Chemistry - Theses, Dissertations, and other Required Graduate Degree Essays

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Tandem Organocatalytic α-Chlorination−Aldol Reactions: A Powerful Tool for Carbohydrate and Iminosugars Synthesis

Date created: 
2015-08-05
Abstract: 

Carbohydrates play a vital role in regulating biological events that range from cell recognition to pathogen/host adhesion. Not surprisingly, inhibitors of carbohydrate binding and cleaving processes, such as iminosugars, have been identified as leads in various therapeutic areas and several glycomimetic drugs have been approved for use in humans. Despite several clinical successes, their de novo synthesis remains a significant challenge that also limits their integration within modern high-throughput screening technologies. Progress in glycomimetic research is often closely tied to advances in the de novo synthesis of unnatural carbohydrates, with much success being realized through the use of organocatalytic reactions. Our continued interest in the use of α-chloroaldehydes as building blocks for natural product synthesis led us to probe their organocatalytic aldol reactions with 2,2-dimethyl-1,3-dioxan-5-one. These efforts resulted in the discovery of a one-pot α-chlorination—aldol reaction that involves the dynamic kinetic resolution of an in situ generated α-chloroaldehyde. This process provides direct access to novel, enantiomerically-enriched building blocks (β-ketochlorohydrins) that are well-suited for the synthesis of carbohydrates and C-glycoconjugates. In this thesis, a unique synthetic strategy to convert a wide range of acetaldehyde derivatives into imino-C-nucleoside analogues in two or three straightforward transformations is described. We also show that this strategy can be readily applied to the rapid production of indolizidine and pyrrolizidine iminosugars. The high levels of enantio- and diastereoselectivity, excellent overall yields, convenience and broad substrate scope make this a promising process for diversity-oriented synthesis and should enable drug discovery efforts. Finally, the synthesis of configurationally divergent iminocyclitols is presented. This study led to the identification of potent, selective and brain penetrant OGA inhibitors as lead candidates for the treatment of Alzheimer’s disease.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Robert A. Britton
Department: 
Science:
Thesis type: 
(Thesis) Ph.D.

Molecular Modeling of Structural Transformations in Ionomer Solutions and Membranes

Date created: 
2016-08-04
Abstract: 

Different functions are expected from the polymer electrolyte membranes used in fuel cells. They work as a proton conduction medium, as a separator, and as an electronic insulator. The current membrane materials of choice are perfluorosulfonic acid (PFSA) ionomers such as Nafion. The two main challenges that PFSAs still face, after three decades of extensive research, are a limited lifetime and a lack of basic structural understanding. To investigate the chemical degradation phenomena, we devised a kinetic model of radical formation and attack to PFSA ionomers. Analytical relations are derived to obtain the content of aggressive radicals as a function of iron ion content and hydrogen peroxide. The mean-field type, coarse-grained ionomer model distinguishes ionomer headgroups, side chains, and ionomer backbone. The model is used to study the impact of different degradation mechanisms and ionomer chemistries on PEM degradation. Application of the model to degradation data of various PFSAs highlights the important role of radical attack to the ionomer headgroups. The insufficient understanding of the membrane structure thwarts further forays in degradation modeling. To this end, we undertook molecular dynamics simulations of the conformation of single chain ionomers as a function of different structural parameters. This study revealed the nonmonotonic effect of the side chain length and density on the conformational behaviour and rigidity of ionomer backbones. We discuss how the changes in these architectural parameters change the ionomer affinity to counterions and the corresponding ion mobility. Studying the aggregation of ionomer chains revealed their spontaneous aggregation in dilute solution. We explored the effect of various parameters such as ionomer hydrophobicity and side chain content on ionomer bundle formation. Minimization of the surface free energy of hydrophobic backbones is the driving force of ionomer aggregation, while the repulsion of anionic headgroups opposes the aggregation. The results rationalize the experimental studies and highlight the role ionomer bundles as the prevailing structural motif in PFSA materials.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Michael Eikerling
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Development of chemical tools for studying human O-GlcNAcase activity

Author: 
Date created: 
2015-11-18
Abstract: 

In recent years, the post-translational modification of nuclear and cytoplasmic proteins with O-linked N-acetylglucosamine (O-GlcNAc) has emerged as playing diverse roles in health and disease. Interestingly, this modification is regulated by only two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). A method to study the effects of elevated levels of O-GlcNAc is to selectively target OGA. Herein, we describe the structure-activity relationships of a family of 2'-aminothiazoline-based inhibitors, one of which shows to be among the most potent inhibitors of human OGA (hOGA) known to date. We present the selectivity ratios of these compounds for hOGA over the structurally-related lysosomal β-hexosaminidases, define them as transition state analogues and rationalize their potencies by using linear free energy analyses. We also identify two fluorescence quenched substrates for hOGA bearing thioamide quenchers having different fluorogenic leaving groups, which reveal design features for substrates to monitor hOGA activity in live cells.

Document type: 
Thesis
File(s): 
Supervisor(s): 
David Vocadlo
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Platinum electrocatalysis: Novel insights into the dissolution mechanism and oxygen reduction reaction

Date created: 
2016-07-29
Abstract: 

Formation of hydrogen peroxide and oxygenated radical species are the leading cause of chemical degradation observed in polymer electrolyte membranes (PEM) in polymer electrolyte fuel cells. Recent experimental studies have shown that Pt nano-deposits in the PEM, which originate from Pt dissolution in the catalyst layer, play an important role in radical-initiated membrane degradation. Surface reactions at Pt particles facilitate the formation of reactive oxygen species. The net effect of Pt surface processes on membrane degradation depends on the local equilibrium conditions around the Pt nano-deposits, specifically, their equivalent local electrode potential. In this thesis, we first present a multi-step theoretical approach, validated by a collaborative experimental study, to understand the impact of environmental conditions around the Pt nanodeposits on membrane chemical degradation. In the first step, we developed a physical analytical model for the potential distribution at Pt nanodeposits in the PEM. Given the local potential, we identify the surface adsorption state of Pt. Thereafter, density functional theory (DFT) was used to investigate the influence of the Pt adsorption state on the mechanism of oxygen reduction reaction (ORR), particularly the formation of hydrogen peroxide and hydroxyl radical as the two important reactive oxygen species for membrane degradation. In a separate work, we employed DFT to study the atomistic mechanism for interfacial place-exchange between surface Pt atom and chemisorbed oxygen at oxidized Pt (111)-water interfaces. Understanding the criteria for Pt oxide growth is a crucial step to comprehend the mechanisms of Pt dissolution during electrochemical processes.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Dr. Michael H. Eikerling
Department: 
Science: Department of Chemistry
Thesis type: 
(Dissertation) Ph.D.

Total Synthesis of Tetrahydrofuranol-Containing Natural Products and Studies Toward Eleutherobin

Date created: 
2016-08-23
Abstract: 

An extension of previously developed methodology towards the synthesis of tetrahydrofuranol rings is demonstrated in the total synthesis of amphirionin-4 in 11 steps comprising the first total synthesis of this natural product. Furthermore, we were able to exploit this methodology toward the total synthesis and structural reassignment of laurefurenyne A. The development of a flexible and concise synthesis allowed for access to the proposed stereostructure of the natural product and, following analysis of spectral data, indicated this structure had been misassigned. Further synthetic efforts completed the synthesis of the correct structure of laurefurenyne A and enabled investigations into the biosynthesis of this natural product. An additional study describes efforts toward the synthesis of the promising anti-cancer natural product eleutherobin. As part of these efforts we have developed a cyclobutanone α-arylation/ring expansion strategy that affords access to α-tetralones. This methodology has been expanded toward the synthesis of a wide range of α-arylcyclobutanones and α-tetralones including the incorporation of heterocycles. Our efforts towards the synthesis of the core of eleutherobin through an α-tetralone intermediate are detailed including a radical cyclization method to form a vital C-C bond required for a proposed retro-aldol fragmentation. Furthermore, we have exploited this approach in our efforts toward the total synthesis of coniothyrinone D. While ultimately unsuccessful in accessing the natural product, this synthesis has demonstrated the utility of this approach towards the synthesis of this natural product scaffold.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Robert Britton
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.

Smartphone-readable barcode assays for quantitative analysis

Date created: 
2016-07-25
Abstract: 

In the literature, there has been a recent surge in smartphone-based bioanalytical techniques, particularly for point-of-care and medical diagnostics. These devices aim to have certain characteristics such as affordability, sensitivity, be user friendly and equipment-free. To add to the growing field, a smartphone-readable, bona fide barcode assay is demonstrated; the work performed to develop the app to read colorimetric assays and the design of the barcode assay is discussed. Paper-printed tests and direct biotin-streptavidin assay were used to test the initial app. Barcode reading abilities in the app allowed for the validation of the barcode assay (for the pregnancy hormone, hCG), which proved to be both qualitative and quantitative when scanned and imaged using a smartphone-app combination. No external accessories are required, thereby highlighting its potential to boost the research and development of POC devices, particularly by minimizing the need for specialized instrumentation and providing instant testing results on-site.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Hua-Zhong Yu
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Electron Density-Matching Diamido Ligands to 1st Row Transition Metals: Coordination and Reactivity Trends

Author: 
Date created: 
2016-04-29
Abstract: 

Amido-based ligands can employ a variable R-group which can be used to “tune” the steric and electronic properties of the resulting metal complex, targeting bond activation and catalytic applications. This thesis explored how the chelating diamido ligand {(tBuNSiMe2)2O}2- interacts with the early transition metals scandium(III), titanium(III) and vanadium(III), to discern how the number of d-electrons affects the coordination and reactivity of the complexes. The coordination motif is oxidation state-dependent, and structural differences are observed as the number of d-electrons changes. Alkylation yielded interesting results: the vanadium complex formed the dinitrogen species {[(tBuNSiMe2)2O]VR}2(μ-N2) (R = CH2SiMe3, CH2Ph), while scandium produced the expected complex, {[tBuNSiMe2]2O}ScCH2SiMe3•THF. Concurrently, a diamido ligand containing electron-withdrawing –CF3 groups, {[3,5-(CF3)2PhNSiMe2]2O}2-, was examined to probe how the altered electronic profile affects the overall coordination and reactivity of later transition metal iron(III) and cobalt(II) complexes. Unusual structural motifs indicated that this ligand warrants additional research.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Daniel Leznoff
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Upgraded resolution and enhanced sensitivity of optical disc-based bioassays: from CD to BD

Date created: 
2016-08-03
Abstract: 

Conventional biomedical diagnosis and chemical analysis are performed by trained professionals in centralized laboratories using specialized instrumentation. Our group has been working on the development of optical disc technology-based molecular detection platforms for on-site chemical analysis and point-of-care diagnosis for the past 15 years. In particular, computer-readable assays on compact discs (CDs) have been demonstrated for the quantitation of various target analytes, such as DNA, proteins, and metal ions. In this thesis, two more advanced disc formats, digital versatile disc (DVD) and Blu-ray disc (BD) have been adapted to improve the assay resolution and detection sensitivity. The DVD assay for quantitative analysis of human chorionic gonadotropin is described first. A multiplex assay-on-a-BD system for the detection of a set of key cardiac markers is then explained in detail. Beyond a different error correction protocol, a new surface activation method has been established for the immobilization of probe molecules on the surface coating of BD-Rs. In addition to the upgraded lateral resolution, the sensitivity of the BD-based bioassays is significantly improved in comparison with those prepared on CDs and DVDs, which is comparable to the well-established enzyme-linked immunosorbent assay (ELISA).

Document type: 
Thesis
File(s): 
Supervisor(s): 
Hua-Zhong Yu
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Studies Toward the Total Synthesis of Tetrahydrofuran-Containing Natural Products

Author: 
Date created: 
2016-07-14
Abstract: 

Natural products have played a significant role as leads and inspiration for many novel therapeutics. Among the most common structural fragments found in biologically active natural products is the tetrahydrofuran, a five membered oxygen-containing heterocycle. As oftentimes very little natural product is available from the producing organism, there has been a longstanding interest in the development of efficient and general synthetic methods to access tetrahydrofurans and tetrahydrofuran-containing natural products. This thesis summarizes recent efforts directed towards the total synthesis of amphirionin-4 and biselide A, two tetrahydrofuran-containing natural products with potentially useful biological activities. Amphirionin-4 is a polyketide isolated from Amphidinium sp. dinoflagellates, and has demonstrated potent proliferation activity in ST-2 stem cells. Biselide A is a marine macrolide isolated from the Okinawan ascidian Didemnidae sp., and has demonstrated potent cytotoxicity towards a variety of human cancer cell lines. Notably, the unifying element in our synthetic approaches to both of these natural products is a reliance on chlorohydrin-based strategies to access the tetrahydrofuran cores in an efficient, diastereoselective and enantioselective manner.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Robert A. Britton
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Preparation and applications of perfluoroalkoxides bearing α-fluorines

Date created: 
2016-04-27
Abstract: 

Partially fluorinated ethers, known as hydrofluoroethers, have been introduced as inert replacements of chlorofluorocarbons and predominately find use as refrigerants and solvents. However, these materials are not inert as purported but readily methylate Group 15 nucleophiles. Not only are hydrofluoroethers reactive, when the reaction is performed under a moisture-free environment, the sole reaction products from the interaction of tertiary amines are quaternary ammonium perfluoroalkoxides bearing α-fluorines. This general route allows for the single-step synthesis of a highly under-represented organofluorine functional group from commercially available reagents negating the use of air-sensitive reagents, anhydrous fluorides, and often highly toxic, expensive precursors. Hence, 30 new perfluoroalkoxides have been prepared from a series of methoxy hydrofluoroethers from CH3OCF3 through to CH3OC4F9 including clinical inhalation anaesthetic methoxyflurane. The products were isolated in 9-99% yield with product conversions commensurate with increasing length of the fluorinated segment of the hydrofluoroether in the presence of sterically unhindered, nucleophilic tertiary amines. Thermal analysis of isolated tetramethylammonium perfluoropropoxides and butoxides indicated stability to 150 degree Celsius before partially decomposing under vacuum at 180 degree Celsius to NMe3 and CH3F as evidenced by thermogravimetric analysis. In two divergent studies, a series of experiments were devised to develop a functional group tolerant protocol for the trifluoromethoxylation of arenes, a current and largely unsolved synthetic problem. A wide range of strategies towards C(aryl)–OCF3 bond formation were attempted using the prepared tetraalkylammonium trifluoromethoxides including both metal and non-metal-mediated protocols. By considering traditional cross-coupling methods with state-of-the-art Ni0-NiII, Pd0-PdII, CuI-CuIII, AgI-AgII, and AuI-AuIII manifolds, it was determined that β-fluorination of aryl precursors from the coordinated OCF3 ligand outcompetes C-O bond formation at temperatures necessary for reductive elimination. The poor nucleophilicity, high moisture sensitivity, and propensity for β-fluoride elimination from -OCF3 precluded its use as a general synthetic building block for many metal-mediated cross-couplings. In a second study, the efficacy of the ostensibly fluoride-free tetraalkylammonium perfluoroalkoxides were tested as initiators for the anionic ring-opening polymerization of the perfluorooxirane monomer, hexafluoropropylene oxide (HFPO). While these perfluoroalkoxides did not outperform the industry optimized CsF/tetraglyme conditions, it was demonstrated that tetraalkylammonium perfluoroalkoxides can successfully ring-open HFPO, provide a direct study of the cation, and a means to measure chain transfer while providing oligomers with DPn = 1-3. The inoperative chain transfer process is likely a multi-faceted problem involving physical properties of the polymerization process. For instance, the phase-transfer mechanism and solvent choice play a critical role in propagation of polymeric based perfluoroalkoxides. Initial synthetic efforts were undertaken to design oligio(HFPO) terminated ethylene glycol surfactants or soluble oligio(HPFO) hydrofluoroethers to overcome the need for polar organic solvents required to dissolve the ionic initiators.

Document type: 
Thesis
File(s): 
Supervisor(s): 
Daniel Leznoff
Department: 
Science: Department of Chemistry
Thesis type: 
(Dissertation) Ph.D.