Rozprawy doktorskie na temat „Facile Michael Addition Reaction”

The work focused on addressing four main objectives. The first objective was to quantify protein and amino acid substitution reactions. Michael addition reactions were used to modify the amino acids and protein. Amino acids alanine, cysteine, and lysine, and protein ovalbumin (OA) were substituted with different concentrations of ethyl vinyl sulfone (EVS). The substituted products were analyzed using Raman spectroscopy and UV-spectroscopy based ninhydrin assay. In case of alanine, Raman and UV results correlated with each other. With cysteine at lower EVS substitutions amine on the main chain was the preferred site while the substitution shifted to thiols at higher substitutions. This could only be discerned using Raman spectroscopy. Lysine has amines on the main chain and side chain while main chain amine was the most reactive site at lower concentrations of EVS while at higher concentrations side chain amines were also substituted. This information could be discerned using Raman spectroscopy only and not UV spectroscopy. In case of protein as observed by Raman and UV spectroscopy the reaction continued at higher concentrations of EVS indicating the participation of glutamine and asparagines at higher substitutions. However, the reaction considerably slowed down at higher EVS substitutions. The second objective of the study was to decrease the glass transition temperature (Tg) of OA through internal plasticization and also study the effects of the substituents on the thermal stability of OA. The hypothesis was by covalently attaching substituents to OA, number of hydrogen bonds can be reduced while increasing the free volume and this would reduce Tg. EVS, acrylic acid (AA), butadiene sulfone (BS) and maleimide (MA) were the four groups used. EVS was the most efficient plasticizer of all the four substituents. The Tg decreased with the increasing concentration of EVS until all of the reactive of groups on OA were used up. Tg decreased slightly with AA and BS while no change was observed with MA. However, the substituents showed exact opposite trend in thermal stability as measured using thermogravimetric analysis (TGA). The thermal stability of MA substituted OA was the highest and that of EVS substituted OA was least. FT-IR spectroscopy results indicated that all four substituents caused structural changes in OA. This implied that there were intermolecular interactions between substituted protein chains in case of AA, BS, and MA. This caused an increase in the thermal stability. EVS on the other hand is a linear chain monomer with a hydrophobic end group and hence could not participate in the intermolecular interactions and hence caused a decrease in Tg. As mentioned above the limitation to this technique is the number of available reactive groups on the protein. However, we successfully demonstrated the feasibility of this method in decreasing Tg of protein. The third objective was to create hydrogels by crosslinking OA with divinyl sulfone (DVS). Protein hydrogels due to their biocompatible nature find applications in drug delivery and tissue engineering. For tissue engineering applications the hydrogels need to be mechanically stable. In this study the protein was substituted with EVS or AA and then crosslinked with DVS. The swelling ratio was measured as a function of pH. All the hydrogels showed the same trend and swelled the least at pH 4.5 which is the isoelectric point of the protein. At basic pH conditions EVS substituted hydrogels swelled the most while AA substituted hydrogels showed least swelling. The static and dynamic moduli of the hydrogels were determined using tensile tester and rheometer respectively. The static modulus values were three times the dynamic modulus. The modulus of the control which is crosslinked OA was least and that of AA substituted OA was highest. The stress relaxation test also showed similar results in which AA substituted OA relaxed the most and the control relaxed the least. FT-IR of the dry hydrogels showed that the amount of hydrogen bonding increased with AA substitution. The hydrophilic AA end groups interacted with each other forming hydrogen bonds. These hydrogen bonds served as additional crosslinks there by increasing the modulus of the hydrogels. EVS on the other hand was incapable of interactions due to the lack of hydrophilic end groups. We were successfully able to create protein hydrogels and control the swelling and mechanical properties by varying the amount of substituted group. The final objective of the study was to create and characterize microstructures from substituted alanine and lysine. Alanine and lysine were substituted with different concentrations of EVS. Bars and fibers were observed for alanine at moderate substitutions while at higher concentrations random structures were observed using scanning electron microscopy (SEM). Lysine formed tubes at moderate EVS substitutions and rosettes at high concentrations of EVS as evidenced by SEM. FT-IR results suggested that instead of carbonyl one of sulfonyl bonded to the available amine in modified amino acids. And only in this case fibers, tubes and rosettes were observed. X-ray diffraction (XRD) results supported this observation. Using these results we hypothesized that the self assembled structures very much depended on the amount of EVS present in the substituted product and sulfonyl forming β-sheet analogs with amine.
Ph. D.

Asymmetric organocatalysed reactions are one of the most fascinating synthetic strategies which one can adopt in order to induct a desired chirality into a reaction product. From all the possible practical applications of small organic molecules in catalytic reaction, amine–based catalysis has attracted a lot of attention during the past two decades. The high interest in asymmetric aminocatalytic pathways is to account to the huge variety of carbonyl compounds that can be functionalized by many different reactions of their corresponding chiral–enamine or –iminium ion as activated nucleophile and electrophile, respectively. Starting from the employment of L–Proline, many useful substrates have been proposed in order to further enhance the catalytic performances of these reaction in terms of enantiomeric excess values, yield, conversion of the substrate and turnover number. In particular, in the last decade the use of chiral and quasi–enantiomeric primary amine species has got a lot of attention in the field. Contemporaneously, many studies have been carried out in order to highlight the mechanism through which these kinds of substrates induct chirality into the desired products. In this scenario, computational chemistry has played a crucial role due to the possibility of simulating and studying any kind of reaction and the transition state structures involved. In the present work the transition state geometries of primary amine–catalysed Michael addition reaction of cyclohexanone to trans–β–nitrostyrene with different organic acid cocatalysts has been studied through different computational techniques such as density functional theory based quantum mechanics calculation and force–field directed molecular simulations.

En raison de leur grande performance, leur prix peu élevé, et leur abondance sur la terre, les catalyseurs de fer ont été choisis pour être testés dans trois différentes transformations de la chimie organique. Le premier projet concerne les réactions asymétriques de Diels-Alder catalysées par Fe⁺¹¹¹ et le ligand bipyridine chiral à des dérivés α, β-insaturés de l’oxazolidin-2-one. Dans un premier temps, nous avons testé différents solvants, diverses quantités en catalyseur, temps de réaction variés et divers sels de fer tels que Fe(ClO₄)₂·6H₂O, Fe(ClO₄)₂·6H₂O, Fe(OTf)₃, Fe(OTf)₂, FeCl₂, FeCl₃, FeBr₃ et FeI₃. Nous avons constaté que 2 mol% de Fe(ClO₄)₃·6H₂O, 2.4 mol% de ligand bipyridine chiral utilisés à –30 °C dans CH₃CN, conduisait à un très bon rendement (99%) et à un bon excès énantiomérique (98%) pour la réaction entre le cyclopentadiène et la 3-alcénoyl-1,3-oxazolidin-2-one. Ensuite, un grand nombre de diénophiles et de diènes moins réactifs ont été testés. Globalement, moins de 10 mol% de catalyseur a été utilisé. L’avantage de ce projet est de pouvoir réaliser la réaction à une température modérée, utiliser de très faibles quantités de catalyseur, obtenir de très bons rendements et d’excellentes énantiosélectivités, et avec une large gamme de substrats. Par la suite, les catalyseurs de fer ont été appliqués aux additions de thia-Michael par deux approches différentes. La première consiste en additions de thia-Michael catalysées par Fe(OTf)₂ dans l’éthanol à température ambiante. Cette méthode permet aux additions de thia-Michael d'être catalysées par un sel de fer vert et beaucoup plus écologique, en quantité catalytique (5 mol% de Fe(OTf)₂), dans un solvant couramment utilisé, EtOH, à température douce, et à atmosphère ambiante. L’avantage de cette réaction a été démontré en l’appliquant à différents accepteurs de Michael et à des thiols aliphatiques et aromatiques. La deuxième méthode consiste en des additions de thia-Michael, catalysées par Fe(OTf)₂ dans le 2-Me-THF, qui est en accord avec les principes de chimie verte en utilisant un sel de vert, Fe(OTf)₂, et un solvant vert 2-Me-THF à température ambiante ou à 50 °C sous air. Le dernier projet est l'allylation asymétrique catalysée par le Fe(OTf)₂ portant un ligand chiral. Avec l'étude d'une variété de ligands chiraux, nous avons sélectionné 5 mol% de Fe(OTf)₂ et 6 mol% de ligand Pybox qui ont catalysé la réaction avec un bon rendement (70%) et 32% d'excès énantiomérique. 20 mol% de TMSCl se sont avérés essentiels pour l'efficacité de la réaction
Iron catalysts are employed in three different organic transformations owing to their advantages: environmental friendliness, being less expensive and abundant on the Earth. The first project deals with asymmetric Diels-Alder reactions of α, β-unsaturated oxazolidin-2-one derivatives catalyzed by Fe¹¹¹ and a chiral bipyridine ligand. In order to obtain the optimized reaction conditions, we screened different solvents, catalyst loading, various reaction times and a variety of iron salts such as Fe(ClO₄)₂·6H₂O, Fe(ClO₄)₂·6H₂O, Fe(OTf)₃, Fe(OTf)₂, FeCl₂, FeCl₃, FeBr₃ and FeI₃. As a result, the reaction between cyclopentadiene and 3-alkenoyl-1,3-oxazolidin-2-one was carried out at –30 °C in CH₃CN in 1.5 h, with Fe(ClO₄)₃·6H₂O (2 mol%) complexed with the chiral bipyridine ligand (2.4 mol%) as catalyst, providing an excellent yield (99%) and an excellent enantiomeric excess (98%). Decreased enantioselectivities were observed for less-reactive dienes. Overall, less than 10 mol% of catalyst loading was employed. The great advantages of this project are the mild reaction temperature, very low catalyst loading, excellent yields and enantioselectivities and the applicability to a wide scope of substrates. Meanwhile, iron catalysts were used in thia-Michael additions by two different approaches. The first one is about thia-Michael additions catalyzed by Fe(OTf)₂ in EtOH at room temperature. This green method allows the thia-Michael additions to be catalyzed by a green iron salt (5 mol% of Fe(OTf)₂), a green and commonly used solvent EtOH at room temperature under ambient atmosphere. The generality of this reaction was demonstrated by applying it to different Michael acceptors, and to aromatic and aliphatic thiols. The second method is about thia-Michael additions catalyzed by Fe(OTf)₂ in 2-Me-THF, which is in agreement with the green chemistry principles by using a green Fe(OTf)₂ and a green solvent 2-Me-THF at room temperature or 50 °C under air atmosphere. The last project is about asymmetric allylation reactions catalyzed by Fe(OTf)₂ using a chiral ligand. With the study of a variety of chiral ligands, we selected 5 mol% of Fe(OTf)₂ and 6 mol% of Pybox ligand which catalyzed the reaction in good yield (70%) and 32% of ee. The utilization of 20 mol% of TMSCl is essential for the effectiveness of the reaction

Il focus di questo dottorato è stato lo sviluppo di due reazioni organocatalitiche e stereoselettive: le addizioni di sulfa-Michael e le condensazioni di Darzens poiché rappresentano degli approcci sintetici interessanti per la sintesi di farmaci chirali e, nell’ambito farmaceutico, ci sono pochi principi attivi (API) sintetizzati con reazioni di SMAs e/o di Darzens organocatalitiche e stereoselettive. Nell’ambito delle addizioni di sulfa-Michael (SMAs), la catalisi mediata da molecole bifunzionali donatrici di legami ad idrogeno (HBD) rappresenta un approccio interessante per l'attivazione sia della componente nucleofila che di quella elettrofila di una reazione. Gli esempi di SMA stereoselettive catalizzate da HBD bifunzionali e aventi il trans-chalcone come accettore di Michael sono pochi. Con l’obiettivo di ottimizzare l’attivitá dei catalizzatori HBD, la letteratura suggerisce come l'aumento dell'acidità dei protoni tioureici NH abbia effetti positivi sulle velocità di alcune reazioni. Spinto da queste informazioni, si è deciso di eseguire un'analisi comparativa di alcuni catalizzatori HBD in SMA stereoselettive aventi il trans-calcone come accettore di Michael. All’inizio, abbiamo studiato l'effetto della quantitá di catalizzatore, del solvente e della temperatura nella reazione modello: l'addizione del fenilmetantiolo al trans-calcone. Successivamente, con le condizioni di reazione ottimizzate, abbiamo valutato la capacità di indurre stereoselezione da parte di alcuni catalizzatori HBDs nelle SMAs stereoselettive del benzentiolo, fenilmetantiolo e 2-feniletantiolo al trans-calcone. L'aumento dell'acidità di Brønsted nella porzione donatrice di legami ad idrogeno ha dato, in alcuni casi, reazioni più rapide ma, in generale, ha avuto un impatto negativo sulla stereoselettività. Inoltre, il prodotto ottenuto dall’addizione del benzentiolo al trans-calcone è risultato stereochimicamente instabile, poiché subisce una reazione di retro-Michael quando lasciato in presenza di catalizzatori, come nel caso di un ritardato work-up della reazione. Per quanto riguarda le condensazioni di Darzens, generalmente, sono condotte in presenza di basi forti come idrossidi o alcossidi di metalli alcalini, sodio ammide, LDA, LiHMDS o n-butil-litio. In letteratura, non ci sono esempi di reazioni di Darzens condotte in presenza di basi organiche neutre. Quindi, si è deciso di studiare la reazione di Darzens in presenza di basi organiche neutre aventi una diversa pKBH+. La reazione, in presenza di una quantità stechiometrica di fosfazene P1-t-Bu, genera gli epossidi cis e trans con una buona resa e con un breve tempo di reazione. Tuttavia, sia i problemi di stabilità che le difficoltà di preparazione delle basi fosfazeniche, rendono importante l’obiettivo di identificare nuove superbasi. A tal fine, è stata valutata la ciclopropenimmina, con una pKBH+ simile a quella di P1-t-Bu. Con l’impiego di una quantità stechiometrica di ciclopropenimmina, l'epossido è stato ottenuto con una resa fino al 34% e 1/0.85 d.r. cis/trans. Usando una quantità catalitica di ciclopropenimmina (30 mol%), i composti α,β-epossicarbonilici sono stati ottenuti con una resa fino all'86% e 1/0.6 d.r. cis/trans; dimostrando di essere tollerante sia alle variazioni strutturali che alle proprietà elettroniche delle aldeidi aromatiche e dei composti carbonilici impiegati.

Ce travail de thèse porte sur la synthèse de nouveaux composés chiraux à partir de l’isosorbide et de l’isomannide en vue de leurs applications en catalyse asymétrique. Dans une première partie, de nouvelles monophosphines ont été synthétisées et appliquées en tant que ligands dans la réaction d'hydrogénation asymétrique d’oléfines. Des excès énantiomériques jusqu’à 96% ont été observés. Elles ont également été employées en tant que catalyseurs organiques dans les réactions de cyclisation [3 +2]. De bonnes activités catalytiques et des excès énantiomériques modestes sont obtenus. Dans une deuxième partie, une série de composés azotés chiraux a été synthétisée en 3 à 4 étapes avec de bons rendements globaux. Ils ont été testés en tant que ligands dans la réaction de réduction de cétones aromatiques par transfert d’hydrogène. Des excès énantiomériques jusqu’à 73% ont été obtenus. La réaction d’addition de phénylacétylène sur d’imines a également été étudiée. Les complexes formés se sont montrés actifs mais pas très énantiosélectifs. Ces composés azotés ont également été utilisés en tant que catalyseurs organiques dans la réaction d’addition de Michael de cétones aromatiques sur le nitrostyrène. Toutefois, ils n’ont permis de conduire qu’à de faibles énantiosélectivités. Dans une dernière partie, des composés de type thiourée ont été synthétisés en 5 étapes. Ces thiourées ont été appliquées en catalyse organique dans la réaction d’alkylation de type Friedel-Crafts entre différents substrats indoliques et nitrooléfines, et dans la réaction d’addition conjuguée des hydroxylamines sur des pyrazoles pour la synthèse de dérivés β-aminoacides. Ces catalyseurs se sont révélés actifs mais peu énantiosélectifs
The Thesis deals with the synthesis of new chiral compounds derived from isosorbide and isomannide and their applications to asymmetric catalysis. The first part of this work consisted in perfecting the chemical and enantioselective hydrogenation conditions of olefins using chiral monophosphines as ligands (up to 96% ee). These phosphines were also used as organocatalysts for [3+2] cyclisation reactions showing good catalytic activity and moderate enantioselectivity. The second part turned to the synthesis of a series of chiral nitrogen compounds which were evaluated in the asymmetric transfer hydrogenation of aromatic ketones giving good enantioselectivity (up to 73% ee). The complexes formed with amine ligands were also applied to the addition reaction of phenylacetylene to imines. Good catalytic activity but low enantioselectivity were observed. These nitrogen compounds were also used as organocatalysts in the Michael addition reaction of aromatic ketones to the nitrostyrene. Again, low enantiomeric excess was obtained. The last part of this work consisted in preparing new chiral thiourea compounds which were applied as organocatalysts to the Friedel-Crafts alkylation reaction of different indoles with nitroolefines, and to the conjugate addition reaction of hydroxylamines to pyrazoles derivatives for the synthesis of β-amino acids. In two cases, these catalysts have proved active but not enantioselective

De nos jours, une des stratégies majeures dans la modulation de la pharmacocinétique des composés bioactifs est leur vectorisation et l’obtention de formes prodrogues. Ce travail est centré sur la vectorisation d’antitumoraux phosphorés à l’aide de peptides favorisant le passage membranaire. Nous avons alors réalisé la conjugaison d’aminoalkyl-bisphosphonates avec des séquences peptidiques afin de modifier leur temps de rétention dans l’organisme et d’augmenter leur internalisation cellulaire. Différents espaceurs possédant un motif carbonylé insaturé ont été évalués dans le couplage par la réaction d’addition aza- et thiaMichael afin d’aboutir à l’obtention d’un conjugué peptide-alendronate. Une approche prodrogue a également été réalisée avec la synthèse de dérivés de type bisphosphinates et l’obtention d’un analogue de l’alendronate
Nowadays, one of the main strategies for pharmacokinetic modifications of bioactive compounds is their vectorization and the synthesis of prodrug derivatives. This work is focused on the vectorization of phosphorus antitumor agents with cell-penetrating peptides. We have then conjugated aminoalkyl-bisphosphonates with peptidic sequence to modify their retention time and increase their cellular internalization. Several linkers bearing an insaturated carbonyl moiety have been evaluated in conjugation by aza- and thia-Michael addition reaction to obtain a conjugated peptide-alendronate compounds. A prodrug approach has been conducted with the synthesis of bisphosphinate derivatives and an analog of alendronate has been obtained

Les énamines β-lithiées sont obtenues par bromation des énamines puis échange halogène-métal et réagissent directement avec les esters α, β-éthyléniques exclusivement en 1,4 conduisant après hydrolyse aux énaminoesters correspondants. Ces composés sont obtenus avec de bons rendements et présentent une rétention de configuration par rapport aux énamines β-bromées de départ. L'énolate intermédiairement formé a été condensé sur l'iodure de méthyle conduisant à la création d'un carbone stéréogénique supplémentaire. Dans ce cas les nouveaux énaminoesters sont obtenus avec une excellente diastéréosélectivité. L'hydrolyse des énaminoesters conduit, selon les conditions utilisées, aux cétoesters ou aux cétoacides correspondants avec en général une très bonne diastéréosélectivité. En utilisant des énamines β-lithiées achirales sur des esters α, β-éthyléniques d'alcool chiral, les excès diastéréoisomériques ont été moyens. Par contre la réaction de Michael entre une énamine β-lithiée chirale et le crotonate de tertiobutyle conduit a une complète diastéréoselectivité au niveau de l'énaminoester. Dans les conditions de réaction de Heck (Pd(OAc)2, PPh3, NEt#3, CH3CN), les énamines beta-halogénées ont été réduites en amines tertiaires avec des rendements corrects. L'utilisation d'énamines β-halogénées à reste aminé chiral conduit aux amines tertiaires chirales correspondantes. L'agent de réduction est vraisemblablement la triéthylamine. La deracémisation d'aldéhydes α-substitués par l'intermédiaire d'énamines β-substituées chirales conduit à des aldéhydes α-substitués optiquement actifs. Les différents paramètres de la réaction ont été étudiés et ont permis d'atteindre des excès énantiomériques de 60%.

Au cours de ces travaux nous nous sommes intéressés au développement de nouvelles transformations énantiosélectives combinant les outils modernes de la synthèse organique que sont les « Multiples Bond-Forming Transformations » et l'organocatalyse afin de synthétiser des molécules d'intérêt structural et biologique. Dans ce contexte, nous avons d'abord mis au point deux nouvelles réactions domino initiées par une addition de Michael. La première, une cascade addition de Michael-acylation, permet la synthèse de spiroglutarimides optiquement actifs à partir de β-cétoamides et de nouveaux bis-électrophiles, les cyanures d'acyle α,β-insaturés. La deuxième, une réaction domino addition de Michaelhémiacétalisation- hémiaminalisation, permet la synthèse de d'hétérocycles azotés à sept chaînons à partir d'α-cétoamides comme nouveaux bis-nucléophiles
This work focused on the development of novel enantioselective transformations combining Multiples Bond-Forming Transformations and organocatalysis which are modern tools of organic synthesis in order to synthetize molecules of structural and biological interests. In this context, we developed two new Michael addition initiated domino reactions. The first one, a domino Michael addition-acylation, allows the synthesis of optically active spiroglutarimides starting from β-ketoamides and α,β-unsaturated acyles cyanides as new biselectrophiles.The second one, a domino Michael addition-hemiaminalizationhemiacetalization, allows the synthesis of seven-membered aza-cycles using α-ketoamides as new bis-nucleophiles

Polymer functional groups have critical impacts upon physical, chemical and mechanical properties, and thus affect the specific applications of the polymer. Functionalization of cellulose esters and ethers has been under extensive investigation for applications including drug delivery, cosmetics, food ingredients, and automobile coating. In oral delivery of poorly water-soluble drugs, amorphous solid dispersion (ASD) formulations have been used, prepared by forming miscible blends of polymers and drugs to inhibit crystallization and enhance bioavailability of the drug. The Edgar and Taylor groups have revealed that some cellulose omega-carboxyalkanoates were highly effective as ASD polymers, with the pendant carboxylic acid groups providing both specific polymer-drug interactions and pH-triggered release through swelling of the ionized polymer matrix. While a variety of functional groups such as hydroxyl and amide groups are also of interest, cellulose functionalization has relied heavily on classical methods such as esterification and etherification for appending functional groups. These methods, although they have been very useful, are limited in two respects. First, they typically employ harsh reaction conditions. Secondly, each synthetic pathway is only applicable for one or a narrow group of functionalities due to restrictions imposed by the required reaction conditions. To this end, there is a great impetus to identify novel reactions in cellulose modification that are mild, efficient and ideally modular. In the initial effort to design and synthesize cellulose esters for oral drug delivery, we developed several new methods in cellulose functionalization, which can overcome drawbacks of conventional synthetic pathways, provide novel cellulose derivatives that are otherwise inaccessible, and present a platform for structure-property relationship study. Cellulose omega-hydroxyalkanoates were previously difficult to access as the hydroxyl groups, if not protected, react with carboxylic acid/carbonyl during a typical esterification reaction or ring opening of lactones, producing cellulose-g-polyester and homopolyester. We demonstrated the viability of chemoselective olefin hydroboration-oxidation in the synthesis of cellulose omega]-hydroxyesters in the presence of ester groups. Cellulose esters with terminally olefinic side chains were transformed to the target products by two-step, one-pot hydroboration-oxidation reactions, using 9-borabicyclo[3.3.1]nonane (9-BBN) as hydroboration agent, followed by oxidizing the organoborane intermediate to a primary alcohol using mildly alkaline H2O2. The use of 9-BBN as hydroboration agent and sodium acetate as base catalyst in oxidation successfully avoided cleavage of ester linkages by borane reduction and base catalyzed hydrolysis. With the impetus of modular and efficient synthesis, we introduced olefin cross-metathesis (CM) in polysaccharide functionalization. Using Grubbs type catalyst, cellulose esters with terminally olefinic side chains were reacted with various CM partners including acrylic acid, acrylates and acrylamides to afford families of functionalized cellulose esters. Molar excesses of CM partners were used in order to suppress potential crosslinking caused by self-metathesis between terminally olefinic side chains. Amide CM partners can chelate with the ruthenium catalyst and cause low conversions in conventional solvents such as THF. While the inherent reactivity toward CM and tendency of acrylamides to chelate Ru is influenced by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides. We observed that the CM products are prone to crosslinking during storage, and found that the crosslinking is likely caused by free radical abstraction of gamma-hydrogen of the alpha, beta-unsaturation and subsequent recombination. We further demonstrated successful hydrogenation of these alpha, beta-unsaturated acids, esters, and amides, thereby eliminating the potential for radical-induced crosslinking during storage. The alpha, beta-unsaturation on CM products can cause crosslinking due to gamma-H abstraction and recombination if not reduced immediately after reaction. Instead of eliminating the double bond by hydrogenation, we described a method to make use of these reactive conjugated olefins by post-CM thiol-Michael addition. Under amine catalysis, different CM products and thiols were combined and reacted. Using proper thiols and catalyst, complete conversion can be achieved under mild reaction conditions. The combination of the two modular reactions creates versatile access to multi-functionalized cellulose derivatives. Compared with conventional reactions, these reactions enable click or click-like conjugation of functional groups onto cellulose backbone. The modular profile of the reactions enables clean and informative structure-property relationship studies for ASD. These approaches also provide opportunities for the synthesis of chemically and architecturally diverse cellulosic polymers that are otherwise difficult to access, opening doors for many other applications such as antimicrobial, antifouling, in vivo drug delivery, and bioconjugation. We believe that the cellulose functionalization approaches we pioneered can be expanded to the modification of other polysaccharides and polymers, and that these reactions will become useful tools in the toolbox of polymer/polysaccharide chemists.
Ph. D.

O trabalho de tese é dividido em dois capítulos e visou explorar a química das diazocetonas α,β-insaturadas bem como dos ilídeos β-cetosulfoxônios. No primeiro capítulo é apresentado o emprego das diazocetonas α,β-insaturadas como novos aceptores em reações de aza-Michael. A adição conjugada de aminas primárias e secundárias foi explorada, assim como o uso de aminas quirais para avaliar a versão assimétrica da reação. Além da formação desses adutos, também foram investigadas estratégias para a construção de heterocíclicos nitrogenados a partir destes ou via protocolos \"one-pot\" (partindo das diazocetonas α,β-insaturadas) levando à formação de 2- e 3-pirrolidinonas. Por fim, foi avaliada a aplicação da metodologia desenvolvida na síntese do produto natural Barmumicina. O segundo capítulo se dispôs a investigar o emprego dos ilídeos β-cetosulfoxônios como substitutos de compostos diazocarbonílicos em reações de inserção. Num primeiro momento, avaliaram-se reações de inserção S-H intermolecular, visando a construção do fragmento β-cetotioéter. Alguns estudos competitivos e mecanísticos, bem como estratégias assimétricas também compõem o escopo. Num segundo momento, os ilídeos foram empregados em reações de inserção N-H intramolecular, no qual, a partir de sulfoxônios derivados de aminoácidos, vislumbrou-se a formação de 3-azetidinonas.
This thesis is divided into two chapters which are related to the chemistry of α,β-unsaturated diazoketones and β-ketosulfoxonium ylides. The first chapter presents the utility of α,β-unsaturated diazoketones as new aza-Michael acceptors. Conjugate addition of primary and secondary amines was explored, as well as the use of chiral amines to evaluate the asymmetric version of the reaction. In addition to the formation of these adducts, it was also investigated some strategies for the synthesis of 2- and 3-pyrrolidinones via the \"one-pot\" protocols (starting directly from the α,β-unsaturated diazoketones). Finally, the synthesis of the natural product Barmumicyn was evaluated from this methodology. The second chapter aimed to investigate the use of β-ketosulfoxonium ylides as diazocarbonyl compounds substitutes in insertion reactions. At first, the intermolecular S-H insertion reaction was studied aiming the construction of the β-ketothioether fragment. Some competitive and mechanistic studies, as well as asymmetric versions are also part of the scope. Secondly, some ylides were also employed in intramolecular N-H insertion reactions (from sulfoxonium amino acid derivatives) aiming the formation of 3-azetidinones.

Ce travail de thèse est dédié au développement des deux familles de complexes chiraux binaphtolates de terres rares et leur application en catalyse asymétrique dans les réactions d’addition de Michael, de Henry, de Strecker et d’hydroalkoxylation. La préparation d’une nouvelle famille de complexes chiraux bisbinaphtolates de terres rares a été optimisée. Ces nouveaux complexes ont été entièrement caractérisés grâce à des analyses RMN, IR, de spectroscopie de masse et des études de DRX de monocristaux isolés. Après une étude de stabilité, nous avons pu montrer que ces nouveaux complexes de terres rares peuvent être pesés à l’air libre et utilisés dans des réactions asymétriques sans dégazage des réactifs ni des solvants. Les comportements catalytiques de ces nouveaux complexes hétérobimétalliques ont été étudiés en détail dans des réactions énantiosélectives de Henry, de Strecker et d’addition de Michael. Une température d’isoinversion et un effet non linéaire ont notamment été mis en évidence dans la réaction d’addition de Michael de malonates sur des énones conduisant à des produits énantioenrichis avec des excès énantiomériques allant jusqu’à 83%. Une seconde famille de complexes monobinaphtolate monoalkyl de terres rares a été synthétisée et complètement caractérisée. Une structure DRX de ce type de complexe a pu être obtenue pour la première fois. Ces complexes ont été évalués dans des réactions de Strecker et d’hydroalkoxylation. Concernant cette dernière, la sélectivité a tout d’abord été étudiée avec ces complexes dans le cas des allènes et un mécanisme a pu être proposé. D’autre part, les premiers exemples d’hydroalkoxylation asymétrique d’alcènes, catalysés par ces complexes monobinaphtolate monoalkyl de terres rares, ont pu être décrits
This thesis is mainly devoted to the development of two families of rare earths chiral binaphtolate complex and their application in asymmetric catalysis such as Michael addition, Henry reaction, Strecker reaction and hydroalkoxylation reaction. At first, the preparation of a new family of rare earth bisbinaphtolate complexes has been optimized with complete characterizations including NMR, IR, mass spectroscopy and XRD studies on isolated single crystals. These new rare earths complexes are relative stable which can be used under air condition. The catalytic behavior of these new heterobimetallic complexes have been studied in detail: an isoinversion temperature was determined and the nonlinear effect was observed for asymmetric Michael additions of malonates on enones wich lead products with enantiomeric excess up to 83%. Secondly, a family of rare earth monobinaphtolate monoalkyl complexs has been synthesized and characterized. The first XRD structure of this family of complex was obtained. Steric substitutions of binaphtolate ligands on position 3,3’ have been proven to be essential for the formation of these complex. The selectivity of reaction of hydroalkoxylation of allene was studied with a proposed mechanism. First examples of asymmetric hydroalkoxylation of alkene catalyzed by rare earth complexes have been achieved by our rare earth monoalkyl monobinaphtolate complex

Pour développer de nouveaux outils synthétiques, nous avons élaboré des variantes de la réaction de Petasis. L’utilisation des α-amino aldéhydes dans la réaction de Petasis a permis de synthétiser des diamines chirales avec une diastéréosélectivité totale. La réaction a donnée de bons résultats avec différents groupements protecteurs de l’amine (sulfonamide, carbamate, amide). Cependant au cours de la réaction, les amino aldéhydes s’épimérisent et l’excès énantiomérique des diamines préparées est donc faible (30%). La réaction de Petasis a été associée à la réaction de Diels-Alder dans un procédé domino pour aboutir à l’obtention de composés de type hexahydroisoindole. La réaction domino est complètement diastéréosélective et les molécules sont obtenues de manière énantiopure. Un second procédé domino, utilisant une réaction de métathèse croisée suivie d’une addition 1,4 intramoléculaire, a permis d’obtenir des composés possédant un motif morpholine de manière diastéréosélective. Une version intramoléculaire de la réaction de Petasis a été mise au point dans le but d’obtenir des carbocycles à six chainons. Cette réaction a permis de préparer la (+)-conduramine C-4 en peu d’étapes. La cyclisation a montré une diastéréosélectivité surprenante puisque la configuration entre l’amine nouvellement formée et l’alcool est trans. Cette configuration est opposée à celle obtenue dans la version intermoléculaire
To develop new synthetic tools, we developed variants of the Petasis reaction. The use of α-amino aldehydes in the Petasis reaction allowed to synthesize chiral diamines with a total diastereoselectivity. The reaction gave good results with different protective groups of the amine (sulfonamide, carbamate, amide). However, during the reaction, the amino aldehydes are epimerized and the enantiomeric excess of the prepared diamines is low (30%). The Petasis reaction was associated with the Diels-Alder reaction in a domino process to achieve the preparation of hexahydroisoindole type compounds. The domino reaction is completely diastereoselective and the molecules are obtained as enantiopure. A second domino process, using a cross-metathesis reaction followed by an intramolecular 1,4-addition, yielded compounds with a morpholine moiety in a diastereoselective manner. Intramolecular version of the Petasis reaction was developed in order to obtain carbon-six-membered rings. This reaction led to the preparation of (+)-conduramine C-4 in few steps. The cyclization has shown a surprising diastereoselectivity since the configuration between the newly formed amine and alcohol is trans. This configuration is opposite to the one obtained in the intermolecular versions

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CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Carboidratos têm sido utilizados como organocatalisadores em síntese orgânica devido a sua quiralidade intrínseca. Neste trabalho foi sintetizado um novo organocatalisador aproveitando a estrutura da D-galactose como indutor de quiralidade. A síntese ocorreu em cinco etapas, a saber: proteção seletiva das hidroxilas das posições 1, 2, 3 e 4, seguida pela iodação da posição 6, substituição nucleofílica pelo grupo azido, redução à amina e por fim uma reação com anidrido ftálico. O rendimento global foi de 60 %. O organocatalisador foi testado na reação de adição de Michael entre o dibenzilideno acetona e a azalactona derivada da alanina. 20 mol% do catalisador conduziu ao produto com 57 % de rendimento e com total controle da régio- e diasteroseletividade. No escopo, vários produtos com funcionalização no esqueleto de dbas foram preparados e devidamente caracterizados pelas técnicas convencionais de análise. A determinação da estereoquímica relativa foi realizada através do uso de HPLC com fase estacionária quiral e foi atribuída como 1,2-anti após a comparação do tempo de retenção com um padrão já descrito na literatura. De maneira geral, é reportada, pela primeira vez, uma metodologia mais geral para a dessimetrização diasterosseletiva entre dbas e azalactonas catalisadas por ácido de Brønsted.
Carbohydrates have been used as organocatalysts in organic synthesis due to its inherent chirality. In this work, D-galactose was choose as a chiral pool in the catalyst design and it was prepared in five steps: selective ketalyzation of hydroxyl groups, following by an iodination and nucleophilic substitution in the presence of azide. To complete, reduction of the azide to amine and a coupling reaction with phthalic anhydride leading to the catalyst. Overall yield was 60 % for five steps. Then, the catalyst was adopted in the Michael addition reaction between dibenzylidene acetone and azalactone derivative of alanine. The product was obtained in 57% yield and with fully control of both regio- and diastereoselectivity. Next, various funcionalizated dbas were evaluated under the optimized reaction condition and the corresponding final products were fully characterized through conventional elemental analysis. The relative stereochemistry was assigned as being 1,2-anti by using chiral HPLC method. To this end, an authentic sample already described in the literature was prepared in order the retention time. In general, for the first time, a method more general to perform a diastereoselective dessymetrization of dbas in presence of azlactones by using a Brønsted acid as catalyst was described.

Ces travaux ont consisté à optimiser une voie de synthèse des spirotétrahydro-β-carbolines. Une stratégie en trois étapes à partir du 3-(2-nitrovinyl)indole a été élaborée avec la séquence linéaire suivante : addition de Michael, réduction de la fonction nitro en amine et cyclisation de Pictet-Spengler. L'addition de Michael a été développée sans protection préalable de l'indole sous activation ultrasons. La réduction de la fonction nitro en amine a été menée en présence d'hypophosphites. Au cours de cette étude, la désoxygénation des cétones aromatiques a été identifiée comme réaction secondaire de la réduction et a fait l'objet d'un développement approfondi. Une nouvelle voie d'accès à des isatines fonctionnalisées en position C-5 par substitution des sels de diazonium a été mise au point notamment par la réaction de Heck-Matsuda qui a fait l'objet d'une étude plus complète. La réaction finale de Pictet-Spengler entre tryptamines et isatines aboutit aux spiroindolones. Finalement, l'activité biologique des dérivés spirotétrahydro-β-carbolines synthétisés a été évaluée et l'un d'entre eux a montré une très bonne activité envers le Plasmodium falciparum

La première partie de ce travail concerne la génération électrochimique d'ylures de phosphore α,α-dihalogénés à partir de sels de phosphonium polyhalogénés et leur utilisation pour la synthèse de gem-dihalogénoalcènes selon une réaction de Wittig. Au cours de l'électrosynthèse de gem-difluoroalcènes, nous observons un phénomène particulier d'activation électrochimique de l'anode de magnésium que nous appelons activation électrochimique du magnésium. Ce phénomène permet la synthèse rapide et efficace de nombreux gem-dihalogénoalcènes. Nous proposons une interprétation pour ce mécanisme d'activation, étayée par la caractérisation des intermédiaires réactionnels. Dans la seconde partie de ce travail, ce phénomène d'activation électrochimique de l'anode de magnésium est utilisé pour la génération électrochimique du carbanion du trichlorométhylphosphonate de diisopropyle qui est engagé dans des réactions d'alkylation, de cyclopropanation et de cycloalkylation. De plus, des électrosynthèses en un seul réacteur de cyclopropylphosphonates β-substitués, de cyclopropylphosphonates α,β-substitués et de cycloalkylphosphonates sont développées.

Synthèse à partir d'o-diformyl N-méthyl pyrroles; additions de Diels-Alder avec le N-phényl maléimide et le butynedioate de diméthyle de benzo dipyrroles, pyrrolo phtalazines, cyclohepta (C) pyrrolones-6 et pyrrolo pyridines

Essais d'induction de tolerance aux haptenes de type alpha-methylene gamma butyrolactones (amgbl) responsables de nombreuses allergies de contact. Synthese de differents tolerogenes potentiels hydrosolubles de la forme lactone-derives lysinyl et lactone-derives cysteinyl. Etude de l'induction asymetrique observee lors de l'addition de michael d'un dipeptide (voc-cys-ala-ome) a differentes amgbl. Observation d'un parallelisme entre cette induction asymetrique et l'enantioselectivite de la reponse immunitaire dans le phenomene de l'allergie croisee

The thesis entitled ‘Engaging Small Organic Molecules and Self-Assemblies for ‘Label-Free’ Recognition of Biologically Relevant Analytes’ mainly deals with design and synthesis of various types of small molecular probes or molecular assemblies for fluorometric recognition of a large number of biologically relevant analytes in water. The first chapter begins with the general overview of various types of biosensors and their working principles. Then we discussed about various small organic molecules or molecular assemblies based systems in optical biosensing. The strategies for designing these sensors have also been discussed in connection with frequently encountered photophysical interactions. Finally, the design principles of some biosensors were highlighted on the basis of the structural aspects of the concerned analytes. The second chapter describes the design and synthesis of various optical probes for selective detections of different warfare materials in water. Chapter 2A: Cyanide Mediated Facile Michael Addition Reaction: A Simple Protocol to Distinguish ‘Tabun Mimic’ DCNP in Solution as well as in Vapor Phase Figure 1. Structures of the molecular probes used in chapter 2A. This chapter discussed about involvement of a series of water soluble bis-indolyl compounds for selective detection of nerve gas mimicking agent, DCNP (Diethyl Cyanophosphonate) at pH 8.0 in water. The mechanism of interaction was proposed as the bis-indole assisted hydrolysis of phosphoester nerve gas agents through hydrogen bonding interaction. Then the Michael addition of the liberated CN- ion to the electron deficient C=C bond of the bisindolyl moiety. This led to a remarkable color change from red to colorless at ambient condition. Further the protocol was exploited in vapor phase detection of DCNP (Tabun mimic) below its toxic level. Chapter 2B: Selective and Efficient Detection of Nitro-Aromatic Explosives in Multiple Media including Water, Micelles, Organogel, and Solid Support Figure 2. Structures of the molecular probes used in chapter 2B. This chapter demonstrated development of phenylenevinylene based optical probes for the selective detection of both DNP (2,4-Dinitrophenol) and TNP (2,4,6-Trinitrophenol) in pure water as well as in micellar medium. The mechanistic investigation suggested that the initial proton transfer caused electrostatic association between the picrate anions and the protonated pyridine ends, which could further promote electron transfer from the electron-rich fluorophore moiety to the electron-deficient nitroaromatics (NACs). Thus the selectivity depends on the pKa of the probe molecules as well as the NACs under consideration. Further portable test strips were made successfully for rapid on-sight detection purpose. The third chapter describes identification of different enzymes in water as well as in biological fluids via disaggregation of template mediated molecular assemblies. Chapter 3A: Employment of ATP-Sensitive Lanthanide Ensemble for the Estimation of Creatine Kinase Level in Blood Serum and Live Cell Imaging Figure 3. Structures of the molecular probes used in chapter 3A. This chapter presents the use of in-situ generated luminescent lanthanide complexes in sensing of adenosine triphosphate (ATP) in water. The indicator tetracarboxylate salt showed rapid quenching in green molecular emission upon coordination with highly paramagnetic lanthanide ion (Gd3+). The addition of ATP could displace the lanthanide ion from the vicinity of the compound and retrieved its original emission. Further this selective ‘Turn-On’ response of the probe towards ATP was utilized to discriminate between the live and dead cells depending upon their ATP/ADP content. Moreover, excellent selectivity of the probe for ATP over ADP was utilized for the detection of Creatine Kinase in human blood serum samples. Chapter 3B: Estimation of Albumin Content in Different Biological Fluids and Monitoring Trypsin Mediated Digestion of HSA Figure 4. Structures of the molecular probes used in chapter 3B. This chapter describes design of several amphipathic carbazole dyes, which could form thermo sensitive, pH dependent fluorescent nano-aggregates in water. This facile nanoclustering behavior of the compounds was then utilized for detection of human serum albumin (HSA). The site-specific nature of the interaction was appeared to be the key reason for the unique selectivity of the probes towards HSA over other structurally resembled albumin proteins. Further the estimation of HSA was achieved in different biological fluids like human urine, blood serum and saliva etc. Finally the protease mediated digestion of protein template was applied as an alternative strategy for detection of trypsin. The fourth chapter describes fluorometric detection of different physiologically relevant monosaccharides by exploiting multi-point hydrogen bonding network. Chapter 4A: Analyte Induced Alteration in the Aggregation Property of Fluorescent Organic Nano-particles: A Simple Recognition Strategy for D-(-)-Ribose in Water Figure 5. Structures of the molecular probes used in chapter 4A. This chapter demonstrated selective detection of D(-)-ribose and ribose containing biomolecules (Adenosine, riboflavin etc.) in water via hydrogen bonding interactions from aceylhydrazone and pyridine units. The interaction with ribose was found to be responsible for dissociation of the preformed molecular assemblies, resulting drastic quenching in luminescent signal. Finally determination of ribose was also performed in presence of complex biological matrix like human urine. Chapter 4B: Restriction in Keto-Enol Tatumerization through Multipoint Hydrogen Bonding Network with D-(+)-Glucosamine Figure 6. Structures of the molecular probes used in chapter 4B. This chapter presents design and synthesis of different chromogenic probes by connecting nicotinic hydrazide with different -hydroxy aromatic aldehydes via carbonyl-nucleophile addition protocol. Addition of D-glucosamine was found to modulate the keto-enol tatumerization of the molecules via formation of multi-point hydrogen bonding network. The rapid change in color from bright yellow to colorless with prominent emission quenching led detection of up to 5.3 mg/L of glucosamine in water. Then monitoring of glucosamine level was also achieved in human blood serum as well as pharmaceutical formulations. Moreover, the probes were found to be competent in detection of glucosamine even in intracellular condition. The fifth chapter describes development of new fluorometric probes for identifying different inflammatory-response markers in water. Chapter 5A: Heparin Triggered Multicolor Emission Switching in Water: A Convenient Protocol for Heparinase I Assay Figure 7. Structures of the molecular probes used in chapter 5A. In this chapter, conjugated bis-pyridinium salts of phenylenevinylene (PPV) have been used for selective detection of heparin in water. The unique dose-dependent emission switching ability of the probes ensured quantitiative estimation of heparin without involving any sofisticated facilities. The higher negative charge density and preferential conformation of sugar dimers faciliated interaction between compounds and heparin. Finally, the heparin induced reversible aggregate formation was utilized to develop an alternative easy-to-operate heparinase I assay protocol. Chapter 5B: Application of Neurotransmitter Induced Emission Switching for Histamine Detection in Biological Fluids and Macrophage Cells Figure 8. Structures of the molecular probes used in chapter 5B. This chapter presents the involvement of well-known fluorescein aldehyde dyes in recognition of histamine below nanomolar concentration in water. Here, the dual mode of detection of histamine was achieved at pH 7.0 without involving any toxic metal ions. The selective response towards histamine was confirmed through secondary hydrogen bonding interaction followed by imine formation. Then the probes were also employed for detection of histamine in different biological fluid matrices (human urine and blood serum). Finally, the rise in endogenous histamine level in macrophage RAW 264.7 was identified under stimuli-responsive condition (treatement with thapsigargin). The sixth chapter describes fluorometric detection of purine alkaloids via their preferential stacking over the electron rich planer dye molecules. Chapter 6A: Hydrogen Bonding Triggered Crumbling of Pyrene Excimer: A Simple Method for Detection of Uric Acid in Human Serum and Infested Grain Extracts This chapter deals with design and synthesis of different amphipathic pyrene molecules for nanomolar detection of uric acid in water. Hydrogen bonding interaction of uric acid with amide functional groups found to push two adjacent pyrene units away from each other, resulting into quenching of blue excimer emission. The optimized liposomal formulation derived from the doping of probe molecules into soya lecithin vesicles was further utilized for estimating uric acid content in blood serum samples. Finally, the present protocol was used for identifying the rise in uric acid content in insect-infested grain samples. Figure 9. Structures of the molecular probes used in chapter 6A. Chapter 6B: Caffeine Modulated Dissociation of Carbazole Based FONs in Water: Excitation Triggered Alteration in Sensing Property Figure 10. Structures of the molecular probes used in chapter 6B. This chapter deals with self aggregation properties of a series of carbazole based ampiphilic dyes, which could be modulated by the micro polarity of the local environment and electronic influence from the functional groups attached to the core organic scaffold. In comparison to other structurally related purine analogs, caffeine exerted most prominent emission response due to its planar electron deficient structure. An optimal balance between selectivity and sensitivity was achieved by varying the excitation wavelengths or electron density over the carbazole core. In application, the sensor was successfully exploited to address diverse real-life problems ranging from applications in ‘dope-analysis in human urine’ to carbonated drinks.

碩士
國立臺灣師範大學
化學系
102
Asymmetric organocatalytic Michael addition has attracted interests due to its environmental friendliness and the generation of multiple stereogenic centers in a single step. In this study‚ treatment of (E)-5-nitro-6-arylhex-5-en-2-one using a catalytic amount of quinine-derived primary amine (20 mol%) and 4-dimethyl aminopyridine (20 mol%) in 1,4-dioxane and DMSO (1:1) at 50 oC to give 3,4-trans- disubstituted cyclohexanones via intramolecular Michael addition process with moderate chemical yields and high-to-excellent stereoselectivities (>95:5 dr and up to 96% ee). We describe a rapid and practical synthetic route involving six-step reaction toward the synthesis of (-)-Epibatidine

Yes
Improved synthetic conditions allow preparation of TMSCCl3 in good yield (70 %) and excellent purity. Compounds of the type NBu4X [X=Ph3SiF2 (TBAT), F (tetrabutylammonium fluoride, TBAF), OAc, Cl and Br] act as catalytic promoters for 1,4‐additions to a range of cyclic and acyclic nitroalkenes, in THF at 0–25 °C, typically in moderate to excellent yields (37–95 %). TBAT is the most effective promoter and bromide the least effective. Multinuclear NMR studies (1H, 19F, 13C and 29Si) under anaerobic conditions indicate that addition of TMSCCl3 to TBAT (both 0.13 M ) at −20 °C, in the absence of nitroalkene, leads immediately to mixtures of Me3SiF, Ph3SiF and NBu4CCl3. The latter is stable to at least 0 °C and does not add nitroalkene from −20 to 0 °C, even after extended periods. Nitroalkene, in the presence of TMSCCl3 (both 0.13 M at −20 °C), when treated with TBAT, leads to immediate formation of the 1,4‐addition product, suggesting the reaction proceeds via a transient [Me3Si(alkene)CCl3] species, in which (alkene) indicates an Si⋅⋅⋅O coordinated nitroalkene. The anaerobic catalytic chain is propagated through the kinetic nitronate anion resulting from 1,4 CCl3− addition to the nitroalkene. This is demonstrated by the fact that isolated NBu4[CH2=NO2] is an efficient promoter. Use of H2C=CH(CH2)2CH=CHNO2 in air affords radical‐derived bicyclic products arising from aerobic oxidation.
Engineering and Physical Sciences Research Council (EPSRC) Grant EP/K000578/1.

碩士
朝陽大學
應用化學研究所
87
We build our lab's method to synthesize β-amino-α,β-unsaturated,γ-thiolactone 1 (achiral)、2 (chiral), and have good yield. From thiolactone 1、2, we have to synthesize thiophene 3、4, and study thiophene's Diels-alder reaction and Lewis acid catalyze Michael addition

碩士
國立臺灣師範大學
化學系
102
This thesis describes the synthesis of benzoyl-substituted chromanol derivatives from α,β-unsaturated ketones and aliphatic aldehydes via Michael addition reaction. These derivatives appear as interesting intermediates in the synthesis of various natural products and biologically active compounds. Different types of α,β-unsaturated ketones (57,63) were allowed to react with aliphatic aldehyde to obtain the same products 64aa and 64ab. It’s worth mentioning that starting from either 57 or 63 as starting material, the diastereo orientation of products were different. For example, using coumarin derivatives (57) as the starting material, the major product was obtained in anti orientation (64aa). But starting from chalcone derivatives (63), the major product was obtained with syn orientation (64ab).

碩士
國立臺灣師範大學
化學系
104
Bifunctional organocatalyst dominated for asymmetric catalysis via utilizing novel 1,3-indandionederived pronucleophiles with wide variety of nitoalkenes for Vinylogous Michael addition/Henry cyclization cascade to generate tetrahydrofluoren- 9-ones derivatives with excellent result. Part I: An unprecedented organocatalytic enantioselective vinylogous Michael addition/Henry cyclization cascade is presented for the synthesis of highly substituted tetrahydrofluoren-9-ones employing novel 1,3-indandionederived pronucleophiles 94 and nitroalkenes. Following a very simple protocol, a wide range of products were obtained in good to excellent yields and with excellent enantioinduction (43−98% yield, up to 98% ee). The reaction proceeded with excellent diastereocontrol despite the simultaneous generation of four stereogenic centers. Surprisingly, when 2- (1- phenylethylidene)-1H-indandione 94h-i was used as a pronucleophile, no cyclization was observed, and only Michael addition adducts 98 were furnished in very good yields and excellent enantioselectivities. Part II: An enantioselective synthesis of benzopyrano[3,4-c]pyrrolidine derivatives via organocatalyzed [3+2] cycloaddition has been achieved. Cinchona alkaloid-derived organocatalysts as Bronsted bases have been examined for this asymmetric cycloaddition of o-hydroxy aromatic aldimines with 3-substituted coumarins. An unexpected rearrangement of the quaternary acyl moiety in the products resulted in an in situ protection of the o-hydroxy group.

碩士
國立清華大學
化學系
102
This thesis dealt with the synthesis and application of novel prolinamide-camphor organocatalysts that derived from the coupling of trans-4-hydroxy-L-proline and camphorsulfonamide. Organocatalyst 11d is proven to be an efficient catalyst for the asymmetric Michael reaction of ketone and a series of chalcone-derived. Treatment of cyclohexanone with chalcone- deriveds which have electron-withdrawing group using organocatalyst 11d provided the desired Michael products with high chemical yields (up to 97% yield), excellent diastereoselectivities (up to 99/1 dr) and high levels of enantioselectivities (up to 93% ee) for syn- products.

碩士
朝陽大學
應用化學系碩士班
88
Abstract 一. Michael Addition Reaction of b-amino, a,b-unsaturated-g-thiolactone under Lewis acid conditions. 4-(1-pyrrolidinyl)-2(5H)thiophenon 1, which developed in our laboratory was used to study it''s Michael reaction under Lewis acid conditions. Their reaction products were analyzed using HPLC techniques to determine diastereoselectivity. 二.Chiral Anti-Aldol Reaction Studies of Chiral Vinylogous Urethane and their Application in Natural Product Synthesis. 1. Camphor derived chiral vinylogous urethane 3 was deprotonated and reacted with aldehyde to from anti-aldol product, the product selectivity was analyzed using chiral column to determine their enantioselectivity. 2. Product 5 was used to synthesize Bafilomycin A1 fragment prelactone B.