<p>Compounds labelled with ¹¹C (<i>β</i>⁺, t_1/2 = 20.4 min) are used in positron emission tomography (PET), which is a quantitative non-invasive molecular imaging technique. It utilizes computerized reconstruction methods to produce time-resolved images of the radioactivity distribution in living subjects. </p><p>The feasibility of preparing [¹¹C]methyl iodide from [¹¹C]methane and iodine via a single pass through a non-thermal plasma reactor was explored. [¹¹C]Methyl iodide with a specific radioactivity of 412 ± 32 GBq/µmol was obtained in 13 ± 3% decay-corrected radiochemical yield within 6 min via catalytic hydrogenation of [¹¹C]carbon dioxide (24 GBq) and subsequent iodination, induced by electron impact. </p><p>Labelled ethyl-, propyl- and butyl iodide was synthesized, within 15 min, via palladium-mediated carbonylation using [¹¹C]carbon monoxide. The carbonylation products, labelled carboxylic acids, esters and aldehydes, were reduced to their corresponding alcohols and converted to alkyl iodides. [1-¹¹C]Ethyl iodide was obtained via palladium-mediated carbonylation of methyl iodide with a decay-corrected radiochemical yield of 55 ± 5%. [1-¹¹C]Propyl iodide and [1-¹¹C]butyl iodide were synthesized via the hydroformylation of ethene and propene with decay-corrected radiochemical yields of 58 ± 4% and 34 ± 2%, respectively. [1-¹¹C]Ethyl iodide was obtained with a specific radioactivity of 84 GBq/mmol from 10 GBq of [¹¹C]carbon monoxide. [1-¹¹C]Propyl iodide was synthesized with a specific radioactivity of 270 GBq/mmol from 12 GBq and [1-¹¹C]butyl iodide with 146 GBq/mmol from 8 GBq. </p><p>Palladium-mediated hydroxycarbonylation of acetylene was used in the synthesis of [1-¹¹C]acrylic acid. The labelled carboxylic acid was converted to its acid chloride and subsequently treated with amine to yield <i>N-</i>[<i>carbonyl</i>-¹¹C]benzylacrylamide. In an alternative method, [<i>carbonyl</i>-¹¹C]acrylamides were synthesized in decay-corrected radiochemical yields up to 81% via palladium-mediated carbonylative cross-coupling of vinyl halides and amines. Starting from 10 ± 0.5 GBq of [¹¹C]carbon monoxide, <i>N-</i>[<i>carbonyl</i>-¹¹C]benzylacrylamide was obtained in 4 min with a specific radioactivity of 330 ± 4 GBq/µmol. </p>

Alcoholic steatosis (AS) is the initial pathology associated with early stage alcoholic liver disease and is characterized by the accumulation of fat in the liver. AS is considered clinically benign as it is reversible, as compared with alcoholic steatohepatitis (ASH) which is the next stage of alcoholic liver disease (ALD), and mostly irreversible. Proteomics were used to investigate the molecular basis of AS to determine biomarkers representative of AS. Liver tissue proteins at different stages of steatosis from a rodent model of AS were separated by two dimensional electrophoresis (2DE), followed by MALDI mass spectrometry (MS) identification of significantly expressed proteins. Expression levels of several proteins related to alcohol induced oxidative stress, such as peroxiredoxin 6 (PRDX6) and aldehyde dehydrogenase 2 (ALDH2) were reduced by 2 to 3-fold in ethanol fed rats, and suggested an increase in oxidative stress. Several proteins involved in fatty acid and amino acid metabolism were found at increased expression levels, suggesting higher energy demand upon chronic exposure to ethanol. In order to delineate between the effects of fat accumulation and oxidative stress, an in vitro hepatocyte cell culture model of steatosis was developed. HepG2 cells loaded with oleic acid surprisingly demonstrated lower cytotoxicity upon oxidative challenge (based on lactate dehydrogenase activity) and inflammation (based on TNF-? induced activation of the pro-inflammatory transcription factor NF-?B). We also examined the effect of oleic acid loading in HepG2 cells on protein carbonylation, which is an important irreversible protein modification during oxidative stress that leads to protein dysfunction and disease. Fat-loaded hepatocytes exposed to oxidative stress with tert-butyl hydroperoxide (TBHP) contained 17% less carbonylated proteins than the non-fat loaded control. Mass spectrometric analysis of carbonylated proteins indicated that known classical markers of protein carbonylation (e.g., cytoskeletal proteins, chaperones) are not carbonylated in oleic acid loaded HepG2 cells, and suggests that the protective effect of fat loading is through interference with protein carbonylation. While counterintuitive to the general concept that AS increases oxidative stress, our fat loading results suggests that low levels of fat may activate antioxidant pathways and ameliorate the effect of subsequent oxidative or inflammatory challenge.

This thesis describes how radical cyclization chemistry can be applied for the construction of heterocyclic compounds. In the first part, a series of electron deficient α-phenylselenenylalkenes were prepared via a PhSeCl-addition/HCl-elimination sequence. Allyl- and propargylamines readily underwent conjugate addition to these species to produce pyrrolidines or dihydropyrrol derivatives, after triethylborane initiated reductive radical cyclization in the presence of tris(trimethylsilyl)silane. The second part describes a convergent synthesis of the pineal hormone melatonin. The indole nucleus is secured via a tris(trimethylsilyl)silane mediated 5-exo radical cyclization. The protocol provides convenient and simple access to compounds useful for studies of biological activity and structure activity relationships. The third part describes construction of substituted tetrahydrofuran-3-ones and pyrrolidin-3-ones. Regioselective ring-opening of epoxides or aziridines with benzeneselenolate/tellurolate, followed by Michael addition to electron deficient alkynes afforded the corresponding O/N-vinylated compounds. The tetrahydrofuran-3-ones and pyrrolidin-3-ones were secured via radical carbonylation/reductive cyclization using pressurized carbon monoxide (80 atm). The fourth part is concerned with the effect of an N-protecting group on the cyclization of 2-substituted-3-aza-5-hexenyl radicals. Relative energies for reactants and transition states were determined using density functional calculations. Reactant and transition state conformers leading to cis-product were lower in energy than those leading to trans-product. The results can be explained by the unfavorable 1,2-strain present in chair-equatorial and boat-equatorial conformers.

Methods for the 11C-labeling of carbonyl compounds applicable in the preparation of radiotracers for Positron Emission Tomography (PET) are described. To this end [11C]carbon monoxide at low concentration was used in transition metal- mediated reactions. Stille couplings were employed in the synthesis of [carbonyl-11C]ketones from methyl and aryl halides with [11C]carbon monoxide. The synthesized [carbonyl-11C]ketones were obtained from the corresponding organostannanes with analytical radiochemical yields up to 98%. A number of synthetic routes were designed using [11C]carbon monoxide and rhodium complexes. Nitrene intermediates were generated from azides and reacted via a rhodium-mediated carbonylation reaction as a general synthetic route to [carbonyl-11C]isocyanates, versatile precursors. [carbonyl-11C]Isocyanate reacted via nucleophilic attack of an amine to form N,N’-diphenyl[11C]urea in 82% analytical radiochemical yield, ethyl phenyl[11C]carbamate was synthesized by the same route, using ethanol as the nucleophile, in 70% radiochemical yield. [11C]Isocyanate was also able to react in a [2+3] cycloaddition with ethylene oxide to form 3-phenyl[carbonyl-11C]oxazolidin-2-one in over 80% analytical radiochemical yield. This method was applied to the synthesis of a potential efflux system tracer [11C]hydroxyurea in 38% isolated radiochemical yield and the derivative 1-hydroxy-3-phenyl[11C]urea in 35% isolated radiochemical yield. Carbene intermediates, generated from diazo compounds, were reacted with [11C]carbon monoxide in the rhodium-mediated synthesis of [carbonyl-11C]ketenes. [carbonyl-11C]Ketene intermediates were utilised in the synthesis of diethyl[carbonyl-11C]malonate, from ethyl diazoacetate and ethanol. The product was obtained with a 20% isolated radiochemical yield. Alkylation of diethyl[carbonyl-11C]malonate, with ethyliodide and tetrabutylammonium fluoride, was successfully accomplished and diethyl diethyl[carbonyl-11C]malonate was synthesized in 50% analytical radiochemical yield. Several (carbonyl-13C)compounds were also synthesized using the described methods as a way of characterizing the position of the label using 13C-NMR.

Hepatitis C is a global health problem that affects approximately 120–180 million people. This viral infection causes serious liver diseases and the therapy available suffers from low efficiency and severe side effects. Consequently, there is a huge unmet medical need for new therapeutic agents to combat the hepatitis C virus (HCV). Inhibition of the viral NS3 protease has recently emerged as a promising approach to defeat this infection, and the first HCV NS3 protease inhibitors have now entered clinical trials. In this project, several novel HCV NS3 protease inhibitors have been designed, synthesized and biochemically evaluated. Inhibitors with various P1 C-terminal functional groups intended as potential bioisosteres to the carboxylic acid found in product-based inhibitors have been revealed. Special focus has been placed on establishing structure–activity relationships of inhibitors containing the promising P1 C-terminal acyl sulfonamide group. The properties of the acyl sulfonamide functionality that are important for producing potent inhibitors have been identified. In addition, the advantages of the acyl sulfonamide group compared to the carboxylic acid have been demonstrated in both enzymatic and cell-based assays. Besides the acyl sulfonamide functionality, the acyl cyanamide and the acyl sulfinamide groups have been identified as new carboxylic acid bioisosteres in HCV NS3 protease inhibitors. The synthetic work included the development of a fast and convenient methodology for the preparation of aryl acyl sulfonamides. The use of microwave heating and Mo(CO)6 as a solid carbon monoxide source provided aryl acyl sulfonamides from aryl halides in excellent yields. This method was subsequently used in the decoration of novel HCV NS3 protease inhibitors comprising a non-natural P1 moiety. This new class of compounds can be used as lead structures in a future optimization process aimed at producing more drug-like HCV NS3 protease inhibitors.

Ce mémoire est articulé autour de trois chapitres. En premier lieu, nos nouveaux résultats concernant la synthèse de 3-silapiperidines par voie dianionique sont présentés. Le chapitre suivant traite de nos premières études sur les mécanismes mis en jeu, au cours de la cycloisomérisation d'enynes-1,5 catalysée par PtCl2, lors de la formation de systèmes [3.1.0]-bicycliques. Enfin, le dernier chapitre concerne nos travaux en collaboration avec l'université préfectorale d'Osaka, sur la formation de résorcinols fonctionnalisés, à partir de pivalate vinylpropargyliques par carbonylation catalytique au [RhCl(CO)2]2.

Compounds labelled with 11C (β+, t1/2 = 20.4 min) are used in positron emission tomography (PET), which is a quantitative non-invasive molecular imaging technique. It utilizes computerized reconstruction methods to produce time-resolved images of the radioactivity distribution in living subjects. The feasibility of preparing [11C]methyl iodide from [11C]methane and iodine via a single pass through a non-thermal plasma reactor was explored. [11C]Methyl iodide with a specific radioactivity of 412 ± 32 GBq/µmol was obtained in 13 ± 3% decay-corrected radiochemical yield within 6 min via catalytic hydrogenation of [11C]carbon dioxide (24 GBq) and subsequent iodination, induced by electron impact. Labelled ethyl-, propyl- and butyl iodide was synthesized, within 15 min, via palladium-mediated carbonylation using [11C]carbon monoxide. The carbonylation products, labelled carboxylic acids, esters and aldehydes, were reduced to their corresponding alcohols and converted to alkyl iodides. [1-11C]Ethyl iodide was obtained via palladium-mediated carbonylation of methyl iodide with a decay-corrected radiochemical yield of 55 ± 5%. [1-11C]Propyl iodide and [1-11C]butyl iodide were synthesized via the hydroformylation of ethene and propene with decay-corrected radiochemical yields of 58 ± 4% and 34 ± 2%, respectively. [1-11C]Ethyl iodide was obtained with a specific radioactivity of 84 GBq/mmol from 10 GBq of [11C]carbon monoxide. [1-11C]Propyl iodide was synthesized with a specific radioactivity of 270 GBq/mmol from 12 GBq and [1-11C]butyl iodide with 146 GBq/mmol from 8 GBq. Palladium-mediated hydroxycarbonylation of acetylene was used in the synthesis of [1-11C]acrylic acid. The labelled carboxylic acid was converted to its acid chloride and subsequently treated with amine to yield N-[carbonyl-11C]benzylacrylamide. In an alternative method, [carbonyl-11C]acrylamides were synthesized in decay-corrected radiochemical yields up to 81% via palladium-mediated carbonylative cross-coupling of vinyl halides and amines. Starting from 10 ± 0.5 GBq of [11C]carbon monoxide, N-[carbonyl-11C]benzylacrylamide was obtained in 4 min with a specific radioactivity of 330 ± 4 GBq/µmol.

Alcoholic steatosis (AS) is the initial pathology associated with early stage alcoholic liver disease and is characterized by the accumulation of fat in the liver. AS is considered clinically benign as it is reversible, as compared with alcoholic steatohepatitis (ASH) which is the next stage of alcoholic liver disease (ALD), and mostly irreversible. Proteomics were used to investigate the molecular basis of AS to determine biomarkers representative of AS. Liver tissue proteins at different stages of steatosis from a rodent model of AS were separated by two dimensional electrophoresis (2DE), followed by MALDI mass spectrometry (MS) identification of significantly expressed proteins. Expression levels of several proteins related to alcohol induced oxidative stress, such as peroxiredoxin 6 (PRDX6) and aldehyde dehydrogenase 2 (ALDH2) were reduced by 2 to 3-fold in ethanol fed rats, and suggested an increase in oxidative stress. Several proteins involved in fatty acid and amino acid metabolism were found at increased expression levels, suggesting higher energy demand upon chronic exposure to ethanol. In order to delineate between the effects of fat accumulation and oxidative stress, an in vitro hepatocyte cell culture model of steatosis was developed. HepG2 cells loaded with oleic acid surprisingly demonstrated lower cytotoxicity upon oxidative challenge (based on lactate dehydrogenase activity) and inflammation (based on TNF-? induced activation of the pro-inflammatory transcription factor NF-?B). We also examined the effect of oleic acid loading in HepG2 cells on protein carbonylation, which is an important irreversible protein modification during oxidative stress that leads to protein dysfunction and disease. Fat-loaded hepatocytes exposed to oxidative stress with tert-butyl hydroperoxide (TBHP) contained 17% less carbonylated proteins than the non-fat loaded control. Mass spectrometric analysis of carbonylated proteins indicated that known classical markers of protein carbonylation (e.g., cytoskeletal proteins, chaperones) are not carbonylated in oleic acid loaded HepG2 cells, and suggests that the protective effect of fat loading is through interference with protein carbonylation. While counterintuitive to the general concept that AS increases oxidative stress, our fat loading results suggests that low levels of fat may activate antioxidant pathways and ameliorate the effect of subsequent oxidative or inflammatory challenge.

Palladium catalysed asymmetric hydroxy- and alkoxycarbonylation reactions of alkenes have the potential to deliver valuable chiral carboxylic acid and ester building blocks from cheap feedstocks: alkenes, carbon monoxide and water (alcohols in the case of alkoxycarbonylation). Despite the attractive nature of these reactions, extensive research has so far been unable to produce effective catalysts which are capable of controlling both regio- and enantioselectivity. Building on exciting recent results involving the use of highly enantioselective palladium catalysts derived from Phanephos-type ligands, this research focuses on paracyclophane-diphosphines and their use in asymmetric hydroxy- and alkoxycarbonylation reactions. An investigation into reaction conditions analysed several factors, including solvents, CO-pressure, acidic additives and halide sources, to provide optimal activity and selectivities. Two novel electron-poor paracyclophane-diphosphines and their mono- and di-palladium complexes were synthesised and shown to provide exceptional levels of regioselectivity while maintaining high levels of asymmetric induction. These are the first such examples of hydroxy- or alkoxycarbonylation catalysts to facilitate simultaneous control over both regio- and enantioselectivity. The most effective catalyst was used to promote the reactions of a selection of aryl alkenes and was shown to be tolerant of several different functional groups. A selection of non-symmetric paracyclophane-diphosphine ligands and their palladium complexes were also synthesised and assessed for their performance in hydroxy- and alkoxycarbonylation. We also report the use of Phanephos-type ligands to promote the highly enantioselective hydroxycarbonylation of N-(p-toluenesulfonyl)-3-pyrroline to deliver a chiral proline derivative in high ee.

No description available.