Research efforts have focused on synthesis of linear, long-chain branched, and novel crosslinked polyesters for applications spanning from pressure sensitive adhesives to biomedical applications. Altering polymer topology and functionality using different synthetic strategies was enabled tailoring the thermomechanical, rheological, and adhesive properties of polyesters. The synthesis and characterization of linear, long-chain branched, and crosslinked networks are described focusing on the structure-property relationships. Aliphatic low-Tg polyesters with linear and long-chain branched topology were synthesized using melt polycondensation for pressure sensitive adhesive applications. Relationships between molecular weight, polymer composition, and adhesive performance were investigated. Melt rheological studies and the characterization of adhesive properties indicated that adhesive performance was enhanced with increasing molecular weight. Moreover, a series of long-chain branched low-Tg polyester were investigated to determine the influence of branching and molecular weight. Tailoring the degree of branching enabled the control of rheological and adhesive properties. Characterization of adhesive properties revealed that long-chain branched polymers displayed an enhanced cohesive strength. In addition, utilization of different comonomer compositions allowed tailoring thermal and adhesive properties of low-Tg polyesters over a wide range. Biodegradable networks were synthesized for the first time using base-catalyzed Michael addition of acetoacetate functionalized polyesters with acrylates. Linear and star-shaped poly(caprolactone) (PCL) oligomers with different molecular weights were functionalized and crosslinked. Thermomechanical properties were evaluated as a function of precursor molecular weight and crosslink density. The glass transition temperature and the extent of crystallinity of the networks were dependent on the molecular weight of the PCL segment. Moreover, dynamic mechanical analysis (DMA) indicated that molecular weight of the oligomeric precursors influenced the plateau modulus of the networks as a result of the differences in crosslink density of the networks. In addition, covalently crosslinked networks were synthesized from Michael addition reaction of acetoacetate-functional oligomeric poly(trimethylene succinate)s and poly(trimethylene adipate)s with neopentylglycol diacrylate. The oligomeric polyesters with telechelic hydroxyl functionality were synthesized from renewable monomers, adipic acid, succinic acid, and 1,3-propanediol using melt polycondensation. The molecular weights of the precursors were varied systematically to probe the influence of molecular weight on thermomechanical properties of the networks. The extent of crystallinity and mechanical properties were dependent on the molecular weight of the oligomeric polyester precursors which also controlled crosslink density. Moreover, Michael addition chemistry was utilized to crosslink low-Tg polyesters to improve cohesive strength for PSA applications. In order to determine the influence of temperature and catalyst levels, crosslinking reactions were monitoring using measurement of loss and storage moduli during the reaction. Networks having different levels of gel fractions were investigated to elucidate the influence of degree of crosslinking on thermomechanical and adhesive properties of low-Tg polyesters. / Ph. D.

Current research efforts have focused on the synthesis of novel, segmented, cross-linked networks and thermoplastics for emerging technologies. Tailoring macromolecular structures for improved mechanical performance can be accomplished through a variety of synthetic strategies using step-growth polymerization. The synthesis and characterization of novel Michael addition networks, ionene families, and ion-containing polyurethanes are described, with the underlying theme of fundamentally investigating the structure-property relationships of novel, segmented macromolecular architectures. In addition, it was discovered that both covalent and electrostatic crosslinking play an important role in the mechanical properties of all types of polymers described herein. Novel cross-linked networks were synthesized using quantitative base-catalyzed Michael chemistry with acetoacetate and acrylate functionalities. These novel synthetic strategies offer unique thermo-mechanical performance due to the formation of a multiphase morphology. In order to fundamentally elucidate the factors that influence the kinetics of the Michael addition reaction a detailed analyses of model compounds were conducted in the presence of an in-situ IR spectrometer to optimize reaction conditions using statistical design of experiments. Networks were then prepared based on these optimized conditions. The mechanical performance was evaluated as a function of molecular weight between crosslink points. Furthermore, the incorporation of hydrogen bonding within the monomer structure enhanced mechanical performance. The changes in morphological, thermal, and mechanical properties evaluated using dynamic mechanical analysis (DMA) and tensile behavior are described. In addition, the use of preformed urethane segments provides a safer method for incorporating hydrogen bonding functional groups into macromolecules. In order to compare the thermomechanical and morphological properties of ion-containing polyurethanes to non-charged polyurethanes, poly(tetramethylene oxide)-based polyurethanes containing either a novel phosphonium diol or 1,4-butanediol chain extenders were prepared using a prepolymer method. The novel phosphonium polyurethane was more crystalline, and it was presumed that hydrogen bonding in the non-charged polyurethane restricted polymer mobility, and reduced PTMO crystallinity, and hydrogen bonding interactions were significantly reduced due to the presence of phosphonium cations. These results correlated well with mechanical property analysis. The phase separation and ionic aggregation were demonstrated via wide-angle X-ray scattering, small-angle X-ray scattering, scanning transmission electron microscopy, and energy-dispersive X-ray spectroscopy during STEM imaging, as described herein. In addition, a novel polyurethane containing imidazolium cations in the hard segment was synthesized and behaved very similarly to the phosphonium cation-containing polyurethane. Ammonium ionenes, which contain quaternary nitrogen in the macromolecular repeating unit, have many potential uses in biomedical applications. They offer interesting coulombic properties, and the charge density is easily controlled through synthetic design. This property makes ionenes ideal polyelectrolyte models to investigate the influence of ionic aggregation on many physical properties. Ammonium ionenes were prepared via the Menshutkin reaction from 1,12-dibromododecane and 1,12-bis(N,N-dimethylamino)dodecane. The absolute molecular weights were determined for the first time using an on-line multi-angle laser light scattering (MALLS) in aqueous size exclusion chromatography (SEC). Tensile testing and DMA were used to establish structure-property relationships between molecular weight and mechanical properties for a series of 12,12-ammonium ionenes. Furthermore, degradation studies in the presence of base support the possibility for water-soluble coatings with excellent mechanical durability that are amenable to triggered depolymerization. A novel synthetic strategy was utilized to prepare chain extended 12,12-ammonium ionenes containing cinnamate functional groups. In the presence of UV light, the polymers chain extended, and the resulting ionenes possessed enhanced thermomechanical properties and increased molecular weight. In addition, the novel synthesis of imidazolium ionenes was demonstrated, and the charge density was tuned for appropriate applications using either low molecular weight segments or oligomeric precursors. The change in charge density had a profound role in imidazolium ionene thermal and mechanical behavior. / Ph. D.

Ion-containing macromolecules continue to stimulate new opportunities for emerging electro-active applications ranging from high performance energy devices to water purification membranes. Progress in polymer synthesis and engineering now permit well-defined, ion-containing macromolecules with tunable morphologies, mechanical performance, ion conductivity, and 3D structure in order to address these globally challenged technologies. Achieving tailored chemical compositions with high degrees of phase separation for optimizing conductivity and water adsorption remains a constant synthetic challenge and presents an exciting opportunity for engineering sophisticated macromolecular architectures. This dissertation will introduce unprecedented charged polymers using conventional free radical and anionic polymerization to incorporate ionic functionalities based on phosphonium cations. This new class of copolymers offers unique properties with ionic functionality for tailorable electro-active performance. / Ph. D.

Die Desymmetrisierung eines p-Benzochinon-Monoacetals durch organokatalytische Sulfa-Michael-Addition stellte den C-Ring-Baustein für eine Formalsynthese von (-)-Codein bereit. Mittels diastereoselektiver 1,2-Addition zur A/C-Ringverknüpfung, intramolekularer Nitron-Cycloaddition zur Konstruktion des Phenanthren-Gerüsts und Sulfoxid-Eliminierung konnte das Schlüsselintermediat einer früheren racemischen Codeinsynthese über 12 Stufen ausgehend von Isovanillin in enantiomerenreiner Form verfügbar gemacht werden.

As lipases têm um papel importante no desenvolvimento da biotecnologia e são empregadas na química orgânica como biocatalisadores com alta regio- quimio- e enantiosseletividade. Além de permitir sínteses mais sustentáveis e que estão em concordância com os princípios da Química Verde. A resolução enzimática de aminas racêmicas tem se mostrado uma maneira eficiente de obter aminas enantiomericamente puras, que podem ser empregadas na síntese assimétrica de fármacos e agroquímicos. Neste trabalho a resolução enzimática de 4 aminas primárias sendo elas 2-amino-heptano 1, 2-metil-cicloexil amina 3, 1-metil-3-fenilpropilamina 2, 1,2,3,4-tetra-hidro-1-naftilamina 4, foram estudadas obtendo-se resultados relevantes. Para a 2-amino-heptano 1 resultados semelhantes aos da literatura foram obtidos com uma redução de 2,4 vezes no tempo reacional quando a resolução cinética foi em hexano na presença de CAL-B e acetato de etila como acilante obteve-se uma conversão na (R)-N-(1-metil-hexil)acetamida 4 de 42% e um excesso enantiomérico de 88% (tempo = 7h). Observaram-se também os efeitos da concentração de lipase no meio reacional, da temperatura e de diferentes solventes frente a 11 lipases. Os primeiros estudos de resolução cinética enzimática com a 2-metilcicloexil-amina 3 são apresentados neste trabalho com conversões de até 98% porém sem excesso enantiomérico. Uma outra característica das lipases é a capacidade de catalisar reações diferentes da sua função natural (promiscuidade), o que permite que elas catalisem reações de adição de Michael, além de suas reações normais que são a hidrólise e esterificação. A adição de Michael catalisada por lipases entre as 4 aminas primárias já citadas e acrilonitrila foi estudada com e sem a influência da irradiação micro-ondas, demonstrando a maior estabilidade de lipases imobilizadas sob irradiação micro-ondas. Os adutos de Michael obtidos (3-[(1-metil-hexil)amino]propanonitrila 9, 3-[(1-metil-3-fenilpropil) amino]propanonitrila 10, 3-[(2-metil cicloexil)amino]propanonitrila 11 e 3-(1,2,3,4-tetra-hidronaftaleno-1-amino)propanonitrila 12) foram sintetizados pela primeira vez com a metodologia onde foi utilizada a água, acrilonitrila e irradiação micro-ondas e os adutos 9, 10 e 11 não são descritos na literatura. Outro viés do trabalho foi a clonagem e expressão da álcool desidrogenase de Bacillus subtilis que foi clonada, expressa e purificada com sucesso. O interesse em tal enzima deve-se a resultados obtidos na literatura onde a utilização de células íntegras de B. subtilis apresentou a redução de cetonas a álcoois com alta enantiosseletividade. / Lipases present an important role in the development of biotechnology and are employed as biocatalysts in organic chemistry with high regio-, quimioand enantioselectivity. Besides allowing more sustainable syntheses that are consistent with the principles of Green Chemistry. The enzymatic resolution of amines has been shown to be an efficient way to obtain enantiomerically pure amines, which can be used in asymmetric synthesis of pharmaceuticals and agrochemicals. In this work the enzymatic resolution of 4 primary amines them being 2-amino-heptane textbf 1, 2-methyl-cyclohexyl amine 3, 1-methyl-3-phenylpropylamine 2 1.2 ,3,4-tetrahydro-1-naphthylamine 4 were studied by obtaining relevant results. For the 2-amino-heptane 1 promoted results similar to the literature and were obtained with a 2.4 times reduction of the reactional time when the kinetic resolution was in hexane in the presence of CAL-B and ethyl acetate as acylating obtained a conversion in (R)-N-(1-methyl-cyclohexyl) acetamide 4 by 42 % and an enantiomeric excess of 88 % (time = 7h). We studied the effects of the concentration of lipase in the reaction, temperature and solvent using 11 different lipases. The first studies of enzymatic kinetic resolution with 2-methyl-cyclohexyl- amine 3 are presented in this work with conversions up to 98% but without enantiomeric excess. The ability of lipases to catalyze reactions with different natural function (promiscuity) is an important property, which allows them to catalyze Michael addition reactions beyond their normal reactions, the hydrolysis and esterification. The Michael addition catalyzed by lipases between the four aforementioned primary amines and acrylonitrile was studied with and without the influence of microwave irradiation, demonstrating the greater stability of immobilized lipases under microwave irradiation. The Michael adducts obtained (3 - [(1-methylhexyl) amino] propanonitrile 9, 3 - [(1-methyl-3-phenylpropyl) amino] propanonitrile 10, 3 - [(2 - methyl cyclohexyl) amino] propanonitrile 11 and 3 - (1,2,3,4-tetrahydronaphthalene-1-amino) propanonitrile 12) were first synthesized with the method where water is used, acrylonitrile and microwave radiation, the adducts 9,10 and 11 are not described in the literature. Another investigation of this study was the cloning and expression of alcohol desidrogrenase of Bacillus subtilis which has been cloned, expressed and purified successfully. Interest in the enzyme due to results in the literature where the use of whole cells of B. subtilis showed the reduction of ketones with high enantioselectivity.

As lipases têm um papel importante no desenvolvimento da biotecnologia e são empregadas na química orgânica como biocatalisadores com alta regio- quimio- e enantiosseletividade. Além de permitir sínteses mais sustentáveis e que estão em concordância com os princípios da Química Verde. A resolução enzimática de aminas racêmicas tem se mostrado uma maneira eficiente de obter aminas enantiomericamente puras, que podem ser empregadas na síntese assimétrica de fármacos e agroquímicos. Neste trabalho a resolução enzimática de 4 aminas primárias sendo elas 2-amino-heptano 1, 2-metil-cicloexil amina 3, 1-metil-3-fenilpropilamina 2, 1,2,3,4-tetra-hidro-1-naftilamina 4, foram estudadas obtendo-se resultados relevantes. Para a 2-amino-heptano 1 resultados semelhantes aos da literatura foram obtidos com uma redução de 2,4 vezes no tempo reacional quando a resolução cinética foi em hexano na presença de CAL-B e acetato de etila como acilante obteve-se uma conversão na (R)-N-(1-metil-hexil)acetamida 4 de 42% e um excesso enantiomérico de 88% (tempo = 7h). Observaram-se também os efeitos da concentração de lipase no meio reacional, da temperatura e de diferentes solventes frente a 11 lipases. Os primeiros estudos de resolução cinética enzimática com a 2-metilcicloexil-amina 3 são apresentados neste trabalho com conversões de até 98% porém sem excesso enantiomérico. Uma outra característica das lipases é a capacidade de catalisar reações diferentes da sua função natural (promiscuidade), o que permite que elas catalisem reações de adição de Michael, além de suas reações normais que são a hidrólise e esterificação. A adição de Michael catalisada por lipases entre as 4 aminas primárias já citadas e acrilonitrila foi estudada com e sem a influência da irradiação micro-ondas, demonstrando a maior estabilidade de lipases imobilizadas sob irradiação micro-ondas. Os adutos de Michael obtidos (3-[(1-metil-hexil)amino]propanonitrila 9, 3-[(1-metil-3-fenilpropil) amino]propanonitrila 10, 3-[(2-metil cicloexil)amino]propanonitrila 11 e 3-(1,2,3,4-tetra-hidronaftaleno-1-amino)propanonitrila 12) foram sintetizados pela primeira vez com a metodologia onde foi utilizada a água, acrilonitrila e irradiação micro-ondas e os adutos 9, 10 e 11 não são descritos na literatura. Outro viés do trabalho foi a clonagem e expressão da álcool desidrogenase de Bacillus subtilis que foi clonada, expressa e purificada com sucesso. O interesse em tal enzima deve-se a resultados obtidos na literatura onde a utilização de células íntegras de B. subtilis apresentou a redução de cetonas a álcoois com alta enantiosseletividade. / Lipases present an important role in the development of biotechnology and are employed as biocatalysts in organic chemistry with high regio-, quimioand enantioselectivity. Besides allowing more sustainable syntheses that are consistent with the principles of Green Chemistry. The enzymatic resolution of amines has been shown to be an efficient way to obtain enantiomerically pure amines, which can be used in asymmetric synthesis of pharmaceuticals and agrochemicals. In this work the enzymatic resolution of 4 primary amines them being 2-amino-heptane textbf 1, 2-methyl-cyclohexyl amine 3, 1-methyl-3-phenylpropylamine 2 1.2 ,3,4-tetrahydro-1-naphthylamine 4 were studied by obtaining relevant results. For the 2-amino-heptane 1 promoted results similar to the literature and were obtained with a 2.4 times reduction of the reactional time when the kinetic resolution was in hexane in the presence of CAL-B and ethyl acetate as acylating obtained a conversion in (R)-N-(1-methyl-cyclohexyl) acetamide 4 by 42 % and an enantiomeric excess of 88 % (time = 7h). We studied the effects of the concentration of lipase in the reaction, temperature and solvent using 11 different lipases. The first studies of enzymatic kinetic resolution with 2-methyl-cyclohexyl- amine 3 are presented in this work with conversions up to 98% but without enantiomeric excess. The ability of lipases to catalyze reactions with different natural function (promiscuity) is an important property, which allows them to catalyze Michael addition reactions beyond their normal reactions, the hydrolysis and esterification. The Michael addition catalyzed by lipases between the four aforementioned primary amines and acrylonitrile was studied with and without the influence of microwave irradiation, demonstrating the greater stability of immobilized lipases under microwave irradiation. The Michael adducts obtained (3 - [(1-methylhexyl) amino] propanonitrile 9, 3 - [(1-methyl-3-phenylpropyl) amino] propanonitrile 10, 3 - [(2 - methyl cyclohexyl) amino] propanonitrile 11 and 3 - (1,2,3,4-tetrahydronaphthalene-1-amino) propanonitrile 12) were first synthesized with the method where water is used, acrylonitrile and microwave radiation, the adducts 9,10 and 11 are not described in the literature. Another investigation of this study was the cloning and expression of alcohol desidrogrenase of Bacillus subtilis which has been cloned, expressed and purified successfully. Interest in the enzyme due to results in the literature where the use of whole cells of B. subtilis showed the reduction of ketones with high enantioselectivity.

Small molecule walkers developed to date take advantage of the reversibility of dynamic covalent bond formation to transport molecular fragments along molecular tracks using both diffusion processes and ratchet mechanisms. However, external intervention (the addition of chemical reagents and/or irradiation with light) is required to mediate each step taken by the walker unit in systems reported so far. In this Thesis, the first synthetic small molecule able to walk back-and-forth upon an oligoethylenimine track without external intervention via intramolecular Michael and retro- Michael reactions is described. The 1D random walk is highly processive and exchange takes place between adjacent amine groups in a stepwise fashion. The walker is used to perform a simple task: quenching of the fluorescence of an anthracene group situated at one end of the track as a result of the walking progress. In the presence of excess of base, the molecule preferentially ‘walks’ towards the favoured final foothold of tracks of increasing length and it is possible to monitor the population of all or a few positional isomers over time. In each case the molar fraction of walkers reaching the final foothold is determined quantitatively by 1H NMR. Control over the rate of exchange is achieved by varying the amount of base added. The dynamic migration of a small molecule upon the track is a diffusion process limited to one dimension and as such can in principle be described using the one dimensional random walk. Chapter I identifies a set of fundamental walker characteristics and includes an overview of the DNA-based and small molecule transporting systems published to date. Chapter II describes the inspiration for this work and model studies which lay the groundwork for the research presented in this thesis. The initial track architecture and optimisation of reaction conditions are demonstrated using a simple model compound which then led to the development and a detailed investigation of a first synthetic small molecule able to walk upon an oligoethylenimine track without external intervention. Chapter III presents a modified synthetic route towards the desired walker-track architectures and a comprehensive investigation of the dynamic properties of a series of tracks of increasing length upon which the walker migrates in a unidirectional fashion. The Outlook contains closing remarks about the scope and significance of the presented work as well as ideas for the design of novel small-molecule walkers, some of which are well under way in the laboratory. Chapter II (with the exception of model studies included at the beginning of the chapter) is presented in the form of article that has recently been published. No attempt has been made to re-write this work out of context other than merging content of the article with the supplementary information published together with the article. Chapter II is reproduced in the Appendix in its published format.

Biomolecules are difficult to investigate in their native environment. The vast complexity of cellular systems and seldom availability of chemical reactions compatible with the physiological milieu make it a challenging task. Bioorthogonal chemical reactions serve as a key to achieve selective ligation, whose components must react rapidly and selectively with each other under physiological conditions in the presence of the plethora of functionalities necessary to sustain life. In this dissertation, we focused on the synthesis of chemical reporters and probe molecules for bioorthogonal labeling through click reaction. Initially, sialic acid derivatives with a linker containing terminal alkyne functionality were synthesized. After the synthesis of azide derivatives of fluorescent dyes as counter partners, they were conjugated with sialic acids through Cu(I) catalyzed alkyne azide cycloaddition (CuAAC). The successful in vitro conjugation of Sia and fluorescent dyes was followed by metabolic tagging of human larynx carcinoma (HEp-2) and the carcinoma of Chinese hamster ovary (CHO­K1) with alkynated Sia that were subsequently ligated with fluorescein azide. Finally, the stained cells were subjected to fluorescent microscopy to obtain their images. To enable the click reaction compatible to in vivo applications, the reactivity of cyclooctyne was enhanced by two different approaches. In a first approach, following the Bertozzi’s strategy, two fluorine atoms were introduced adjacent to the alkyne to lower the LUMO. In a second strategy the ring strain of cyclooctyne was attempted to be enhanced by the introduction of an amide group. In addition, glutarimide derivatives with free amino and carboxylic acid functional groups were synthesized by domino-Michael addition-cyclization-reaction. / Biomoleküle sind schwer in ihrer natürlichen Umgebung zu untersuchen. Die enorme Komplexizität zellulärer Systeme und die geringe Verfügbarkeit von chemischen Reaktionen, welche mit physiologischen Bedingungen kompatibel sind, stellen eine große Herausforderung dar. Bioorthogonale Reaktionen dienen hierbei als Schlüssel für eine selektive Ligation, bei der die Komponenten schnell, selektiv und unter genannten Bedingungen miteinander reagieren. Der Fokus dieser Dissertation lag auf der Synthese von chemischen Reportermolekülen, welche für bioorthogonale Markierungsversuche mithilfe einer Klick-Reaktion eingesetzt werden können. Dafür wurden zunächst Derivate der Sialinsäure mit einem Linker, der eine endständige Alkinfunktion trägt, synthetisiert und diese mit ebenfalls in dieser Arbeit dargestellten Azidofluoreszenzfarbstoffen in einer Cu(I)-katalysierten Alkin-Azid-Cycloaddition (CuAAC) konjugiert. Nach erfolgreicher in vitro Durchführung wurden Zellen des menschlichen Larynx Karzinoms (HEp-2) und Zellen des Ovariumkarzinoms des chinesischen Hamsters metabolisch mit alkinfunktionalisierten Sialinsäuren markiert und anschließend mit Fluoresceinazid ligiert. Fluoreszenzmikroskopie an diesen Zellen demonstrierte den erfolgreichen Einbau der Sialinderivate. Um die Klickreaktion verträglicher für in vivo Anwendungen zu gestalten, wurde versucht die Reaktivität des Cyclooctin durch zwei verschiedene Herangehensweisen zu erhöhen. Zum einen wurden nach Strategie von Bertozzi zwei Fluoratome benachbart zur Alkingruppe eingeführt, um die LUMO-Energie zu erniedrigen. Zum anderen wurde versucht die Ringspannung des Cyclooctin durch Einführung einer Amidgruppe zu erhöhen. Neben dem Klickprojekt wurden in dieser Arbeit außerdem Glutarimidderivate mit freien Amino- und Carbonsäuregruppen über eine Domino-Michael-Additions-Zyklisierungsreaktion dargestellt.

Notre thèse s'intéresse à l'étude de séquences réactionnelles permeettant la création de carbones quaternaires. Deux séquences de réactions sont envisagées : - La première s'inscrit dans le prolongement des travaux de J-M. Adam et combine une réaction d'allylmétallation asymétrique et une réaction de cycloaddition [2+2] intramoléculaire. Elle conduit à des cyclobutanones bicycliques portant un substituant méthyle en tête de pont. La réaction d'allylmétallation a tout d'abord été étudiée en version catalytique pour la réaction modèle d'addition d'un dérivé d'allylsilane, le 1,3-bis-triméthylsilylpropène, sur le benzaldéhyde, en présence d'une quantité catalytique d'inducteur de chiralité. Différents catalyseurs ont pour ce faire été envisagés. La réaction d'allylmétallation asymétrique en version non catalytique a ensuite été reprise en vue de la synthèse de différents alcools homoallyliques porteurs d'un groupement silylé en a de la fonction hydroxyle. Deux inducteurs de chiralité différents ont été testés : le (R,R)-ClCpTiTADDOL et le (-)-(b)-méthoxydiisopinocamphéylborane. Dans cette réaction, la sélectivité est contrôlée par les ligands chiraux du métal. La réaction de cycloaddition [2+2] intramoléculaire a lieu entre une oléfine terminale et un cation cétène-iminium formé in situ ; elle conduit à des cyclobutanones bicycliques. Le contrôle de la sélectivité de cette étape est régi par l'effet b du silicium. Nous avons étudié les limitations de la méthode en synthétisant des cyclobutanones bicycliques de différentes tailles et porteuses d'un carbone quaternaire en tête de pont. - La seconde séquence étudiée implique une addition de Michaël, suivie d'une cyclopentannélation symétrique. Dans cette partie de notre travail, nous avons poursuivi les travaux de P. Schanen en vue de la catalyse organique de la réaction d'addition de Michaël. Nous avons étudié la réaction d'addition de différents nucléophiles sur la cyclohexénone en présence de catalyseurs dérivés de la (L)-proline ou d'imidazolidinone. Une étude de la variation de la nature du nucléophile ainsi que du contre-ion est proposée. / Our thesis studies reactions sequences leading to the formation of quaternary carbons. Two reactions sequences are envisaged: - The first one follows the work done by J-M. Adam and combines an asymmetric allylmetallation and an intramolecular [2+2] cycloaddition. This sequence leads to bicyclic cyclobutanones bearing a methyl substituent in bridgehead position. The allylmetallation has first been studied catalytically for the model reaction of addition of 1,3-bis-triméthylsilylpropene on benzaldehyde in the presence of a catalytic amount of chiral inducer. Various catalysts have been tested. The non catalytic asymmetric allylmetallation has then been used towards the synthesis of various homoallylic alcohols bearing a silyl group poistioned a to the hydroxyl function. Two chiral inducers have been tested: (R,R)-ClCpTiTADDOL and (-)-(b)-methoxydiisopinocampheylborane. At this step, selectivity is directed by chiral ligands on the metal. The intramolecular [2+2} cycloaddition reaction takes place between a terminal olefin and a ketene iminium cation formed in situ. This reaction leads to bicyclic cyclobutanones. The selectivity control at this step is directed by the b-effect of silicon. We have studied the limitations of the method by synthesizing bicyclic cyclobutanones of various sizes and bearing a bridgehead quaternary carbon. -The second reaction sequence combines a Michael addition and an asymmetric cyclopentannulation. In this part, we have pursued the work done by P. Schanen and studied the organic catalysis of the Michael addition reaction. We heva studied the addition reaction of various nucleophiles on cyclohexenone in the presence of catalysts derived from (L)-proline or imidazolidinone. A study of the variation of the nature of thee nucleophile as well as of the counter-ion is proposed.

A number of 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-m</strong>) were prepared from the reaction between triallylborane and the corresponding 3,3'-disubstituted binaphthols. These chiral allylboronates could allylate carbonyl compounds to produce chiral homoallylic alcohols in high chemical and optical yields. Chiral ligands were readily recycled through simple acid-base extraction. Among all allylboronates tested, 3,3'-(CF₃)₂-BINOL-modified allylboronate (<strong>2. 42b</strong>) is an especially effective reagent that allows for allylborations of both aldehydes and ketones in high enantioselectivities (up to 98% yield and >99% <em>ee</em>). Reagent <strong>2. 42b</strong> represents one of the best allylation reagents for carbonyl compounds developed thus far. <br /><br /> Allylations of cyclic imines using 3,3'-disubstituted binaphthol-modified allylboronates (<strong>2. 42a-j</strong>) were carried out at low temperature. 3,3'-Bis[3,5-(CF₃)₂-C₆H₃]-binaphthol-modified allylboronate (<strong>2. 42j</strong>) gave the best enantioselectivities (91% <em>ee</em> to >99% <em>ee</em>) in the allylation of a variety of cyclic imines. This methodology represents the first successful enantioselective allylboration of cyclic imines. The versatility of the allylation products (chiral a-allyl cyclic amines) was demonstrated through efficient total syntheses of several naturally occurring alkaloids such as coniine, crispine A and corynantheidol. <br /><br /> 3,3'-Disubstituted binaphthol-modified alkynylboronates (<strong>4. 47a-g</strong>) were synthesized according to a reported procedure. It was found that these chiral alkynylboronates add to <em>N</em>-acylaldimines in an enantioselective manner to produce chiral propargylamides in excellent yields and enantioselectivities. Up to >99% <em>ee</em> could be obtained with 3,3'-diphenyl binaphthol-modified alkynylboronates (<strong>4. 47f</strong>). This represents the first direct asymmetric synthesis of chiral propargylamides. Using this methodology, an antitubulin agent (-)-<em>N</em>-acetylcolchinol (AstraZeneca® ZD6126 phenol) was synthesized in 4 steps from commercially available 3-hydroxybenzaldehyde. <br /><br /> During a study of the asymmetric conjugate alkynylation of enones via chiral alkynylboronates, it was found that achiral dialkyl alkynylboronates could add to enones enantioselectively in the presence of catalytic amounts of chiral bidentate ligands (such as 3,3'-disubstituted binaphthols, diisopropyl tartrate and activated chiral amino acids). A catalytic cycle driven by "ligand-exchange" processes was proposed to rationalize this asymmetric induction. This is the first reported example of an asymmetric reaction that is promoted by a catalytic amount of an exchangeable chiral ligand on the boron reagent. More importantly, we have demonstrated a proof of principle that ligand exchange with boronates can be sufficiently fast that catalytic amounts of chiral ligands can be used to effect high levels of stereoselectivity. This catalytic protocol can potentially be applied to other asymmetric reactions providing the following three requirements are met: (1) the starting achiral boronate does not react with the electrophile (no background reaction); (2) the chiral boronate reacts with the electrophile and (3) ligand exchange or transesterification occurs under the reaction conditions. Potential applications of this principle include asymmetric allylboration, hydroboration, aldol reaction and reduction, just to name a few.