Dissertations / Theses on the topic 'Azide-alkyne cycloaddition'

The bioorthogonal copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction exhibits complex but well-defined kinetics in aqueous and organic solution for soluble azides, alkynes, and ligand-bound copper(I). The kinetic profile in two dimensions, however, for CuAAC systems within a lipid bilayer membrane, has yet to be defined. The effect of triazole formation with lipid membrane-bound components on membrane properties such as fluidity and permeability is also of interest. Azide- and alkyne-functionalized lysolipids were synthesized and incorporated into non-fluid vesicles, which were then subject to CuAAC. The rate order for membrane-bound lipid substrates in non-fluid vesicles was observed to be comperable to that of the reaction in solution. Reactions between vesicles showed evidence of lipid transfer between non-fluid membranes, which has not been previously reported. For intervesicular and intravesicular reactions in non-fluid membranes, the observed reactivity was found to be opposite that of previously published reactions between nucleophiles and electrophiles in fluid lipid systems. Applications of this work include the potential for novel symmetric membrane leaflet labeling, bioorthogonal manipulation of cell and tissue function, and the creation of membranes with precisely controlled properties that may not be available in naturally-occurring membranes.

The copper-catalysed azide-alkyne cycloaddition (CuAAC) is a highly efficient reaction and is the cornerstone of “click” chemistry. However, unlike many common metal-mediated transformations asymmetric CuAAC variants are relatively sparse. This thesis details asymmetric “click” reactions with Chapter 1 introducing the CuAAC and the asymmetric variants already present in the literature. Chapter 2 outlines research demonstrating the first example of kinetic resolution of an alkyne via a CuAAC reaction. Selectivity factors of up to 22.1 ± 0.5 were obtained and triazoles and alkynes were obtained in ≤ 80% enantiomeric excess (ee). This chapter also contains a study on the simultaneous kinetic resolution of azides and alkynes; azides were obtained in >30% \(e\)\(e\), alkynes in >40% \(e\)\(e\) and a triazolic diastereomeric product was obtained in up to 90% \(e\)\(e\). In Chapter 3 the Bull-James three-component boronic acid assembly is successfully employed for the kinetic resolution of primary amine alkynes with selectivity factors of up to 4.1 obtained. The principle behind the assembly is also elaborated upon in this chapter leading to its use in both dynamic combinatorial chemistry and as a pedagogical tool. Chapter 4 details work on atropisomerism in triazolic systems. A series of novel triazoles, iodotriazoles and triazolium salts were successfully synthesised and their atropisomeric stability probed. Chapter 5 presents feasibility studies towards the asymmetric synthesis of 5,5’-bis(triazoles) and ruthenium olefin metathesis catalysts in the formation of 1,5-triazoles.

La présente thèse décrit la synthèse de briques de base de fullerènes pour la préparation de dispositifs moléculaires photoactifs combinant C60 et porphyrines. La cycloaddition alcyne-azoture catalysée au cuivre (I) a été utilisée comme outil de synthèse pour la préparation des dérivés C60 complexes.L’utilité synthétique de synthons C60 a été montrée avec la préparation d’édifices moléculaires complexes présentant des propriétés spécifiques pour diverses applications. Ainsi, un système photoactif flexible combinant C60 et porphyrine a été synthétisé. Cependant la flexibilité de l’espaceur liant les sous-unités de ce composé conduit à des variations de structurales importantes et complique ainsi l’analyse des études photophysiques.Dans ce contexte, nous nous sommes proposé dans une première partie de la présente thèse de parfaitement contrôler l’orientation et la distance des différentes sous-unités au sein de systèmes C60-donneurs. Afin de répondre à ce besoin, nous avons construit une brique de base de C60 rigide ayant un groupe azoture aromatique. Ainsi, la réaction « click » avec un phénylacétylène conjugué au groupement donneur conduit à un espaceur rigide entre les deux sous-unités.La deuxième partie de ce travail a été consacrée à la synthèse d’hexa-adduits du C60 portant différents groupements fonctionnels. Une méthode de synthèse permettant de préparer des hexa-adduits du C60 fonctionnalisés a été mise au point au laboratoire.Cette stratégie a été modifiée et des composés de C60 comportant dix fonctions azotures et une fonction alcyne protégée ont été synthétisés; dans ce cas il est possible d’introduire dans un premier temps par une réaction click dix groupes fonctionnels. Et dans un second temps; après déprotection de la fonction alcyne, une seconde réaction de click permet alors de greffer un fonctionnel différent
The present PhD thesis manuscript is focused on the use of fullerene building blocks for the preparation of photoactive molecular devices combining C60 and porphyrins. Cu(I) Catalyzed alkyne-azide cycloaddition was used as a synthetic tool for the preparation of complex C60 derivatives. Specifically, in the first part (Chapter II-B), a flexible fullerene-porphyrin triad has been developed and the photophysical studies were performed. The flexible linker between the fullerene core and the azide groups prevented any conformational control on the relative orientation and distance between the two photoactive subunits connected together. This prompted the development of an analogous building block in which the azide unit is directly connected to the bridging phenyl ring (Chapter II-C). In this way, the click reaction with porphyrin-alkyne derivatives give access to hybrid systems with a controlled relative orientation of the two moieties. This is of fundamental importance for a better understanding of the structural parameters affecting the electron and/or energy transfer kinetic in such dyads.In the second part (Chapter III), a fullerene hexaadduct scaffold is used to build up sophisticated multiporphyrin systems for various applications. The preparation of these multi-chromophoric ensembles relies on the click-click approach developed in our group

Click chemistry is a molecular synthesis strategy based on reliable, highly selective reactions with thermodynamic driving forces typically in excess of 20 kcal mol-1. The 1,3-dipolar cycloaddition of azides and alkynes developed by Rolf Huisgen saw dramatic rate acceleration using Cu(I) as a catalyst in 2002 reports by Barry Sharpless and Morten Meldal enabling its click chemistry eligibility. Since these seminal reports, the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) has become the quintessential click reaction finding diverse utility. The popularity of the CuAAC has naturally led to interest in new catalyst systems with improved efficiency, robustness, and reusability with particular focus on nanomaterial catalysts, a common trend across the field of catalysis. The high surface area of nanomaterials lends to their efficacy as colloidal and heterogeneous nanocatalysts, but the latter boasts the added benefit of easy separation and recyclability. With any heterogeneous catalyst, a common question arises as to whether the active catalyst species is truly heterogeneous or rather homogeneous through metal ion leaching. Differentiating these processes is critical, as the latter would result in reduced efficiency, higher cost, and inevitable environmental and heath side effects. This thesis explores the CuAAC from an interdisciplary approach. First as a synthetic tool, applying CuAAC-formed triazoles as functional, modular building blocks in the synthesis of optical cation sensors by combining azide and alkyne modified components to create a series of sensors selective for different metal cations. Next, single-molecule spectroscopy techniques are employed to observe the CuNP-catalyzed CuAAC in real time. Combining bench-top techniques with single-molecule microscopy to monitor single-catalytically generated products proves to be an effective method to establish catalysis occurs directly at the surface of copper nanoparticles, ruling out catalysis by ions leached into solution. This methodology is extended to mapping the catalytic activity of a commercial heterogeneous catalyst by applying super-localization analysis of single-catalytic events. The approach detailed herein is a general one that can be applied to any catalytic system through the development of appropriate probes. This thesis demonstrates single-molecule microscopy as an accessible, effective, and unparalleled tool for exploring the catalytic activity of nanomaterials by monitoring single-catalytic events as they occur.

Protein-protein interactions (PPIs) are responsible for the regulation of a variety of important functions within living organisms. Compounds which can selectively modulate aberrant PPIs are novel therapeutic candidates for treating human diseases. Whilst PPIs have traditionally been considered as "undruggable", research in this area has led to the emergence of several effective methodologies for targeting PPIs. One such methodology is peptide stapling, which involves constraining a short peptide into its native alpha-helical form by forming a covalent link between two of its amino acid side-chains. The Sondheimer dialkyne reagent has previously been used in strain-promoted double-click cycloadditions with diazidopeptides to generate stapled peptides that are capable of inhibiting PPIs. However, the Sondheimer dialkyne suffers from poor water-solubility; it decomposes rapidly in aqueous solutions which limits its application in biological systems. This dissertation describes the design and synthesis of new substituted variants of the Sondheimer dialkyne with increased solubility and stability, that are suitable for application in strain promoted double click peptide stapling. In total, ten different derivatives were generated; of these, a meta-trimethylammonium substituted variant was found to have particularly high water-solubility and aqueous stability, as well as high azide reactivity. The substituted Sondheimer dialkynes were applied to the strain promoted double click stapling of p53-based diazido peptides in an effort to generate stapled peptide-based inhibitors of the oncogenic p53 MDM2 PPI, a validated target for anticancer therapeutics. Three stapled peptides were found to have inhibitory activity, thus demonstrating the utility of the novel dialkynes in the preparation of PPI inhibitors. The functionalised stapled peptide formed from a meta-fluoro substituted Sondheimer dialkyne was found to be the most potent inhibitor. All ortho-substituted Sondheimer dialkynes were found to be unreactive, whereas those with a meta-trimethylammonium substituent were highly reactive when compared to other meta-substituted dialkynes. These patterns in azide reactivity could be explained through X-ray crystallographic studies and density functional theory calculations.

Immobilization of different bio- and organic molecules on solid supports is fundamental within many areas of science. Sometimes, it is desirable to obtain a directed orientation of the molecule in the immobilized state. In this thesis, the copper (I) catalyzed Huisgen 1,3-dipolar cycloaddition, referred to as a “click chemistry” reaction, was explored as a means to perform directed immobilization of small molecule ligands on gold surfaces. The aim was to synthesize alkyne- and azide-terminated alkanethiols that would form well-organized self assembled monolayers (SAMs) on gold from the commercially available substances orthoethylene glycol and bromo alkanoic acid. N-(23-azido-3,6,9,12,15,18,21-heptaoxatricosyl)-n-mercaptododekanamide/hexadecaneamide (n = 12, 16) were successfully synthesized and allowed to form SAMs of different compositions to study how the differences in density of the functional groups on the surface would influence the structure of the monolayer and the click chemistry reaction. The surfaces were characterized by different optical methods: ellipsometry, contact angle goniometry and infrared reflection-absorption spectroscopy (IRAS). The click reaction was found to proceed at very high yields on all investigated surfaces. Finally, the biomolecular interaction between a ligand immobilized by click chemistry on the gold surfaces and a model protein (bovine carbonic anhydrase) was demonstrated by surface plasmon resonance using a Biacore system.

Les carbènes N-hétérocycliques (NHC) sont très utilisés pour complexer les métaux de transition. Ils quittent rarement ce rôle de ligand ancillaire et trouvent, depuis une vingtaine d’années, des applications en catalyse ou, plus récemment, en chimie médicinale. Dans ce travail, nous discuterons d’une méthode de synthèse douce conduisant à la formation de complexes AgI – NHC via une source d’argent soluble. Cette méthode nous a permis d’obtenir des complexes bien connus mais également d’accéder à une nouvelle série de complexes NHC-Ag-phosphine. Nous présenterons également une nouvelle réaction où des NHC portant une fonction azoture à proximité du carbone du carbène quittent leur rôle de ligand ancillaire et conduisent à la formation d’hétérocycles azotés par cyclisation carbène-nitrène. Cette réaction sera présentée en détail, ainsi que la caractérisation spectroscopique concernant une sous-série de composés fluorescents obtenus par cette méthode. Enfin, nous présenterons une stratégie de post-fonctionnalisation de complexes développée dans notre équipe. Des complexes argent(I)-NHC portant un azoture proches du centre carbénique catalysent leur propre fonctionnalisation. De plus, des complexes de cuivre(I) portant des azotures en position éloignée du centre métallique seront greffés sur des nanoparticules magnétiques pour servir de catalyseur recyclables
N-heterocyclic carbenes (NHC) are widely used to complex transition metals. They rarely leave their role as ancillary ligand and find, since 20 years, applications in catalysis or, more recently, in medicinal chemistry. In this work, we will discuss a mild synthetic method leading to the formation of AgI – NHC complexes via a soluble silver species. This method allowed us to obtain well known complexes but also to access a new series of NHC-Ag-phosphine complexes. We will also present a new reaction where NHC ligands bearing an azide function close to the carbenic center leave their role as ancillary ligand and lead to the formation of nitrogen rich heterocycles by a carbene-nitrene cyclization. This reaction will be presented in detail, along with the spectroscopic characterization regarding a sub-series of fluorescent compounds obtained by this method. Finally, we will present a post-functionalization strategy of complexes developed in our team. Silver(I)-NHC complexes tagged by an azide close to the carbenic center catalysed their own functionalization. Moreover, copper(I) complexes tagged by an azide function in a distant position from the metallic centre will be grafted on magnetic nanoparticles to act as recyclable catalysts

Cette thèse est consacrée à la mise au point d'une machine moléculaire artificielle sous la forme d'un [1]rotaxane, capable de synthétiser différents polymères de façon autonome. Au cours de cette étude, nous avons réalisé la première synthèse hautement diastéréosélective de [1]rotaxanes par la méthode de reconnaissance active catalysée au cuivre(I). Nous avons montré qu'un frein moléculaire est nécessaire pour assurer la stabilité de l'architecture entrelacée. De plus, l'utilisation d'un macrocycle avec une chaine latérale courte est indispensable pour favoriser la synthèse de lassos moléculaires. Enfin, le centre asymétrique du frein moléculaire guide la stéréosélectivité de la réaction. Ceci permet de faire la synthèse stéréodivergente de [1]rotaxanes à partir de macrocycles énantiomériquement purs. La seconde partie du projet concerne et de la processivité potentielle de ce type d'architecture moléculaire. Dans ce cadre, nous avons construit un [2]rotaxane présentant un stoppeur labile et une fonction thiol protégée sur la chaine latérale du macrocycle. La libération contrôlée du thiol induit la formation d'un [1]rotaxane piégé in situ par un nucléophile indiquant le potentiel de cette approche pour la conception de machines moléculaires fonctionnant de façon itérative
This thesis is devoted to the development of an artificial molecular machine in the form of [1]rotaxane, designed to synthesize different kind of polymers autonomously. During this study, we accomplished the first highly diastereoselective synthesis of [1]rotaxanes by the copper(I)-catalysed active template method. We showed that a molecular brake was necessary to ensure the stability of the interlocked architecture. Moreover, the use of a short lateral chain of the macrocycle is essential to promote the synthesis of molecular lassos. Finally, the asymmetric center of the molecular brake induces the stereoselectivity of the reaction. This allows us to accomplish the stereodivergent synthesis of [1]rotaxanes from enantiomerically pure macrocycles. The second part of this project concerns the study of the potential processivity of this kind of molecular architecture. In this context, we built a [2]rotaxane which has a labile stopper and a protected thiol moiety on the lateral chain of the macrocycle. The controlled release of the thiol leads to the formation of a [1]rotaxane trapped in situ by a nucleophile, showing the potential of this approach for the design of molecular machines working processively

In bacteria, protein synthesis can occur tightly coupled to transcription. In eukaryotes, it is believed that translation occurs solely in the cytoplasm; I test whether some occurs in nuclei and find: (1) L-azidohomoalanine (Aha) – a methionine analogue (detected by microscopy after attaching a fluorescent tag using ‘click’ chemistry) – is incorporated within 5 s into nuclei in a process sensitive to the translation inhibitor, anisomycin. (2) Puromycin – another inhibitor that end-labels nascent peptides (detected by immuno-fluorescence) – is similarly incorporated in a manner sensitive to a transcriptional inhibitor. (3) CD2 – a non-nuclear protein – is found in nuclei close to the nascent RNA that encodes it (detected by combining indirect immuno-labelling with RNA fluorescence in situ hybridization using intronic probes); faulty (nascent) RNA is destroyed by a quality-control mechanism sensitive to translational inhibitors. I conclude that substantial translation occurs in the nucleus, with some being closely coupled to transcription and the associated proof-reading. Moreover, most peptides made in both the nucleus and cytoplasm are degraded soon after they are made with half-lives of about one minute. I also collaborated on two additional projects: the purification of mega-complexes (transcription ‘factories’) containing RNA polymerases I, II, or III (I used immuno-fluorescence to confirm that each contained the expected constituents), and the demonstration that some ‘factories’ specialize in transcribing genes responding to tumour necrosis factor α – a cytokine that signals through NFκB (I used RNA fluorescence in situ hybridization coupled with immuno-labelling to show active NFκB is found in factories transcribing responsive genes).

The use of advanced functional polymer materials has gained an enormous impact during the past decades. Due to the fact that the physical properties of macromolecules are inherently dependent on their structure and connectivity on the nanoscale, precisely control over polymer architecture has been a longstanding goal for polymer chemists. The recent development of copper catalyzed azide-alkyne click chemistry provides a nearly quantitatively tool for macromolecular coupling. Through the combination of living polymerization and click chemistry, novel complex polymer architectures can be readily constructed, including star polymers, brush polymers, cyclic polymer and ladder polymers. While amphiphilic block copolymers have demonstrated their utility for a range of practical applications, the behavior of block copolymers that contain cyclic topologies remains largely unexplored due to limited synthetic access. In order to investigate their micelle formation, biocompatible cyclic amphiphilic poly(ethylene glycol)-block-polycaprolactone, c-(PEG-b-PCL), and tadpole shaped PEG-PCL, were synthesized by a combination of ring opening polymerization (ROP) and click chemistry. In addition, exactly analogous linear block copolymers have been prepared as control samples to elucidate the role of polymer architecture in their self-assembly and acid-catalyzed degradation. High purity homo-arm and mikto-arm poly(ethylene glycol) (PEG) stars were successfully prepared by the combination of epoxide ring openings and azide-alkyne click reactions. First, monohydroxy-PEG was modified via epoxide chemistry to bear one hydroxyl and one azide functionality at the same polymer chain end. An alkyne functionalized PEG chain was then coupled to the azide. Subsequently, the remaining hydroxyl could be reactivated by epoxide chemistry again to an azide and alcohol group. This enabled a step-wise coupling and reactivation of the end group to add a series of well-defined polymer arms onto a star polymer. The use of efficient reactions for this iterative route provided star polymers with an exact number of arms, and a tailorable degree of polymerization for each arm. Detailed characterization confirmed the high purity of multi-arm polyethylene glycol products. Novel cyclic brush-shaped polymers can be successfully prepared by using the CuAAC click coupling reaction. First, cyclic-shaped polymer bearing a single hydroxyl group can be synthesized by CuAAC click cyclization. After a one-step modification of the hydroxyl group by esterification with an azido-carboxylic acid, a “clickable†polymer ring was obtained. A linear polymer backbone with an alkyne functional group on every repeat unit was prepared by ATRP of acetoxystyrene followed by reduction to poly(4-hydroxystyrene) and esterification with pentynoic acid. Finally, by coupling multiple equivalents of the cyclic precursor onto the linear backbone, a cyclic brush-shaped polymer was prepared. This provides a highly efficient approach to prepare novel polymer architectures containing multiple cyclic components.
acase@tulane.edu

Copper-catalyzed regeneration in atom transfer radical addition (ATRA) utilizes reducing agents, which continuously regenerate the activator (CuI) from the deactivator (CuII) species. This technique was originally found for mechanistically similar atom transfer radical polymerization (ATRP) and its application in ATRA and ATRC has allowed significant reduction of catalyst loadings to ppm amounts. In order to broaden the synthetic utility of in situ catalyst regeneration technique, this was applied in copper-catalyzed atom transfer radical cascade reaction in the presence of free radical diazo initiators such as 2,2’-azobis(isobutyronitrile) (AIBN) and (2,2’-azobis(4-methoxy-2,4-dimethyl valeronitrile) (V-70), which is the first part of this dissertation. This methodology can be translated to sequential ATRA/ATRC reaction, in which the addition of CCl4 to 1,6-dienes results in the formation 5-hexenyl radical intermediate, which undergoes expedient 1,5-ring closure in the exo- mode to form 1,2-disubstituted cyclopentanes. When [CuII(TPMA)Cl][Cl] complex was used in conjunction with AIBN at 60 0C, cyclic products derived from the addition of CCl4 to 16-heptadiene, diallyl ether and N,N­-diallyl-2,2,2-trifluoroacetamide were synthesized in nearly quantitative yields using as low as 0.02 mol% of the catalyst (relative to 1,6-diene). Even more impressive were the results obtained utilizing tert­-butyl-N,N-diallylcarbamate and diallyl malonate using only 0.01 mol% of the catalyst. Cyclization was also found to be efficient at ambient temperature when V-70 was used as the radical initiator. High product yields (>80%) were obtained for mixtures having catalyst concentrations between 0.02 and 0.1 mol%. Similar strategy was also conducted utilizing unsymmetrical 1,6-diene esters. It was found out that dialkyl substituted substrates (dimethyl-2-propenyl acrylate and ethylmethyl-2-propenyl acrylate) underwent 5-exocyclization producing halogenated g-lactones after the addition of CCl4 in the presence of 0.2 mol% of [CuII(TPMA)Cl][Cl]. Based on calculations using density functional theory (DFT) and natural bond order (NBO) analysis, cyclization of 1,6-diene esters was governed by streoelectronic factors. <br>As a part of broadening the synthetic usefulness of in situ copper(I) regeneration, scope was further extended to sequential organic transformations. Based on previous studies, copper(I) catalyzed [3+2] azide-alkyne cycloaddition is commonly conducted via in situ reduction of CuII to CuI species by sodium ascorbate or ascorbic acid. At the same time, ATRA reactions have been reported to proceed efficiently via in situ reduction of CuII complex to the activator species or CuI complex has been fulfilled in the presence of ascorbic acid. Since the aforementioned reactions share similar catalyst in the form of copper(I), a logical step was taken in performing these reactions in one-pot sequential manner. Reactions involving azidopropyl methacrylate and 1-(azidomethyl)-4-vinylbenzene in the presence of a variety of alkynes and alkyl halides, catalyzed by as low as 0.5 mol-% of [CuII(TPMA)X][X] (X=Br-, Cl-) complex, proceeded efficiently to yield highly functionalized (poly)halogenated esters and aryl compounds containing triazolyl group in almost quantitative yields (>90%). Additional reactions that were carried out utilizing tri-, di- and monohalogenated alkyl halides in the ATRA step provided reasonable yields of functionalized trriazoles. A slightly different approach involving a ligand-free catalytic system (CuSO4 and ascorbic acid) in the first step followed by addition of the TPMA ligand in the second step was applied in the synthesis of polyhalogened polytriazoles. Sequential reactions involving vinylbenzyl azide, tripropargylamine and polyhalogenated methane (CCl4 and CBr4) provided the desired products in quantitative yield in the presence of 10 mol% of the catalyst. Modest yields of functionalized polytriazoles were obtained from the addition of less active tri- and dihalogenated alkyl halides utilizing the same catalyst loading. <br>The last part focuses on copper(I) complexes, which were used catalysts in cyclopropanation reaction. One class represented cationic copper(I)/2,2-bipyridine complexes with p-coordinated styrene [CuI(bpy)(p-CH2CHC6H5)][A] (A = CF3SO3- (1) and PF6- (2) and ClO4- (3). Structural data suggested that the axial coordination of the counterion in these complexes observed in the solid state weak to non-coordinating (2.4297(11) Å 1, 2.9846(12) Å 2, and 2.591(4) Å 3). When utilized in cyclopropanation, complexes 1-3 provided similar product distribution suggesting that counterions have negligible effect on catalytic activity. Furthermore, the rate of decomposition of EDA in the presence of styrene catalyzed by 3 (kobs=(7.7±0.32)´10-3 min-1) was slower than the rate observed for 1 (kobs=(1.4±0.041)´10-2 min-1) or 2 (kobs=(1.0±0.025)´10-2 min-1). On the other hand, tetrahedral copper(I) complexes with bipyridine and phenanthroline based ligands have been reported to have strongly coordinated tetraphenylborate anions. CuI(bpy)(BPh4), CuI(phen)(BPh4) and CuI(3,4,7,8-Me4phen)(BPh4) complexes are the first examples in which BPh4- counterion chelates a transition metal center in bidentate fashion through h2 p-interactions with two of its phenyl rings. The product distribution revealed that the mole percent of trans and cis cyclopropanes were very similar. The observed rate constants (kobs) shown in for decomposition of EDA in the presence of externally added styrene were determined to be kobs=(1.5±0.12)´10-3 min-1, (6.8±0.30)´10-3 min-1 and (5.1±0.19)´10-3 min-1.
Bayer School of Natural and Environmental Sciences
Chemistry and Biochemistry
PhD
Dissertation

La préparation de polymères à base d’acides biliaires, molécules biologiques, a attiré l'attention des chercheurs en raison des applications potentielles dans les domaines biomédicaux et pharmaceutiques. L’objectif de ce travail est de synthétiser de nouveaux biopolymères dont la chaîne principale est constituée d’unités d’acides biliaires. La polymérisation par étapes a été adoptée dans ce projet afin de préparer les deux principales classes de polymères utilisés en fibres textiles: les polyamides et les polyesters. Des monomères hétéro-fonctionnels à base d’acides biliaires ont été synthétisés et utilisés afin de surmonter le déséquilibre stoechiométrique lors de la polymérisation par étapes. Le dérivé de l’acide lithocholique modifié par une fonction amine et un groupement carboxylique protégé a été polymérisé en masse à températures élevées. Les polyamides obtenus sont très peu solubles dans les solvants organiques. Des polyamides et des polyesters solubles en milieu organique ont pu être obtenus dans des conditions modérées en utilisant l’acide cholique modifié par des groupements azide et alcyne. La polymérisation a été réalisée par cycloaddition azoture-alcyne catalysée par l'intermédiaire du cuivre(Ι) avec deux systèmes catalytiques différents, le bromure de cuivre(I) et le sulfate de cuivre(II). Seul le bromure de cuivre(Ι) s’est avéré être un catalyseur efficace pour le système, permettant la préparation des polymères avec un degré de polymérisation égale à 50 et une distribution monomodale de masse moléculaire (PDI ˂ 1.7). Les polymères synthétisés à base d'acide cholique sont thermiquement stables (307 °C ≤ Td ≤ 372 °C) avec des températures de transition vitreuse élevées (137 °C ≤ Tg ≤ 167 °C) et modules de Young au-dessus de 280 MPa, dépendamment de la nature chimique du lien.
Bile acids have drawn attention in the synthesis of polymers for biomedical and pharmaceutical applications due to their natural origin. The objective of this work is to synthesize main-chain bile acid-based polymers. The step-growth polymerization was used to prepare two important classes of polymers used in textile fibers, polyamides and polyesters. Heterofunctional bile acid-based monomers were synthesized and used in order to overcome stoichiometric imbalances during step-growth polymerization. The lithocholic acid derivative bearing amine and protected carboxylic functional groups was polymerized in bulk at high temperatures, yielding polyamides that were poorly soluble in common organic solvents. Soluble triazole-linked polyamides and polyesters were obtained when the cholic acid derivative bearing azide and alkyne functional groups was polymerized under mild conditions via copper(Ι)-catalyzed azide-alkyne cycloaddition. Two different catalytic systems, copper(Ι) bromide and copper(ΙΙ) sulfate, were tested. Only copper(Ι) bromide proved to be an effective catalyst for the system, allowing the synthesis of the polymers with a degree of polymerization of ca. 50 and an unimodal molecular weight distribution(PDI ˂ 1.7). The main-chain cholic acid-based polymers are thermally stable (307 °C ≤ Td ≤ 372 °C) with high glass transition temperatures (137 °C ≤ Tg ≤ 167 °C) and Young’s moduli in excess of 280 MPa, depending on the chemical structure of the linker.

yes
The synthesis of cyclic amphiphilic graft copolymers with a hydrophobic polycarbonate backbone and hydrophilic poly(N-acryloylmorpholine) (PNAM) side arms via a combination of ring-opening polymerization (ROP), cyclization via copper-catalyzed azide–alkyne cycloaddition (CuAAC), and reversible addition–fragmentation chain transfer (RAFT) polymerization is reported. The ability of these cyclic graft copolymers to form unimolecular micelles in water is explored using a combination of light scattering, small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryoTEM) analyses, where particle size was found to increase with increasing PNAM arm length. Further analysis revealed differences in the solution conformations, loading capabilities, and morphologies of the cyclic graft copolymers in comparison to equivalent linear graft copolymer unimolecular micelle analogues. Furthermore, the cyclic and linear graft copolymers were found to exhibit significantly different cloud point temperatures. This study highlights how subtle changes in polymer architecture (linear graft copolymer versus cyclic graft copolymer) can dramatically influence a polymer’s nanostructure and its properties.
Royal Society (Great Britain), Engineering and Physical Sciences Research Council (EPSRC), European Research Council (ERC)

博士
國立清華大學
化學系
103
In the first part of this thesis, we reported the synthesis of glycosyl azides from peracetylated sugars (or glycosyl trichloroacetimidates) using VO(OTf)2 as the catalyst which can improve 1,2-trans selectivity to understand the role of this oxometallic species, we monitor the reaction progress by 1H NMR spectroscopic analysis of the reaction mixtures to confirm the different catalytic exerted by VO(OTf)2. An intermediate resulting from glycosyl rearrangement to α-form starting materialwas identified in the catalytic reaction mediated by TMSOTf. This novel vanadyl triflate also provided access to catalyze azidation of various, disaccharides and trisaccharides in high 1,2-trans stereoselectivity and good yields (92-99 %) under mild conditions in CH2Cl2. Not only does VO(OTf)2 enhance β-stereoselective glycosyl azidation but also avoids the rearrangement of C2 acetate group and the formation of orthoester byproducts. The second part is dealt with azide-alkyne cycloaddition (CuAAC) in mild and green conditions by a combination of VOSO4 and Cu(0) for in-situ generation of Cu(I) in aqueous media. Vanadium compounds can exist in oxidation states ranging from -3 to +5 and their interconversion between different oxidation states is achieved by one-electron redox process. Its intrinsic redox nature permits the catalysis of a wide range of organic reactions by judicious combination with suitable metal reductants. Through an extensive survey of various conditions, we have established an effective recipe to generate Cu(I) speceies for the CuAAC reaction in both homogeneous (CH3CN) and heterogeneous (Methanol, t-BuOH/H2O, H2O) solvent systems. In this new click reaction, mild acidic condition plays an important role to stabilize the incipient Cu(I) species and a pronounced ligand effect on the vanadyl species is observed. This new catalytic methodology is attractive because it can be applied to aqueous solution which is important in biological systems at ambient temperature and physiologic pH conditions. In the third part, we have disclosed an elegant and pragmatic catalytic system by using VO(OTf)2 catalyst for 1.2-trans β-selective and 1,2-cis α-selective glycosylationof thioglycosides. The catalytic strategy described herein can achieve stereospecific glycosylation in excellent yields. When low-concentration (10 mM) mixed solvent systems (CH2Cl2-CH3CN-EtCN) with N-Iodosuccimide (NIS, 1.25 equiv) as the activator was employed, preferential 1.2-trans glycosides(-selectivity) was attained. When VO(OTf)2-xCH3CN was used as a solution in DMF for catalytic glycosylation, highly 1,2-cis (α-selectivity) glycosylation was achieved. Finally, a reduced loading of VO(OTf)2-xCH3CN (3M in DMF) to 0.05 equiv still led to efficient catalysis and 1,2-cis -selective glycosylation can still be maintained. In the second chapter of this thesis, a series of oxometallic species and metal acetylacetonates (acac) was examined as catalysts for oxidative beta-carbonylation of styrenes with benzaldehyde by using t-butylhydroperoxide as co-oxidant and trapping agent in warm acetonitrile. Among them, VO(acac)2 and vanadyl(IV) chloride were found to be the only two catalyst classes to achieve the cross-coupling processes by judicious turning the ligand electronic attributes, leading to β-hydroxylation and β-peroxidation of styrenes, respectively, in a complementary manner. Mechanistic studies indicated that vanadyl associated, acyl radicals generated by t-butoxy radical-assisted, homolytic cleavage of aldehyde C-H bond were involved in the tandem processes with exclusive syn diastereoselectivity in the case of -methylstyrene.

La réaction de macrocyclisation est une transformation fondamentale en chimie organique de synthèse. Le principal défi associcé à la formation de macrocycles est la compétition inhérente avec la réaction d’oligomérisation qui mène à la formation de sousproduits indésirables. De plus, l’utilisation de conditions de dilutions élevées qui sont nécessaires afin d’obtenir une cyclisation “sélective”, sont souvent décourageantes pour les applications à l’échelle industrielle. Malgré cet intérêt pour les macrocycles, la recherche visant à développer des stratégies environnementalement bénignes, qui permettent d’utiliser des concentrations normales pour leur synthèse, sont encore rares. Cette thèse décrit le développement d’une nouvelle approche générale visant à améliorer l’efficacité des réactions de macrocyclisation en utilisant le contrôle des effets de dilution. Une stratégie de “séparation de phase” qui permet de réaliser des réactions à des concentrations plus élevées a été developpée. Elle se base sur un mélange de solvant aggrégé contrôlé par les propriétés du poly(éthylène glycol) (PEG). Des études de tension de surface, spectroscopie UV et tagging chimique ont été réalisées afin d’élucider le mécanisme de “séparation de phase”. Il est proposé que celui-ci fonctionne par diffusion lente du substrat organique vers la phase ou le catalyseur est actif. La nature du polymère co-solvant joue donc un rôle crutial dans le contrôle de l’aggrégation et de la catalyse La stratégie de “séparation de phase” a initiallement été étudiée en utilisant le couplage oxidatif d’alcynes de type Glaser-Hay co-catalysé par un complexe de cuivre et de nickel puis a été transposée à la chimie en flux continu. Elle fut ensuite appliquée à la cycloaddition d’alcynes et d’azotures catalysée par un complexe de cuivre en “batch” ainsi qu’en flux continu.
Macrocyclization is a fundamentally important transformation in organic synthetic chemistry. The main challenge associated with the synthesis of large ring compounds is the competing oligomerization processes that lead to unwanted side-products. Moreover, the high dilution conditions needed to achieved “selective” cyclization are often daunting for industrial applications. Despite the level of interest in macrocycles, research aimed at developing sustainable strategies that focus on catalysis at high concentrations in macrocyclization are still rare. The following thesis describes the development of a novel approach aimed at improving the efficiency of macrocyclization reactions through the control of dilution effects. A “phase separation” strategy that allows for macrocyclization to be conducted at higher concentrations was developped. It relies on an aggregated solvent mixture controlled by a poly(ethylene glycol) (PEG) co-solvent. Insight into the mechanism of “phase separation” was probed using surface tension measurments, UV spectroscopy and chemical tagging. It was proposed to function by allowing slow diffusion of an organic substrate to the phase where the catalyst is active. Consequently, the nature of the polymer co-solvent plays a role in controlling both aggregation and catalysis. The “phase separation” strategy was initially developed using the copper and nickel co-catalyzed Glaser-Hay oxidative coupling of terminal alkynes in batch and was also transposed to continuous flow conditions. The “phase separation” strategy was then applied to the copper-catalyzed alkyne-azide cycloaddition in both batch and continuous flow.

Over the last decade, the domain of click chemistry has grown exponentially and has significantly impacted the fields of organic synthesis, medicinal chemistry, molecular biology, and materials science. The ideal model of a click reaction has become the copper-catalyzed azide-alkyne cycloaddition (CuAAC). Inherent limitations of CuAAC, including high temperatures, long reaction times, and difficult purifications, have been minimized by the development of nitrogen-based ligands. Herein, we present a novel application of 1,2,4-triazines by investigating their use as accelerants for CuAAC. A diverse library of 1,2,4-triazines were synthesized in order to examine the molecular determinants of their catalytic activity. These ligands were found to be potent accelerants, at catalytic concentrations, in the presence of both copper(I) and copper(II) salts. Remarkably, these catalyzed reactions proceeded at room temperature, generating high isolated yields, in both polar and nonpolar solvents. 5,6-Diphenyl-3-(pyridin-2-yl)1,2,4-triazine was the most active ligand studied, producing an 89% yield in a model click reaction within one hour. Additional experiments with an array of azides and alkynes yielded similar results, defining a broad substrate scope for 1,2,4-triazines as catalysts for click chemistry. Heterogeneous 1,2,4-triazines were designed using different solid supports and different sites of attachment with respect to the 1,2,4-triazine ligand. The primary advantages offered by these immobilized catalysts are the prevention of metal contamination in 1,2,3-triazole products and the recyclability of the catalyst. Results indicated that 1,2,4-triazine-functionalized silica was a more effective accelerant of CuAAC, whereas polystyrene-supported 1,2,4-triazines displayed modest activity. In coordination with copper(II), 1,2,4-triazines appended onto silica generated isolated yields greater than 90% after four consecutive reaction cycles with minimal copper leaching. Further research will utilize both homogeneous and heterogeneous 1,2,4-triazine-accelerated CuAAC in the derivatization of solid supports for energy-related chemical processes and in the synthesis of novel enzyme inhibitors.

Le traitement du cancer est l’un des plus grands défis en chimie médicinale moderne. La majorité des traitements utilisés repose sur la chimiothérapie, impliquant l’emploi de molécules bioactives cytotoxiques. Bien qu’efficaces, ces molécules présentent, pour la plupart, des désavantages notoires tels que le manque de spécificité cellulaire et une solubilité limitée en phase aqueuse. Une façon de remédier aux problèmes exposés est de solubiliser ces molécules au sein de matrices polymères. Il existe différents types de matrices qui sont : les liposomes, les micelles, les nanosphères, les nanocapsules, les dendrimères (et les polymères en étoile), et les polymères conjugués et linéaires. Dans cette thèse, nous faisons l’étude de deux matrices polymères potentielles composées de matériaux biocompatibles : le polylactide et la poly(2-isopropyl-2-oxazoline). La première partie de la thèse, est consacrée à l’étude des polyester-co-éthers portant des groupements pendants fonctionnalisables. Nous avons développé ces copolymères par polymérisation aléatoire en masse de lactones (le lactide ou la caprolactone) et différents taux d’éthers de propargyle et de glycidyle (GPE), à 120°C, en utilisant l’octanoate d’étain comme catalyseur. L’efficacité de la copolymérisation a été mise en évidence par des analyses FTIR, RMN 1H et COSY. Toutefois, L’analyse GPC a montré une diminution de la masse molaire des polymères et un élargissement de la dispersité en rapport avec l’augmentation du taux de glycidyle initial. De plus, les analyses RMN 1H ont montré que le taux de propargyl (provenant de l’éther de glycidyle) au sein du copolymère ne dépassait pas 50%. La faisabilité des modifications post-polymérisation a été évaluée en couplant le (9-azidomethyl) anthracène au chaîne de poly(ester-co-éther)s via la chimie clic CuAAC. Cette méthode s’est révélée inoffensive pour la chaîne de polyesters. Des études de cytotoxicité ont prouvé l’innocuité des poly(ester-co-éther)s. Des nanoparticules sphériques ont été préparées à partir de ces polymères et peuvent être utilisées comme nanosphères pour le transport de molécules bioactives hydrophobes. La copolymérisation des lactones avec des éthers de glycidyles s’avère être une stratégie intéressante de fonctionnalisation des chaînes des polyesters permettant la synthèse d’une large gamme de copolymères pour des applications biomédicales. Afin d’améliorer la synthèse des poly(ester-co-ether)s, nous avons proposé une approche mécanistique tenant compte des réactions de transfert de chaînes. Dans la deuxième partie de la thèse, nous avons étudié un polymère en étoile composé d’un polymère thermosensible : la poly(2-isopropyl-2-oxazoline) PIPOZ. Nous avons premièrement exploré deux approches synthétiques afin d’obtenir une série d’étoiles de PIPOZ (S-PIPOZ) de structure bien définié à savoir l’approche « coupling-onto » et l’approche « core-first ». Une première série de S-PIPOZ a été réalisée directement à partir d’un coeur pentaérythrityl tétratosylés par polymérisation cationique par ouverture de cycle (CROP) de 2-isopropyl-2-oxazoline pour l’approche « core-first ». Pour l’approche « coupling-onto », une deuxième série de S-PIPOZ a été réalisée par couplage via la CuAAC entre des PIPOZ-N3 linéaire (L-PIPOZ N3) et un cœur à 4 bras portant des alcynes terminaux. Tous les S-PIPOZs obtenus ont été analysés par RMN 1H, IR, MALLS-LS, des analyses UV et par microcalorimétrie différentielle à balayage (HS-DSC). Les polymères obtenus par l’approche « core-first » ont montré une microstructure mal-définie comparé à ceux obtenus par l’approche « coupling-onto ». Suite à ces résultats, nous avons défini l’approche « coupling-onto » comme voie d’obtention des S-PIPOZ. Une explication sur la structure mal-défini des polymères obtenus par l’approche « core-first » sera développée dans cette section. Nous exposerons aussi une méthode de purification permettant l’élimination rapide et efficace des L-PIPOZ N3 qui contaminent les échantillons de S-PIPOZ faits par l’approche « coupling-onto ». Cette méthode peut être applicable à d’autres polymères thermosensibles dans une certaine gamme de température. Dans la troisième partie, nous avons étudié l’effet de l’architecture et de la composition des bras-polymères sur la température de transition de phase et les propriétés des S-PIPOZs. Afin d’étoffer notre étude nous avons synthétisé un polymère en étoile à bloc composé de PIPOZ et de poly(éthylène glycol) PEG. Cette étude a été réalisée en examinant des solutions chauffées de polymères (S-PIPOZ, S-PIPOZ-b-PEG et tous les précurseurs linéaires) par des analyses de spectrométrie d’absorption UV, HS-DSC, diffusion de la lumière LS. Nous avons évalué la présence ou l’absence de cristaux au sein d’échantillons de S-PIPOZs provenant de solutions chauffées. Cette évaluation a été réalisée par diffusion des rayons-X aux grands angles (WAXS) et par microscopie électronique à transmission (TEM) et à balayage (SEM). La présence de cristaux est néfaste pour la conception de nanomatériaux destinés à des applications biomédicales. Nous exposons aussi dans cette section une méthode basée sur l’amination réductrice permettant de fonctionnaliser les S-PIPOZ avec différents types de macromolécules. Cette thèse expose les avantages et les inconvénients (synthèses, fonctionnalisation, structures…) des PLA-co-GPE et des S-PIPOZs et constitue dans son ensemble à une première ébauche vers une conception améliorée de futurs nanomatériaux.
Treatment of cancer is one of the biggest challenges in modern medicinal chemistry. The vast majority of treatments are based on chemotherapy, involving the use of cytotoxic bioactive molecules. Although effective, most of these bioactive molecules have notorious drawbacks, such as the lack of cellular specificity and limited solubility in aqueous media. A way to address these problems is to dissolve these bioactive compounds into polymer matrices. There are different types of matrices, including liposomes, micelles, nanospheres, nanocapsules, dendrimers (and star-polymers), and conjugate and linear polymers. In this thesis, we explored two different prospective polymers that can be used as matrices. Both are composed of biocompatible materials: polylactide and poly(2-isopropyl-2-oxazoline). The first part of the thesis is dedicated to the investigation of polyester-co-ether with functionalizable pendant groups. First, we developed the polyester-co-ether by copolymerization of lactones (lactide or caprolactone) with different ratios of glycidyl propargyl ether (GPE) in the bulk at 120°C in the presence of Sn(Oct)2. The efficiency of the copolymerization was evidenced by FTIR, 1H and COSY NMR analyses. However, GPC analyses displayed a decrease of molecular weights and a broadening of the molecular weight dispersity with increasing of the epoxide molar ratio in the feed. 1H NMR analyses showed that the propargyl content from the epoxide does not exceed 50%. The feasibility of post-polymerization functionalization was evaluated by coupling anthracene to the poly(ester-co-ether)s through copper-catalyzed alkyne-azide cycloaddition (CuAAC). The polyester chain was found to support this reaction. Toxicity studies showed that the poly(ester-co-ether) was non-toxic. Spherical nanoparticles were prepared from these polymers. They can be suitable nanospheres for drug delivery. The copolymerization of lactone with glycidyl ether is an interesting approach to functionalize the PLA (or poly(ester)) main chain. It is also a powerful and straightforward strategy to synthesize a large array of functionalized polymers for biomedical applications. In order to improve the synthesis of the polyester-co-ether, we investigated the copolymerization mechanism of the chain transfer reactions leading to the chain reductions and we suggested a mechanistic explanation. In the second part of this thesis, we focused on developing star-polymers from the thermosensitive (2-isopropyl-2-oxazoline) polymer. In order to prepare a well-defined set of star-poly(2-isopropyl-2oxazoline) S-PIPOZs, we explored two different synthetic approaches: the “coupling-onto” and the “core-first” approach. Two sets of S-PIPOZs were prepared by these approaches. For the “core-first” approach, a set of S-PIPOZ was prepared by direct cationic ring opening polymerization (CROP) from a tetra tosylate-functionnalized pentaerythrityl core. For the “coupling-onto approach”, the S-PIPOZs were prepared by ligation between L-PIPOZ-N3 and a 4-arm core with an alkyne group via CuAAC. The prepared polymers were analysed by 1H NMR, IR, Multi Angles Laser Light Scattering - Gel Permeation Chromatography (MALLS-GPC), UV absorption spectroscopy and High Sensitive Differential Scanning Microcalorimetry (HS-DSC). Polymers obtained by the “core-first” approach shows ill-defined microstructure compared to those obtained by the “coupling-onto” approach. In light of these encouraging results, the “coupling-onto” method was pursued for preparing S-PIPOZ. An explanation on the ill-defined structure will be provided within this thesis. Moreover, we developed a purification method for the fast and efficient removal of free PIPOZs, which otherwise contaminate the star-PIPOZ samples that are prepared by the coupling-onto approach. This method is applicable to other thermosensitive polymers within a certain range of temperature. In the third part, we focused on the effect of the architecture and composition of the S-PIPOZs on the phase transition temperature of the polymer. For this, we synthesized a hetero-star block copolymer composed of PIPOZ and poly(ethylene glycol) PEG. This study was carried out by examining the aqueous polymer solution (the linear precursors, S-PIPOZs, S-PIPOZ-b-PEG) upon heating via UV spectroscopy, HS-DSC and light scattering. We also assessed the temperature-induced crystallinity of the Star-PIPOZs by Transmission (TEM) and Scanning (SEM) Electron Microscopy, WAXS. This is important for biomedical nanodevices. We also provided a straightforward method, based on aminative reduction, to functionalize the S-PIPOZ with different macromolecules. This thesis discusses the advantages and the drawbacks related to the synthesis, functionalization, structures of PLA-co-GPE and the star-PIPOZs. Overall, this represents a pioneering study for improving the design of prospective nanodevices.