This thesis describes the development of transition metal catalyzed transformations towards the synthesis of stereochemically rich motifs and heterocycles. The main themes present throughout this thesis are rhodium-catalysis in reactions of boronic acids with alkenes and alkynes, the use of alkynes as a key motif in the synthesis of heterocycles, and the use of domino and one-pot processes to effect high efficiency in multistep transformations. In Chapter 1, a rhodium-catalyzed desymmetrization of diazabicyclic alkenes with boronic acids is discussed. In this work a chemodivergent and enantioselective process for the synthesis of substituted cyclopentenes and cyclopentanes is developed. Both the chemo- and the enantioselectivity of the reaction are shown to be highly dependent on the phosphine ligand structure. The observed reactivity of rhodium is further applied to a domino reaction to synthesize highly substituted benzofuranones. In Chapter 2, the reactivity of boronic acids and alkynes under rhodium catalysis is exploited as a key step to access polycyclic motifs. In the first part of this chapter the development of a domino process using both rhodium and palladium catalysis is described. Detailed mechanistic investigations allow some insight into the interactions between two catalysts. In the last part of this chapter, preliminary experiments in the application of multimetallic catalysis in the synthesis of azadibenzoxepines are discussed. Chapter 3 summarizes work on the arylation of propargylic alcohols with boronic acids under rhodium catalysis. This reaction is shown to proceed with high regioselectivity and can be conducted under mild conditions. The resulting allylic alcohols are shown to be versatile motifs and are applied in a synthesis of indenes and quinolines. In the final chapter of this thesis, iodotriazoles are explored as key intermediates in the synthesis of fused triazole-containing heterocycles. Palladium-catalyzed cyclization, either through C-H functionalization or through Heck coupling, is achieved. Furthermore, it is shown that the copper-catalyzed azide-alkyne cycloaddition and palladium-catalyzed C-H arylation can be combined into a one-pot process.

A synthetic approach to produce lysergic acid by virtue of an asymmetric ring opening (ARO) of symmetrical 3,6-disubstituted-7,10-hydroxymethyl bridgehead substituted oxabicycles is described. The use of a Rhodium(I)/JosiPhos(R,S) catalyst system to effect an ARO using an amine nucleophile furnishes an enantiopure tetrahydronapthalene intermediate with the amine conveniently installed at the 6 position as in lysergic acid, with appropriate stereochemistry; further which, two subsequent annulations are necessary to form the fused 3,5-substituted indole and tetrahydropyridine to complete the synthesis. Progress of this work is described herein along with future directions. The second chapter in this thesis describes the modular and stereoselective synthesis of tetrasubstituted helical alkenes via a palladium-catalyzed domino reaction under Catellani conditions. These helical alkenes possess potentially interesting photochemical properties as molecular motors / switches, and can be applicable in the materials sciences as molecular machines.

A synthetic approach to produce lysergic acid by virtue of an asymmetric ring opening (ARO) of symmetrical 3,6-disubstituted-7,10-hydroxymethyl bridgehead substituted oxabicycles is described. The use of a Rhodium(I)/JosiPhos(R,S) catalyst system to effect an ARO using an amine nucleophile furnishes an enantiopure tetrahydronapthalene intermediate with the amine conveniently installed at the 6 position as in lysergic acid, with appropriate stereochemistry; further which, two subsequent annulations are necessary to form the fused 3,5-substituted indole and tetrahydropyridine to complete the synthesis. Progress of this work is described herein along with future directions. The second chapter in this thesis describes the modular and stereoselective synthesis of tetrasubstituted helical alkenes via a palladium-catalyzed domino reaction under Catellani conditions. These helical alkenes possess potentially interesting photochemical properties as molecular motors / switches, and can be applicable in the materials sciences as molecular machines.

This thesis describes the development of transition metal catalyzed transformations towards the synthesis of stereochemically rich motifs and heterocycles. The main themes present throughout this thesis are rhodium-catalysis in reactions of boronic acids with alkenes and alkynes, the use of alkynes as a key motif in the synthesis of heterocycles, and the use of domino and one-pot processes to effect high efficiency in multistep transformations. In Chapter 1, a rhodium-catalyzed desymmetrization of diazabicyclic alkenes with boronic acids is discussed. In this work a chemodivergent and enantioselective process for the synthesis of substituted cyclopentenes and cyclopentanes is developed. Both the chemo- and the enantioselectivity of the reaction are shown to be highly dependent on the phosphine ligand structure. The observed reactivity of rhodium is further applied to a domino reaction to synthesize highly substituted benzofuranones. In Chapter 2, the reactivity of boronic acids and alkynes under rhodium catalysis is exploited as a key step to access polycyclic motifs. In the first part of this chapter the development of a domino process using both rhodium and palladium catalysis is described. Detailed mechanistic investigations allow some insight into the interactions between two catalysts. In the last part of this chapter, preliminary experiments in the application of multimetallic catalysis in the synthesis of azadibenzoxepines are discussed. Chapter 3 summarizes work on the arylation of propargylic alcohols with boronic acids under rhodium catalysis. This reaction is shown to proceed with high regioselectivity and can be conducted under mild conditions. The resulting allylic alcohols are shown to be versatile motifs and are applied in a synthesis of indenes and quinolines. In the final chapter of this thesis, iodotriazoles are explored as key intermediates in the synthesis of fused triazole-containing heterocycles. Palladium-catalyzed cyclization, either through C-H functionalization or through Heck coupling, is achieved. Furthermore, it is shown that the copper-catalyzed azide-alkyne cycloaddition and palladium-catalyzed C-H arylation can be combined into a one-pot process.

L’objectif a été de développer de nouvelles stratégies d’accès à des hétérocycles soufrés originaux, impliquant des processus domino métallo-induits. Une première étude a consisté en la synthèse de nouveaux hétérocycles soufrés pas des réactions domino pallado-catalysées impliquant une réaction de cyclocarbopalladation 5 ou 6-exo-dig suivie d’un couplage croisé C-C. A partir de substrats soufrés pré-organisés comportant une triple liaison CC, nous avons synthétisé des molécules comportant un hétérocycle soufré fusionné à un cycle benzénique, présentant une double liaison exocyclique tétrasubstituée stéréodéfinie. Ensuite, nous avons développé une méthode de synthèse d’aryle thiocyanates à partir de thiols ou dedisulfures, en utilisant pour la première fois le CuCN comme agent de S-cyanation. Cette transformation a été intégrée dans une réaction domino tricomposante. A partir d’un 2-aminobenzènedisulfure, du CuCN et d’un électrophile, des 2-aminobenzothiazoles ont été synthétisés. / The objective was to develop new accesses to original sulfur heterocycles involving metal-mediated processes.The first study allowed the development of new palladium-mediated syntheses of original sulfur heterocycles involving a 5 or 6-exo-dif cyclocarbopalladation reaction followed by a C-C crosscoupling. Starting from pre-organized sulfur substrates containing a C-C triple bond, we have synthesized original benzene-fused sulfur rings bearing an exocyclic, stereodefined, all-substituted double bond. In a second study, we have developed a new synthesis of aryl thiocyanates starting from thiols or disulfides using for the first time CuCn as S-cyanation agent. Then, this method taking place through a copper-mediated oxidative coupling, under mild conditions, was integrated in a three-component domino reaction involving a 2-aminobenzene disulfide, copper cyanide and an electrophile allowing the synthesis of polyfunctionalized 2-aminobenzothiazoles in good yields.

Le développement de nouvelles méthodes de synthèse de molécules hétérocycliques originales représente un enjeu actuel majeur en chimie organique. L’objectif est de fournir de nouveaux outils chimiques pour le développement de molécules actives en chimie médicinale et/ou pour l’étude de la biologie chimique, tout en contribuant à l’exploration de l’espace chimique.Dans ce contexte, le travail effectué au cours de cette thèse de doctorat a visé à élaborer de nouvelles voies de synthèse de motifs tétrahydro-[1,6]-naphtyridines. La pierre angulaire des méthodologies développées réside dans l’utilisation des 3-vinyl-1,2,4-triazines comme des plateformes synthétiques bifonctionnelles. Ces composés ont été développés pour réagir à la fois comme accepteurs de Michael et comme aza-diènes dansdes cycloadditions de Diels-Alder à demande électronique inverse. Un intérêt tout particulier a été porté à lamise au point de stratégies synthétiques innovantes, par des réactions en cascade permettant une synthèse rapide et efficace des molécules cibles, et des approches de catalyse organique visant des transformations énantiosélectives.La synthèse de nouvelles 3-vinyl-1,2,4-triazines et le développement de stratégies de réactions d’addition conjuguée/cycloadditions en cascade et de synthèses monotopes organocatalysées ont fournis l’accès à une vaste gamme de nouvelles tétrahydro-[1,6]-naphthyridines diversement substituées. / The development of new methods for the synthesis of original heterocyclic molecules represents a current concern in organic chemistry, aiming to furnish medicinal chemistry and chemical biology with new chemical tools and contribute to the exploration of chemical space.In this context, the work which was carried out during this PhD thesis focused on the elaboration of new approaches for the synthesis of tetrahydro-[1,6]-naphthyridine scaffolds. The original use of 3-vinyl-1,2,4-triazines as bifunctional synthetic platforms, able to react both as Michael acceptor and as aza-diene in inverse-electron-demand Diels-Alder cycloadditions, is the keystone our methodology is based upon. The development of domino reactions – allowing quick and efficient synthesis of targeted compounds – remaineda perpetual concern evolving along side our preoccupation to access enantioselective transformations relying on organocatalysis.The synthesis of new 3-vinyl-1,2,4-triazines platforms and the elaboration of domino conjugate addition/cycloadditions and orgonocatalyzed one-pot synthesis strategies enabled to synthetize a wide panelof new diversly substituted tetrahydro-[1,6]-naphthyridines compounds.

Au cours de ce travail, nous nous sommes intéressés à explorer le potentiel d’une réaction multicomposés initiée par une addition de Michael conduisant à des dérivés de 2,6-DABCO. Dans ce contexte, nous avons tout d’abord étudié l’étendue de la réaction en modifiant les différents partenaires et paramètres réactionnels. Dans le but de rendre ce procédé plus éco-compatible, l’utilisation de liquides ioniques recyclables a aussi été étudié. Dans certains cas, les liquides ioniques ont permis de s’affranchir du solvant organique toxique et du catalyseur hétérogène de la réaction. Enfin, afin de mettre en œuvre une synthèse multicomposés énantiosélective de 2,6-DABCO, nous avons été amenés à développer une nouvelle méthodologie d’addition de Michael énantiosélective organocatalysée de béta-cétoamides sur des dérivés carbonylés alpha,béta-insaturés. Ainsi, des adduits comportant un centre stéréogène quaternaire entièrement carboné ont pu être obtenus avec de bons rendements et des excès énantiomériques qui atteignent 99%. Une étude sur la réactivité de ces adduits nous a permis d’accéder à différentes familles de composés poly(hétéro)cycliques optiquement actifs d’un grand intérêt synthétique. / In this work, we explored the potential of a Michael addition-initiated multicomponent reaction leading to 2,6-DABCO derivatives. In this context, we first studied the scope of the reaction by changing the partners and the parameters of the reaction. In view of making the process more eco-friendly, the use of ionic liquids was also investigated and found that in some cases, the ionic liquids could replace the toxic organic solvent and the heterogeneous catalyst of the reaction. Finally, the implementation of an enantioselective multicomponent synthesis of 2,6-DABCO led us to develop a new methodology of an organocatalytic enantioselective Michael addition of beta-ketoamides to alpha, beta-unsaturated carbonyls. In this way, adducts containing an all-carbon quaternary stereocenter were obtained in good yields and high to excellent enantiomeric excesses (up to 99%). The study of the reactivity of these adducts allowed the access to different families of optically active poly(hetero)cyclic compounds of high synthetic interest.

Dans le contexte de la synthèse éco-compatible, la réactivité et le transfert de chiralité de sulfoximines dans quelques réactions domino ou consécutives diastéréosélectives ont été étudiés pour la synthèse de carbocycles et d’hétérocycles d’intérêt. L’emploi de béta-cétosulfoximines comme pronucléophiles dans des additions de Michael diastéréosélectives a aussi été étudié. Dans la plupart de ces cas, l’induction asymétrique de l’atome de soufre chiral s’est révélée faible. Dans un second temps, nous avons étudié l’addition de Michael énantiosélective des cyclobutanones activées sur les nitroalcènes par une approche organocatalytique. En utilisant un catalyseur bifonctionnel, les produits attendus présentant deux centres stéréogènes contigus dont un quaternaire, ont pu être obtenus avec de très bons rendements et d’excellentes diastéréo- et énantiosélectivités. Le potentiel synthétique de ces dérivés cyclobutaniques a pu être démontré, en particulier pour la synthèse de gamma-lactones optiquement actives. / In the context of eco-compatible synthesis, reactivity and chirality transfer of sulfoximines in some domino or consecutive diastereoselective reactions have been studied for the synthesis of carbocycles and heterocycles of interest. The use of béta-ketosulfoximines as pronucleophiles in diastereoselective Michael additions has also been studied. In most of these cases, the asymmetric induction of chiral sulfur atom was low. Then, we investigated the enantioselective Michael addition of activated cyclobutanones onto nitroalkenes by an organocatalytic approach. The resulting adducts exhibit two contiguous chiral carbon atoms including an all-carbon quaternary stereocenter. They were obtained with very good yields and excellent diastereo-and enantioselectivities by using a bifunctional catalyst. The synthetic potential of these cyclobutane derivatives could be shown, especially for the synthesis of optically active gamma-lactones.

Le projet scientifique a consisté au développement de nouveaux processus domino ayant pour étape clé la fonctionnalisation d’une liaison C-H. L’introduction de cette étape de fonctionnalisation C-H a permis d’améliorer significativement l’efficacité moyenne de la réaction et a offert de nouvelles perspectives du point de vue synthétique. Ainsi, nous avons exploité des stratégies se basant sur des séquences Heck / fonctionnalisation C-H, des réactions de difonctionnalisation d’alcènes en conditions oxydantes et un processus d'aminopalladation / fonctionnalisation C-H. Ces méthodologies nous ont permis un accès rapide aux motifs spiroquinolinones, spirooxindoles, oxindoles disubstitués en position 3, oxindoles tétracycliques et pyrrolo[1,2-a]indoles. / The projet consists in developing new domino processes involving C-H functionalization as the key steps. The introduction of C-H functionalization in the domino reaction leads to the enhancing significantly the efficiency of the reaction and offers new perspectives in a synthetic point of view. In this context, we have exploited different strategies basing on Heck/C-H functionalization process, difunctinalization of alkenes reactions through oxidative addition and a sequencial intramolecular aminopalladation/C-H functionalization. These methodologies allow rapid constructions of spiroquinolines, spirooxindoles, 3,3'-disubstituted oxindoles, tetracyclic oxindoles and pyrrolo[1,2-a]indoles cores.

Im Rahmen dieser Arbeit wird eine neuartige Deoxygenierungskaskade von Flavanonen bzw. Isoflavanonen via asymmetrischer Transferhydrierung (ATH) beschrieben. Diese Methodik ermöglicht einen einstufigen Zugang zu enantiomerenreinen Flavanen bzw. Isoflavanen aus entsprechenden racemischen Ketonen. Unter Verwendung der ATH-Deoxygenierungskaskade werden hoch enantioselektive Naturstoffsynthesen elaboriert. So erfolgt eine effiziente Darstellung der Flavane Brosimin A, Brosimin B, Brosimacutin L, Kazinol U und 7,3‘-Dihydroxy-4‘-methoxyflavan. Darüber hinaus wird mittels dynamischer kinetischer Racematspaltung die Totalsynthese der Isoflavane Equol, Manuifolin K und Eryzerin D beschrieben.