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<strong>Introduction</strong> The introduction describes the importance of arylamine compounds to society and provides a brief overview of the methods available for their synthesis. The application of metathesis catalysis to the de novo synthesis of heteroaromatic compounds is also described. <strong>Results and discussion</strong> The first section describes efforts towards the de novo synthesis of arylamines using a cross metathesis/oxidation protocol to form a 1,5-unsaturated dicarbonyl followed by an amine mediated cyclisation. The scope with respect to the 1,5-unsaturated dicarbonyl and amine is covered as well as the utility of some of the products. The section concludes with a modification of the Bohlmann Rahtz pyridine synthesis to furnish arylamines. The next section describes the applications of our methodology to the synthesis of naphthylamines, specifically using the palladium catalysed &alpha;-arylation reaction. A discussion of the α-arylation reaction is included as well as our efforts to explore the scope of the reaction. The third section follows our efforts to apply this methodologyy to the synthesis of five benzo[c]phenanthridine alkaloids including the first reported synthesis of maclekarpine B and C. The final section concludes with a discussion of our efforts towards the de novo synthesis of furans bearing a benzylic stereocentre.

L’acide (L)-tartrique, co-produit de l’industrie vinicole, est une petite molécule chirale, polyfonctionnelle et peu coûteuse. L’association de la chiralité de ce synthon aux propriétés physico-chimiques de l’atome de fluor a permis d’accéder à des hétérocycles azotés polyfonctionnels énantiopurs contenant un groupement trifluorométhyle porté par un carbone quaternaire.Les synthons de départ, les hémiaminals cycliques trifluorométhylés dérivés de l’acide (L)-tartrique diversement substitués, ont été obtenus par deux voies de synthèse : l’une basée sur une réaction de cyclisation d’un céto-amide trifluorométhylé en présence d’une amine ; l’autre sur une réaction de trifluorométhylation nucléophile d’un imide cyclique.Les dérivés de ces hémiaminals sont des précurseurs d’ions N-acyliminiums dans diverses réactions d’α-amidolakylations diastéréosélectives. Toutefois, l’addition de nucléophiles carbonés a été réalisée avec une efficacité variable. L’addition hautement diastéréosélective de nitriles selon une variante de la réaction de Ritter sur ces hémiaminals a permis de synthétiser divers oxazolines et (amido)pyrrolidin-2-ones originaux, énantiopurs, porteur d’un carbone chiral trifluorométhylé.Mots-clés : Acide tartrique, Trifluorométhylation nucléophile, Synthèse asymétrique, Hémiaminal, N-acyliminium, Carbinamide, Réaction de Ritter. / (L)-tartaric acid, a by-product of the wine industry, is a small chiral and polyfunctional molecule, affordable at low cost. Its chirality combined with the physical and chemical properties of fluorine enabled to afford original polyfunctional and optically pure nitrogen-containing heterocycles, incorporating a quaternary trifluoromethylated carbon.Our starting materials, the variously substituted trifluoromethylated cyclic hemiaminals derived from the (L)-tartaric acid, have been synthesized using two different methods : one is based on the cyclization of a trifluoromethylated keto amide in the presence of an amine, and the other one consists in a nucleophilic trifluoromethylation of a cyclic imide.These hemiaminal derivatives constitute N-acyliminium precursors in various diastereoselective α-amidoalkylations. However, the addition of C-nucleophiles has shown varying efficacy. The highly diastereoselective addition of nitriles on these hemiaminals, according to a Ritter-type reaction, led to the synthesis of original and optically pure oxazolines and (amido)pyrrolidin-2-ones including a chiral trifluoromethylated carbon.Key-words : Tartaric acid, Nucleophilic trifluoromethylation, Asymmetric synthesis, Hemiaminal, N-acyliminium, Carbinamide, Ritter reaction.

The ligand activated transcription factor retinoid X receptor (RXR) forms a DNA binding heterodimer with pregnane X rseceptor (PXR) in response to foreign xenobiotics. In addition to RXR and PXR there are other proteins involved in the RXR/PXR signaling pathway. Many proteins involved in this pathway are still unknown. This study documents the production of RXR and PXR in a bacterial recombinant fusion system. These proteins were expressed in a system that allowed purification with six histidine residues. Once the proteins were expressed and purified from E. coli, they were solublized and tested for function. Different strategies were employed including temperature and inducer studies and denaturing and renaturing techniques to solublize PXR. Following the solubilzation of each protein, all proteins were subjected to a method of functional analysis. RXR function was assessed by electrophoretic mobility shift assay (EMSA) and proved to effectively form a DNA binding heterodimer with PXR. These studies involving RXR and PXR demonstrate that these proteins can be efficiently produced in a functional manner utilizing an inexpensive bacterial system. In addition, this study documents various strategies for combating "inclusion body" formation in the overexpression ofPXR. Also, it describes the production of plasmid pCMV-RXR for transfection into the HepG2 cell line to monitor the levels of cellular RXR in various tissue types.

Total synthesis of the pyrrolizidine alkaloid NP25302: (+)-NP25302 is an unusual vinylogous urea containing pyrrolizidine alkaloid shown to exhibit cell adhesion inhibition. It was envisaged that this natural product could be accessed by a novel 5-endo-dig cyclisation to construct the pyrrolizidine core, and a Curtius rearrangement to install the vinylogous urea motif. This methodology was first tested on a model system, furnishing nor-NP25302 from L-proline in 12 steps and 9% overall yield. The total synthesis of (±)-NP25302 was completed in 9 steps and 26% overall yield from ethyl 2-nitropropionate using similar methodology. Studies into the stereospecificity of the Au(I)-catalysed cyclisation of monoallylic diols: During the synthesis of (+)-isoaltholactone in the Robertson group, the key Au(I)-catalysed cyclisation was observed to occur with some stereospecificity. Further investigations were therefore conducted into the stereochemical outcome of this reaction using stereodefined allylic alcohols, and from the combined results a mnemonic was proposed to predict the stereochemistry of the products of this reaction. Studies into the total synthesis of ascospiroketals A and B: Investigations were conducted into the total synthesis of the recently isolated natural products ascospiroketals A and B. A second generation synthesis was used to construct advanced intermediates 1 and 2.

Dans un premier temps, ce travail décrit la méthodologie de synthèse vers de nouveaux coilants bipyridines-bis-α-cyclodextrines comportant deux ou trois unités bipyridines pour la réalisation de systèmes coordinants tétra- ou octaédriques singuliers. La réactivité des différentes étapes a été étudiée et des molécules clés de la synthèse totale des ces systèmes ont été synthétisées grâce à des réactifs ou réactions issus du laboratoire. Dans un deuxième temps, la synthèse d'un nouveau podant tris-bipyridines-α-cyclodextrine a également été réalisée et ses propriétés de complexation avec les cations de transition ont été étudiées par spectroscopie UV-visible et dichroïsme circulaire. La géométrie hélicoïdale fortement chirale a également été résolue dans le cas de certains complexes de ce podant avec des métaux de transition de dureté intermédiaire / Firstly, this work describes the synthesis methodology toward new bipyridines-bis-α-cyclodextrins coilants with two or three bipyridine units for the achievement of tetra- or octahedral coordinant systems. The reactivity has been studied and key molecules have been synthesisedthanks to our laboratory's methodologies. Sedondly, the synthesis of a new tris-bipyridines-α-cyclodextrin podand has also been performed and its complexation properties with transition cations have been studied by UV-visible spectroscopy and circular dichroism. The highly chiral helix geometry has also been resolved in the case of some metal podendates with borderline transition metals

Ce manuscrit décrit des approches synthétiques de la benzosceptrine, pyrrole-2-aminoimidazole (P-2-AI) d'origine marine, via la création de liaisons C-N et une photodimérisation [2+2]. La synthèse totale de cette molécule originale et unique présente plusieurs challenges : la construction du motif benzo-bis-2-aminoimidazole et la synthèse régio- et stéréo-sélective du motif benzocyclobutanique. C’est dans ce but qu’une nouvelle méthodologie de diamination de 2-cyclohexènones par la 2-aminopyrimidine en présence du système catalytique fer/diiode/dioxygène a été mise au point et étendue aux 2-aminopyridines, chalcones et la chromone. L’application de cette méthode a permis d’achever la synthèse du motif benzo-bis-2-aminoimidazole de la benzosceptrine via l’installation de 4 liaisons C-N, en 6 étapes avec un rendement global de 28 % ; et d’explorer la réactivité de ce motif. La deuxième partie cyclobutanique a pu être réalisée grâce au développement d’une photodimérisation stéréo- et régio- sélective d’un acide (E)-3-(imidazo[1,2-a]pyrimidin-2-yl)acrylique. Bien que la synthèse totale de la benzosceptrine n’ait pas été achevée, ce travail nous a permis de préparer une chimiothèque de 50 dérivés simplifiés destinée aux évaluations biologiques. Ces évaluations en inhibition de kinases et en cytotoxicité ont mis en évidence un produit cytotoxique original et intéressant. Ce travail de recherche a donc permis d’avancer la synthèse de la benzosceptrine, de mettre au point une nouvelle méthode de diamination et de créer une chimiothèque de dérivés simplifiés d’un produit naturel. / This manuscript describes synthetic approaches of benzosceptrin, a pyrrole-2-aminoimidazole (P-2-AI) isolated from a marine sponge, via C-N bond formation and a [2+2] photodimerization. Its synthesis presents the challenges of the benzo-bis-2-aminoimidazole moiety construction and the regio- and stereoselective synthesis of the benzocyclobutanic motif. With this objective, a new methodology of diamination of 2-cyclohexenones by 2-aminopyrimidine and 2-aminopyridines in the presence of the very simple iron/iodine/dioxygen catalytic system has been developed. It was also extended to chalcones and chromone. The application of this method allowed the synthesis of the benzo-bis-2-aminoimidazole moiety of benzosceptrin via the formation of 4 C-N bonds, in 6 steps in an overall yield of 28 % and to explore the reactivity of some intermediates. The second cyclobutanic moiety has been completed thanks to the development of a stereo- and regioselective photodimerization [2+2] of a (E)-3-(imidazo[1,2-a]pyrimidin-2-yl)acrylic acid. Although the total synthesis of benzosceptrin was not achieved, this work allowed the preparation of a chemical library of 50 simplified derivatives for biological evaluations. Those evaluations in kinases inhibition and cytotoxicity helped to highlight an original and interesting cytotoxic product. This research permitted to progress the synthesis of benzosceptrin, to develop a new method of diamination and to create a chemical library of simplified derivatives of a natural product.

Healthcare decision-makers need high quality evidence to inform policy and practice decisions. Systematic reviews of randomized controlled trials (RCTs), including meta- analyses of study effects, are considered one of the highest forms of evidence to inform such decisions. Most applications of systematic reviews and meta-analyses are based on a standardized cannon of methods that seek to collect, abstract, assess, and synthesize evidence from primary studies to produce a comprehensive and unbiased summary of the evidence. While useful, standard synthesis methods tend to assume simple data structures (e.g., two-arm comparison of a single intervention vs. a similar control evaluated in a parallel individual randomized design) and some practices (e.g., author contact) may not always be supported by empirical evidence. Complex interventions are of increasing focus in healthcare and public health and pose challenges to the standard methods of systematic review and meta-analysis. While different definitions of complex interventions have been proposed, most definitions assume: i) multiple intervention ‘components’ that may or may not interact with each other to increase or decrease observed intervention effects and ii) effect modification by study-specific characteristics (e.g., healthcare setting, patient population). At least three challenges may result from this complexity. First, reviewers will likely have to contact authors for additional information about intervention components and contextual factors that may operate as effect modifiers. Unfortunately, evidence supporting optimal strategies for achieving response from author contact is lacking. Second, complex interventions are often evaluated using a cluster randomized trial (CRT) design that randomize units of patients to different healthcare/health policy interventions. Analyses from CRTs that are not adjusted for the clustering effect are said to have unit of analysis errors, which if incorporated in meta-analyses could lead to biased summary estimates and overly precise confidence intervals (CIs). Methods for reviewers to appropriately appraise abstract evidence from CRTs are limited. Thirdly, standard meta-analyses estimate an overall effect of a singular ‘complex intervention’. Such analyses answer the question “Do complex interventions as a whole lead to a difference in observed outcomes?” and tend to exhibit high statistical heterogeneity since variation in intervention components and effect modifiers are not accounted for. Hierarchical multivariate meta-regression models have been proposed as an alternative synthesis approach for complex interventions to better account for observed heterogeneity and answer the question decision-makers are really interested in; that is “What component(s) (or combination of components) work and under what conditions?”. Hierarchical multivariate meta-regression models however have yet to be applied in the review of complex healthcare interventions. The overall aim of my doctoral research was to explore the utility of three methodological approaches to address these challenges and optimize the synthesis of complex interventions using a large systematic review of diabetes quality improvement interventions as a case study. The first objective of this thesis was to do an RCT evaluation of the effect of telephone call versus repeated email contact of non-responding authors for additional study information on response rates and research costs. We found authors contacted by telephone call were more likely to complete requests for additional information (response rate 36.7% vs. 20.2%; adjusted odds ratio 2.26 [95% CI 1.10-4.76]) but the intervention took more time to deliver in total (20 vs. 10 hours over several months vs. one month) and was more expensive overall (approximately $505 vs. $253). The second objective of this thesis was to better account for evidence from CRTs and involved a descriptive study and a methodological study. The descriptive study described the proportion of studies with unit of analysis errors and the nature of the error (inappropriate analysis versus unclear or incomplete reporting). The methodological study investigated the utility of building a database of intracluster correlation coefficients (ICCs) and use of an ICC posterior predictive distribution model to correct unit of analysis errors identified in the descriptive study. We found that although trials often adjusted for the cluster effect (67% across outcomes; range 25%-81%), most did not report enough information to extract adjusted effect estimates required for meta-analysis (an average of 77% of studies with remaining unit of analysis errors across outcomes; range 42%-100%). We were able to construct a posterior predictive distribution of the ICC for most outcomes in our review using estimates of the ICC obtained from the descriptive study combined with external estimates and use these distributions to impute missing ICCs to correct unit of analysis errors. Finally, the third objective of this thesis was to illustrate the use of hierarchical multivariate meta-regression for quantitative synthesis when estimating the effects of complex interventions and exploring effect heterogeneity. Using an arm-based analysis of post-treatment means of one continuous outcome, we demonstrated that hierarchical multivariate meta-regression models can be used to estimate a ‘response surface’ that accounts for complex intervention multiple components and study characteristics, and these models can be used to infer estimates of component effects, interactions among components, and effect modification by study covariates. Collectively the results from this thesis suggest three methodological approaches (contacting authors by telephone, imputing missing ICCs using a predictive distribution, estimating complex intervention effects using a hierarchical multivariate meta-regression) can be used to optimize the processes of synthesizing complex interventions. Further work is needed to evaluate the impact of additional study-covariates on explaining residual heterogeneity and testing these methods in other reviews of complex interventions.

La lutte contre le cancer est certainement l’un des défis majeurs de ce 21ème siècle. Les résistances qui émergent contre les agents de thérapie ciblée présentent un aspect particulièrement épineux de cette problématique. La thèse présentée ici s’inscrit dans ce cadre. Elle vise à développer des molécules bioactives pouvant circonvenir les résistances apparues contre les traitements de certaines hémopathies malignes : la leucémie myéloïde chronique (LMC) et le syndrome myélodysplasique (SMD). Après avoir mis au point une méthodologie de synthèse monotope permettant de transformer un azoture en un 5-alcynyl-1,2,3-triazole, nous avons synthétisé deux séries de produits : nucléosidique et non nucléosidique. Pour chacune de ces séries, des relations structure-activité ont été établies. Après plusieurs cycles d’optimisation, trois composés lead très efficaces contre des lignées cellulaires résistantes de LMC et SMD, ont été sélectionnés. De surcroît, leur mode d’action s’est révélé très intéressant : il repose (partiellement ou entièrement, suivant le composé) sur un processus cellulaire qui connaît un véritable regain d’intérêt, à savoir l’autophagie. Une évaluation in vivo a été réalisée et a permis de valider l’activité prometteuse de notre composé lead nucléosidique. Par ailleurs, des études visant à déterminer la localisation intracellulaire et les cibles moléculaires de nos produits sont actuellement en cours / The fight against cancer is certainly one of the biggest challenges of the 21st century. Resistance that comes up against targeted therapy agents presents a particularly important aspect of this issue. The thesis presented here takes part within that framework. It aims at developing bioactive molecules able to circumvent resistance that have emerged against the treatment of certain hematological malignancies: chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS). Having developed a one-pot synthesis methodology that converts azides into 5-alkynyl-1,2,3-triazole, we synthesized two series of products: nucleosidic and non-nucleosidic. For each of these series, structure-activity relationships have been established. After running several cycles of optimization, three lead compounds particularly active on resistant cell lines of CML and MDS were selected. Further, their mode of action proved to be very interesting. It is based (partially or fully, depending on the compound) on a cellular process, which is experiencing a real renewed interest, the autophagy. An in vivo evaluation confirmed the promising activity of our nucleosidic lead compound. Moreover, studies aiming at determining the intracellular localization and molecular targets of our products are currently in progress