The research presented within this dissertation explores the photocatalytic deposition of metal carried out within sealed microfluidic channels. Micro scale patterning of metals inside sealed microchannels is investigated as well as nanoscale control over the surface morphology of the nanoparticles making up the patterns. This is achieved by controlling solution conditions during deposition. Finally, the nanoparticle patterns are used in fabricating a sensor device, which demonstrates the ability to address multiple patches within a sealed channel with different surface chemistries. Also presented here is the construction of the first epifluorescence/total internal reflection macroscope. Its ability to carry out high numerical aperture imaging of large arrays of solid supported phospholipid bilayers is explored. For this, three experiments are carried out. First, imaging of a 63 element array where every other box contains a different bilayer is preformed, demonstrating the ability to address large scale arrays by hand. Next, a protein binding experiment is preformed using two different arrays of increasing ligand density on the same chip. Finally, a two-dimensional array of mixed fluorescent dyes contained within solid supported lipid bilayers is imaged illustrating the ability of the instrument to acquire fluorescent resonance energy transfer data. Additionally, the design and fabrication of an improved array chip and addressing method is presented. Using this new array chip and addressing method in conjunction with the epifluorescence/total internal reflection macroscope should provide an efficient platform for high throughput screening of important biological processes which occur at the surfaces of cell membranes.

Ionic-type transistors are important devices for precise chemical control and biosensing applications. Previous work by Tybrandt et al. has demonstrated a novel approach to constructing an ionic transistor using conducting polymers poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) and quarternized- polyvinyl benzyl chloride (q-PVBC). This approach could be combined with the 3D stamp method of generating concentration gradients in supported lipid bilayers (SLBs) as shown by Liu et al. to create a charged lipid-based ionic polar junction transistor. An electric potential applied across the SLB would drive charged lipids towards the opposite electrode, thus generating current flow across the SLB. Incorporation of a charged-lipid functionalized PEDOT derivative as demonstrated by Johansson et al. would allow a longer period of current flow before charge carriers are depleted. Such a device could offer novel approaches to biosensing.

Bifunctional iminophosphoranes, containing a triaryl-substituted iminophosphorane and bis(3,5- trifluoromethyl)phenyl thiourea on a single enantiomer scaffold are novel asymmetric superbase organocatalysts reported by the Dixon group in 2014. This thesis describes our efforts to expand their scope and utility in a variety of challenging chemical transformations. Chapter 2 describes the development and application of immobilised bifunctional iminophosphorane organocatalysts. We have successfully immobilised bifunctional iminophosphoranes on a crosslinked polystyrene support and applied this sold-supported catalyst to three challenging asymmetric reactions; namely the nitro-Mannich reaction of phosphinoyl ketimines and the conjugate addition of alkylmalonates and N,N-dimethyl β-keto amides to nitrostyrene. Very good yields, enantio- and diasteroselectivities were obtained in all cases. We have also demonstrated their use in a range of conjugate additions of cyclic 1,3-dicarbonyl compounds to nitroalkenes, which suffered from very slow reaction rates under tertiary amine-based bifunctional catalysis. In all cases, the immobilised bifunctional iminophosphoranes performed very well in comparison to their homogeneous counterparts. We have also demonstrated catalyst recycling over 10 cycles and application in a continuous flow system with a productivity of 7.20 mmol _producth^-1g_catalyst^-1. to the ring-opening polymerisation (ROP) of cyclic esters. We have demonstrated the performance of bifunctional iminophosphorane organocatalysts in the ROP of L-lactide (LA), δ-valerolactone (VL) and ε-caprolactone (CL). The polymerisation of LA and VL proceeded rapidly and was well controlled, while only short lengths (> 100 DP) of poly(CL) could be prepared in a controlled fashion due to hypothesised competing initiation from the catalyst. We have shown that the polymerisation of LA using our catalyst may be considered a living polymerisation. Di-block co-polymers could also be successfully prepared via sequential monomer addition or through the use of macroinitiators. We then investigated the roles of the iminophosphorane and the thiourea component of the catalyst.

No description available.

No description available.

Les glycosides sont reconnus pour leur potentiel pharmaceutique tels que les antibiotiques, les agents anticancéreux et antiviraux. Ils sont impliqués dans plusieurs processus biologiques entre autres la reconnaissance cellulaire, l’inflammation, la réponse immunitaire, la croissance, le transport cellulaire, l’adhésion cellulaire et les groupes sanguin. Notre groupe excelle dans la glycosidation stéréocontrôlée avec un minimum de protection suivant le concept d’activation à distance d’aglycones hétérocycliques anomériques. La présence d’une quantité sous stoechiométrique d’acide de Lewis, les (2-pyridyl)-β-D-glycosides déprotégés sont d’excellents donneurs permettant de haute sélectivité pour l’anomère- α-D de glycosides simples et complexes. Inversement, (2-pyridyl)-α-D-glycosides donnent les β-D-glycosides avec de bonne sélectivité. Des exemples de formation stéréocontrôlée de glycosides sont présentés dans cette thèse avec des accepteurs tels que les phénols, les stéroïdes, les terpènes et les acides hydroxyaminés. Cette méthodologie de glycosidation a été appliquée sur support solide. / Glycosides are well-known to be components of important antibiotics, anticancer agents and antiviral drugs. They are also involved in many biologically relevant processes such as cell-cell recognition, inflammation, immunity, cell transport, cell adhesion, and as determinants of blood group types. Our group has championed stereocontolled methods of glycoside synthesis with minimal donor protection using the concept of remote activation of anomeric heterocyclic aglycones. In the presence of sub-stoichiometric amounts of Lewis acids, unsubstituted beta-D-pyridyl glycosides are excellent donors affording simple and complex glycosides usually with high alpha-anomeric selectivity. Conversely, alpha-D-pyridyl glycosides give the inverted beta-glycosides with equally good selectivity. Examples of stereocontrolled glycoside synthesis with acceptor molecules include among others, phenols, steroids, terpenes, and hydroxyamino acids. Applications to glycoside synthesis on solid support have been pursued with promising results.

Bien que la synthèse peptidique en phase solide (SPPS) soit maintenant une technique mature et très largement popularisée pour des peptides simples, certaines séquences restent encore compliquées à produire, comme les peptides riches en ponts disulfure (DRPs). Ces produits naturels, ligands sélectifs d’un grand nombre de cibles thérapeutiques, sont des outils pharmacologiques de premier ordre et sont considérés comme de bons candidats médicaments. La proportion importante de cystéines dans leur séquence (plus de 10%) leur confère des propriétés remarquables, mais limite aussi leur synthèse,conduisant à des purifications HPLC délicates, associées à des rendements faibles et une pureté médiocre.Dans l’optique de simplifier la production de DRPs par voie chimique, notre but est de proposer une méthode de purification non-chromatographique. Pour cela, nous avons développé un bras N-terminal conçu pour être complètement compatible avec les peptides riches en cystéines: Boc-Cys(Trt)-1-{6-[1,3-diméthyl-2,4,6(1H,3H,5H)trioxopyrimidine-5-ylidène]hexyle}. A la fin de l’élongation sur support solide, ce bras est introduit sélectivement à l'extrémité N-terminale du peptide cible, sans réagir avec les peptides tronqués acétylés qui constituent les principales impuretés de la SPPS. Après coupure de la résine SPPS, le peptide cible est immobilisé sur un second support solide par le biais d’une réaction de ligation chimique native(NCL). Les peptides tronqués sont alors éliminés par simple filtration, puis le peptide cible est relargué en solution par coupure du bras N-terminal. Ayant comme objectif d’élargir par la suite notre stratégie à la synthèse de très longs DRPs via l’assemblage de multiples segments peptidiques par NCLs successives enphase solide, nous avons étudié en détail la stabilité et les conditions de coupure du bras.La méthode a été appliquée à la purification de deux séquences naturelles riches en cystéines et biologiquement pertinentes : AvBD2 (36 AA), un peptide antimicrobien appartenant à la famille des β défensines aviaires et Bv8 (77 AA) un peptide d’amphibien de la famille des prokinéticines. / Although solid phase peptide synthesis (SPPS) is a mature and widely popularized technique for simple peptides, some sequences are still complicated to produce, such as disulfide-rich peptides (DRPs). These natural products are able to selectively bind a wide number of therapeutically relevant targets, hence they are considered as promising drug candidates and pharmacological tools. The large proportion of cysteines in their sequence (more than 10%) confers them remarkable properties, but also limits their synthesis, lead ingto delicate HPLC purifications associated with low yields and poor purity.With the aim to simplify the chemical production of DRPs, we have developed an N-terminal linker: Boc-Cys(Trt)-1-{6-[1,3-dimethyl-2,4,6(1H,3H,5H)trioxopyrimidine-5-ylidene]hexyl}, which can be used for non chromatographiccatch-and-release purifications. It has been designed to be completely compatible with unprotected cysteine-containing peptides. Following solid phase elongation, this linker is selective lyintroduced at the N-terminus of the target peptide, leaving unreacted truncated acetylated peptides which are the main co-products of SPPS. After cleavage from the SPPS resin, the target peptide is immobilized on a second solid support through native chemical ligation (NCL). The truncated peptides are then removed by simple filtration. Cleavage of the linker finally releases the purified peptide into solution.Having in mind the future extension our strategy to the synthesis of very long DRPs through successive solid-supported NCLs of multiple peptide segments, we have studied in detail the stability and cleavage conditions of the N-terminal linker.To explore the scope and limitations of the method, it has been applied to the purification of two biologically-relevant cysteine-rich peptide sequences: chicken AvBD2 (36 AA), a β defensin antimicrobial peptide, and Bv8 (77 AA), a prokineticin-like peptide from yellow-bellied toad.

Die im Jahre 1963 von Robert Bruce Merrifield vorgestellte festphasengebundene Peptidsynthese beeinflusste in hohem Maße verschiedene Bereiche der Naturwissenschaften. Doch trotz zahlreicher neuer Entwicklungen hat sich in der das Prinzip der eingesetzten Trägermaterialien nicht grundlegend geändert. Geringfügig quervernetzte Polystyrol-Harze sind immer noch die meist verwendeten Trägermaterialien in der standardisierten Peptidsynthese. In dieser Arbeit wurden superparamagnetische Kern-Schale-Nanopartikel entwickelt und erstmals deren Einsatz als neues Trägermaterial für die Synthese von Peptiden, Peptid-Polymer-Konjugaten und Oligonucleotiden demonstriert. Unter Verwendung einer mikrowellenunterstützten Syntheseroute gelang es zunächst superparamagnetische Magnetitpartikel mit einem Durchmesser von durchschnittlich 6 nm darzustellen. Anschließend wurde ein neu entwickelter mikrowellenunterstützter Stöber-Prozess zur Herstellung von Magnetit-Silica-Kern-Schale-Nanopartikel angewendet, welche im dritten Schritt mit Aminopropyltrimethoxysilan funktionalisiert wurden. Es wurden hochpräzise, monodisperse Kern-Schale-Nanopartikel mit einem Durchmesser von durchschnittlich 69 nm und einem Beladungswert von 0.11 mmol/g erhalten, welche in durchgeführten Stabilitätstests hervorragende Ergebnisse zeigten und als neue Trägermaterialien für festphasengebundenen Synthesen getestet wurden. Die erforderliche Produktaufreinigung erfolgte durch ein externes Magnetfeld, durch welches die Partikel reversibel sedimentierbar sind. Erste Studien der Synthese einer 4-mer-Peptidsequenz zeigten Ausbeuten von über 70% und mit herausragender Reinheit von über 95%. Besonders eindrucksvolle Ergebnisse erzielten die Partikel bei der Synthese von Peptid-Polymer-Konjugaten, bei denen die Ligationsreaktionen mit vorher nicht dokumentierten Umsatzraten verliefen. Außerdem konnte die Anwendbarkeit bei der Synthese eines Trinucleotids nachgewiesen werden. / In 1963 Merrifield introduced the method of solid-phase supported synthesis and thus revolutionized peptide synthesis. In spite of several new developments, the main principle of established solid supports has not changed much. Still lightly cross linked poly(styrene) resins dominate the used supports. This work reports on surface amino functionalized, superparamagnetic nanoparticles with a protective silica shell to be applicable as colloidal supports for organic synthesis of peptides, peptide polymer conjugates and oligonucleotides. A microwave supported synthesis route lead to superparamagnetic magnetite particles with an average particle diameter of 6 nm. Subsequently a new developed microwave assisted Stöber process was used to build up magnetite-silica-core-shell-nanoparticles, which were functionalized in a third step with aminopropyltrimethoxysilane. Defined monodisperse core-shell nanoparticles were obtained with an average diameter of 69 nm and a concentration of free amino groups of 0.11 mmol/g, which showed excellent results in conducted stability tests and were used as new support materials for solid-supported syntheses. Convenient magnetic sedimentation proved to ensure ease of purification after each reaction step. Initial studies of a synthesis of a tetramer peptide sequence showed yields of more than 70% and an outstanding purity of more than 95%. The particles also showed impressive results in the synthesis of peptide-polymer conjugates, in which the ligation reactions proceeded conversion rates, which had not been published before. In addition, the applicability of the particles was demonstrated in the synthesis of a trinucleotide.

No description available.

No description available.