Les spirooxindoles se retrouvent fréquemment dans les produits naturels et les composés biologiquement actifs. Certains principes actifs pharmaceutiques contenant un motif spirooxindole ont également été décrits, stimulant un grand intérêt pour la construction et la modification de ce squelette. Cependant, peu de travaux ont été réalisés pour remplacer le carbonyle en position 2 par un autre groupe fonctionnel d’intérêt. Basées sur l’expertise reconnue de notre équipe en désaromatisation d’indoles par umpolung et l’importance des fonctions CF₃ et PO(OR)₂ nous avons entrepris la synthèse de 3,3-spiroindolines substitueés en position 2 par un trifluoromethyl ou un phosphonate. Nous avons ainsi généré des radicaux trifluoromethyl ou phosphonyl par oxydation respective de trifluoromethyl sulfinate de sodium et de phosphites. Les espèces radicalaires obtenues peuvent ensuite s’additionner sur la position 2 des indoles et effectuer la désaromatisation d’indoles. / Spirooxindoles are frequently found in natural products and biologically active compounds. Certain pharmaceutical active ingredients containing a spirooxindole motif have also been described, stimulating great interest in the construction and modification of this structures. However, not a lot of work has been done to replace the carbonyl in position 2 with another functional group of interest. Based on the recognized expertise of our team in deflation of indoles by umpolung and the importance of CF₃ and PO(OR)₂ functions, we have undertaken the synthesis of 3,3-spiroindolines substituted in position 2 by a trifluoromethyl or a phosphonate . We have thus generated trifluoromethyl or phosphonyl radicals by respective oxidation of sodium trifluoromethyl sulfinate and phosphites. The radical species obtained can then be added to the position 2 of the indoles and perform the dearomatization of indoles.

N-Hetereocyclic carbenes (NHC) have been intensively investigated since Ukai et al had reported the first NHC-catalyzed coupling of two equivalents of benzaldehyde, to form what is known as the benzoin product. A plethora of reports have since been published on NHC-catalyzed reactions, such as the cross-benzoin, Stetter, redox reactions, and many others. An attractive feature of NHCs is their ability to effect the umpolung (inversion of reactivity) of aldehydes. The efforts in the introduction of β,γ-unsaturated-α-ketoesters as acceptors for the Stetter reaction have led to the first highly enantioselective intermolecular Stetter reaction with β-aryl substituted Stetter acceptors (up to >99% ee). The synthetic applications of the Stetter adducts generated from the α-ketoester acceptors were demonstrated to give access to a diverse number of useful building blocks. Furthermore, the α-ketoester substrates were found to also be applicable for the cross-benzoin reaction. Through the development of a new electron-deficient, morpholine-based triazolium-derived carbene, a highly chemo- and enantioselective cross-benzoin reaction was achieved using aliphatic aldehydes and α-ketoesters. This methodology constitutes as the first highly enantioselective intermolecular cross-benzoin reaction with aliphatic aldehydes (up to 93% ee). In addition, a highly divergent synthesis of Stetter adducts and cross-benzoin products could be achieved in excellent regioselectivity. Interested in utilizing NHCs as organocatalysts for the development of new reactions, tetrahydrofuran and prolinal derivatives were found to undergo efficient ring-expansions. This methodology gives access to highly functionalized lactones and lactams, which could serve as synthetically useful building blocks for the synthesis of natural products and biologically active compounds.

Creating new carbon-carbon bonds is one of the most important and challenging reactions in organic synthesis. Metal-catalyzed cross-coupling reactions have emerged as one of the preferred methods of producing new carbon-carbon bonds, and this work led to the 2010 Nobel Prize in Chemistry. This thesis was aimed at expanding the current research in the area of metal-catalyzed cross-coupling reactions to include new applications with dithiolane and dithiane protecting groups. 1,3-Dithiolane and 1,3-dithiane derivatives are particularly interesting molecules in that they can be deprotonated by a strong base to form anions, which can then be used for carbon-carbon bond synthesis. This thesis describes the investigation into the use of dithiolanes and dithianes in metal-catalyzed cross-coupling reactions, as well as some of the challenges faced in performing this sulfur-based chemistry.

Creating new carbon-carbon bonds is one of the most important and challenging reactions in organic synthesis. Metal-catalyzed cross-coupling reactions have emerged as one of the preferred methods of producing new carbon-carbon bonds, and this work led to the 2010 Nobel Prize in Chemistry. This thesis was aimed at expanding the current research in the area of metal-catalyzed cross-coupling reactions to include new applications with dithiolane and dithiane protecting groups. 1,3-Dithiolane and 1,3-dithiane derivatives are particularly interesting molecules in that they can be deprotonated by a strong base to form anions, which can then be used for carbon-carbon bond synthesis. This thesis describes the investigation into the use of dithiolanes and dithianes in metal-catalyzed cross-coupling reactions, as well as some of the challenges faced in performing this sulfur-based chemistry.

This work covers recent advances in the Stetter reaction, including two novel domino Stetter reactions and preliminary studies on quaternary center formation via the intermolecular Stetter reaction. The N-heterocyclic carbene (NHC) catalyzed domino Stetter-aldol-Michael dimerization of o-formyl chalcone derivatives 36 affords spiro bis-indane homo-dimers 38 in good yields and moderate to high diastereomeric ratios. Three carbon-carbon bonds, including the hindered quaternary center at the spiro ring junction, form at a remarkable rate under mild reaction conditions. Spiro bis-indanes 39 are also produced in moderate to good yields through the Stetter-aldol-aldol reactions of o-formyl chalcones 36 with phthalaldehyde derivatives 27. The scope, limitations, and potential applications of these remarkable complexity-generating domino reactions are discussed. Preliminary results in the formation of quaternary centers via the intermolecular Stetter reaction are also disclosed. The viability of β,β-disubstitued Meldrum’s acid, diethyl malonate, and malononitrile alkylidenes as well as diphenylcyclopropenone and 3-phenylcyclobutenone as acceptors in the Stetter reaction are discussed.

La méthodologie MAC consiste à employer des réactifs umpolung pour permettre l’insertion formelle d’une fonction carbonyle entre un électrophile et un nucléophile. Cette thèse est consacrée à l’oxyhomologation diastéréosélective de la L-sérine grâce à un développement significatif de la méthodologie MAC à trois composants en one-pot, conduisant à l’obtention de dérivés orthogonalement protégés de l’acide α, γ-dihydroxy-β-aminobutyrique. Ce dernier est une brique moléculaire acyclique à 4 atomes de carbone hautement fonctionnalisée qui est souvent intégrée dans les squelettes de molécules biologiquement actives.Nous avons tout d’abord étudié la synthèse de réactifs MAC silylés à partir du malononitrile. La synthèse du H-MAC-TBS a été optimisée et deux nouveaux réactifs MAC silylés, le H-MAC-TES et le H-MAC-TBDPS, ont été préparés.Dans un premier temps, nous avons étudié l’oxyhomologation du N-Boc-O-Bn-L-sérinal avec le H-MAC-TBS en présence de différents alcools dans des conditions réactionnelles douces. En présence de méthanol, des α, γ-dihydroxy-β-aminobutanoates de méthyle orthogonalement protégés ont été préparés avec des bons rendements et avec un ratio diastéréoisomérique syn/anti = 80/20.L’utilisation du H-MAC-TBDPS a permis d’améliorer la diastéréosélectivité de la réaction MAC (syn/anti = 90/10). L’étude des différents modes de cyclisation des α, γ-dihydroxy-β-aminobutanoates de méthyle a été réalisée par la suite. Des hétérocycles fonctionnalisés à 3, 5 et 6 chaînons ont été ainsi sélectivement synthétisés.De nouvelles oxazolidinones et oxazolines hautement fonctionnalisées ont été préparées de cette façon. En revanche, malgré nos efforts approfondis, une cyclisation pour donner un hétérocycle à 4 chaînons n’a pas été réalisée.L’absence de réactivité de la fonction alcool libre en α de ces esters N-protégés et γ activés a été inattendue.Dans un deuxième temps, nous avons étudié l’oxyhomologation de l’aldéhyde de Garner, un dérivé cyclique N,O-protégé du L-sérinal, par des réactions MAC. En présence de divers nucléophiles, cette réaction a conduit diastéréosélectivement à des esters et des amides protégés de l’acide α, γ-dihydroxy-β-aminobutyrique avec des bons rendements et avec une diastéréoselectivité anti, allant jusqu’à un ratio diastéréoisomérique syn/anti = 10/90 en utilisant le H-MAC-TBDPS. Il s’agit des premiers exemples de diastéréosélectivité antiobservée pour une réaction MAC. Des hétérocycles fonctionnalisés à 3 et 5 chaînons ont été sélectivement synthétisés et, grâce à une oxydation sélective en position γ, des dérivés de l’acide érythro-β-hydroxyaspartique et de l’érythro-β-hydroxyasparagine orthogonalement protégés ont été préparés. / MAC methodology is a synthetic technique which employs an umpolung reagent to formally insert a carbonyl function between an electrophile and a nucleophile. This thesis is devoted to the diastereoselective oxyhomologation of L-serine thanks to a significant development of 3-component one pot MAC methodology, providing a synthesis of orthogonally-protected derivatives of α, γ-dihydroxy-β-aminobutyric acid. This latter is a highly functionalized, acyclic, 4-carbon molecular building block which is a constituent part of various biologically active molecules.The synthesis of silylated MAC reagents from malononitrile was first studied. H-MAC-TBS’s synthesis was optimized and two new silylated MAC reagents, H-MAC-TES and H-MACTBDPS,were prepared.In a first study, the oxyhomologation of N-Boc-O-Bn-L-serinal was examined using H-MACTBS and a panel of alcohols in mild conditions.Methyl esters of orthogonally-protected α, γ-dihydroxy-β-aminobutanoic acid were prepared in good yields and with a diastereoisomeric ratio syn/anti = 80/20. The use of H-MAC-TBDPS improved the diastereoselectivity of the MAC reaction to syn/anti = 90/10.Subsequently, different cyclization modes of methyl α, γ-dihydroxy-β-aminobutanoate were investigated, leading to the selective synthesis of functionalized 3-, 5- and 6-membered ring heterocycles, including new highly functionalized oxazolidinones et oxazolines. In contrast, despite considerable efforts, we were unable to induce cyclisation to forma a 4-membered ring heterocycle, due to the surprising lack of nucleophilicity of the free alcohol function in the acyclic precursors.In a second study, we examined the oxyhomologation of Garners aldehyde, a cyclicN,O-protected derivative of L-serinal, using a selection of nucleophiles via one-pot MAC methodology. These reactions furnished protected ester and amide derivatives of α, γ-dihydroxy-β-aminobutyric acid in good yields with an anti diastereoselectivity with a ratio as high as syn/anti = 10/90 when H-MAC-TBDPS was used as the MAC reagent. These are the first known examples of MAC reactions which proceed with anti diastereoselectivity.Functionalized 3- and 5-membered ring heterocycles were prepared from these adducts,and via selective oxidation at the γ-position,orthogonally-protected derivatives of erythro-β-hydroxyaspartic acid and erythro-β-hydroxyasparagine were prepared.

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles. / October 2008

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles.

A method for the synthesis of a symmetrical fluorous tagged benzodithiol support has been developed through a seven-step synthetic pathway. The Wittig olefination and catalytic hydrogenation reactions were employed to attach two perfluoroalkyl chains in the o-positions of phthalaldehyde. These fluorous tags were used as soluble supports which facilitated the purification of the crude reaction mixtures using fluorous solid phase extraction (FSPE). A selective and high yielding dibromination reaction was developed to synthesize a fluorous tagged 1,2-dibromo aryl compound. A thorough study was carried out to demonstrate the ease of an aryl-sulfur bond formation with the 1,2-dibromo compound varying palladium catalysts and ligands. A new palladium catalyzed dithiolation reaction is reported to synthesize a surrogated dithiol, which was exploited as a precursor for the synthesis of hitherto inaccessible symmetrical fluorous tagged benzodithiol support. The utility of the benzodithiol was explored by the synthesis of benzodithianes with two aldehydes. The lithiated dithiane generated was further used to form a C-C bond employing the umpolung reaction. The ring-closing metathesis reaction using Grubbs II catalyst was performed to construct 5-membered and 6-membered spiro-ring systems. Several approaches were made to form a C-C bond with lithiated dithianes using various nitrogen containing electrophiles leading to N-heterocycles.

Le couplage croisé entre les esters allyliques et les composés carbonylés promu par le diiodure de samarium est une méthode efficace pour la formation de liaisons carbone-carbone. Une approche « umpolung » de réaction entre un composé carbonylé électrophile et un allylsamarien nucléophile, obtenu sans la réduction préalable d’espèces de type π-allylmétal de transition intermédiaires, fournirait une nouvelle voie plus simple pour la construction de cette liaison dans des conditions douces.Les esters allyliques de type dihydropyranyle se sont montrés d’excellents substrats dans les réactions d'allylation, d’aldéhydes ou de cétones, induites par le diiodure de samarium évitant ainsi l'utilisation de catalyseurs au palladium ou d’un autre additif. En série glycal, la nature et la configuration du substituant en position C-4 jouent un rôle très important à la fois sur le rendement et sur la structure des produits modifiés. Les couplages réducteurs directs ont lieu régiosélectivement en C-3 avec une stéréochimie relative 3,4-trans. La même stratégie appliquée aux dérivés Neu5Ac2en de l’acide sialique a permis d’obtenir par réactions à basse température, les produits de couplage en C-2 avec des rendements quantitatifs et une parfaite régio- et stéréosélectivité. Cette transformation donne un nouvel accès facile, rapide et très efficace aux α-C-sialosides. / The cross-coupling of allylic esters and carbonyl compounds promoted by samarium diiodide is an efficient method for the formation of carbon-carbon bonds. An umpolung approach, reaction between a carbonyl electrophile and an allyl samarium nucleophile, without the prior reduction of the intermediate π-allyl transition metal complexes, would provide a simple route for this bond construction under mild conditions.Dihydropyranyl allylic esters have been found to be excellent substrates for carbonyl allylation reactions mediated by samarium diiodide – without the use of palladium catalysts or any other additive. In glycal series, the nature and the configuration of the substituent at the C-4 position play crucial roles both on yields and structures of the modified products. The direct reductive couplings take place regioselectively at C-3 with a 3,4-trans relationship. Applied to Neu5Ac2en derivatives of sialic acid, the same strategy furnished the coupling products at the anomeric position in quantitative yields and with a perfect regio- and stereoselectivity. This transformation provides an easy, rapid and efficent access to α-C-sialosides.