In the last decade, there has been a surge of interest from the chemistry community in developing synthetic catalysts that emulate the remarkable rate accelerations observed for enzymatic reactions. One approach utilized by enzymes involves preorganization of substrate(s) using a favourable binding event to orient the substrate(s) in a reactive arrangement. Although the “induced intramolecularity” is entropically unfavourable, it is facilitated by the enzymes and utilized to accelerate the subsequent chemical transformation. Chemists have often used a conceptually related stepwise approach in which temporary tethers are assembled to induce a temporary intramolecularity. This preorganization often enables difficult intermolecular reactions, and typically leads to increased regio-, chemo-, and stereoselectivity in chemical reactions. Seeking to develop a catalytic approach, we focused our efforts in developing a mild, carbonyl-catalyzed hydration protocol for - and -amino nitriles to give the corresponding - and -amino amide and acid. This work highlights the value of employing induced intramolecularity in accessing structurally important chemical motifs that otherwise require harsh reaction conditions. Additionally, this thesis presents the background material, design process, optimization and scope of this reactivity.

In the last decade, there has been a surge of interest from the chemistry community in developing synthetic catalysts that emulate the remarkable rate accelerations observed for enzymatic reactions. One approach utilized by enzymes involves preorganization of substrate(s) using a favourable binding event to orient the substrate(s) in a reactive arrangement. Although the “induced intramolecularity” is entropically unfavourable, it is facilitated by the enzymes and utilized to accelerate the subsequent chemical transformation. Chemists have often used a conceptually related stepwise approach in which temporary tethers are assembled to induce a temporary intramolecularity. This preorganization often enables difficult intermolecular reactions, and typically leads to increased regio-, chemo-, and stereoselectivity in chemical reactions. Seeking to develop a catalytic approach, we focused our efforts in developing a mild, carbonyl-catalyzed hydration protocol for - and -amino nitriles to give the corresponding - and -amino amide and acid. This work highlights the value of employing induced intramolecularity in accessing structurally important chemical motifs that otherwise require harsh reaction conditions. Additionally, this thesis presents the background material, design process, optimization and scope of this reactivity.

Choline oxidase catalyzes the two-step oxidation of choline to glycine betaine, one of limited osmoprotectants, with the formation of betaine aldehyde as an enzyme bound intermediate. Glycine betaine accumulates in the cytoplasm of plants and bacteria as a defensive mechanism to withstand hyperosmolarity and elevated temperatures. This makes the genetic engineering of relevant plants which lack the property of salt accumulation of economic interest, and the biosynthetic pathway of the osmolyte a potential drug target in microbial infections. The reaction of alcohol oxidation occurs via a hydride ion tunneling transfer from the substrate donor to a flavin acceptor within a highly preorganized active site environment in which choline and FAD are in a rigidly close proximity. In this dissertation, factors contributing to the enzyme-substrate preorganization which is required for the hydride ion tunneling reaction mechanism in choline oxidase have been investigated. Crystallographic studies of wild-type choline oxidase revealed a covalent linkage between C8M atom of the FAD isoalloxazine ring and the N(3) atom of the side chain of a histidine at position 99, and a solvent excluded cavity in the substrate binding domain containing glutamic acid at position 312 as the only negatively charged amino acid residue in the active site of the enzyme. The role of the histidine residue and the contribution of the 8á-N(3)-histidyl covalent linkage of the flavin cofactor to the reaction of alcohol oxidation was investigated in a variant form of choline oxidase in which the histidine residue was replaced with an asparagine. The role of the glutamate residue and the importance of the spatial location of the negative charge at position 312 was investigated in variant forms of choline oxidase in which the negatively charged residue was replaced with glutamine and aspartate. Mechanistic data obtained for the variant enzymes and their comparison to previous data obtained for wild-type choline oxidase are consistent with the residues at positions 99 and 312 being important for relative positioning of the hydride ion donor and acceptor. The residues are important for the enzyme-substrate preorganization that is required for the hydride tunneling reaction in choline oxidase.

Ein Ansatz der Darstellung von neuartigen funktionalen Materialien basiert auf der Synthese von Foldameren mit charakteristischen Eigenschaften, die eine Kontrolle über Formgebung und Gestaltung der Makromoleküle und derer Aggregate zulassen. Bislang sind gerade größere Foldamerstrukturen definierter Größe und Form meist schwer darstellbar und eine strukturelle Modifizierbarkeit nicht ohne weiteres möglich. In dieser Arbeit konnte gezeigt werden, dass die hohe Effizienz der seit 2002 bekannten Kupfer(I)-katalysierten 1,3-dipolaren Azid-Alkin-Cycloaddition, kurz “Klick“-Reaktion genannt, verwendet werden kann, um neuartige heteroaromatische Gerüste für die Konstruktion von diversen (makromolekularen) Strukturen zu generieren. Hierbei wird der bei der Reaktion entstehende Triazol-Ring gezielt als funktionale und strukturgebende Einheit genutzt. Zunächst wurden auf einfache und hochmodulare Weise 2,6-Bis(1-aryl-1,2,3-triazol-4-yl)pyridine (BTPs) dargestellt, die in einer hufeisenförmigen, planaren Konformation vorliegen und sich daher als helikogene Einheiten für die Konstruktion von helikalen aromatischen Foldameren eignen. Zudem stellen die BTP-Strukturen eine neue Klasse von pyridinzentrierten, tridentaten Liganden dar. Sie koordinieren an eine Vielzahl von Übergangsmetallionen unter Ausbildung von Metallkomplexen, die über interessante magnetische und lumineszierende Eigenschaften verfügen. Durch die Koordination, aber auch bei Protonierung, lassen sich die BTP-Gerüste von der gebeugten anti-anti-Konformation in eine gestreckte syn-syn-Konformation schalten. Dies wurde in Lösung, im kristallinen Festkörper und an der Flüssig-Fest-Grenzfläche zu Graphit untersucht. Über Selbstorganisation großflächig ausgebildete hochgeordnete BTP-Monoschichten an der Graphitoberfläche lassen sich mit Hilfe der Rastertunnel-Mikroskopie visualisieren und durch oben genannte externe Stimuli umstrukturieren. Eine neue Klasse von (BTP-basierten) responsiven heteroaromatischen oligomeren und polymeren Foldameren wurde mit Hilfe der „Klick“-Reaktion generiert. Die Oligomeren, sogenannte ”Klickamere“, mit einer Länge von 17 aromatischen Ringen zeigen in polaren Lösungsmitteln ein ausgeprägtes helikales Faltungsverhalten. Ein aus 17 aromatischen Ringen bestehender Foldamerstrang ist gegenüber Chloridionen responsiv, wobei es durch die Wechselwirkung mit diesem achiralen Stimulus bemerkenswerter Weise zu einer Helixinversion kommt. Die entsprechenden responsiven Polymere falten in eine stabile helikale Konformation, die bei Zugabe von Metallionen aufbricht und zu der Bildung von koordinativ kreuzverlinkten, stark viskosen Gelen führt. / One approach to develop novel functional materials is based on the synthesis of macromolecules with characteristic properties, in particular foldamers. However, preparation and structural variation of macromolecules of controllable size and specific shape are often cumbersome and versatile synthetic routes are still needed. In this dissertation, the high efficiency of the so called “click”-reaction, i.e. the Cu(I)-catalyzed Huisgen-type 1,3-dipolar cycloaddition, has been used to design a novel class of heteroaromatic (macromolecular) scaffolds. In these structures the formed triazole moieties constitute an essential integral part rather than a mere connecting unit. In a first step, structurally varying 2,6-Bis(1-aryl-1,2,3-triazolyl-4-yl)pyridines (BTPs) have been generated in an easy and modular way. The BTP scaffold adopts a kinked conformation and therefore functions as helicogenic building block for the construction of helical foldamers. Additionally, the BTP framework is responsive towards protonation and transition metal ion complexation, thereby undergoing a significant structural change from the kinked anti-anti into the extended syn-syn conformation. The conformational switching has been investigated in solution and in the solid state but can also be visualized at the liquid-solid interface on graphite by STM imaging. The BTPs represent a novel class of pyridine-centered, tridentate ligands, which form complexes with interesting magnetic and luminescent properties by the coordination to numerous transition metal ions. Varying heteroaromatic oligomeric and polymeric foldamers with remarkable properties have been generated using the “click”-reaction as synthesis tool. The BTP building blocks, which have (partly) been integrated into the backbones, support the stability of the helical conformation and provide responsiveness towards external stimuli. Three oligomer series of different length have been synthesized and analyzed. Oligomers consisting of 17 aromatic rings, termed clickamers, fold into a helical conformation in polar solvents. One of the three clickamers shows an unexpected phenomenon of helix inversion upon interaction with chloride ions as an achiral stimulus. The corresponding polymeric strands fold into an even more stable helical conformation, which breaks up upon exposure to transition metal ions leading to coordinatively crosslinked, highly viscous gels.