This thesis is divided into four chapters that describe the new development in rhodium-catalyzed addition reactions and asymmetric ring opening (ARO) reactions of strained alkenes. Chapter 1 describes a regioselective Rh(I)-catalyzed addition reaction of arylboronic acids to unactivated alkenes - protected allylic amines and allyl sulfones. These formal hydroarylation processes have significantly advanced the substrate scope. Comprehensive studies were carried out to optimize the reaction conditions and a wide range of arylboronic acids were employed. The reaction was found to be linear-selective and a mechanism based on functional group- directing effects has been proposed. Chapter 2 discloses the discovery of Rh(I)-catalyzed addition of arylboronic acids to (benzyl- /arylsulfonyl)acetonitriles. Novel β-sulfonylvinylamine products were formed in a stereoselective fashion (Z-alkene). Upon hydrolysis, β-keto sulfones were obtained with a broad scope of aryl and sulfonyl substituents. These (Z)-β-sulfonylvinylamines were useful synthons in the synthesis of unsymmetrical polysubstituted pyridines via 1-aza-allyl anion intermediates as well as 1,4- benzothiazine derivatives via intramolecular cyclization. Chapter 3 reports the use of two new nucleophiles in Rh(I)-catalyzed ARO of oxabicyclic alkenes - water and triethylamine trihydrofluoride. In the water-induced ARO, an unprecedented domino ARO/isomerization process was discovered which led to the formation of 2-hydroxy-1- tetralones. By modifying the reaction conditions, trans-1,2-diols can be obtained in excellent enantioselectivity. Using triethylamine trihydrofluoride as a nucleophile, an aliphatic C-F bond was constructed enantioselectively in the ring-opening process which provided fluorinated building blocks containing both allylic fluoride and fluorohydrin units. Finally, Chapter 4 details the development of a one-pot synthesis of a chiral dihydrobenzofuran framework using Rh-catalyzed asymmetric ring opening and Pd-catalyzed C-O coupling. The product can be obtained in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an indicator.

La mélatonine est une neurohormone synthétisée au niveau de la glande pinéale durant la période nocturne chez l'ensemble des mammifères. Les sécrétions de cette hormone circulante par voie sanguine permette à tout système doté de récepteurs mélatoninergiques (MT1, MT2) de transmettre l'information de photopériode entrainant ainsi une adaptation aux périodes jour/nuit. La mélatonine est impliquée dans de nombreuses fonctions biologiques mais aussi dans diverses pathologies du système nerveux central tel que les troubles du rythmes circadien, l'anxiété, la dépression… A l'heure actuelle, il existe de nombreux ligands affins des ces récepteurs, cependant le manque de marqueurs sélectifs ralentit les recherches associées (pharmacologie). Partant de ce constat, nous avons conçu et synthétisé, selon deux approches différentes, des ligands fluorescents utilisant comme squelette de base, la structure de la mélatonine et certains analogues. Dans une première approche dite conventionnelle, les ligands mélatoninergiques sont associés à un fluorophore organique au moyen d'un bras espaceur et dans une seconde approche plus novatrice, le noyau indolique du ligand endogène est fusionné avec un pyrrole par analogie avec les fluorophores de types BODIPYs ®, puis dans une troisième partie, dérivée de la précédente, la mélatonine est fonctionnaliser par un hétérocycle azoté capable de chélater un atome de bore. Les évaluations pharmacologiques de ces composés ont montré de bonnes affinités de l'ordre du nanomolaire pour les récepteurs MT1 et MT2. Les études photophysiques ont confirmé la fluorescence induite par les fluorophores dans l'approche conventionnelle, et ont surtout montré l'existence de fluorescence par simple modification structurale de la mélatonine endogène. Les tests d'imagerie cellulaire ont également permis de valider ces méthodologies. / Melatonin is a main neurohormone synthesized in the pineal gland during the night in all mammals. Secretions of the blood circulating hormone through any system endowed melatoninergic receptors (MT1, MT2) transmit information leading to photoperiod and adaptation of the day / night periods. Melatonin is involved in many biological functions but also in various diseases of the central nervous system such as circadian rhythm disorders, anxiety, depression... Actually, there are many affinity receptors ligands, however, research on the pharmacology and the functionality of melatonin receptors suffers from the lack of selective probes for these two receptors. In order to overcome this scientific obstacle, we designed and synthesized fluorescent melatonin ligands according two different approaches. In a first conventional approach the melatoninergic ligands are tagged with an organic fluorophore via a linker. In a second approach more innovative, the indole ring of the endogenous ligand is fused with a pyrrole in order to obtain a structural analogy with the fluorophores BODIPYs types. In a third series derived from the previous one, melatonin is functionalized with a aza-heterocycle able to chelate a boron atom. Pharmacological evaluations of these compounds have shown nanomolar affinity for the receptors. Photophysical studies confirmed the fluorescence induced by the fluorescent dye in the conventional approach, and induced by simple melatonin structural modifications in the orthers. Preliminary cell imaging have also validated the methodologies.

Neste trabalho promovemos a síntese de sulfóxidos vinílicos ?-substituídos através da reação de acoplamento cruzado de Suzuki-Miyaura. Também foi feita a síntese de sulfóxidos enínicos inéditos, pela adição do nucleófilo no carbono β-sulfóxido. Esses compostos eram passíveis de serem submetidos a reação de rearranjo de Pummerer aditivo e assim gerarem uma pequena biblioteca de compostos α-tioaldeídos. Um desses aldeídos sintetizados foi empregado na reação de formação de uma imina propargílica, com consequente reação de CuAAC formando iminas triazólicas. Outras iminas arílicas foram sintetizadas, passando por uma etapa de redução, com intuito de se obter a amina livre, para que fosse feita a reação de ciclização com auxílio de um agente eletrofílico. Outra classe de composto organoenxofre foi sintetizada, as N-sulfinil imina, que após a reação de acoplamento cruzado de Sonogashira, com consequente remoção de um grupo protetor e a formação do anel heterocíclico, foram obtidos compostos triazólicos N-sulfinil imínicos. / In this work we promote the synthesis of α-substituted vinylic sulfoxides through the Suzuki-Miyaura cross coupling reaction. Also the synthesis of unpublished enynic sulfoxides was made, by the addition of the nucleophile in the β-sulfoxide carbon. These compounds were susceptible to additive Pummerer rearragement reaction and thus generated a small library of compounds. One of these aldehydes synthesized was used in the formation reaction of a propargyl imine, with consequent CuAAC reaction, forming triazol imines. Other aryl imines were synthesized, undergoing a reduction step, in order to obtain the free amine, so that the cyclization reaction was carried out with the aid of an electrophilic agent. Another class of organosulfur compound was synthesized, the N-sulfinyl imine, which after the Sonogashira cross-coupling reaction, with consequent removal of a protecting group and formation of the heterocyclic ring, N-sulfinyl imine triazolic compounds were obtained.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / We have shown that supramolecular synthons can be used to construct discrete two or three component co-crystals and 1-D inorganic-organic chains and dramatically influence the arrangement of nanoparticle assemblies. A collection of supramolecular reagents (SR's) have been designed and synthesised to carry out a systematic study into hydrogen bonding. In order to test Etter's guideline "the best proton donor and acceptor remaining after intramolecular hydrogen-bond formation will form an intermolecular hydrogen-bond" and to develop a hierarchy of interactions, a series of co-crystals between the supramolecular reagents and hydrogen-bond donors (carboxylic acids) have been synthesised. Co-crystals with pyrazole benzamide SR's have demonstrated the ability to fine-tune hydrogen-bond formation. By utilising a poor hydrogen-bond acceptor (pyrazole) the incoming carboxylic acid opts to form a heteromeric acid-amide dimer via N-H[three dots]O hydrogen bonds. Additionally, we have shown that the hydrogen-bond acceptor strength of the pyrazole can be turned up through simple covalent modifications (i.e. isomer change or addition of methyl groups to the pyrazole ring). Although the heteromeric acid-amide dimer is observed, O-H[three dots]N hydrogen bonds to the pyrazole are also observed in cases when more than one donor site is present (i.e. di-carboxylic acids and 4-hydroxybenzoic acid). Furthermore, co-crystals with picolyl-indazole and pyrimidine-pyrazole SR's agree with Etter's guideline. In all cases, the incoming carboxylic acid forms an O-H[three dots]N hydrogen bond to the best acceptor (pyridine and pyrazole, respectively). The homomeric amide-amide dimer has been used to construct inorganic-organic hybrid materials. The reaction between the pyrazole benzamide ligands with acac or "paddle-wheel" complex ions yielded 1-D chains. Furthermore, pyrimidine-bispyrazole and functionalised 1,3-bisbenzylpyrazole ligands have been utilised as chelating-ligands for reliable metal coordination. Finally, the power of supramolecular synthons to control the arrangement of much larger nanoparticle assemblies has been shown. Both homomeric (acid-acid, alcohol-alcohol) and heteromeric (acid-imidazole, alcohol-imidazole) hydrogen bonding cause significant changes in nanoparticle assemblies.

The last decade has been marked by a large increase of demand for green chemistry processes. Consequently, chemists have focused their efforts on the development of more direct routes toward different classes of targets. In that regard catalysis has played a crucial role at enabling key bond formations that were otherwise inaccessible or very energy and resources consuming. The central theme of this body of work concerns the formation of C–N bonds, either through transition metal catalysis or organocatalysis. These structural units being highly recurrent in biologically active molecules, the establishment of more efficient routes for their construction is indispensable. The first part of this thesis describes a new method for the synthesis of isoquinolines from the oxidative coupling/annulation of alkynes with N-tert-butyl benzaldimines via Rh(III) catalysis (Chapter 2). Preliminary mechanistic investigations of this system pointed to the involvement of Rh(III) in the C–H bond cleavage step as well as in the C–N bond reductive elimination that provides the desired heterocycle. Following this oxidative process, a Rh(III)-catalyzed redox-neutral approach to isoquinolones from the reaction of benzhydroxamic acids with alkynes is presented (Chapter 3). The discovery that an N–O bond contained in the substrate can act as an internal oxidant was found to be very enabling. Indeed, it allowed for milder reaction conditions, broader scope (terminal alkyne and alkene compatible) and low catalyst loadings (0.5 mol%). Mechanistic investigations on this system were also conducted to identify the nature of the C–N bond formation/N–O bond cleavage as well as the rate-determining step. The second part of this work presents mechanistic investigations performed on a recently developed intermolecular hydroamination reaction catalyzed through tethering organocatalysis (Chapter 4). This transformation operates via the reversible covalent attachment of two reactants, a hydroxylamine and an allylamine, to an aldehyde catalyst by the formation of a mixed aminal. This allows a difficult intermolecular Cope-type hydroamination to be performed intramolecularly. The main kinetic parameters associated with this reaction were determined and they allowed the generation of a more accurate catalytic cycle for this transformation. Attempts at developing new families of organocatalysts are also 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.

No description available.

<p dir="ltr">Ring strain is the driving force for numerous ring-opening reactions of three- and four-membered heterocycles. By comparison, five-membered heterocycles lack this thermodynamic driving force. As a result, only a few methods exist for the ring-opening of five-membered heterocycles using transition metal catalysts. For unstrained and unactivated 2,5-dihydrofurans this is achieved via a β-O elimination process, wherein, gaining selectivity over a competing β-H elimination is challenging. We report a novel strategy for the asymmetric ring-opening of 2,5-dihydrofurans with dichloroalkenes utilizing an earth-abundant cobalt catalyst. We propose that the dichloroalkenes form reactive vinylidene intermediates with the chiral catalyst, followed by a [2+2] cycloaddition with the heterocyclic alkene. This cobaltacyclobutane exclusively undergoes an outer-sphere β-O elimination assisted by zinc halide. Alternative inner-sphere β-O and β-H elimination pathways are inaccessible from this four-membered metallacycle. This is followed by a transmetallation step to form a zinc metallacycle, which subsequently gives rise to homoallylic alcohols, upon quenching, with high diastero- and enantioselectivity. Additionally, the organozinc intermediate can be trapped in situ by various electrophiles for further derivatizations. DFT model predicts the origin of the high diastereo- as well as enantioselectivity observed in the reaction.</p><p dir="ltr">Furthermore, the cobaltacyclobutane intermediate serves as a dynamic platform, facilitating access to a diverse array of products depending on the alkene partners employed. Utilizing chiral allylic alcohols as alkene partners leads to the translation of stereochemical information enabling the stereospecific synthesis of both <i>E</i>- and <i>Z</i>-isomers of alkenes. Alkenes are important motifs found in various natural products and bioactive compounds. A catalytic approach for the precise control of the alkene geometry is highly valuable since the stereochemistry of alkenes plays a pivotal role in determining the properties of molecules. Our strategy provides access to organozinc dienes which could be functionalized further to form highly substituted 1,4-skipped dienes. Additionally, meso-diols can undergo a desymmetrizing β-O elimination from the cobaltacyclobutane intermediate yielding chiral cyclopentenols with contiguous stereocenters</p>

No description available.

No description available.