Thesis (M. Phil.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 252-300).

The marine diterpene (–)-stolonidiol (1) has been shown to upregulate neuronal levels of acetylcholine. The mechanism through which a small molecule can impart this allosteric-like effect is currently unknown. A laboratory preparation of the natural product was undertaken in order to produce matieral for biological testing and elucidation of the unknown mechanism of action. During the course of this study, a tandem enyne-Suzuki reaction was investigated to form both rings of the fused bi-cyclic structure 26 in a single operation, but was met with undesired diastereoselectivity in the first cyclization step. The directing effect was found to be general on 1,6-homopropargyl enynes. Further efforts toward the molecule focused on an enantioselective formation of the cyclopentane core through an extension of a copper-mediated silylcyclization of epoxyalkyne 71. Using this intermediate two routes involving acrylate as a lynchpin to close the large ring were investigated. Additionally, a route designed to employ an intramolecular Knoevenagel condensation was explored to generate this ring system. / text

Injuries to the central nervous system are irreversible and debilitating due to the limited regrowth of damaged or severed neurons. Two small molecules, xanthofulvin and vinaxanthone, isolated from P. vinaceum and P. glabrum promote spinal cord regeneration in animal models. It is speculated that these natural products inhibit semaphorin 3A, a chemorepellent that mitigates axonal growth-cone formation. In addition to promoting axonal growth, rats treated with vinaxanthone and xanthofulvin following complete spinal cord transection experienced greater remyelination, increased angiogenesis, attenuated apoptosis, and depressed scaring of the lesion site. The only prior synthesis of vinaxanthone speculated that the xanthone core is constructed via enzyme-catalyzed intermolecular Diels-Alder reaction. We have demonstrated, however, that warming a functionalized acetoacetyl chromone in water, furnishes vinaxanthone in good yield, providing an alternative biosynthetic pathway. With a robust syntheses of both natural products, we determined the protein target of the observed regeneration: succinate receptor 1, providing a new therapeutic target to promote neuronal regeneration. Among the various methods of incorporating oxygen into aryl rings, the direct conversion of a C-H bond into a C-OH bond is ideal. The metal-free hydroxylation of arenes developed in our laboratory, utilizing phthaloyl peroxide, marks the first disclosure of this transformation using mild conditions. Computational and experimental evidence obtained thus far has supported a mechanism involving a diradical intermediate. The reactivity of phthaloyl peroxide was increased by the incorporation of two chlorine atoms onto the ring. To minimize the accumulation of large quantities of peroxide, the optimization of the preparation of the peroxide in flow has been developed. This protocol immediately consumes the peroxide as it is generated. Finally, a new dearomatization reaction has been optimized. This reaction forms two carbon-oxygen bonds and dearomatizes the ring system.

Abstract Research has revealed that many of the historically disadvantaged schools in South Africa experience difficulty in implementing policies aimed at restoring the quality of teaching and learning. The difficulty has been attributed to several factors such as poor conceptualisation and implementation of quality management systems at school level. This article reports on empirical research that investigated the possibility of applying Total Quality Management principles in schools for the purpose of restoring the culture of learning and teaching. Data was collected through qualitative and quantitative methods in selected schools situated in the Tshwane North District. The findings revealed that there is a gap between what is provided in the policy framework on the management of quality teaching and learning. It is recommended that in order to fill the gap, schools need to apply customised principles of Total Quality Management. The primary aim of this research was to develop such an integrated framework that is not only theoretically sound but that has been customised for schools’ contexts and conditions.

Part one of this two-part thesis describes my efforts toward the total syntheses of the complex polycyclic alkaloids himeradine A and fastigiatine, which are members of the Lycopodium family of natural products. A cascade reaction sequence featuring a biosynthesis-inspired transannular Mannich reaction was planned to construct the strained and densely functionalized pentacyclic cores of the molecules from acyclic starting materials. After difficulties were encountered in a first-generation synthesis plan toward himeradine A, a second-generation synthesis plan was eventually successful in accomplishing the first total synthesis of fastigiatine via a formal [3+3]-cycloaddition reaction and a retro-aldol tandem transannular Mannich reaction sequence. In part two of this thesis, syntheses of the hibarimicin aglycons, including HMP-Y1, atrop-HMP-Y1, hibarimicinone, atrop-hibarimicinone, and HMP-P1, are reported. These natural products are amongst the largest and most complex type-II polyketides isolated. A novel benzylic fluoride Michael-Claisen reaction sequence was developed to construct the complete carbon skeleton of HMP-Y1 and atrop-HMP-Y1 via a symmetrical bidirectional double annulation reaction. Through efforts to convert HMP-Y1 derivatives to hibarimicinone and HMP-P1, a biomimetic mono-oxidation to desymmetrize protected HMP-Y1 was realized. A bidirectional unsymmetrical double annulation and biomimetic etherification were developed to construct the polycyclic and highly-oxidized skeleton of hibarimicinone, atrop-hibarimicinone, and HMP-P1. Lastly, a pH-dependent rotational barrier about the C2-C2' bond of hibarimicinone was discovered, which provides valuable information for achieving the syntheses of the glycosylated congeners of hibarimicinone. / Chemistry and Chemical Biology

Studies directed toward the total synthesis of the cytotoxic steroidal alkaloid cortistatin A were carried out. In a model system, it was determined that a sequence of reactions involving a lithiocyclopropene addition-intramolecular [4 + 2] cycloaddition cascade and subsequent cyclopropylcarbinyl rearrangement allowed for ready access to the BCD rings of the core steroid. Implementation of this methodology en route to the fully functionalized natural product proved an effective means for the elaboration of the A ring carbocyclic framework. / text

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A mass-balance modeling approach has been applied to gain an improved understanding of the relative contributions of phosphorus loading from various sources into a freshwater lake with cage-aquaculture in Ontario. All cage-aquaculture in Ontario is located within Lake Huron and Georgian Bay of the Great Lakes where concerns about potential environmental issues are constraining growth of the industry. Phosphorus is of particular concern for cage-aquaculture operations in Ontario since this nutrient may accelerate eutrophication of freshwater. Sound scientific information is needed for the Ministry of Environment lake managers to make defensible decisions to move the industry forward in a sustainable manner. Lake Wolsey is located on Manitoulin Island in Lake Huron, Ontario. The lake is connected to the North Channel by a small inlet where water exchanges periodically. A cage-aquaculture operation was established in 1986 and has an average annual production of approximately 250 metric tonnes of rainbow trout. We have estimated total phosphorus loadings from eight sources of inputs and three sinks from the lake. We then applied a sensitivity analysis to establish parameters that require empirical measurement and field validation. Results show non-point sources as the leading contributor of total phosphorus to Lake Wolsey (40%, 1120 kg) followed by the farm (32%, 915 kg), groundwater (11%, 305 kg), and dwellings (8%, 219 kg), internal phosphorus load from the hypoxic hypolimnion mid-lake (7%, 186 kg), precipitation (3%, 79 kg) and leaf litter (0.3%, 8 kg). Results of the sensitivity analysis show non point sources to be the most significant parameter in terms of total phosphorus loading, followed by the lake sedimentation, then the contribution by the aquaculture operation. This is followed by the exchange via the inlet, groundwater, dwellings, the internal phosphorus, sportfishing, precipitation and leaf litter. Information from this project will provide water quality managers with scientific information to aid in decisions pertaining to policy and regulatory approaches for water quality risk assessment and management of cage-aquaculture in Ontario. / Great Lakes Sustainablility Fund, Great Lakes Action Plan V, Ontario Sustainable Aquaculture Working Group

The objective of this thesis was to develop a concept and methodologies for designing a total knee replacement (TKR) with normal kinematics and a high range of motion. The design philosophy was that a TKR can function similar to the normal knee, provided that after TKR the inherent passive characteristics of the joint are restored to normal with minimum disruption in the functions of the remaining structures of the joint. As the first step prior to design, cadaver experiments were conducted and biomechanical models of the passive knee were developed to study the mechanics of the normal knee. The guiding roles of the tibial articular surface including the menisci, the combined effects of the cruciates and contact forces, and the elongation patterns of the cruciates were investigated. Based on the results obtained from these studies and the relevant information in the literature, design requirements for a TKR with normal kinematics were identified, and an innovative design concept was introduced. On the medial compartment of this design the shape of the articular surfaces resembled a ball-and-socket joint, and on the lateral side a pair of guiding bearing surfaces mimicked the guiding roles of the cruciate ligaments. The novelty in the design concept lies in the design of the shape of the lateral articular surfaces. The progressive variations of the curvature of the medial and lateral aspects of the lateral condyle generate the desired guiding effect for the full cycle of extension and flexion. The bearing spacing defined as the distance between the medial and lateral contact points was kept constant throughout the motion, as this was proved to be necessary to ensure compatibility between the geometry of the bearing surfaces and the desired pattern of motion. Appropriate methodologies were developed to generate the complete shapes of the bearing surfaces and to build the prototypes based on the constraints of the bone geometries and kinematics of a sample cadaver knee. The kinematic test of the prototype proved the viability of the design concept and methodologies. The novel design philosophy, concept and methodologies developed in this thesis provide a foundation for a new generation of TKR with normal kinematics. / Thesis (Ph.D, Mechanical and Materials Engineering) -- Queen's University, 2008-09-18 16:56:02.502

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