This work was initially launched to study the synthesis of low-valent group 13 compounds bearing the bis(imino)pyridine ligand framework. Since its inception, this project has grown beyond the boundaries of group 13 to include low valent tin, silver, and rhenium. Alongside the reports of novel coordination compounds, we utilized computational chemistry to uncover unprecedented interactions which challenge conventional concepts of bonding. Synthesis, characterization, and complimentary computational studies are presented herein. Chapter 1 presents a historical overview of the bis(imino)pyridine ligand as well as our synthetic methodology and characterization of new ligand variants we have contributed to the literature. Chapter 2 presents the synthesis of a series of In(I) and In(III) bis(imino)pyridine complexes with varied sterics. Ligand-metal interaction and effect of ligand steric bulk on complex stability, as well as computational studies highlighting weak covalent interactions will be discussed. Chapter 3 presents the synthesis of Ga(III) bis(imino)pyridine complexes. Reactivity with “GaI” synthon as well as varied-stoichiometry one-pot synthesis attempts to generate low valent Ga-bis(imino)pyridine complexes will be discussed. Chapter 4 presents the synthesis of a series of Tl(I) bis(imino)pyridine complexes with varied sterics analogous to the approach taken with indium(I). Unprecedented weak ligand-metal as well as Tl-arene interactions will be discussed. Chapter 5 presents the synthesis of a series of Sn(II) bis(imino)pyridine complexes with varied sterics and halide substituents. Preferential cation-anion pair formation and attempted reactivity will be discussed. Chapter 6 presents the synthesis of a series of Ag(I) bis(imino)pyridine complexes with varied sterics. Resulting ligand-metal interactions as well as reactivity towards Lewis basic donor ligands will be discussed. Chapter 7 presents the synthesis of first crystallographically authenticated examples of rhenium(I) pincer complexes utilizing the bis(imino)pyridine ligand. Chapter 8 presents a general conclusion to the work.

Pseudomonas aeruginosa ᴅ-arginine dehydrogenase (PaDADH) is a flavin-dependent enzyme. The enzyme catalyzes the oxidative deamination of a broad range of ᴅ-amino acids to their corresponding imino-acids, which are non-enzymatically hydrolyzed to α-keto-acids and ammonia. A46, S45 and I335 residues are located in flexible loops, which form a flask-like substrate-binding pocket. In this study, I335, A46, and S45 were mutated to histidine, glycine, and alanine, respectively and individually, through site-directed mutagenesis, to investigate their role in binding and catalysis in PaDADH. The results showed that A46 and S45 residues participate in the optimal orientation of the substrate α-amino group and I335 modulate the active site flexibility.

This thesis describes the development of new catalytic systems based upon iron complexes and their reactivity toward ethylene. First, we focused our interest on the synthesis of iron(III) precursors chelated by monoanionic ligand. Those complexes were obtained either by reaction of the monoanionic ligand with FeCl3 or through oxidation of the iron(II) complex. The second reaction led to binuclear complexes. Then, another aim of the thesis was to design new well-defined cocatalysts for the activation of iron complexes. The study of the reaction between an alcohol and the trimethylaluminum allowed us to reach this aim. Aluminum complexes adopted either a binuclear framework or a trinuclear one, depending on the nature of alcohol reagent. Besides this work, new iron(II) and nickel(II) complexes chelated by imino-imidazole ligands bearing a pendant donor function L were synthesized. All complexes have been evaluated for the oligomerization of ethylene in the presence of EtAlCl2 or MAO as cocatalyst. Only nickel complexes were active toward ethylene transformation.

This work was initially launched to study the synthesis of low-valent group 13 compounds bearing the bis(imino)pyridine ligand framework. Since its inception, this project has grown beyond the boundaries of group 13 to include low valent tin, silver, and rhenium. Alongside the reports of novel coordination compounds, we utilized computational chemistry to uncover unprecedented interactions which challenge conventional concepts of bonding. Synthesis, characterization, and complimentary computational studies are presented herein. Chapter 1 presents a historical overview of the bis(imino)pyridine ligand as well as our synthetic methodology and characterization of new ligand variants we have contributed to the literature. Chapter 2 presents the synthesis of a series of In(I) and In(III) bis(imino)pyridine complexes with varied sterics. Ligand-metal interaction and effect of ligand steric bulk on complex stability, as well as computational studies highlighting weak covalent interactions will be discussed. Chapter 3 presents the synthesis of Ga(III) bis(imino)pyridine complexes. Reactivity with “GaI” synthon as well as varied-stoichiometry one-pot synthesis attempts to generate low valent Ga-bis(imino)pyridine complexes will be discussed. Chapter 4 presents the synthesis of a series of Tl(I) bis(imino)pyridine complexes with varied sterics analogous to the approach taken with indium(I). Unprecedented weak ligand-metal as well as Tl-arene interactions will be discussed. Chapter 5 presents the synthesis of a series of Sn(II) bis(imino)pyridine complexes with varied sterics and halide substituents. Preferential cation-anion pair formation and attempted reactivity will be discussed. Chapter 6 presents the synthesis of a series of Ag(I) bis(imino)pyridine complexes with varied sterics. Resulting ligand-metal interactions as well as reactivity towards Lewis basic donor ligands will be discussed. Chapter 7 presents the synthesis of first crystallographically authenticated examples of rhenium(I) pincer complexes utilizing the bis(imino)pyridine ligand. Chapter 8 presents a general conclusion to the work.

Over the past recent years, β-aminocarbonyls have been of great interest to medicinal chemists. As a practical method to obtain these moieties, alkene aminocarbonylation, accounting for the formation of a C-N and a C-C bond, has been the subject of limited research efforts (very specific intramolecular metal-catalyzed variants have been reported). Direct aminocarbonylation of alkenes constitutes a challenging and an important potential innovation in the synthesis of β-aminocarbonyls such as β-amino acids. The research efforts described in the present thesis have been primarily directed towards the development of concerted pathways for the amination of alkenes using hydrazine derivatives as bifunctional reagents. Building on our previous report on the reactivity of hydrazides, progress on the aminocarbonylation of alkenes along with the synthetic scope of this reactivity are herein provided. Therefore, the first part of the present thesis (Chapter 2) focuses primarily on the development of thermolytic conditions for the intramolecular aminocarbonylation of alkenes using amino-isocyanates. Alongside, development of imino-isocyanates have provided complementary synthetic tools for aminocarbonylation. The second part (Chapter 3) describes the work accomplished towards intermolecular aminocarbonylation of alkenes and the synthesis of complex azomethine imine products (Chapter 3). Finally, the last part of the discussion (Chapter 4) will be on the development of new hydrazide reagents for the intramolecular Cope-type hydroamination of alkenes. In doing so, description of the synthetic utility of amino-isocyanates as amphoteric reagents for cascade reactions and heterocyclic synthesis will be provided.

In modern synthetic organic chemistry, chemists are driven to develop efficient methods for important C-C and C-N bond formation reactions. The challenge lies with establishing new uses for readily available substrates. In this regard, the synthesis of β-aminocarbonyl compounds from alkenes remains a long-standing challenge. Innovation in reaction discovery often requires finding new reagents, or rare reagents with underappreciated value in synthesis. In Chapter 1, N-isocyanates and other heterocumulenes are introduced as versatile amphoteric reagents. Their amphoteric properties are valuable in the discovery of new synthetic approaches, especially in cycloaddition reactions. While C-isocyanates are bulk industrial chemicals, the formation and reactivity of N-isocyanates remains underexplored. Chapter 2 describes the development of reactivity with rare imino-isocyanates. This includes methods to access the reagent in situ with a blocking group approach, and the establishment of intermolecular cycloaddition reactivity with a variety of alkenes. This stereospecific reaction provides complex N,N’-cyclic azomethine imines, and enables access to β-aminocarbonyl compounds from alkenes. β-Amino amides and esters, pyrazolidinones, and pyrazolones were accessed by reductive derivatization of the aminocarbonylation products. Exploration into the limits of this reactivity gave insight into fundamental properties of imino-isocyanates. This includes the first detection of imino-isocyanates by IR spectroscopy. A kinetic resolution of the azomethine imines obtained from this alkene aminocarbonylation reaction was then developed, which gave access to enantioenriched β-amino carbonyl compounds (Chapter 3). This was accomplished by Brønsted acid catalysed reduction, with a selectivity factor of 13-43. This was the first example of the enantioselective reduction of azomethine imines, and represents a new activation mode for reactions of N,N’-cyclic azomethine imines. Using this reductive method, both enantiomers of the β-amino amide could be obtained from a racemic azomethine imine in ≥ 97% ee. The discovery of new reactivity of imino-isocyanates with imines in described in Chapter 4, which allowed the synthesis of eight new azomethine imines with the triazolone core. Our initial scope studies revealed different trends with imines than with alkenes, including increased reactivity, which led to investigation of the mechanism of this reaction. In addition, this was shown to be a valuable new approach for the synthesis of triazolones from imines.

Branched chain sugars display a varied and valuable range of biological activities. This thesis concerns the synthesis of 3,5-di-C-methyl-D-glucose, a potential inhibitor of glycogen phosphorylase (GP), and therefore a proposed therapeutic agent for type 2 diabetes. Chapter 1 looks at the occurrence of branched sugars in the natural world and current therapies for type 2 diabetes. Inhibition of GP is explored, and the molecular modelling studies which led to the design of the project target. Chapter 1 also looks into the development of new foodstuffs, the chemistry and biochemistry of imino sugars and branched hydroxy proline analogues. In Chapter 2, a range of different approaches to 3,5-di-C-methyl-D-glucose are investigated. Most of the initial investigations were carried out on the L-enantiomer, a readily available test system deriving from 2-C-methyl-D-ribono lactone. 2-C-Methyl-D-ribono lactone is synthesised rapidly from D-glucose in a one-pot reaction; as the key starting material for this work, the scalability of this process was investigated. One of the attempted syntheses of di-C-methyl glucose lead to the development of a route towards 3,5-di-C-methyl fructose, a novel dibranched ketose sugar. It was envisaged that through an enzymatic transformation, it might be possible to produce 3,5-di-C-methyl glucose stereoselectively. Synthesis of both enantiomers of 3,5-di-C-methyl glucose and mannose are reported, alongside results of GPb inhibition studies. Analysis of the preferred ring size of a range of di-C-methyl branched sugars and sugar lactones generated in this work is also presented. Chapter 3 explores the chemistry of 2,4-di-C-methyl-L-arabinono lactone, a key intermediate in the synthesis of 3,5-di-C-methyl-L-glucose. From this lactone a novel deoxy sugar, 2-deoxy-2,4-di-C-methyl-L-arabinono lactone, was generated. Routes towards a selection of imino sugars were explored, resulting in the synthesis of a methyl branched isofagomine analogue. A substituted aziridine was synthesised, from which a route to a di-C-methyl branched piperidine was proposed, and a pyrrolidine. Also presented is a synthesis of a dihydroxy di-C-methyl branched proline analogue. Detailed NMR analysis of several of the sugars generated in this work was carried out by Dr M. Wormald, of the University of Oxford Biochemistry department. The results of these investigations are presented in the Appendix. Throughout this work, the presence of quaternary centres has posed a problem with the assignment of relative configuration. As a result, this work has been greatly supported by X-ray crystallography, and the structures shown herein were wholly generated by me. Several other crystals were run during the course of this work, not all pertaining to these projects, and are provided in the CD appendix.

Dans le contexte de la recherche de molécules actives agissant spécifiquement sur des microorganismes pathogènes tels que les mycobactéries, la biosynthèse du galactofuranose (Galf) constitue une cible chimiothérapeutique intéressante. Notre approche consiste à concevoir et synthétiser des iminosucres originaux comme inhibiteurs potentiels et/ou sondes mécanistiques des enzymes mises en jeu : l'UDP-Galp mutase (UGM) et les Galf transférases (GlfT). Pour cela nous avons développé deux approches stéréodivergentes conduisant à des imino-C-galactosides originaux.<br>Nous avons mis au point une méthodologie performante basée sur l'addition de nucléophiles silylés, assistée par acide de Lewis, sur une N-glucosylamine protégée qui a permis la synthèse d'une petite librairie de dérivés alpha-1,4-didésoxy-1,4-imino-D-galactitols substitués en position C-1. L'utilisation de séquences synthétiques convergentes, notamment une métathèse croisée, nous a ensuite conduits à des analogues de l'UDP-Galf possédant un squelette iminosucre diversement lié à l'UridineMonoPhosphate.<br>D'autre part, la cycloaddition 1,3-dipolaire entre un phosphonate fonctionnalisé et une nitrone cyclique de configuration D-galacto a conduit régio- et stéréosélectivement à l'isoxazolidine, analogue de l'UDP-Galf et précurseur d'UMP-beta-1,4-iminogalactitol. Cette approche concise et efficace permet également l'obtention d'analogues disaccharidiques du Galf. En effet, nous avons constaté qu'une nitrone polyhydroxylée non protégée réagit facilement, dans l'eau, avec des oléfines de sucre pour conduire au cycloadduit correspondant, précurseur d'imino-disaccharide.<br>L'évaluation biologique de ces composés comme inhibiteurs de l'UGM et de GlfT2 a montré qu'un analogue de l'UDP-Galf présente une activité intéressante de GlfT2.

This thesis is concerned with the development of methodology for the asymmetric synthesis of a range of amino polyol containing compounds. Chapter 1 highlights the abundance of the amino polyol motif in nature, the wide range of biological activities displayed by amino polyol containing compounds, and their occurrence in drug molecules. A variety of different methods for the synthesis of stereodefined amino polyols is then discussed. Chapter 2 details a full investigation into the doubly diastereoselective conjugate addition reactions of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to enantiopurealpha,beta-unsaturated esters which contain a dioxolane unit. The “matched” conjugate addition reactions were further coupled with a highly diastereoselective in situ enolate oxidation using camphorsulfonyloxaziridine for the synthesis of keyalpha-hydroxy-beta-amino ester intermediates. Subsequent cyclisation and further elaboration allowed access to a range of amino polyol containing compounds including imino sugars, amino sugars, and amino acids. Chapter 3 extends the investigation into the doubly diastereoselective lithium amide conjugate addition reaction to enantiopure alpha,beta-unsaturated esters which contain two dioxolane units. A full assessment into the conjugate addition of the antipodes of lithium N-benzyl-N-(alpha-methylbenzyl)amide to a series of D-pentose derived alpha,beta-unsaturated esters is reported. Subsequent elaboration of thebeta-amino ester products of these conjugate addition reactions resulted in the synthesis of (2'S,3'S,4'R)-dihydroxyhomoproline and (2'S,3'R,4'S)-dihydroxyhomoproline. Chapter 4 describes the asymmetric syntheses of protected forms of APTO and AETD, the 2,4,5-trihydroxy substitutedbeta-amino acid residues found within the hexapeptide marine natural products microsclerodermins C, D and E. The optimised synthetic routes to APTO and AETD involved three key steps: a diastereoselective aminohydroxylation [via conjugate addition of lithium (R)-N-benzyl-N-(alpha-methylbenzyl)amide to an achiralalpha,beta-unsaturated ester followed by in situ enolate oxidation with camphorsulfonyloxaziridine], a diastereoselective dihydroxylation, and an olefination. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in chapters 2, 3 and 4.

This work comprises two main parts. The first part outlines our efforts to expand on the recent work of Gütlich et.al. by synthesizing Co(II) based spin crossover systems within a dendritic framework. We wanted to investigate the possibility of synthesizing different first generation, triazole containing dendrimers using “click” type reactions and their coordination ability with Co(II) ions. To this end we have had limited success mainly due to the numerous challenges in synthesizing a pure dendrimer product. The second part details our efforts in the synthesis of a mononuclear Co(II) based single molecule magnet. This comes as an extension to recent reports by Chang and Long where they have successfully obtained mononuclear Fe(II) single molecule magnets by inducing structural distortions within the complexes to amplify the spin-orbit coupling. We postulated that the use of Co(II) in conjunction with a bulky ligand framework would lead to desirable magnetic properties. We chose the known bis(imino)pyridine ligand scaffold due to its rich chemistry and its interesting and unexpected coordination behaviour, as we have seen in previous research efforts by our lab. To this end we were successful in isolating and characterizing 4 compounds, and we have carried out detailed magnetic measurements on the two most magnetically interesting species.