Les réactifs iodés hypervalents (i.e. iodanes) et les complexes métalliques en milieu oxydant sont des outils particulièrement efficaces pour réaliser la réaction de désaromatisation oxydante de phénols et donner ainsi accès à des motifs cyclohexa-2,4-diénone. Ces travaux de thèse ont permis d'étudier le développement de versions asymétriques de cette réaction de désaromatisation contrôlée soit par le substrat dans le cas de l’utilisation d’iodanes, soit par le réactif lorsqu’un complexe métal/ligands chiraux est privilégié. Cette méthodologie a ensuite été appliquée à la synthèse de la (+)-scyphostatine, un inhibiteur naturel de la sphingomyélinase neutre. / Abstract

Directed metalation reactions are an interesting area of synthetic chemistry. They provide a powerful regiospecific method for functionalizing complex aromatic rings. Presently, directed ortho metalations are well understood. However, there has been very little progress in the remote metalation of naphthalene derivatives. Presently the peri lithiation of naphthalamides is a reaction that has not been solved to a level that allows for it to be deployed in a vast number of synthetic schemes. The processes by which peri functionalized naphthalamides are present obtained required several steps and give poor yields. Previously attempts directed toward the peri lithiation in the Schwan lab have met with little success. Herein experiments were preformed to understand why the pervious attempts failed and other experiments were performed in an effort to acheive the peri lithiation of a specific naphthalamide. The mechanism of previous chemical observations was understood by trapping experiments and clearly demonstrated how problematic acidic sites can interfere with intended directed metalation. The acidic site was sterically hindered by employing strategic protecting groups. However, the steric demand of the protecting groups considered was not sufficient to eliminate the problematic acidic site. This led to the consideration of an alternative strategy for the peri lithiation by removing the acidic center of the specific substrate. This however, resulted in remote addition of lithiating reagents to the naphthalamide and clearly showed that several naphthalamides are not a suitable directed metalation group for the peri lithiation.

Four new synthetic methods employing an oxidative dearomatization - rearomatization strategy are presented. In Chapter 2, a new oxidative dearomatization - radical cyclization - rearomatization approach to form fused oxygen-containing heterocycles is presented. Origins, design, reaction, and optimizations are discussed. In Chapter 3, meta-selective alkylation of catechol mono-ethers is described employing an oxidative dearomatization - radical addition - rearomatization approach using trialkylboranes as source of alkyl radicals. In Chapter 4, a metal-free method to synthesize fluorinated indoles from aniline starting materials is described. Chapter 5 lays the groundwork for para-selective functionalization of catechol mono-ethers. Chapters 6 and 7 highlight the work related to pharmaceutical drug analyses. Chapter 6 presents the FDA approved drugs organized in Disease Focused Posters. Chapter 7.1 and 7.2 present the drug analysis of Sulfur- and Fluorine-Containing Drugs, and Nitrogen-Heterocycle Containing Drugs, respectively.

L’epicocconone est un produit naturel tricyclique de la famille des azaphilones isolé en 2003 d’un champignon Epicoccum nigrum. Ce composé se lie de façon covalente aux amines, conduisant à la formation d’une énamine fluorescente. Cette réaction, réversible en fonction du pH, fait de ce composé un excellent marqueur de protéines pour la détection sur gels d’électrophorèse compatible avec une analyse par spectrométrie de masse. La synthèse d’analogues de l’épicocconone a été engagée au sein de notre laboratoire, en basant sur une étape clé d’oxydation désaromatisante. Une étude approfondie de cette réaction a permis de mettre en évidence une haute diastéréosélectivité en fonction des conditions opératoires.Après introduction d’un cycle acylfuranonique diversement fonctionnalisé, une série d’analogues de l’épicocconone a été obtenue permettant d’établir la relation structure fluorescence et évaluer l’utilisation de ces biomarqueurs en protéomique. / Epicocconone is a tricyclic natural product of azaphilone family, isolated from the fungus Epicoccum nigrum. This compound covalently binds to primary amines, leading to a protein linked conjugate which is strongly fluorescent. This reaction, reversible according to the pH, makes of this compound an excellent proteins dye compatible with an analysis by mass spectrometry. Synthesis of epicocconone’s analogues has been undertaken in our laboratory.This synthesis is based on a key oxidative dearomatization. A study of this reaction allowed us to shed light on a high diastereoselectivity according to reaction conditions. After introduction of functionalized acylfuranone ring, a library of epicocconone’s analogues was obtained allowing us to establish the structure-fluorescence relationship and to estimate the use of these biomarkers in proteomics.

Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.

La réaction de désaromatisation oxygénante de phénols est une transformation très utile en tant qu’étape clé dans la synthèse de substances naturelles complexes. Elle permet de préparer des intermédiaires de type cyclohexa-2,4-diénones à partir de phénols ortho-substitués, notamment en utilisant des réactifs iodés hypervalents (i.e., iodanes) qui constituent une alternative moderne aux réactifs à base de métaux lourds toxiques (e.g., Pb, Tl, Hg). Notre équipe s’intéresse plus particulièrement à la désaromatisation hydroxylante de 2-alkylphénols (réaction HPD) par des iodanes, transformation qui engendre la création d’un centre carboné quaternaire stéréogène. Le contrôle de la configuration de ce centre chiral par l’utilisation d’un substrat ou d’un réactif approprié est un de nos objectifs. Des iodanes chiraux récemment développés au laboratoire ont permis d’atteindre des excès énantiomériques de plus de 90% dans des réactions HPD modèles. Nous avons exploité avec succès ces iodanes chiraux pour réaliser les premières synthèses totales de la (–)-bacchopétiolone et de la (+)-mayténone, ainsi que pour élaborer la tête polaire de type ortho-quinol époxydé de la (+)-scyphostatine. / The oxygenative phenol dearomatization reaction is a very useful transformation, as a key step in the synthesis of complex natural substances. It gives access to cyclohexa-2,4-dienones from ortho-substituted phenols, through the use of hypervalent iodine reagents (i.e., iodanes), which constitutes a modern alternative to toxic heavy-metal-based reagents (e.g., Pb, Tl, Hg). Our team is interested in the hydroxylative dearomatization of 2-alkylphenols (HPD reaction) by iodanes, a transformation that results in the formation of one quaternary stereogenic center. Control of the absolute configuration of this chiral center through the use of an appropriate substrate or reagent is amongst our goals. Chiral iodanes recently developed in the laboratory allowed us to reach enantiomeric excesses above 90 % in model HPD reactions. Successful application of these chiral iodanes led us to achieve the first total syntheses of (–)-bacchopetiolone and (+)-maytenone, as well as that of the epoxy ortho- quinol polar head of (+)-scyphostatine.

Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.

Palladium-catalyzed reactions for carbon-carbon bond formation have had a significant impact on the field of organic chemistry in recent decades. Illustrative is the 2010 Nobel Prize, awarded for “palladium-catalyzed cross couplings in organic synthesis”, and the numerous applications of these transformations in industrial settings. This thesis describes recent developments in C(sp2)-C(sp3) bond formation, focusing on alkane arylation reactions and arylative dearomatization transformations. In the first part, our contributions to the development of intramolecular C(sp3)-H arylation reactions from aryl chlorides are described (Chapter 2). The use of catalytic quantities of pivalic acid was found to be crucial to observe the desired reactivity. The reactions are highly chemoselective for arylation at primary aliphatic C-H bonds. Theoretical calculations revealed that C-H bond cleavage is facilitated by the formation of an agostic interaction between the palladium centre and a geminal C-H bond. In the following section, the development of an alkane arylation reaction adjacent to amides and sulfonamides is presented (Chapter 3). The mechanism of C(sp3)-H bond cleavage in alkane arylation reactions is also addressed through an in-depth experimental and theoretical mechanistic study. The isolation and characterization of an intermediate in the catalytic cycle, the evaluation of the roles of both carbonate and pivalate bases in reaction mechanism as well as kinetic studies are reported. Our serendipitous discovery of an arylation reaction at cyclopropane methylene C-H bonds is discussed in Chapter 4. Reaction conditions for the conversion of cyclopropylanilines to quinolines/tetrahydroquinolines via one-pot palladium(0)-catalyzed C(sp3)-H arylation with subsequent oxidation/reduction are described. Initial studies are also presented, which suggest that this transformation is mechanistically unique from other Pd catalyzed cyclopropane ring-opening reactions. Preliminary investigations towards the development of an asymmetric alkane arylation reaction are highlighted in Chapter 5. Both chiral carboxylic acid additives and phosphine ligands have been examined in this context. While high yields and enantiomeric excesses were never observed, encouraging results have been obtained and are supported by recent reports from other research groups. Finally, in part two, the use of Pd(0)-catalysis for the intramolecular arylative dearomatization of phenols is presented (Chapter 7). These reactions generate spirocyclohexadienones bearing all-carbon quaternary centres in good to excellent yields. The nature of the base, although not well understood, appears to be crucial for this transformation. Preliminary results in the development of an enantioselective variant of this transformation demonstrate the influence of catalyst activation on levels of enantiomeric excess.

L'epicocconone est un produit naturel tricyclique, de la famille des azaphilones, isolé en 2003 d'un champignon Epicoccum nigrum. Ce composé se lie de façon covalente aux amines, conduisant à la formation d'une énamine fluorescente. Cette réaction, réversible en fonction du pH, fait de ce composé un excellent marqueur de protéines pour la détection sur gels d'électrophorèse compatible avec une analyse de spectrométrie de masse. La synthèse de ce produit naturel a été débutée au sein de notre laboratoire en s'appuyant sur les travaux réalisés précédemment et mettant en jeu une étape clé de désaromatisation oxydante à l'aide d'iode hypervalent. Une étude méthodologique de réaction clé a permis de comparer l'efficacité et la diastéréosélectivité de l'oxydation effectuée par l'iode (III) ou l'iode (V). / Epicocconone is a tricyclic natural product of the azaphilone family, isolated from the fungus Epicoccum nigrum. This compound covalently binds to primary amines, leading to a protein conjugate which is highly fluorescent. This reaction, reversible according to the pH, make this compound an excellent protein stain compatible with mass spectrometry analysis. The synthesis of this natural product has been started in our laboratory based on the previous work in involves a key oxidative dearomatization using hypervalent iodine. Methodological studies of this key reaction allowed us to compare the efficiency and diastereoselectivity of iodine (III) and iodine (V) mediated oxidations.

Die Nitron-Cycloaddition an ein dearomatisiertes Phenol ermöglichte den leichten Aufbau des Phenanthrengerüstes von Codein in der gewünschten Konfiguration. Weitere Schritte führten mit kompletter Diastereoselektivität zu Allopseudocodein und nach Allylverschiebung durch Hydrolyse der Chlorcodide schließlich zu (±)-Codein.