Im Rahmen der vorliegenden Dissertation wurden drei neue Zugangswege zu kettenverlängerten Kohlenhydraten aus ungeschützten Aldosen entwickelt. Dabei ermöglichen diese Protokolle die Synthese verschiedener Klassen von kettenverlängerten Strukturen. Neben der selektiven Darstellung von 2-Ketoaldonsäurederivaten konnten effiziente Zugangsstrategien zu hoch funktionalisierten bizyklischen C-Glycosiden und polyhydroxylierten Pseudopeptiden präsentiert werden. Dabei konnte gezeigt werden, dass ein breites Spektrum dieser verschiedenen Arten kettenverlängerter Kohlenhydrate aus ungeschützten natürlichen Hexose- und Pentose-Substraten zugänglich ist. Durch den Einbezug der natürlich vorhandenen Hydroxylgruppen der Aldosen ermöglichen die präsentierten Kaskadenreaktionen einen sehr effektiven Zugang zu hoch funktionalisierten Produkten, welche in Sequenzen unter Verwendung von Schützungsstrategien nur in aufwendigen, mehrstufigen Reaktionen zugänglich wären. Zudem konnte gezeigt werden, dass die natürlich vorkommende Chiralität in den verwendeten Substraten für ein stereoselektives Dirigieren der neu installierten Stereozentren nutzbar ist. Damit konnte eine bedeutende Erweiterung des bestehenden Repertoires von Methoden für die Verlängerung ungeschützter Kohlenhydrate erreicht werden.. Die entwickelten Transformationen bestechen durch ihre hohe Atomökonomie, wie auch durch ihre sehr gute ökologische und ökonomische Bilanz und erfüllen damit die Anforderungen an nachhaltige Synthesemethoden. / The scope of the presented work was the investigation of new organocatalysed synthesis strategies of carbon chain elongated carbohydrates. Here three new accesses to three different structure motifs of these biologically highly important and manifold compounds from unprotected carbohydrates were developed. Using naturally occurring, unprotected pentoses and hexoses, a wide variety of keto aldonic acids, bicyclic C-glycosides and glycosylated pseudopeptides are accessible in three different cascade reactions. All of the presented strategies enable the C-chain elongation by employment of the naturally occurring aldehyde motive without tedious protection ad deprotection protocols or synthetic modifications of the substrates. By utilisation of the chiral hydroxyl moieties of the carbohydrate chain, diastereoselective control of the installation of the stereocenters formed in the cascade reactions is achieved. The high regio- and diastereoselectivities, high yields as well as the convenient synthesis conditions of the presented protocols make the presented cascade reactions valuable tools among the already described accesses to the biological important compounds of chain elongated carbohydrates. The presented cascades enable the diastereoselective synthesis of a high variety of these motifs in only one synthetic step from readily available unprotected carbohydrates without additional modification steps. These advantages give rise to a very high atom economy of the transformations, which therefore fulfil the requirements to green chemistry and sustainable synthesis methods.

Notre étude porte sur le développement de réactions énantiosélectives organocatalysées de type aza-Morita-Baylis-Hillman (azaMBH). Nous avons commencé par synthétiser de nouveaux catalyseurs bifonctionnels dérivés de la β-isocupréidine. Nous avons ensuite utilisé ces catalyseurs pour mettre au point une version multi-composants monotope séquentielle de la réaction d’azaMBH à partir d’aldéhydes aliphatiques.Une méthode de synthèse efficace d’adduits d’azaMBH N-Boc protégés a ensuite été développée, à partir d’imines, d’amidosulfones, ainsi qu’en version multi-composants.Afin de mieux comprendre le processus réactionnel, nous nous sommes ensuite intéressés en détail aux études mécanistiques réalisées sur les réactions de MBH et d’azaMBH, avant de réaliser une étude de modélisation moléculaire avec le Dr Elise Tran.Puis nous avons utilisé des allènoates en tant qu’accepteurs de Michael, ce qui nous a conduit à la formation de deux produits : l’adduit d’azaMBH et une azétidine, issue d’une cyclisation [2+2]. Une nouvelle série d’organocatalyseurs dérivés de la quinidine ont alors été synthétisés, ce qui a permis de former exclusivement le produit azétidine avec d’excellents rendements et énantiosélectivités / This study is about the development of enantioselective, organocatalyzed aza-Morita-Baylis-Hillman’s type reactions (azaMBH). First, new bifunctionnal catalysts derived from the β-isocupreidin ewere synthetized. They were used to elaborate a one-pot multi-component aza-MBH reaction, involving aliphatic aldehydes.A new synthetic method for N-Boc protected azaMBH adducts has then been developed, starting from imines and amidosulfones.In order to better understand the transformation process, the mechanistic studies on the MBH and azaMBH reactions were examined. Then, we carried out a molecular modeling study with Dr Elise Tran.Finally, we disclosed abnormal aza-Baylis-Hillman reactions of imines with allenoates as Michael acceptors providing an easy access to azaMBH adducts and azetidines. A new series of organocatalysts derived from the quinidine was synthetized. Those were used to obtain exclusively the azetidine compounds, with excellent yields and enantioselectivities.

Cette thèse se divise en trois parties. La première partie concerne nos approches vers la fonctionnalisation régiosélective d’imines, générées in situ dans le milieu réactionnel. En particulier, nous avons développé une méthode de synthèse d’α-amidosulfures qui furent ensuite utilisés comme plateforme pour accéder à des α-aryles amines aliphatiques par réaction de Friedel-Crafts déclenchée par du NIS. La seconde partie de ce travail rapporte la synthèse de spirobiindane rigides optiquement actifs, que nous avons ensuite utilisés comme plateforme pour former des organocatalyseurs de type acides phosphoriques. Ces derniers furent ensuite exploités dans le développement d’une réaction de cycloaddition [3+2] -optionnellement amorcée par du PIDA- donnant accès à des 2,3-dihydrobenzofuranes optiquement actifs. Enfin, dans une dernière partie, deux séquences réactionnelles furent développées, donnant accès à des iodoarènes iodés : les BINIs et SPINIs ortho-diarylés. Ces structures furent engagées en organocatalyse, et ont permis d’apporter une approche rationnelle aux mécanismes d’induction asymétrique impliquant des espèces iodés hypervalentes. / This thesis is divided in three parts. The first part deals with our approaches toward regioselective functionalization of in situ generated imines. In particular, we had developed a synthesis of α-amidosulfides, which were used as substrates to access aliphatics α-aryles amines through a NIS-triggered Friedel-Crafts reaction. Second part of this work describe the synthesis of spirobiindane-based organocatalysts, which were used in a [3+2] cycloaddition - optionally triggered with PIDA - leading to optically actives 2,3-dihydrobenzofurans. Finally, two synthetic pathways were developed to form new class of aryliodides: diaryls BINIs & SPINIs. Those scaffolds were exploited to bring a rational explanation of chirality transfer in reactions using hypervalent iodine species.

O dióxido de carbono no estado supercrítico (CO2-SC) tem despertado considerável interesse nos últimos anos como um novo solvente para reações orgânicas. Nesta tese foi investigada a influência do uso de CO2 supercrítico, associado ou não a líquidos iônicos ou cossolventes, como solvente em reações químicas visando à obtenção de precursores quirais. Foram estudadas as reações de condensação Aldólica, de Morita-Baylis-Hillman (MBH) e do tipo adição de Michael, empregando Organocatálise quando conveniente, isto é, catalisadores provenientes de aminoácidos e ácidos carboxílicos. As reações de MBH foram otimizadas através de um planejamento experimental e sua condição ótima se deu a 70°C, 110 bar, com 6 equivalentes de H2O, tempo reacional de 2h30 min e sem a presença de liquido iônico, tendo um rendimento de 84,6%. Para as condensações aldólicas os melhores resultados com acetona e p-nitrobenzaldeido como materiais de partida foram obtidos a 150 bar e 40°C, com a presença de liquido iônico, em 2 horas de tempo reacional com um rendimento de 54,0% e um excesso enantiomérico de 79,0% utilizando o catalisador (2S,4R)-4-(terc-butildimetilsililoxi)pirrolidina-2-ácido carboxílico. Com ciclohexanona como material de partida foram obtidos a 150 bar e 40°C com a presença de um doador de prótons (resina de troca iônica) em 2 horas de tempo reacional com um rendimento de 70,9% e um excesso enantiomérico de 91,2%, utilizando o catalisador (2S,4R)-4-(terc-butildimetilsililoxi)pirrolidina-2-ácido carboxílico. Outros aldeídos e cetonas utilizados como materiais de partida apresentaram rendimentos menores. Estudos de comportamento de fases foram feitos para os materiais de partida, catalisadores e produtos da reação de condensação Aldólica. Os melhores rendimentos foram obtidos em situações em que os materiais de partida e os catalisadores eram solúveis na fase supercrítica, mas os produtos não, formando uma segunda fase. / Supercritical carbon dioxide (sc-CO2) has attracted considerable interest in the last years as a new solvent for organic reactions. In this thesis, the influence of supercritical CO2 use, associated or not to ionic liquids or cosolvents, as a solvent for chemical reactions aiming at the synthesis of chiral precursors was studied. Aldol condensation, Morita-Baylis-Hillman (MBH) and Michael addition reactions were studied, employing organocatalysis when it was convenient, i.e., catalysts derived from aminoacids or carboxylic acids. MBH reactions were optimized through experimental design, resulting in a maximum yield of 84.6% for the optimal condition at 70°C, 110 bar, and 6 equivalents of H2O, reaction time of 2h30 min and the absence of ionic liquids. For the Aldol condensation reactions employing acetone and p-nitrobenzaldehyde, a maximum yield of 54.0%, with an enantiomeric excess of 79.0% was obtained at 150 bar, 40°C, 2h reaction time, in the presence of ionic liquid, using the catalyst (2S,4R)-4-(terc-butyldimethylsililoxy)pirrolidine-2-carboxylic acid. The yields were significantly lower for other aldehydes and ketones. Yields for Michael addition reactions were very low and their study was discontinued. Phase behavior studies were performed with starting materials, catalysts and products for the Aldol condensation reactions. The best yields were obtained for situations where the starting materials and catalysts were soluble in the supercritical phase and the products were not, forming a second phase.

La formation de liaisons carbone-carbone est primordiale dans le domaine de la chimie organique. Parmi les nombreuses méthodes existantes, les réactions de métathèse des oléf ines et de chimie radicalaire constituent deux techniques de choix mais n'ont été que très rarement utilisées de façon concomitante en synthèse organique. Cette constatation a été le point de départ de ces travaux de thèse dont le but a alors été d'appliquer ces deux réactions à la synthèse de molécules aux possibles propriétés biologiques. Une première étude combinant les réactions de métathèse qu'elles soient croisées ou d'énynes, et de cyclisation de type radicalaire ou de Heck, a été menée et a permis l'obtention de molécules à forte valeur ajoutée : des sultames à six chaînons et une nouvelle famille de spiro-sultames. Une seconde étude a quant à elle utilisé pour la première fois de façon séquentielle et en un seul pot les réactions de photodéconjugaison et de métathèse cyclisante permettant d'aboutir à la synthèse de composés intéressants mais difficiles à préparer, à savoir des lactones α,β-insaturées possédant un groupement alkyle en position α. Un troisième sujet utilisant à la fois les réactions d'addition de Michael asymétrique organocatalysée et de cyclisation radicalaire induite par le diiodure de samarium a permis de synthétiser des cyclopentanols trisubstitués comportant trois stéréocentres contigus. Enfin, une approche synthétique vers la nhatrangine A, molécule naturelle possédant six centres stéréogènes, et la synthèse totale du (+)-guaymasol ont été réalisées / Carbon-carbon bond formation constitutes a crucial research field in organic chemistry. Among all existing methods, olefin metathesis and radical reactions are particularly attractive ones but were rarely used in a concomitant way. That was the starting point of this PhD work, whose aim was to apply these two reactions to the synthesis of molecules having a potential biological interest. The first topic which was taken up was the use of cross- or enyne metathesis combined with a radical or an Heck cyclization for the synthesis of very valuable compounds : sultams and their spirocyclic derivatives. The second subject allowed the synthesis of α,β-unsaturated lactones bearing an alkyl group at the α position by using for the first time, in a one-pot and sequential manner, photochemistry and ringclosing metathesis. The third study led to cyclopentanol derivatives bearing three contiguous stereocentres by associating organocatalysis and radical cyclization induced by the use of samarium diiodide. Last but not least, a synthetic approach to nhatrangin A, natural compound holding six stereocentres, and total synthesis of (+)-guaymasol were carried out

En la present Tesi s’han abordat dos camps de gran actualitat en la Química Orgànica actual, l’organocatàlisi i la catàlisi promoguda per complexos d’Au(III). En ambdós blocs s’han orientat els esforços en la recerca de nous mètodes sintètics o en aprofundir en els ja existents a fi de millorar−los; sense perdre de vista en cap cas la seva aplicabilitat a casos sintètics reals. En el primer Bloc s’ha tractat de solucionar el problema de la lentitud de moltes de les transformacions organocatalíques. S’ha trobat com la oxazolidinona derivada de la condensació de la L−prolina amb el pivalaldehid (oxazolidinona de Seebach, d’ara endavant SolPro) permet dur a terme reaccions aldòliques entre cetones i aldehids en tan sols dues hores, millorant significativament molts dels temps de reacció descrits en la literatura. Els estudis per RMN de 1H van permetre de determinar que el procés clau era el bescanvi del pivalaldehid amb la cetona corresponent. També es van realitzar una sèrie de càlculs teòrics a fi d’esbrinar quin o quins podien ser els mecanismes implicats en aquests bescanvis. En el darrer capítol del Bloc 1 s’ha avaluat l’activitat catalítica de la SolPro en la reacció de Michael entre nitroalcans i cetones alfa,beta−insaturades, trobant−se que també l’accelera però no de manera tan espectacular com en el cas de l’aldòlica. En el segon Bloc s’han estudiat diverses transformacions que involucren, directa o indirectament, el grup nitro. En el capítol 2.2 s’han preparat diverses N−sulfenilimines quirals amb un procediment desenvolupat recentment en el nostre grup de recerca. En el capítol 2.3 s’ha posat a punt un mètode d’hidròlisi d’N−sulfenilimines realment suau i que evita la racemització dels estereocentres en alfa. Després d’haver provat diversos àcids de Lewis s’ha trobat que l’ús de quantitats catalítiques d’AuBr3 més l’addició de nitrit d’isoamil, permet d’obtenir cetones quirals a partir de la corresponent N−sulfenilimina. A més, és possible acoblar el mètode de formació d’N−sulfenilimines amb el d’hidròlisi d’aquestes, de manera que s’ha desenvolupat una reacció de Nef formal que transcorre en condicions molt suaus (pH pràcticament neutre) i sense racemització dels estereocentres en alfa. En el capítol 2.4 s’ha estudiat la transformació d’oximes a carbonils. De nou, l’AuBr3 s’ha mostrat com l’únic àcid de Lewis que permet la formació de cetones (o aldehids) a partir d’oximes. S’ha aconseguit que el procés sigui catalític si s’empra biacetil o isovaleraldehid com additius. Les condicions en les que té lloc la reacció són suaus (si bé el pH baixa lleugera o moderadament durant el decurs de la reacció). S’ha fet un estudi pioner per Espectrometria de Masses en Electroesprai en mode negatiu a fi de conèixer els detalls mecanístics, trobant−se que les espècies de tipus AuBrx(OH)y─ són les predominants i com la oxima s’hi coordina desplaçant Br─. El mètode s’ha aplicat a més d’una vintena de cetoximes i aldoximes obtenint−se resultats excel•lents. / This Thesis deals about Organocatalysis and gold−mediated catalysis, two fields that have experienced a rapid growth in recent years. In both sections, the efforts have been focused in the development of new synthetic methodologies or in gaining insight into existing procedures in order to improve them. In the first section, we attempted to solve the problem of the slow rate of some organocatalytic transformations. Several oxazolidinones were prepared and then were tested in aldol reactions between ketones and aldehydes. The most efficient was Seebach’s oxazolidinone (SolPro). With this catalyst aldol reaction take less than 2 hours. Exchanges between pìvalaldehyde and different ketones were proved by 1H-NMR studies which suggested that these exchanges are essential in the mechanism. Finally, in chapter 1.5, the scope of the catalytic activity of SolPro was evaluated in a Michael reaction between nitroalkanes and alpha, beta-unsaturated ketones. Transformations in which the nitro group is involved were studied in the second section. In chapter 2.2 several chiral N-sulphenylimines were prepared according a novel procedure developed in our group. In chapter 2.3 a novel method to hydrolyze N-sulphenylimines was developed, which works in very mild conditions (room temperature, almost neutral pH) and avoids the racemization of alpha stereocenters. After an exhaustive screening of several Lewis acids, only AuBr3 catalyzed the reaction at neutral pH and afforded the corresponding ketone without racemization of alpha-stereocenters. Finally, in chapter 2.4, the transformation of oximes into carbonyl compounds was studied. Again, only AuBr3 was able to perform the hydrolysis of oximes into ketones (or aldehydes) in mild conditions (although the pH decreased slightly or moderately during the reaction). A pioneering study by Mass Spectroscopy (Electrospray in negative mode) showed that oximes coordinate to species like AuBrx(OH)y─ and this coordination is crucial in order to obtain the carbonyl compound.

<p>This thesis describes strategies for and examples ofcellulose fiber modification.The ability of an engineered biocatalyst, acellulose-binding module fused to the<i>Candida antarctica</i>lipase B, to catalyze ring-openingpolymerization of e-caprolactone in close proximity tocellulose fiber surfaces was explored. The water content in thesystem was found to regulate the polymer molecular weight,whereas the temperature primarily influenced the reaction rate.The hydrophobicity of the cellulose sample increased as aresult of the presence of surface-deposited polyester.</p><p>A two-step enzymatic method was also investigated. Here,Candida antarctica lipase B catalyzed the acylation ofxyloglucan oligosaccharides.The modified carbohydrates werethen incorporated into longer xyloglucan molecules through theaction of a xyloglucan endotransglycosylase. The modifiedxyloglucan chains were finally deposited on a cellulosesubstrate.</p><p>The action of<i>Candida antarctica</i>lipase B was further investigated inthe copolymerization of e-caprolactone and D,L-lactide.Copolymerizations with different e-caprolactone-to-D,L-lactideratios were carried out. Initially, the polymerization wasslowed by the presence of D,L-lactide. During this stage,D,L-lactide was consumed more rapidly than ε-caprolactoneand the incorporation occurred dimer-wise with regard to thelactic acid units.</p><p>Morphological studies on wood fibers were conducted using asol-gel mineralization method. The replicas produced werestudied, without additional sample preparation, by electronmicroscopy and nitrogen adsorption. Information concerning thestructure and accessibility of the porous fiber wall wasobtained. Studies of never-dried kraft pulp casts revealedmicro-cavities and cellulose fibrils with mean widths of 4.7(±2) and 3.6 (±1) nm, respectively.</p><p>Finally, cationic catalysis by simple carboxylic acids wasstudied. L-Lactic acid was shown to catalyze the ring-openingpolymerization of ε-caprolactone in bulk at 120 °C.The reaction was initiated with methylß-D-glucopyranoside, sucrose or raffinose, which resultedin carbohydrate-functionalized polyesters. The regioselectivityof the acylation was well in agreement with the correspondinglipase-catalyzed reaction. The polymerization was alsoinitiated with a hexahydroxy-functional compound, whichresulted in a dendrimer-like star polymer. The L-lactic acidwas readily recycled, which made consecutive reactions usingthe same catalyst possible.</p><p><b>Keywords:</b><i>Candida antarctica</i>lipase B, cationic catalysis,cellulose-binding module, dendrimer, enzymatic polymerization,fiber modification, silica-cast replica, sol-gelmineralization, organocatalysis, xyloglucanendotransglycosylase</p>

This thesis is divided into three main results chapters that reflect the path my research took. In the first results chapter, the first organocatalyst for the carbonyl-ene reaction was discovered and found to give high conversion using 1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea. Various carbonyl and alkene precursors were examined in the ene reaction in both catalysed and uncatalysed reactions. It was found that ene reactions using fluoral and ethyl trifluoropyruvate give higher rates of reaction when compared to other carbonyl compounds. A novel enantiopure thiourea was synthesised and the ene reaction was catalysed enantioselectively to 33% e.e. In an attempt to catalyse the reaction to a further extent a new thiourea bonded to a P(=S)R2 group was developed. However, the intramolecular hydrogen bonding of this catalyst was thought to be so strong that this it did not catalyse the reaction. The synthesis of a chiral phosphoric acid was achieved but this was an unsuccessful catalyst in the ene reaction. Two component achiral thiourea and chiral acids were also examined in the ene and Mannich-type reaction. The new easily synthesised thiourea for this reaction has an interesting intermolecular hydrogen bonding coordination in the solid state. Asymmetric fluorination of ketoesters using palladium is a dynamic kinetic resolution. In the 2nd chapter cationic palladium complexes were synthesised and used to determine the optimum parameters for bidentate ligands in this reaction. Four carbon chain phosphines were found to give the highest conversion for this reaction among those ligands tested such as 1,4-bisdiphenylphosphinobutane (bite angle 99º). A new bis-phosphinous amide chiral ligand was developed with a bite angle of 96.7º. The dichloropalladium complex of this phosphine was isolated and structurally characterised. The use of the palladium complex in asymmetric fluorination was attempted however this was found to be unsuccessful. Mechanistic studies reveal that the formation of the desired cationic catalyst did not occur under conditions shown to work well for other palladium phosphine complexes. The ligand was investigated further in hydrogenation reactions. The phosphinous amide was protected as its borane and was used in the rhodium catalysed hydrogenation of alkenes to give high conversion and up to 93% e.e. The borane protected phosphinous amide was also found to catalyse the hydrogenation of acetophenone using copper complexes with up to 84% e.e for the hydrogenation of acetophenone, although conversion was quite low.

The first part of the thesis deals with the synthesis and biological evaluation of new platelets aggregation inhibitors, based on 12-HETE, 13-HODE and their analogues. In the second part we are interested in novel methodologies for the preparation of CF₂-containing molecules : First, a flexible strategy for the synthesis of gem-difluoro-bisarylic derivatives and heteroaromatic analogues was designed based on the easy synthesis and the reactivity of gem-difluoro propargylic intermediates, which by Diels-Alder cycloaddition and 1,3-dipolar cycloadditions afforded respectively the bisarylic and mixed arylic heteroarylic scaffolds. In addition, two small libraries were constructed around a bisarylic scaffold as representative examples. Second, we were interested in the synthesis of optically active functionalized molecules containing a gem-difluoro group, using asymmetric organocatalysis protocols. After preparation of the gem-difluoro enals, from their difluoropropargylic precursors, asymmetric organocalytic Diels-Alder cycloaddition and 1,4-conjugated additions were successfully performed.

Au cours des dernières années, l'utilisation des carbènes N-hétérocycliques (NHCs) en tant qu'organocatalyseurs a connu un succès impressionnant. Dans ce manuscrit, nous présentons le design et la synthèse de nouveaux organocatalyseurs NHC bifonctionnels, et leurs applications pour la chimie énantiosélective des homoénolates. En parallèle de ces études, une approche conceptuellement nouvelle aux carbènes de pyridine est proposée et exploitée dans une réaction à trois composants originale. Globalement, ce travail contribue au progrès de la connaissance sur l'utilisation des carbènes comme organocatalyseurs et intermédiaires réactionnels. / N-heterocyclic carbenes (NHCs) have become extremely popular organocatalysts in last decade. In this manuscript, we present our work in the design and the synthesis of a new class of bifunctional NHC organocatalysts, and their applications in enantioselective reactions with homoenolate equivalents. Additionally, a conceptually new synthetic approach to pyrid-2-ylidene carbenes is proposed and used in an original three-component reaction. In a broad sense, this work contributes to the progress of knowledge on the use of NHCs as organocatalysts and reaction intermediates.