Ce mémoire de thèse se concentre sur le développement de réactions multicomposants énantiosélectives de dérivés 1,3-Dicarbonylés en présence d'un organocatalyseur, en vue de préparer des motifs polyhétérocycliques fusionnés.Dans un premier temps, nous décrivons nos résultats initiaux sur une réaction multicomposants énantiosélective avec des énals et des amines primaires simples. Au vu des faibles énantiosélectivités obtenues, des amines fonctionnalisées ont ensuite été introduites dans ces réactions, permettant ainsi de synthétiser des pyrrolopiperazines et d'autres molécules hétérocycliques polyfonctionnalisées énantioenrichies, toutes obtenues avec des rendements intéressants et des énantiosélectivités élevées.Ayant utilisé avec succès des β-Cétoamides α-Méthyléniques dans ces réactions multicomposantes, nous avons réalisé par ailleurs que leur simple addition de Michael sur des oléfines pauvres en électrons n'avait jamais été décrite en version organocatalysée. Nous avons donc étudié leur réaction avec des nitrooléfines en présence d’organocatalyseurs chiraux, et les produits attendus ont alors été obtenus avec de bons rendements et d'excellentes diastéréo- et énantiosélectivités. / This thesis focuses on the development of enantioselective multicomponent reactions with 1,3-Dicarbonyls in the presence of an organocatalyst, to synthesize fused polyheterocyclic motives.At first, we describe our initial results on an enantioselective multicomponent reaction with enals and simple primary amines. In view of the low enantioselectivities achieved, functionalized amines were then introduced in these reactions, thereby synthesizing enantioenriched pyrrolopiperazines and other polyfunctionalized heterocyclic molecules, all obtained with attractive yields and high enantioselectivities.Having successfully used methylene β-Ketoamides in these enantioselective MCRs, we realized also that their simple Michael addition to electron-Poor olefins had never been described in organocatalytic conditions. We therefore studied their reaction with nitroolefins in the presence of various chiral organocatalysts, and the expected products were pleasingly obtained with high yields, excellent diastereo- and enantioselectivities.

Ce mémoire de thèse se concentre sur la mise au point de nouvelles réactions mettant en jeu des composés 1,3-cétoamides en organocatalyse énantiosélective, enfin d’accéder à des structures inaccessibles jusqu’alors, ainsi que sur le développement d’une nouvelle synthèse de composés 1,3-dicarbonylés originaux et leur utilisation dans des réactions orgcanocatalysées.Dans un premier temps, nous décrivons tous nos essais de fonctionnalisation stéréosélective en des 1,3-cétoamides acycliques non substitués, par réaction de Mannich énantio- et diastéréosélective, par réaction d’amination énantiosélective et par réarrangement de Lossen énantiosélectif. Puis, nous abordons comment les 1,3-cétoamides nous ont permis de réaliser la synthèse multi-composés régio-, énantio-, et diastéréocontrôlée de 1,2,3,4-tétrahydropyridines, motif qui n’avait jamais été obtenu en organocatalyse auparavant et que la synthèse d’une autre famille d’hétérocycles complexes, les 2,6-DABCO.Dans un second temps, nous détaillons la mise au point d’une nouvelle méthode de synthèse, basée sur l’addition de nucléophiles silylés sur des intermédiaires -oxocétènes, générés par réarrangement de Wolff initié par irradiation micro-ondes. Ainsi, des 1,3-cétoaldéhydes masqués des 1,3-cétoamides primaires, des composés bicycliques fusionnés furan-3-ones et un 1,3-cétoazoture d’acyle masqué, ont pu être synthétisés. L’utilisation en organocatalyse énantiosélective de ces substrats originaux est également détaillée. / This thesis focuses on the development of new reactions using 1,3-ketoamides in enantioselective organocatalysis to access structures never obtained before and on the development of a new synthesis of original 1,3-dicarbonyl compounds and their use in organocatalyzed reactions.Firstly, we describe all our attemps of -functionalization of acyclic unsubstituted 1,3-ketoamides by enantio- and diastereoselective Mannich reaction, by enantioselective amination reaction and by enantioselective Lossen rearrangement. Then, we address how 1,3-ketoamides allow us to achieve the regio- enantio- and diastereoselective multicomponent synthesis of 1,2,3,4-tetrahydropyridines, a scaffold never reached previously as well as the synthesis of another family of complex heterocycles, 2,6-DABCO.Secondly, we detail the development of a new synthetic methodology, based on the addition of silylated nuclophiles to -oxoketene intermediates, generated by Wolff rearrangement triggered by microwave irradiation. This way, masked 1,3-ketoaldehydes, primary 1,3-ketoamides, fused bicylic furan-3-ones and a masked 1,3-ketoacyl azide have been synthesized. The use of these original substrates in enantioselective organocatalysis will be discussed as well.

Depuis les années 2000, le domaine de l’organocatalyse est en plein essor. Une vue d’ensemble des différents modes d’activation organocatalytique fera l’objet du premier chapitre. Malgré les avancées considérables faites dans l’activation par liaison covalente, particulièrement dans l’aminocatalyse par activation iminium, des progrès sont encore possibles au niveau de l’activité catalytique des organocatalyseurs. Une large partie du travail détaillé dans le deuxième chapitre concerne le design puis le développement de deux voies de synthèse permettant de préparer une nouvelle classe d’organocatalyseurs pour l’activation iminium ainsi que leurs tests d’activité catalytique. Enfin, le troisième chapitre est consacré à l’étude de réactions d’échange H/D organocatalysées par les carbènes N-hétérocycliques. / Since the begining of 2000, the field of organocatalysis has performed a lot of improvements. An overview of the different modes of activation of this field will constitute the first chapter. Despite the improvements in the domain of activation by covalent bond, specially for the iminium activation, some enhancements of the catalytic activity of organocatalysts are still possible. A major part of the work developped in the second chapter will be focused on the design then the synthesis of a new class of organocatalysts for iminium activation and their catalytic activity tests. Then the third chapter will be dedicated to the H/D exchange reactions organocatalyzed by N-heterocyclic carbenes.

Asymmetric synthesis and catalysis is one of the leading research areas in chemistry society, for its versatility and efficiency in obtaining chiral molecules that found the vast majority in natural active compounds and synthetic drugs. Developing asymmetric catalytic methodology is at the frontier in both industrial and academic research laboratories. Enantioselective organocatalysis has emerged as a powerful synthetic tool that is complementary to metal-catalyzed transformations. The development of chiral phosphoric acid and metal phosphate as catalysts has been a breakthrough in recent years. Chiral phosphoric acids have been shown to be powerful catalysts in many organic transformations. Moreover, chiral metal phosphates, which formed by simply replacing the proton in phosphoric acid with metals, have introduced new catalytic activations and broaden the scope of phosphoric acids. This thesis details new highly enantioselective chiral phosphoric acid-catalyzed Pinacol rearrangement and robust alkaline phosphates catalytic system, which utilizes novel carbonyl activation. The Pinacol rearrangement has long been known to be difficult to control in terms of regioselectivity and stereoselectivity. The initial studies found that indolyl-diol compounds can be treated with chiral phosphoric acids to afford the Pinacol rearrangement with high regio- and enantioselectivity. Over 16 chiral phosphoric acids were screened, and it was found an H8-BINOL-phosphoric acid variant with 1-naphthyl groups at 3 and 3' position was the excellent catalyst. This asymmetric transformation is tolerant toward variety of substituents both on the indole ring and migrating groups. During the study, it was found that different ways to generate the catalyst had critical effect on this catalytic transformation. Only those phosphoric acids washed with HCl after column chromatography afforded the rearrangement products with high enantioselectivity. And those without treating with HCl were found contaminated by alkaline metals. These "contamination" catalysts were also found active with carbonyl activations. A highly enantioselective catalytic hetero-Diels-Alder reaction of alpha-keto esters has been developed with chiral alkaline metal phosphates. A calcium 1-naphthyl-BINOL phosphate was found to be the optimum catalyst. A large range of alpha-keto esters as well as isatins can be applied in this alkaline phosphates catalytic system with high efficiency and selectivity. The structure of the catalyst is detailed for the first time by X-ray crystal structure analysis. A proposed Transition state model is provided based on the catalyst crystal structure and Raman spectroscopy analysis. This methodology was further developed with an asymmetric Mukaiyama-Michael addition of beta,gamma-unsaturated alpha-keto ester. The best catalyst was found to be a magnesium chiral phosphate. And the transformation was found capable of tolerating a wide variety of beta,gamma-unsaturated alpha-keto esters.

Photoredox catalysis applications for the purpose of new synthetic routes in organic and sustainable chemistry are hot topics in organic synthesis today. In the present study, the synthesis of a chiral proline-based organocatalyst functionalized with 10-phenyl-10H phenothiazine (PTH) photocatalytic moietiesis investigated and attempted for the first time. PTH, an organic photocatalyst, isstudied for its photocatalytic activity in different organic reactions, such as dehalogenation of aromatic halides and the pinacol coupling reaction between aromatic aldehydes. These transformations are otherwise difficult to achieve without a suitable catalyst and the reactions were performed with moderate to high yields. / Applikationer av photoredox-katalys med syftet att generera nya syntetiska vägar inom organisk och hållbar kemi är populära ämnen i organisk syntes idag. I denna studien undersöktes för första gången syntesen av en kiral prolinbaserad organokatalysator som är funktionaliserad med fotokatalytiska enheter (10-fenyl-10H-fenotiazin (PTH)). Den fotokatalytiska aktiviteten av PTH studerades för olika organiska reaktioner, såsom t.ex. dehalogenering av aromatiska halider och pinacolkopplingar mellan aromatiska aldehyder. Dessa transformationer är annars svåra att uppnå utan en lämplig fotokatalysator och reaktionerna utfördes med måttliga till höga utbyten.

<p>This thesis deals with synthetically modified chiral molecules and their application in asymmetric catalysis. The first part of the thesis describes the use of commercially available chiral diamine ligands in the iridium catalyzed transfer hydrogenation of aromatic ketones. The chiral diamine ligands were mixed with an appropriate transition-metal complex, which after addition of suitable base provided a chiral transition metal complex capable of reducing a range of different aromatic ketones in high yields and enantioselectivities. The developed methodology constitutes a cost effective and readily available procedure for transfer hydrogenation reactions. The following chapters in the thesis are completely devoted to rational design of small organic molecules acting as catalyst in various organocatalytic transformations. Organocatalytic methodology, represent a new and complementary approach to asymmetric organic synthesis, as compared to e.g. transition metal based methodology. Advantages of this methodology typically include mild and less stringent reaction conditions. This, in combination with the lack of toxic transition metal by-products, makes the process more environmentally benign; the organocatalytic methodology, therefore represent a promising approach towards implementation of green chemistry in organic synthesis. Despite this promise, typical drawbacks of the current methodology are long reaction times and the need for high catalyst loadings. Thus, a large demand exists for enhancing reactivity and increasing selectivity in organocatalytic reactions. The present thesis describes several efforts where we have tried to rationally design improved catalysts for various enantioselective organocata-lytic reactions. First, a structurally modified L-proline, incorporating a 1H-tetrazolic acid, was synthesized and evaluated in the direct asymmetric organocatalytic aldol reaction. As shown in Paper II, the catalyst displayed very high reactivity and subsequent studies were initiated in order to rationalize the reactivity enhancement (Paper III). Delightfully, the design principle of a 1H-tetrazolic acid as replacement for a carboxylic acid has since been widely used in the community, including our own efforts in organocatalytic asymmetric cyclopropanations (Paper V)and Diels-Alder reactions (Paper VII). Novel catalysts, including other functionalizations, were also designed for organocatalytic asymmetric addition of nitroalkanes to α,β-unsaturated aldehydes (Paper IV) and for cyclopropanations (Paper VI).</p>

This thesis deals with synthetically modified chiral molecules and their application in asymmetric catalysis. The first part of the thesis describes the use of commercially available chiral diamine ligands in the iridium catalyzed transfer hydrogenation of aromatic ketones. The chiral diamine ligands were mixed with an appropriate transition-metal complex, which after addition of suitable base provided a chiral transition metal complex capable of reducing a range of different aromatic ketones in high yields and enantioselectivities. The developed methodology constitutes a cost effective and readily available procedure for transfer hydrogenation reactions. The following chapters in the thesis are completely devoted to rational design of small organic molecules acting as catalyst in various organocatalytic transformations. Organocatalytic methodology, represent a new and complementary approach to asymmetric organic synthesis, as compared to e.g. transition metal based methodology. Advantages of this methodology typically include mild and less stringent reaction conditions. This, in combination with the lack of toxic transition metal by-products, makes the process more environmentally benign; the organocatalytic methodology, therefore represent a promising approach towards implementation of green chemistry in organic synthesis. Despite this promise, typical drawbacks of the current methodology are long reaction times and the need for high catalyst loadings. Thus, a large demand exists for enhancing reactivity and increasing selectivity in organocatalytic reactions. The present thesis describes several efforts where we have tried to rationally design improved catalysts for various enantioselective organocata-lytic reactions. First, a structurally modified L-proline, incorporating a 1H-tetrazolic acid, was synthesized and evaluated in the direct asymmetric organocatalytic aldol reaction. As shown in Paper II, the catalyst displayed very high reactivity and subsequent studies were initiated in order to rationalize the reactivity enhancement (Paper III). Delightfully, the design principle of a 1H-tetrazolic acid as replacement for a carboxylic acid has since been widely used in the community, including our own efforts in organocatalytic asymmetric cyclopropanations (Paper V)and Diels-Alder reactions (Paper VII). Novel catalysts, including other functionalizations, were also designed for organocatalytic asymmetric addition of nitroalkanes to α,β-unsaturated aldehydes (Paper IV) and for cyclopropanations (Paper VI).

The thiopyran route to polypropionates is an attractive strategy that involves a stepwise iterative aldol homologation of tetrahydro-4H-thiopyran-4-one (I) with thiopyran aldehyde (II) followed by desulfurization to rapidly assemble stereochemically complex polypropionate synthons. <p>In chapter 1, the thesis is summarized in the context of relevant background research including; a) the basic principle of the thiopyran route; b) dynamic kinetic resolution of -substituted aldehydes; c) previous syntheses of serricornin; iv) previous syntheses of membrenones.<p>In chapter 2, proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various achiral aldehydes were studied. The results provided insights on the behaviour and stereoselectivity profile of thiopyranone (a crucial starting block in the thiopyran design) in the proline-catalyzed aldol reaction.<p>In chapter 3, inspired by the results of the aldol reaction of ketone (I) with achiral aldehydes, we next investigated the proline-catalyzed asymmetric aldol reactions of (I) with racemic thiopyran aldehyde (II) as a strategy to rapidly prepare enantiomerically pure tetrapropionate synthons without any requirement of enantioenriched aldehyde. The reaction occurred with high enantiotopic group selectivity and dynamic kinetic resolution.<p>In chapter 4, a detailed study to ascertain the scope and limitations of the design strategy described in chapter 3 was extended towards other catalysts, aldehydes and ketones. <p>Finally, applications of the above mentioned strategy towards the synthesis of serricornin and membrenones A and B are elaborated in chapters 5 and 6 respectively.

The thiopyran route to polypropionates is an attractive strategy that involves a stepwise iterative aldol homologation of tetrahydro-4H-thiopyran-4-one (I) with thiopyran aldehyde (II) followed by desulfurization to rapidly assemble stereochemically complex polypropionate synthons. <p>In chapter 1, the thesis is summarized in the context of relevant background research including; a) the basic principle of the thiopyran route; b) dynamic kinetic resolution of -substituted aldehydes; c) previous syntheses of serricornin; iv) previous syntheses of membrenones.<p>In chapter 2, proline-catalyzed enantioselective direct intermolecular aldol reactions of tetrahydro-4H-thiopyran-4-one with various achiral aldehydes were studied. The results provided insights on the behaviour and stereoselectivity profile of thiopyranone (a crucial starting block in the thiopyran design) in the proline-catalyzed aldol reaction.<p>In chapter 3, inspired by the results of the aldol reaction of ketone (I) with achiral aldehydes, we next investigated the proline-catalyzed asymmetric aldol reactions of (I) with racemic thiopyran aldehyde (II) as a strategy to rapidly prepare enantiomerically pure tetrapropionate synthons without any requirement of enantioenriched aldehyde. The reaction occurred with high enantiotopic group selectivity and dynamic kinetic resolution.<p>In chapter 4, a detailed study to ascertain the scope and limitations of the design strategy described in chapter 3 was extended towards other catalysts, aldehydes and ketones. <p>Finally, applications of the above mentioned strategy towards the synthesis of serricornin and membrenones A and B are elaborated in chapters 5 and 6 respectively.

This thesis details investigations into the generation and synthetic utility of α,β-unsaturated acyl ammonium intermediates using isothioureas as Lewis base organocatalysts to generate a range of heterocyclic products. Initial investigations focussed on the development of a Michael addition-lactonisation protocol utilising α,β-unsaturated acyl ammonium intermediates (generated in situ from HBTM 2.1 and α,β-unsaturated homoanhydrides) and a range of 1,3-dicarbonyl nucleophiles. Products could be isolated as lactones or as ring-opened highly functionalised esters, giving good yields and excellent enantioselectivity. 1,3-Diketones were shown to generate a mixture of regioisomers and whereas 1,3-ketoesters afforded only a single regioisomer. A crystal structure of an α,β-unsaturated acyl ammonium intermediate was obtained that clearly demonstrated steric blocking of the Si- face of the alkene by the catalyst stereodirecting groups, therefore it can be postulated that enantiocontrol in the addition occurs by selective nucleophilic addition from the Re- face. α,β-Unsaturated acyl ammonium species were then shown to participate in asymmetric annulation processes with benzazole nucleophiles to afford highly functionalised heterocyclic products, with both lactone and lactam formation observed. The relationship between nucleophile structure and process regioselectivity was investigated and it was demonstrated that benzothiazole and benzimidazole nucleophiles afforded preferential N-cyclisation to give lactams whilst benzoxazoles exhibited O-cyclisation to form lactones. It was also possible to influence the regioselectivity by changing the electronic properties of the acyl group (R'). Due to the reactivity of this class of nucleophiles it was possible to access products with quaternary centres. Palladium-catalysed cross coupling reactions were also successful on 3-bromo substituted lactams, demonstrating the potential for further derivatising these interesting heterocyclic products. Finally, a cascade protocol was developed that employed Michael-Michael-lactonisation steps to give tricyclic products from enone malonate nucleophiles and α,β-unsaturated acyl ammonium intermediates (generated in situ by addition of HBTM 2.1 into acid chlorides). Interestingly, the reaction showed higher enantioselectivity at elevated temperatures (70 ˚C) and moderate regioselectivity (1,4- vs. 1,2-addition), which could not be improved after extensive screening. A range of lactones was isolated in moderate yields and enantioselectivity.