3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Enaminones as precursors for lamellarin akaloids and related heterocycles(2020) Klintworth, RobinThe synthesis of alkaloids at the University of the Witwatersrand (Wits) has been led by Professor Joseph Michael for more than thirty years now. Throughout this time he has pioneered the use of enaminones as building blocks to provide alkaloids and other nitrogen-containing heterocycles. The ambident nucleophilicity and electrophilicity of the enaminone scaffolds makes them particularly suited to annulation reactions, allowing these positions to be chemically stitched together with suitable linkers to provide nitrogen-containing rings. In this thesis, we present the successful application of this kind of strategy to the synthesis of pyrrolizines and indolizines, as well as a variety of natural and synthetic lamellarin alkaloids. Chapter 1 provides some background into alkaloids, concentrating on the lamellarins themselves, including a selection of some of the most significant contributions to their synthesis published thus far. Thereafter, the Wits enaminone strategy for the construction of heterocyclic alkaloids is discussed in greater detail, alongside a selection of pertinent examples that have been published by the group. This leads up to Section 1.3.3, in which previous Wits contributions to this lamellarin project are described. Chapter 2 summarizes the preliminary investigations carried out during the first year of this project, beginning with a methodological study into the cyclization of simple N-(ethoxycarbonyl) methylpyrrolidine-derived enaminones to pyrrolizines under acidic conditions. This reaction was discovered almost twenty years ago in our laboratories and ever since then it has been investigated as a potential route to making the pyrrole component of lamellarins. The culmination of this work, past and present, paved the way for the development of our [4 + 1] cycloaddition strategy that is introduced in Section 2.3.2. The strategy entails the reaction of suitable enaminones with ethyl bromoacetate, which respectively contribute NC3 and C1 units to the newly formed pyrrole. This reaction serves as a key step in all three of the relevant publications that constitute Chapters 3, 4 and 5 of this thesis, and is arguably one of the most reliable and convenient methods for the preparation of these kinds of pyrrole systems now available. Chapter 3 details the successful application of our [4 + 1] enaminone cycloaddition strategy to the synthesis of lamellarin G trimethyl ether, during a collaborative green chemistry project with Professor Till Opatz at the Johannes-Gutenberg University in Mainz, Germany. This approach from an enaminone precursor was an exceptionally efficient method for the preparation of lamellarins, providing the target alkaloid in the second-highest yield ever reported at the time. Chapter 4 details how the introduction of the alkaloids’ lactone ring was tackled in a unique way, using a late-stage demethylative lactonization reaction between an aryl methyl ether and a nearby carboxylic acid. This reaction, in combination with the [4 + 1] cycloaddition strategy, allowed the completion of the synthesis of the trimethyl ethers of lamellarins G and D, as well as the naturally occurring lamellarins H and A4, in overall yields of above 80%, making this by far the most efficient route to these targets ever reported. Furthermore, this was the first-ever reported synthesis of a lamellarin at the gram-scale. Chapter 5 then describes how this game-changing methodology was successfully applied to the synthesis of the pharmacologically active, though more complex, hydroxylated lamellarins. The naturally occurring lamellarin ɛ as well as the synthetic dehydrolamellarin J were selected as targets, because they are representatives of the two ring-A structural variations that provide optimal cytotoxic potency. While our [4 + 1] cycloaddition strategy and the demethylative lactonization reaction remained pivotal, significant methodological adaptations were required for the synthesis of the enaminone precursors to allow for the inclusion of isopropyl-ether protecting groups of the obligatory phenols. Three unique reactions were developed, including a one-pot phenol esterification-Fries rearrangement to form the phenolic deoxybenzoin ketone precursor, a mild isothiocyanate cyclization reaction to prepare the thiolactam precursors, as well as a particularly noteworthy novel isopropyl ether deprotection method. All three of these methodologies were facilitated with the use of the topical and “green” organic acid methanesulphonic acid. During these investigations, various methodological alterations were made to avoid the use of column chromatography altogether, whilst maintaining the excellent efficiency of our strategy. The culmination of this work gave rise to the first-ever reported chromatography-free synthesis of more than 25 g of the active lamellarin analogue dehydrolamellarin J, which was prepared in two decagram-scale batches in order to prove the reproducibility of our resultsItem Earth's field nuclear magnetic resonance measurement of blood pressure metrics in a compliant vessel model(2019) Frohlich, Steven RonnyThe following experimental design and setup have been created by the author and supervisor. Current methodologies for non-invasive blood pressure measurement are flawed due to the subjective nature of measurement. Experimentation has been performed to determine to what degree relevant cardiovascular metrics can be noninvasively extracted from idealised software and hardware models of a human upper limb. The physical model is constructed to replicate the dimensions of major arteries and veins of the upper limb and is filled with water to approximate the vessels in the upper arm. Static water tests are performed to calibrate the model in order to obtain appropriate parameter values. Pulse and collect experiments have been performed on volumes of water flowing through cardiovascular analogues that are polarised upstream by 300 mT annular Halbach arrays. Testing is performed using the TerraNova-MRI Earth’s Field Nuclear Magnetic Resonance apparatus from Magritek. Signal models obtained from literature have been modified to determine the effect of vessel compliance on flow measurements. A direct positive correlation (p= 0.88) between signal level received and the increasing pressure and volume of water within the model is observed. The average standard error between measurements is 0.04 µV, or 10% of the magnitude of the smallest measured signal. The relative error between theoretical and measured signals is 30%. The relative error is unreliable as the theoretical model does not include the effects of noise. The compliance of the model’s vessel analogues is estimated to be 1.48 ml/mmHg compared to normal healthy young human compliance values of ~ 2 ml/mmHg. An empirical relationship between the pressure and signal captured by the apparatus is found. The problem is ill-posed with many possible pressure-volume relationships able to output the same signal result. Calibration of the signal and model needs to be performed to determine a direct causal relationship between blood pressure and the EFNMR signal captured.Item The development of novel pterin chemistry leading to potential dihydrofolate reductase inhibitors with potential antimalarial activity(2012-01-31) Nxumalo, WinstonThis thesis describes the application pteridine chemistry in various aspects of methodology development and natural product synthesis. The introductory chapter sets the scene by describing naturally occurring pteridines, their applications in biological systems, and recent synthetic strategies. Firstly, Sonogashira coupling reactions employing benzenesulfonyloxy-O-pteridine (27) and terminal alkynes to give various 6-substituted pteridines are described. This methodology allowed for the total synthesis of a natural occurring pteridine, Sepiapterin-C (46). Negishi coupling reactions involving benzenesulfonyloxy-O-pteridine (27) and various Znreagents are also reported. This methodology, representing the first Negishi coupling on a pteridine nucleus, allowed for the introduction of both aryl- and heteroaryl- substituents at the 6- position of the pteridine ring. The use of methanesulfonyloxy-O-pteridine (26) as a coupling partner is also described. Selective deprotection and hydrolysis of the formamidine protecting groups to give either the 6- substituted 2,4-diaminopterine or 2-amino-4-oxo-pteridine (pterin), is described. The synthesized structures are supported by NMR and mass spectral data and melting points where applicable. Novel compounds are verified by NMR spectroscopy, infrared and mass spectrometry.