subsequently we converted the α, β-unsaturated oximes obtained in isoxazoles by an oxidizing cyclization. Finally, in Chapter IV, we continued the reactions of Tsuji-trost by developing a synthesis of dienes from allylic nitro derivatives. This reaction has been extended to the synthesis of naphatlene substituted at the 1-position.

No description available.

No description available.

<p dir="ltr">Cancer is the second leading cause of death worldwide, and there is a continued need for effective treatments to combat the disease. A key challenge in cancer therapy persists in the form of therapeutic resistance. While kinase inhibitors (KIs) have shown promise in treating cancer patients with dysregulated protein kinases, treatment failures are common, highlighting the urgent need to address this issue. Despite the approval of 80 protein kinase inhibitors by the United States Food and Drug Administration (FDA), and numerous others in clinical trials, the chemical space explored for protein kinase inhibitors remains limited. Most FDA-approved kinase inhibitors share common core moieties, such as indazole, quinoline, pyrazole, and pyrimidine, indicating a lack of diversification in drug development in this area.</p><p dir="ltr">Efforts to expand the chemical space have led to the identification of a novel 3<i>H</i>-pyrazolo-[4,3-<i>f</i>]quinoline core by the Sintim group. This scaffold can be efficiently synthesized through the Doebner–Povarov multicomponent reaction using readily available ketones, heteroaromatic aldehydes, and 5-aminoindazole. This multicomponent chemistry affords small molecules which inhibit disease-associated protein kinases with sub-nanomolar IC₅₀ values. Additionally, the scaffold presents a unique opportunity to tune for selectivity via judicious substitution patterns, allowing us to target numerous disease-driving kinases, such as FLT3, haspin, and CLK, with the use of simple multi-component chemistry.</p><p dir="ltr">From this work emerged lead amide-containing compound HSK205, which potently inhibits FLT3 and haspin and shows impressive potencies against FLT3-driven acute myeloid leukemia cell lines, with GI₅₀ values between 2 and 20 nM. Western blot analyses indicate that HSK205 inhibits the phosphorylation of FLT3 and histone H3 (substrate of haspin) in Molm-14 AML cells. Further exploration led to the discovery of lead CLK inhibitors, such as HSK1132 and HSK3110, which inhibit the growth of multiple myeloma cell lines <i>in vitro</i> with GI₅₀ values as low as 17 nM. Additionally, these compounds are orally bioavailable and reduce the growth of multiple myeloma RPMI-8226 xenograft model in mice by 69%.</p>

No capítulo 1 apresentamos uma síntese eficiente de compostos 5-organoteluro-1H- 1,2,3-triazóis realizada via reação de cicloadição [3+2] entre azidas orgânicas e alquinos substituídos com organotelúrio. Além disso, os 5-organoteluro-1H-1,2,3-triazóis foram funcionalizados na posição 5 do anel triazólico por reação de acoplamento cruzado de Sonogashira. A regioquímica dos produtos de cicloadição foram descritas com base em experimentos de RMN, cálculos teóricos e cristalografia de raio-x. Apresentamos uma proposta mecanística para a cicloadição mediada por cobre, baseada em experimentos de espectrometria de massas de alta resolução. No capítulo 2, investigamos a eficiência de reações one-pot com indol, cloreto de oxalila e diferentes nucleófilos para obtermos derivados do indol-3-glioxila em condições adequadas. Do mesmo modo, envolvendo a adição de azidas orgânicas, levando à síntese de indol-3-glioxil-1,2,3-triazóis, os produtos foram obtidos com rendimentos que variaram de 59 a 85%. / In chapter 1 we present an efficient synthesis of 5-organotelluro-1H-1,2,3-triazole compounds that was accomplished via the [3+2]-cycloaddition reaction of organoazides and organotelluro alkynes. Additionally, 5-organotelluro-1H-1,2,3-triazoles were readily functionalized at the 5-position via the Sonogashira cross-coupling reaction, leading to highly functionalised triazoles. The regiochemistry of the products was assessed by bidimensional NMR experiments, theoretical calculations and x-ray crystallography. We presented a mechanistic proposal for the cycloaddition mediated by copper, based on high resolution mass spectrometry experiments. In chapter 2 we investigated a general and efficient reaction of indole with oxalyl chloride and nucleophiles providing indole-3-glyoxyl derivatives which has been developed in mild conditions. In the same fashion, the other reaction involved the addition of organic azides leading to the synthesis of indole-3-glyoxyl-1,2,3-triazoles, which proceeds smoothly generating the products in moderate to high yields.