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Although the use of Ln(^2+) species as one electron reducing agents has recently become popular, relatively few processes have focused on the control of stereochemistry by the incorporation of chiral auxiliaries at the metal centre. This thesis discusses work aimed at the synthesis of chiral bis(pentaalkylcyclopentadienyl) and polyaza/oxo ligands for Ln(II) ions, and their subsequent application in asymmetric organic synthesis. Synthesis of enantiomerically pure bis(pentaalkylcyclopentadienyl) ligands was attempted via a novel double Nazarov cyclisation of 5,6-di-(methyl)-decane-3,8-dione. A competing intermolecular aldol reaction reduced the efficiency of this route, although subsequent work suggests that the alternative ketone, (3,4-RR/SS)-bis(2'- oxobutyl)tetrahydrofuran, could inhibit aldol formation. In addition, a route for bis(tetramethylcyclopentadienyl) ligands was developed via oxidative coupling of 4-(S)-isopropyl-3-propionyl-oxazolidin-2-one.A range of tetradentate polyaza/oxo ligands have been prepared and their application in enantioselective carbon-carbon bond formation, in particular the Barbier reaction between 2-octanone and bromobutane, investigated. Using N,N'-bis(3'- propionamide)cyclohexane-l,2-diamine, asymmetric induction and a marked acceleration in reaction rate was observed. This represents the first enantioselective Sm(II)-mediated Barbier reaction. The use of aryl ketones affords pinacols with low enantioselectivity.

The generation and isolation of two novel borenium cations has been described. The observation that the reaction of the Lewis acid B(C6F5)3 and the Lewis base diazabicyclo[2.2.2]octane (DABCO) with pinacol borane (HBpin) resulted in the activation of the B–H bond of HBpin and formation of a stable borenium cation/borohydride salt. This stable salt was used as a catalyst in the hydroboration reaction. It was shown to catalytically reduce a wide array of substrates including imines, N-heterocycles, nitriles, and ketones using pinacol borane as the source of hydride. Another borenium ion, synthesized from trityl tetrakis-pentafluorophenyl borate, DABCO, and HBpin did not contain a nucleophilic borohydride counterion and it was isolated in the solid state. This salt was also found to reduce the same substrates with similar yields and reaction times. The mechanisms of both of these catalysts were investigated and were found to be proceeding by a similar borenium catalyzed process. Quantitative analysis of the initial rates of each catalyst under identical conditions yielded rate constants on the same order of magnitude which strongly suggested that both catalysts operated via similar mechanisms. Stoichiometric experiments and isotope labelling using deuterated pinacol borane demonstrated that the nucleophilic counterion was not a kinetically relevant reducing agent under the reaction conditions. Furthermore, these reactions and the use of an isolable iminium ion as a hydride acceptor indicated that the hydride delivery agent was a DABCO•HBpin adduct. The DABCO•HBpin adduct was observed spectroscopically at ambient and subzero temperatures. Lastly, the rate of reduction using pinacol borane and [d1]-pinacol borane were significantly different and produced a high kinetic isotope effect (KIE = kH/kD = 6.6 ± 0.2). This high KIE strongly indicates that hydride delivery is the rate limiting step in the catalytic cycle. With this knowledge an asymmetric model is discussed and the beginnings of the development of an asymmetric borenium cation catalyzed process are described. / Thesis (Master, Chemistry) -- Queen's University, 2012-10-13 08:48:37.506

This thesis examines the catalytic characteristics of two materials with respect to the decomposition of Formic Acid. The decomposition of formic acid proceeds via two principal reaction pathways: dehydration and dehydrogenation. Dehydrogenation is a valuable reaction producing Hydrogen suitable for use in fuel cells whereas the dehydration pathway produces carbon monoxide, a poison for many fuel cell materials. One of the surface species, the formate ion, is also implicated in other important chemical reactions, most notably the water gas shift and the decomposition of methanol. The author seeks to document various intermediate surface species associated with the two reaction pathways with hope to use this information to future tailoring of catalysts for greater selectivity.

Directed evolution studies by Whitehouse et al. identified several variants of P450BM3 (CYP102A1) with enhanced substrate oxidation rates across a range of substrates. This thesis describes the use of these ‘generic accelerator’ variants, in combination with selectivity altering mutations to engineer P450BM3¬ for the oxidation of pharmaceuticals. Using engineered variants the non-steroidal anti-inflammatory drug diclofenac was metabolised to the primary human metabolites 4′- and 5-hydroxydiclofenac, with total conversion of 2 mM substrate by 5 μM enzyme. The local-anaesthetic lidocaine and the steroid testosterone were similarly metabolised to human metabolites. This is the first report of a drug compound being totally converted to the human metabolites by a P450BM3 variant, and is also the first report of lidocaine metabolism by a P450¬BM3 variant. The engineered variants are akin to CYP3A4, the primary human drug metabolising enzyme, as they show activity towards a range of compounds including anionic, cationic and neutral drugs. This range of activity is at the expense of NADPH coupling, which remains low with these substrates. In order to more fully understand the origin of the rate enhancing properties of the generic accelerator variants, spectroelectrochemical, stopped-flow and kinetic studies were performed. A custom optically transparent thin layer electrode system was designed and fabricated for use in spectroelectrochemical titrations. A spectroelectrochemical cell and gold mesh electrode were designed and used in spectroelectrochemical investigations of P450BM3 variants, as well as other P450s and their redox partners. These spectroelectrochemical, stopped-flow and kinetic studies, in combination with X-ray crystal structures provided insight into the origin of the rate enhancing properties of these enzymes and supplied the first example of the complete characterization of the thermodynamic and kinetic properties of WT and mutant P450BM3 for the oxidation of a non-natural substrate. The generic accelerator variants are, in the resting state, in a more catalytically ready conformation than the WT enzyme, and reorganization energy barriers appear to be lowered, so that fewer substrate-induced structural changes are required to promote electron transfer and initiate the catalytic cycle.

Thesis advisor: Amir H. HOveyda / Chapter 1: Ag-Catalyzed Enantioselective Vinylogous Mannich Reactions of Ketoimines Few catalytic methods have been reported for the enantioselective synthesis of N-substituted quaternary carbon stereogenic centers, typically the low reactivity of the electrophilic partner cannot be overcome. Herein, a silver-based catalyst is described which promotes highly site-, diastereo-, and enantioselective additions of siloxyfurans to ansidine-derived ketoimino esters. Mechanistic investigations, undertaken to elucidate the nature of the active silver-phosphine complex, supported the proposed origin for the anti-selective Mannich-type additions. Chapter 2: New Catalysts for the Enantioselective Cu-Catalyzed Additions of Allyl Groups to Phosphinoylaldimines The deficiencies in modern organic synthesis regarding the preparation of chiral molecules bearing amines, despite their incredible significance, are addressed. The development of a new method and catalyst for the preparation of enantiomerically enriched allyl-substituted alpha-chiral amines is described. Copper based catalysts bearing chiral C1-symmetric N-heterocyclic carbenes promote reactions between diphenylphosphinoyl aldimines and allyl boronic acid pinacol ester affording the homoallylic amines with high levels of efficiency and selectivity. Furthermore, the mechanistic rationale describing the selectivity patterns of the designed catalysts is analyzed. Chapter 3: NHC-Cu-Catalyzed Enantioselective Propargyl Group Additions to Phosphinoylaldimines The copper complex of a chiral N-heterocyclic carbene is found to be uniquely effective at promoting highly selective reactions of a commercially available allenylboron reagent and diphenylphosphinoyl aldimines. The enantiomerically enriched homopropargylic amines are exclusively afforded within an hour in the presence of as low as 0.25 mol % catalyst. The utility of the method is further demonstrated through the elaboration of the appended alkyne to difficult-to-access functionalities, highlighted by the synthesis of a key fragment for the preparation of the aza-epothilones, macrocyclic lactams which exhibit acute cytotoxicity. Chapter 4: Metal-Free Catalysts for Enantioselective Synthesis of Allenic Carbinols A metal-free catalyst, unique in structure and mechanism, is developed to address the remaining deficiencies in allyl addition chemistry, an area dominated by metal catalysis. The key organizational and enabling feature of the catalyst is a proton, a simple point charge which affects the facility of the C-C bond formation through electrostatic interactions. The unique alpha-selectivity delivered by the boron-based catalyst, a product of a catalytic cycle characterized by two gamma-selective allyl transfer processes, allows for the unprecedented synthesis of enantiopure allenyl-substituted tertiary alcohols. Moreover, the described transfomations can be performed in a matter of minutes with ˂0.5 mol % catalyst.

Thesis advisor: Jason S. Kingsbury / The research of diazoalkanes dates back more than 100 years, yet a disproportionally small number of methods have been developed to utilize their unique reactivity patterns. This review seeks to analyze the history of methods used to synthesize diazoalkanes and to highlight the parallel growth in methods for their use in carbonyl expansion reactions. The development of Sc(III)-catalyzed ring expansion of cyclic ketones with non-stabilized diazoalkanes is presented. A brief overview of previous contributions to ring expansion methodology is presented in order to provide appropriate context to newly discovered methods. Our strategy for method development centered on several issues of practicality with regard to efficient synthesis of diazo nucleophiles as well as their safe handling. The results of this initial discovery laid the groundwork for the development of the first catalytic enantioselective ring expansion of cyclic ketones with diazoalkanes. As well as an improved methylene insertion reaction of silyl-substituted diazomethanes. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis (M.Sc.)--University of the Witwatersrand, Faculty of Science (Chemistry), 1990 / Deactivation studies; making use of fixed bed reactors, wet chemical analysis, surface area, pore volume determinations and X-ray diffraction—, scanning electron microscope— and secondary ion mass spectrometry techniques; were performed on a low temperature iron Fischer—Tropsch catalyst. It was revealed that this catalyst is mainly deactivated by sulphur poisoning, oxidation of the catalytic reactive phases, sintering of the iron crystallites and to a lesser extent deactivation through fouling of the catalytic surface by carbonaceous deposits. It was found that the top entry section of the catalyst bed deactivated relatively fast, the bottom exit section also deactivated, but not as fast as the top section The central portion of the catalyst bed was least affected. Sulphur contaminants in the feed gas, even though present in only minute quantities, results in a loss of catalyst performance of the top section of the catalyst bed, while water, produced as a product from the Fischer—Tropsch reaction, oxidized and sintered the catalyst over the bottom section of the catalyst bed.

Thesis advisor: Shih-Yuan Liu / Described herein are two distinct research projects focused on the development of metal-catalyzed late-stage functionalization strategies for 1,2-dihydro-1,2-azaborines separated into three chapters. The first chapter discusses the development, synthesis, and recent contributions to the field of azaborine chemistry. The second chapter details the development of rhodium catalyzed B-H bond activation for the synthesis of a new class of BN-stilbenes as well as the discovery of a novel B-H to B-Cl transformation that is successful both with B-H azaborines as well as other B-H containing compounds. The third chapter pertains to the development of a B-H and B-Cl tolerant C(3) functionalization strategy through the use of Negishi cross-coupling. Using this methodology, previously unreported isomers of BN-naphthalene and BN-indenyl have been synthesized and characterized. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.