Asymmetric hydrophosphination, the addition of a P-H bond across a C-C double bond, is an attractive potential route to chiral phosphines, which have important applications in many other types of asymmetric catalysis. However, a highly active and stereoselective catalyst for this reaction has yet to be identified. The ruthenium indenyl complex [RuCl(η5-indenyl)(PPh3)2] (1) was investigated as a potential catalyst for hydrophosphination through an exploration of the steps involved in this process: substrate coordination, P-H bond activation, and P-C bond formation. Substitution of triphenylphosphine ligands at the metal centre of 1 by alkyl- and aryl-substituted secondary phosphines (PR2H: R = Cy (a), Pri (b), Et (c), Ph (d) or Tolp (e)) gave predominantly the monosubstituted secondary phosphine complexes [RuCl(η5-indenyl)(PR2H)(PPh3)] (3a-e). Hydride ([RuH(η5-indenyl)(PR2H)(PPh3)] (6a,d)) and cationic nitrile ([Ru(η5-indenyl)(NCR')(PR2H)(PPh3)][PF6] (7a,d: R' = CH=CH2; 8a-b,d: R = CH3)) derivatives of 3 were prepared and in all cases the potentially reactive P-H bond of the secondary phosphine ligand did not interfere with the chemical transformation. Deprotonation of the P-H bond of the bulky dialkylphosphine-substituted chloro complexes 3a-b with KOBut gave five-coordinate, planar terminal phosphido complexes [Ru(η5-indenyl)(PR2)(PPh3)] (10a-b) that contain a unique Ru-PR2 π-bond. The analogous phosphido complexes 10d-e, containing less bulky aryl substituents at phosphorus, were found to be unstable at room temperature and were observed only by low temperature 31P{1H} NMR spectroscopy. Phosphido complexes 10a-b were found to be highly P-basic, capable of deprotonating the C-H bond of acetonitrile (pKa = 24) to give the metallated acetonitrile complex [Ru(CH2CN)(η5-indenyl)(PR2H)(PPh3)] (9a-b), and to be very P-nucleophilic, reacting with iodomethane (MeI) to give a new P-C bond in [RuI(η5-indenyl)(PCy2Me)(PPh3)] (17a). As might be expected, the addition of donor ligands to low-coordinate 10a-b was found to disrupt the Ru-PR2 π-bond to give six-coordinate terminal phosphido complexes [Ru(η5-indenyl)(L)(PR2H)(PPh3)], with pyramidal, instead of planar, geometry at phosphorus. These additions are irreversible in the case of CO (19a-b) or PCy2H (21a), while pyridine (23a-b) or NCPh (24a-b) adducts were shown by 31P{1H} NMR spectroscopy to be in equilibrium with 10a-b and the uncoordinated ligand. The addition of known substrates for transition metal-mediated hydrophosphination, phenylacetylene and acrylonitrile, to 10a-b resulted in a [2+2] cycloaddition of the unsaturated C-C bond at the Ru-PR2 π-bond to give metallacyclic complexes [Ru(η5-indenyl)(κ2-PhC=CHPR2)(PPh3)] (27a-b) and [Ru(η5-indenyl)(κ2-NCCHCH2PR2)(PPh3)] (32a-b) respectively. Surprisingly the addition of simple non-activated olefins (i.e. ethylene, 1-hexene, or norbornene), which were not previously known to be active substrates for this reaction, also gave [2+2] cycloaddition products. These cycloaddition reactions were found to be 100% regioselective, and are also stereoselective in the case of substituted alkenes (>96%). Experimental evidence suggests that these P-C bond forming reactions proceed via a concerted [2+2] cycloaddition pathway.

The glassy copolyimide 6FDA-DAM:DABA was investigated as a polymer backbone for membranes used in aggressive sour gas separation applications. An esterification crosslinking mechanism enabled the synthesis of materials with augmented H₂S/CH₄ selectivity and plasticization resistance. These materials make use of polyethylene glycol (PEG) crosslinking agents and are referred to as PEGMC polymers. Rigorous dense film characterization of the novel crosslinkable materials indicates that excellent H₂S/CH₄ selectivity (24) is achievable while still maintaining high CO₂/CH₄ selectivity (29) under high pressure ternary mixed gas (CO₂/H₂S/CH₄) feeds. Defect-free asymmetric hollow fiber membranes were formed and appropriate crosslinking conditions were determined, allowing for the characterization of these fibers under realistic sour gas feed conditions. Also, a PDMS post-treatment was used to give ultra-high permselectivity for aggressive feeds. Using several mixed gas feeds containing high concentrations of CO₂ and H₂S at feed pressures up to 700 psig, it is shown that the crosslinked asymmetric hollow fiber membranes developed and manufactured through this work are capable of maintaining excellent separation performance even under exceedingly taxing operating conditions. For example, CO₂/CH₄ and H₂S/CH₄ permselectivity values of 47 and 29, respectively, were obtained for a 5% H₂S, 45% CO₂, 50% CH₄ feed at 35°C with 700 psig feed pressure. An extremely aggressive 20% H₂S, 20% CO₂, 60% CH₄ mixed gas feed with 500 psig feed pressure was also used; the maximum CO₂/CH4 and H₂S/CH₄ permselectivity values were found to be 38 and 22, respectively.

Cell polarity is fundamental to numerous cellular processes including migration, molecular transport, and cell division. The establishment and organization of polarity is crucial to the maintenance of cellular homeostasis in mammalian systems. Deregulation of cell polarity is observed in disease states, including cancer. Numb is an adaptor protein that functions in regulating endocytic trafficking events. Numb was originally identified in Drosophila as an asymmetrically localized cell fate determinant, and was subsequently found to be conserved in vertebrates. In mammalian polarized epithelial cells, Numb is distributed asymmetrically along the basolateral membrane domain. The work herein describes phosphorylation of Numb by the Par complex protein, atypical Protein Kinase C (aPKC), as a means of regulating membrane localization and asymmetric distribution of Numb. A mutant of Numb that cannot be phosphorylated by aPKC accumulates on the plasma membrane and localizes to both apical and basolateral membranes. In aPKC-depleted cells, endogenous Numb is unable to achieve polarized distribution and localizes around the entire cell cortex. We demonstrate that this mechanism is conserved in Drosophila as mutation of the corresponding phosphorylation sites disrupts Numb asymmetric localization in dividing sensory organ precursor cells. In polarized epithelial cells, one function of Numb is to promote epithelial morphology when cells are challenged with external stimuli that disrupt cell-cell adhesion. For example, depletion of Numb results in enhanced sensitivity of cells to lose cell-cell contacts when treated with calcium chelating agents. Loss of Numb potentiates hepatocyte growth factor (HGF)-induced lamellipodia formation and cell dispersal – early steps in epithelial-mesenchymal transition (EMT). In Numb-depleted cells, Rac1-GTP loading is enhanced, which corresponds with increased rate in loss of cell-cell adhesion and increased lamellipodia formation, following depletion of extracellular calcium and HGF stimulation, respectively. Together, this work identifies a mechanism that regulates polarized distribution of Numb and provides insight into its function in polarized epithelial cells.

Cell polarity is fundamental to numerous cellular processes including migration, molecular transport, and cell division. The establishment and organization of polarity is crucial to the maintenance of cellular homeostasis in mammalian systems. Deregulation of cell polarity is observed in disease states, including cancer. Numb is an adaptor protein that functions in regulating endocytic trafficking events. Numb was originally identified in Drosophila as an asymmetrically localized cell fate determinant, and was subsequently found to be conserved in vertebrates. In mammalian polarized epithelial cells, Numb is distributed asymmetrically along the basolateral membrane domain. The work herein describes phosphorylation of Numb by the Par complex protein, atypical Protein Kinase C (aPKC), as a means of regulating membrane localization and asymmetric distribution of Numb. A mutant of Numb that cannot be phosphorylated by aPKC accumulates on the plasma membrane and localizes to both apical and basolateral membranes. In aPKC-depleted cells, endogenous Numb is unable to achieve polarized distribution and localizes around the entire cell cortex. We demonstrate that this mechanism is conserved in Drosophila as mutation of the corresponding phosphorylation sites disrupts Numb asymmetric localization in dividing sensory organ precursor cells. In polarized epithelial cells, one function of Numb is to promote epithelial morphology when cells are challenged with external stimuli that disrupt cell-cell adhesion. For example, depletion of Numb results in enhanced sensitivity of cells to lose cell-cell contacts when treated with calcium chelating agents. Loss of Numb potentiates hepatocyte growth factor (HGF)-induced lamellipodia formation and cell dispersal – early steps in epithelial-mesenchymal transition (EMT). In Numb-depleted cells, Rac1-GTP loading is enhanced, which corresponds with increased rate in loss of cell-cell adhesion and increased lamellipodia formation, following depletion of extracellular calcium and HGF stimulation, respectively. Together, this work identifies a mechanism that regulates polarized distribution of Numb and provides insight into its function in polarized epithelial cells.

The products of organic synthesis affect countless aspects of our everyday lives, from our medicines to our fuels, plastics and more. The discovery of new methods for organic synthesis is of paramount importance if we are to find greener and more efficient ways to synthesize commodity and fine chemicals, and lower the impact of the chemical industry on our environment. The aim of my doctoral thesis is to discover fundamentally new enantioselective transformations using transition metal catalysis, which can be applied to the synthesis of pharmaceutical agents, natural products or other fine chemicals. Hydroacylation is the atom economical addition of an aldehyde C–H bond across an unsaturated functional group such as an olefin or ketone. Theoretical studies on an intramolecular ketone hydroacylation catalyzed by rhodium were performed. The insights gained from this mechanistic study were then applied to the development of an asymmetric olefin hydroacylation using ethers, sulfides and sulfoxides as directing groups. Motivated by a desire to discover new catalysts with high activity and selectivity in rhodium catalyzed transformations, a chiral tridentate sulfoxide ligand was designed and synthesized. This ligand was found to be highly enantioselective in rhodium catalyzed 1,4-addition reactions. The use of allylic sulfoxides in a dynamic kinetic resolution was then investigated. The sulfoxide was found to direct a rhodium catalyzed olefin hydrogenation with simultaneous substrate racemization through a rhodium π-allyl pathway. Progress was made towards the total synthesis of a complex polyketide natural product, 6-deoxyerythronolide B. The key macrocyclization step was achieved in a model system by ring closing metathesis, and future work will be directed at completing the synthesis of the natural product.

The products of organic synthesis affect countless aspects of our everyday lives, from our medicines to our fuels, plastics and more. The discovery of new methods for organic synthesis is of paramount importance if we are to find greener and more efficient ways to synthesize commodity and fine chemicals, and lower the impact of the chemical industry on our environment. The aim of my doctoral thesis is to discover fundamentally new enantioselective transformations using transition metal catalysis, which can be applied to the synthesis of pharmaceutical agents, natural products or other fine chemicals. Hydroacylation is the atom economical addition of an aldehyde C–H bond across an unsaturated functional group such as an olefin or ketone. Theoretical studies on an intramolecular ketone hydroacylation catalyzed by rhodium were performed. The insights gained from this mechanistic study were then applied to the development of an asymmetric olefin hydroacylation using ethers, sulfides and sulfoxides as directing groups. Motivated by a desire to discover new catalysts with high activity and selectivity in rhodium catalyzed transformations, a chiral tridentate sulfoxide ligand was designed and synthesized. This ligand was found to be highly enantioselective in rhodium catalyzed 1,4-addition reactions. The use of allylic sulfoxides in a dynamic kinetic resolution was then investigated. The sulfoxide was found to direct a rhodium catalyzed olefin hydrogenation with simultaneous substrate racemization through a rhodium π-allyl pathway. Progress was made towards the total synthesis of a complex polyketide natural product, 6-deoxyerythronolide B. The key macrocyclization step was achieved in a model system by ring closing metathesis, and future work will be directed at completing the synthesis of the natural product.

A new class of oxazolidinone chiral auxiliary has been synthesized from various α-amino acids, incorporating a perfluoroalkyl functional chain as a soluble support. This feature allows the chiral auxiliaries to be employed under standard solution-phase reaction conditions, and rapidly purified from crude mixtures using fluorous solid phase extraction (FSPE). Our investigation of these new materials has been divided into two main sections. To obtain the chiral auxiliaries in multi-gram quantities a synthetic protocol was designed, where efficiency and reproducibility were the primary objectives. Meeting these goals required an extensive study of the reactivity of perfluoroalkyl nucleophiles. This study identified a versatile and scalable protocol for the perfluoroalkylation of the required amino acid starting materials. These results have allowed us to design a general, five-step synthetic pathway to create the fluorous chiral auxiliaries quickly and effectively. The new auxiliaries were then applied in several model reactions, specifically chosen to examine the reactivity and behavior of these compounds. In particular, the auxiliaries were tested for their stereoselectivity, recyclability, and ease of purification, in a series of Aldol reactions, 1,3 dipolar cycloadditions, and radical conjugate additions. This set of model reactions, combined with the facile and efficient synthesis clearly demonstrates that these new chiral auxiliaries are useful alternatives to the non-fluorous oxazolidinone chiral auxiliaries currently employed in stoichiometric asymmetric syntheses.

Transition-metal-catalyzed asymmetric hydrogenation is one of the most efficient, straightforward, and well-established methods for preparing enantiomerically enriched compounds. Over the past decades, significant progress has been made with iridium, rhodium and ruthenium complexes to asymmetric hydrogenate a selection of olefins, such as, α,β-unsaturated carboxylic acid derivatives, ketones, imines and phosphonates. Although these metals have been applied successfully in the hydrogenation of olefins, they differ in their substrate tolerance.  Ruthenium and rhodium based catalysts require a coordinating group in the vicinity of the C=C bond. However, iridium based catalysts do not require this coordinating group, hence, asymmetric hydrogenation with iridium catalysts has been widely used for both functionalized and unfunctionalized olefin substrates. This thesis focuses on expanding the substrate scope for asymmetric hydrogenation using chiral N,P-ligated iridium catalysts. Papers I and II investigate the asymmetric hydrogenation of prochiral N-heterocyclic compounds prepared by ring-closing metathesis using the iridium catalysts developed in our group.  These substrates are interesting as they bear resemblance to pharmaceutically active compounds and therefore have tremendous value in medicinal chemistry.  Excellent enantioselectivities, up to >99% ee and conversions were obtained. In papers III and IV we synthesized many unsaturated acyclic and cyclic sulfones with varying substitution patterns.  The sulfones were subjected to hydrogenation using our N,P-ligated iridium catalysts, producing the chiral sulfone products in high enantiomeric excess (up to 99% ee). This methodology was combined with the Ramberg-Bäcklund reaction, offering a novel route to chiral allylic and homoallylic compounds. In addition to obtaining these chiral compounds in good yields, no decrease in enantiomeric excess was observed after the Ramberg-Bäcklund reaction. This strategy has been applied in the preparation of the chiral building block for renin inhibitors.

This thesis discusses the preparation and use of transition-metal catalysts for selective organic chemical reactions. Specifically, two different matters have been studied; the asymmetric hydrogenation of carbon-carbon double bonds using N,P-ligated iridium catalysts and the metal-catalyzed transfer of small molecules from biomass to synthetic intermediates. In the first part of this thesis, chiral N,P-ligands were synthesized and evaluated in iridium catalysts for the asymmetric hydrogenation of non- and weakly functionalized alkenes (Papers I & II). The new catalysts were prepared via chiral-pool strategies and exhibited superior properties for the reduction of certain types of alkenes. In particular, some of the catalysts showed excellent activity and selectivity in the enantioselective reduction of terminal alkenes, and the preparation of a modular catalyst library allowed the asymmetric hydrogenation of a wide range of 1,1-disubstituted alkenes with unprecedented efficiency and enantioselectivity (Paper III). Methods for the selective preparation of chiral hetero- and carbocyclic fragments using iridium-catalyzed asymmetric hydrogenation as an enantiodetermining key step were also developed. A range of elusive chiral building blocks that have applications in pharmaceutical and natural-product chemistry could thus be conveniently prepared (Papers IV & V). The second part of this thesis deals with the catalytic decomposition of polysaccharides into sugar alcohols and the incorporation of their decomposition products into alkene substrates. Iridium-catalyzed dehydrogenative decarbonylation was found to decompose polyols into CO:H2 mixtures that could be used immediately in the ex situ low-pressure hydroformylation of styrene (Paper VI). The net process was thus the hydroformylation of alkenes with biomass-derived synthesis gas.

Asymmetric dependence (AD) is defined as dependence that differs across opposing regions of the joint return distribution. Recent evidence of AD between equity returns suggests that dependence can be decomposed into a linear component, captured by the correlation matrix, and a higher order component. When these higher order terms are characterised by increased correlation in bear or bull markets, the effectiveness of diversification strategies is reduced. To the extent that an investor is unable to completely diversify these higher order terms of dependence, it follows that they should be reflected in asset prices and managed explicitly during the portfolio construction process. The aim of this thesis is to determine the extent of AD amongst asset returns, to investigate whether AD is priced and to develop a means of managing AD in the portfolio. I justify the existence of AD and the separation of AD from linear dependence via the bivariate Edgeworth expansion, finding that the joint return distribution may be described by an infinite number of higher order co-moments. Correlation (and hence β) describes one dimension of an infinite number of higher dimensions describing dependence. To determine the importance of AD in finance, I first develop measures that can detect AD independent of the level of linear dependence and idiosyncratic risk. These measures are used to determine the extent of AD amongst US stock returns and the market, to obtain an understanding of how AD changes through time and to re-examine the evidence of AD between equity portfolios. By measuring AD separate from linear dependence, I demonstrate several findings. First, I find evidence of non-stationary AD that can exists irrespective of the magnitude of linear dependence, measured by β. This time-varying AD consists of both significant upper tail dependence (UTD) and significant lower tail dependence (LTD), although LTD is found to occur more frequently than UTD, especially for small stocks and stocks displaying high idiosyncratic risk. Significant time-varying AD is also detected between domestic equity indices and international equity markets, implying that if a portfolio is weighted towards certain industries or countries, portfolio construction methods may need to be adjusted in order too meet risk and return targets, particularly if future AD cannot be adequately forecasted. Next, I investigate whether AD is priced in US equities using the Fama and MacBeth (1973) regression methodology in conjunction with my β invariant AD metrics. I find that AD is as important as linear dependence in explaining the variation in returns. In particular, a positive relationship between LTD and return is found. I document an AD risk premium of 2.7% pa, compared to a β risk premium of 6.18% pa. The AD risk premium increases to 6.9% pa for stocks with significant LTD. This result holds after controlling for size, book-to-market ratio, downside β and coskewness. I also find past AD is a significant variable in predicting the future returns of small firms, whilst neither AD nor linear dependence predict the future returns of large firms. I subsequently demonstrate a means of incorporating AD structures during the portfolio construction process using copula functions. I then investigate how asymmetric return dependencies affect the efficient frontier and subsequent portfolio performance under a dynamic rebalancing framework. By considering the problem of tactically allocating a small set of domestic equity indices, I demonstrate several findings. First, I show that a Mean-Variance efficient frontier differs from the efficient frontier constructed under AD. Constructing paper portfolios based upon these differences, I find that real economic value lies in correctly accounting for AD structures. The primary source of this economic value stems from the ability to better protect portfolio value and reduce the size of any erosion in return relative to the normal portfolio. Finally, I document the benefits of actively managing AD during the portfolio construction process and determine a number of portfolio management principles required to successfully manage AD. I illustrate that managing asymmetry risk in a portfolio of international equity indices results in increased return, decreased risk and decreased transaction costs. I show that in order to yield these benefits, investors must actively and dynamically manage their portfolio. Furthermore, I illustrate that the ability to short-sell assets provides most of the benefits described.