Les ligands bis(hémicages) représentent un motif structurel non exploité qui ont attiré notre attention. Ces ligands peuvent complexer jusqu'à deux analytes en même temps. Ceci permet d'obtenir une lecture luminescente en trois volets : une première étant le ligand sans analyte, puis deux signaux distincts pour le ligand + 1 analyte et le ligand + 2 analytes. Dans notre étude, nous avons inclus un [3.3.3](1,3,5)cyclophane comme architecture de base pour les bis(hémicages). Des calculs ont démontré que dans ces bis(hémicages)-cyclophane, le noyau cyclophane est directement impliqué dans le système électronique du ligand. La synthèse du noyau [3.3.3](1,3,5)cyclophane pose un grand défi de synthèse puisque peu d'exemples sont rapportés. Afin de moduler les défis, une étude modèle comportant la préparation d'une seule hémicage sera développée. Ces hémicages modèles seront utilisés afin d'optimiser la synthèse et seront des composés de référence importants pour les études électroniques et photophysiques.

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The electron rich and aromatic character of the indole group allows for a wide range of oxidative and substitution reactions, creating a versatile platform for generating structurally diverse molecules. This thesis explores enzyme and synthetic chemistries that act upon indoles and related molecules. Chapter 1 describes the results of in vivo studies of RebC, an enzyme that plays a pivotal role in the biosynthesis of the indolocarbazole alkaloid rebeccamycin. A homologous enzyme, StaC, exists in the biosynthetic pathway for staurosporine, a related indolocarbazole. Structural differences between the RebC and StaC active sites were hypothesized to play a pivotal role in determining the oxidation state in the corresponding natural products. Sequence alignment of RebC and StaC with homologous enzymes from related indolocarbazole biosynthetic pathways revealed six non-conserved residues in the active site. Three RebC variants were generated by replacement of all six, four, or two specific residues with their StaC counterparts. It was demonstrated that only two substitutions, F216V and R239N, are required to convert the specificity of RebC to that of StaC. Analysis of the structure of the RebC bound to a putative reaction intermediate supports the importance of F216 and R239 in catalysis. Based on these results, contrasting mechanisms for RebC and StaC are proposed to account for their differing specificities. Chapter 2 describes a synthetic approach to primarily heterocyclic analogues of lycogarubin C. Suzuki coupling of appropriately functionalized 3,4-dibromopyrrole or 3,4-bis(trifluoromethanesulfonyl)pyrrole was effective for numerous π-excessive five-membered heterocyclic-3-boronic acids. The optimized conditions were less effective for cross-couplings involving heteroaromatic-2-boronic acids, π-deficient heteroaromatic boronic acids, and heteroaromatic boropinacolate esters. Oxidative cyclization of the 3,4-bis(thiophen-3-yl)pyrrole and 3,4-bis(benzothiophen-3-yl)pyrrole to give analogues of the corresponding indolocarbazoles was demonstrated. Chapter 3 describes preliminary results on the development of regioselective C-5 and C-7 indole metalation tactics of indole-6-carboxamides, in order to provide new functionalized indoles. The use of an indole C-2 silicon protection strategy in combination with a sterically bulky C-6 N,N-di-isopropyl carboxamide directed metalation group overcame undesired side reactions observed with the analogous N,N-diethyl indole-6-carboxamide, affording the C-5 and C-7 substituted products in 40% and 13% yields, respectively. / Thesis (Ph.D, Chemistry) -- Queen's University, 2013-02-13 11:14:49.599

Square planar metal bis-dithiolenes are interesting targets for incorporation into electronic and optoelectronic devices as they characteristically display multiple stable redox states, coupled with strong absorption at particularly low energies. This work focuses on novel methods for the formation of thin films of metal bis-dithiolenes for incorporation into devices. The synthesis, structure and spectroscopic properties of a novel class of polymerisable heteroleptic nickel dithiolene complex, containing pendent thiophene units, [Ni(R2pipdt)(b-3ted)] are described [R = Bz (3a), iPr (3b); pipdt = piperazine- 3,2-dithione; b-3ted = bis-(3-thienyl)-1,2-ethylenedithiolene]. Electrooxidation of (3a) showed it to incorporate into a polymeric film over an electrode surface, which consisted of intact dithiolene units, by covalent linking of the pendent thienyl groups. This polymer film showed some redox activity, with the intense, low energy, absorption red-shifted by 4360 cm-1. Co-polymerisation of (3a) with thiophene yielded a highly conductive film, with the intense, low energy, absorption red-shifted to a lesser extent (3500 cm-1). The films displayed interesting optical properties, however, their use was restricted by their poor redox activity, thought to be due to poor ion transport through the films. The synthesis of two novel dithiolene ligand systems, containing pendent polymerisable indolyl groups (mi-5edt and mi-5hdt), are described, and their incorporation into complexes investigated for nickel [Ni(mi-5edt)2 (6) and Ni(mi-5hdt)2 (8)], and copper f[Cu(mi-5edt)2][TMA] ([7][TMA]) and [Cu(mi-5hdt)2][TMA] ([9][TMA])g investigated [(mi-5edt) = 1-(N-methylindol-5-yl)-ethane-1,2-dithiolate and (mi-5hdt) = 1- (N-methylindol-5-yl)-hex-1-ene-1,2-dithiolate, TMA = tetramethylammonium]. Each complex was characterised in terms of its structure, redox and optical properties, and the effect of the ligand design, and the metal centre, compared. The complexes of nickel were shown to yield polymer films under electrooxidative conditions, through covalent linking of the indolyl groups, with superior redox activity to 3a, and with an equally intense low energy absorption. The monoanionic complexes of copper were shown to deposit, under electrooxidative conditions, as neutral molecular films that were otherwise unobtainable by conventional solution techniques. The incorporation of the more soluble novel indolyl functionalised nickel dithiolene 8 into electronic devices was investigated. Electrochromic devices were formed using poly- 8 as the active layer. The devices were able to switch their optical absorption profile at 860 nm through three absorbing states by application of a suitable potential difference across the film. Field-effect transistors were fabricated using a molecular film of 8 as the active layer. The devices showed ambipolar charge transport properties, though with a bias for n-channel operation, with mobilities μ ≈ 1 x 10-4 cm2V-1s-1. Photovoltaic devices were formed from a blended film of 8 with P-3HT and with MDMO-PPV [P-3HT = regioregular poly-3-hexylthiophene, MDMO-PPV = poly(2-methoxy-5- (3',7'-dimethyloctyloxy)-1,4-phenylene-vynylene)]. 8 was shown to contribute to the photocurrent at wavelengths beyond the polymer component, thus harvesting more visible light, however efficiencies below 0.1 % suggested inefficient charge transport by 8 in the film. Structurally continuous films of Ni(b-3ted)2 (10) could be formed by a process of electrodeposition. The formed films displayed conductivities 40 times greater than for conventional solution cast films. By a detailed study of the level of residual ion doping, the molecular packing, and the morphology of the films, this improved performance was attributed to the formation of a more dense polycrystalline array, with larger crystallites, which formed good electronic contact with the electrodes, and with each other. This electrodeposition technique was used to fabricate field-effect transistors from 10. The devices showed poor mobilities (μ ≈ 1 x 10 -8 cm2V-1s-1), owing to the poor intermolecular overlap of the dithiolene units in the solid-state, but suggested this technique to be suitable for a wide range of semiconductors, with more favourable electronic properties, as an alternative to conventional vapour or solution deposition.

Six bis(silyl)acetylenes with the following varied silicon substituents were prepared: I (Me, Me); II (H, H); III (Cl, H); IV (Cl, Cl); V (OMe, H); VI (OMe, OMe). While I and II may be prepared by the reaction of dilithio- or bis(bromomagnesium)-acetylide with appropriate chlorosilane, similar reactions designed to give III - VI give oligomers, YMe_2Si(C≡C-SiMe_2)_nY, VII, Y = Cl, OMe, as the major products indicating that the acetylenic functionality on silicon activates the chlorosilane toward nucleophilic substitution. Compounds III and IV were prepared by free radical chlorination of II. Methanolysis of III and IV gave quantitative yields of V and VI, respectively. In the presence of mineral acid, VI readily cyclized to give high yields of the cyclic siloxane octamethyl-4,9-dioxa-3,5,8,10-tetrasila-cyclodeca-1,6-diyne, VIII, and the analogous triyne, IX. It was determined that V and VI could be prepared directly from II in high yield by methanolysis with palladium catalyst. Vaska's complex also accomplished the conversion. I attempted to prepare bis(ethoxydimethylsilyl)acetylene by using of Wilkinson 's catalyst for hydrosilylation with acetaldehyde. The principal product of this reaction was 1-(dimethylsilyl)-3,5,5-trimethyl-4-oxa-3-silacyclopent-1-ene, XI.

Thesis advisor: Thomas N. Seyfried / Thesis advisor: Charles Hoffman / Bis(monoacylglycero)phosphate, BMP, is a negatively charged glycerol-phospholipid with an unusual sn-1;sn-1’ structural configuration. BMP is primarily enriched in endosomal/lysosomal membranes. BMP is thought to play a role in glycosphingolipid degradation and cholesterol transport. It constitutes only about 1-2% of the total phospholipids in most mammalian cells, but is abundant in lung alveolar macrophages where it can comprise up to 16% of the total phospholipids. BMP also accumulates in tissues of humans and animals with lysosomal storage disorders. However, little information is available on BMP levels in gangliosidosis brain tissue. In this work, I found that total BMP content was significantly greater in cells of macrophage/microglial origin than in cells of macroglial origin (astrocyte, oligodendrocyte progenitor), whether normal or tumorigenic. I also observed that BMP in brain was significantly greater in humans and in animals (mice, cats, American black bears) with either GM1 or GM2 ganglioside storage diseases, than in brains of normal subjects. Since BMP is associated with macrophages, I also analyzed the BMP levels in relation to disease-associated inflammation in gangliosidoses. I found that BMP levels were increased due to accumulation of primary storage material gangliosides, rather than an outcome of disease-associated inflammation. In addition, in this thesis I also explored the effect of new ketogenic diet formula from Solace Nutrition (KetoGen) on the growth and metastatic spread of the VM-M3 tumor. Most current drug therapies for cancer are toxic and only marginally effective in providing long-term management. Respiratory insufficiency with compensatory aerobic fermentation (Warburg effect) is the hallmark biochemical phenotype of nearly all neoplastic cells within tumors. Calorie restriction, which lowers blood glucose and elevates ketone bodies, is known to reduce tumor growth to a certain extent, however it does not reduce systemic metastasis. Tumor bearing VM mice were fed either a standard lab chow diet in unrestricted amounts (SD-UR), a standard lab chow restricted to obtain an 18% reduction in body weight (SD-R), or the KetoGen diet restricted (KG-R) to match the body weights of the SD-R group. Tumor size was significantly smaller and organ metastasis was significantly less in the KG-R group than in the SD-UR or SD-R groups. Even though blood glucose was reduced similarly in both the SD-R and KG-R groups, blood ketones were 3-fold higher in the KG-R group than in the SD-R group. These results show that VM-M3 tumor growth and systemic metastasis were managed better with the restricted KetoGen KD than with calorie restriction of a high carbohydrate standard diet. As all human and mouse tumors cells suffer from respiratory insufficiency, my findings suggest that the restricted KetoGen diet should be an effective non-toxic therapy against tumor growth and systemic metastatic cancer. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

A doença de Alzheimer (DA) é uma doença neurodegenerativa que causa perda progressiva e irreversível das funções cerebrais, atualmente não tem cura e não existe um tratamento específico eficaz. Uma estratégia para o tratamento paliativo é restaurar o neurotransmissor acetilcolina utilizando fármacos inibidores das enzimas colinesterase (ChEI), nesse contexto a tacrina foi o primeiro fármaco aprovado para o tratamento da DA. Há mais de uma década os análogos dímeros da tacrina, conhecidos como bis-tacrina, mostraram maior eficiência na inibição da enzima acetilcolinesterase (AChE) comparativamente ao fármaco tacrina e seus análogos, devido à ação simultânea em dois sítios da enzima, catalítico e periférico. Desde então, vários compostos dímeros e híbridos contendo o núcleo tacrina tem sido sintetizados e testados como ChEI. Neste trabalho realizou-se a síntese de dímeros quirais do tipo bis-tacrina, onde dois núcleos da tacrina com substituintes quirais estão conectados por uma cadeia espaçadora de carbonos metilênicos. A reação de condensação de Friedlander foi a estratégia adotada para a obtenção do núcleo tacrina, onde uma ciclocetona quiral de origem terpênica foi condensada com um ácido o-aminobenzóico na presença de POCl3, formando os intermediários do tipo 9-cloroacridinas quirais. As ciclocetonas quirais foram sintetizadas a partir da reação de retro-aldol do monoterpeno natural pulegona, comercialmente disponível nas formas (R)-(+)- e (S)-(-). A preparação dos homodímeros envolveu a reação de substituição nucleofílica aromática (SNAr) entre as 9-cloroacridinas e a 1,7-heptanodiamina, que contém a cadeia alquílica espaçadora. A síntese dos heterodímeros necessitou a preparação dos precursores 9-(1,7-diaminoeptil)-1,2,3,4-tetraidroacridina, contendo o núcleo tacrina e o grupo amino separados pela cadeia espaçadora, para posterior reação de SNAr com as 9-cloroacridinas. Os produtos obtidos neste trabalho foram purificados por cromatografia em coluna e caracterizados por espectroscopia de ressonância magnética nuclear (RMN) de 1H e 13C, no infravermelho (IV), atividade óptica e medidas de ponto de fusão. As análises de atividade óptica mostraram que a quiralidade foi mantida nos intermediários e nos produtos finais sintetizados. Foram realizados ensaios biológicos de inibição das enzimas AChE e BuChE com os compostos quirais disponíveis, e os dímeros da série (R) mostraram ser ativos como inibidores das enzimas. / Alzheimer’s disease (AD) is a progressive neurodegenerative disorder which causes progressive and irreversible loss of brain functions and currently has no cure and no effective specific treatment. A strategy for palliative treatment of AD is the restoration of neurotransmitter acetylcholine using drugs cholinesterase inhibitors (ChEI) and tacrine was the first drug approved for the treatment of AD. About fifteen years ago, bis(n)-tacrine analogues linked by an alkylene chain were prepared, and it was proved that these dimeric molecules of tacrine offered a much stronger potency and selectivity toward AChE. Bis(7)-tacrine simultaneously binds at both the CAS and the PAS sites and provides a higher selectivity towards AChE over BuChE.. Since then, several dimmers and hybrid compounds containing the nucleus tacrine, have been synthesized and tested as cholinesterase inhibitors. In this work were carried out the syntheses of chiral homodimers and heterodimers of bis-tacrine type, where two nucleus of tacrine with chiral substituents were connected by an alkyl chain as spacer. The Friedländer condensation reaction was performed to obtain the tacrine nucleus, the cycloketone from a chiral terpene source was condensed with an o-aminobenzoic acid in the presence of POCl3, forming 9-chloroacridine intermediates. The chiral cycloketone were obtained from natural monoterpene pulegone, commercially available in (R)-(+)- and (S)-(-) enantiomers. The preparation of homodimers involved the nucleophilic aromatic substitution (SNAr) reaction between 9-chloroacridines and 1,7-diaminoheptane, which contains the spacer alkyl chain. The synthesis of heterodimers required the preparation of precursor 9-(1,7-diaminoheptyl)-1,2,3,4-tetraydroacridine, containing tacrine nucleus and the amino group separated by spacer chain, for subsequent SNAr reaction with the 9-chloroacridines. The products obtained in this work were purified by column chromatography and characterized by nuclear magnetic resonance (NMR) spectroscopy of 1H and 13C, infrared spectroscopy (IR), optical activity and melting point measurements. The analysis of optical activity showed that the chirality was maintained in the intermediate and final products synthesized. Biological assays of inhibition of AChE and BuChE enzymes were performed with chiral compounds. The dimers of (R)-series were active as cholinesterase inhibitors.

Nature provides fascinating and complicated molecular structures which offer synthetic organic chemists amazing opportunities for the design of new strategies for natural product synthesis. Among these, nitrogen containing aza-heterocycles are of unparalleled importance in natural product, bioorganic, and medicinal chemistry. Pyridine and its derivatives in particular are the most common aza-heterocycles encountered in natural products, medicinal and materials chemistry. Pyridine derivatives also serve as precursors to functionalized piperidines, which are likewise common structural motifs in bioactive and functionalized materials. Thus, developing synthetic methods suitable for the manipulation of pyridine ring systems remains an important objective in synthetic organic chemistry. The functionalization of pyridine derivatives via manipulation at the benzylic position has been investigated. First, the nucleophilicity of the benzylic position of the 4-alkyl pyridine substrates was used to engage in Brønsted acid-catalyzed aldol-like cyclizations with attached carbonyl electrophiles. These conditions afforded substituted pyridines with functionalized lactams. These substrates underwent an unusual dehydration/oxidation reaction when treated with thionyl chloride. In a similar study, 1,2-dialkylimidazoles afforded nucleophilic 2-alkylidene imidazolines upon treatment with an electrophilic activating group such as Boc2O. Positioning a ketone electrophile with in an N1-alkyl side chain results in cyclization at the imidazole 2-position to afford fused ring imidazoles through an aldol-like cyclization reaction. The stereoselective synthesis of a tricyclic analogue of the bis(piperidine) alkaloid xestoproxamine C was also investigated. Dearomatization of a tricyclic pyridine derivative afforded an alkylidene dihydropyridine (anhydrobase) intermediate which was subjected to catalytic heterogeneous hydrogenation to install the correct relative stereochemistry about the bis(piperidine) ring system. Other key features of these model studies included development of an efficient ring-closing metathesis procedure to prepare macrocyclic derivatives of 3,4-disusbstituted pyridines, intramolecular cyclizations of alkylidene dihydropyridines to establish pyridine-substituted pyrrolidines and piperidines, successful homologation of pyridine-4-carboxaldehydes using formaldehyde dimethyl thioacetal monoxide (FAMSO), and application of B-alkyl Suzuki coupling to assemble substituted pyridines. Lastly, a study was done to assess the feasibility of synthesizing one of the two chiral precursors needed for the asymmetric synthesis of xestoproxamine C via enzyme catalyzed transesterification of symmetric 1,3-diols. This resulted in successful transesterification of a symmetric 1,3-diol substrate with high enantioselectivity.

The design, effectiveness and versatility of the self-assembled monolayer-immobilized aza-bis(oxazoline) catalysts was explored here. The first part of this dissertation focuses on the immobilization of aza-bis(oxazoline) ligand with three different C2 groups onto self-assembled monolayer support material. In the homogeneous phase, the more steric bulk present at the C2 position of the catalytic system, the greater the selectivity. In the heterogeneous systems, those with the least amount of steric bulk had the greatest increase in selectivity compared to their respective homogeneous phase. The supports not only allowed for selectivity enhancements not observed in the homogeneous phase, but also demonstrated the effectiveness of this support material in the cyclopropanation reaction. <br>Self-assembled monolayer supports allowed for modification of the surface steric environment around the catalytic site. This was accomplished by varying the length of the background alkenethiol chains so that three steric environments were created. The three steric environments were the catalyst above the monolayer surface, level with the monolayer surface, and below the monolayer surface. Modification of the steric environment around the catalyst, in turn allows for control of the selectivity of the heterogeneous catalytic system. <br>Modification of the surface electronic environment around the catalytic site is accomplished by modification of alkanethiol tail groups. The five background tail groups investigated were hydroxyl, bromide, carboxylic acid, methyl ester, and nitrile. Modification of the background tail groups allows for control of the enantioselectivity in the cyclopropanation reaction. <br>Self-assembled monolayer supports also allow for the generation of effective reusable heterogeneous catalytic systems. One of the main positive aspects of heterogeneous catalysis is the ability to recycle the catalytic system multiple times without major reduction in selectivity. The duration of these heterogeneous aza-bis(oxazoline) systems is dependent on the stability of the gold substrate layer and the reaction solvent. <br>The last section of this dissertation focuses on the versatility of the aza-bis(oxazoline) copper complex immobilized onto self-assembled monolayers. The homogeneous and heterogeneous catalysts were investigated in the carbonyl-ene reaction of ethyl glyoxylate and á-methylstyrene. The three heterogeneous catalytic systems were the carboxylic acid surface, hydroxyl surface, and the catalyst above the methyl monolayer surface. / Bayer School of Natural and Environmental Sciences / Chemistry and Biochemistry / PhD / Dissertation

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