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

Receive updates for this collection

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): 
Senior supervisor: 
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): 
Senior supervisor: 
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): 
Senior supervisor: 
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): 
Senior supervisor: 
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): 
Senior supervisor: 
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): 
Senior supervisor: 
Daniel Leznoff
Department: 
Science: Department of Chemistry
Thesis type: 
(Dissertation) Ph.D.

Copper catalysed formation of copper chelators: A new approach to the treatment of Wilson’s disease

Date created: 
2016-01-05
Abstract: 

Wilson’s disease is characterized by an increased concentration of copper in the liver, which damages liver tissue and eventually leads to neurological impairment. This disease affects an estimated 1/30,000 people worldwide. Current treatments for this disease can have severe side-effects, including neurological problems in approximately 20-50 % of the patients. The goal of this thesis is to develop compounds that will strongly bind to copper to remove it from the liver. The mechanism for selectivity in binding copper over other endogenous metals (e.g, zinc and iron) is to utilize copper-activated alkyne-azide cycloaddition to couple two moderate binding moieties to form a ligand with a much greater metal-binding affinity. The HepG2 cell line was used as an in vitro model for Wilson’s disease. A methodology to evaluate the efficacy of chelators to remove copper from the cell model was developed, and tested with a series of new copper chelating compounds.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Tim Storr
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Co(III) Complexes as Pro-drugs for Cancer Therapy

Author: 
Date created: 
2016-05-13
Abstract: 

Cancer is the leading cause of death in Canada and is characterized by irregular and uncontrolled cell growth. In many cases this uncontrolled cell growth results in a solid mass of cells called a tumor. When the inner part of a tumor is sequestered from blood vessels, the nutrient and oxygen levels decrease. The term “hypoxia” is used to describe low oxygen level in tissue. Hypoxia induces more reducing conditions in a tumor in comparison to normal tissue. The objective of this project was to generate a series of octahedral Co(III) complexes for the treatment of cancer. We designed pro-drugs that are initially administered to the body in an inactive form, and can be selectively activated under the hypoxic (reducing) conditions in tumors. In this work, a series of octahedral Co(III) salen complexes were synthesized incorporating 1-methylimidazole in axial positions. We investigated the stability of the complexes in solution, and the effect of different para-ring substituents on the Co(III) / Co(II) reduction potential. We concluded that the reduction potentials of the complexes were correlated with the electron donating ability of the para-ring substituents, and that a geometry change from octahedral to square-planar upon reduction leads to axial ligand release. Building on these results, coumarin fluorophores were then attached to the Co(III) complexes via a functionalized imidazole. We found that the fluorescence of the coumarin was largely quenched while bound to the Co(III) center. Ligand release was then studied in the presence of excess competing ligands and in the presence of a reducing agent. Our results suggest that both ligand exchange and reduction play a role in axial ligand release in these systems.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Tim Storr
Charles Walsby
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

Synthesis and evaluation of novel carbocyclic carbohydrate analogues

Date created: 
2016-04-15
Abstract: 

Carbohydrate analogues play an indispensible role in the study of glycan processing enzymes. These compounds have attracted attention as probes of enzyme mechanisms, as chemical tools for the elucidation of enzyme function and as potential pharmaceuticals. The development of organocatalytic aldol chemistry has fundamentally altered the way chemists approach the synthesis of carbohydrate analogues. In this thesis I highlight a novel strategy toward the synthesis of carbocyclic carbohydrate analogues which utilizes a proline-catalyzed aldol reaction and a metal-catalyzed carbocyclization as key steps. This strategy was successfully implemented in the synthesis of an ensemble of galactose and N-acetylgalactosamine analogues. Furthermore, I present preliminary results toward the biological evaluation of these compounds.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Robert A. Britton
Andrew J Bennett
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.

The Photochromism of a Diester Linked Bisanthracene

Author: 
Date created: 
2016-04-15
Abstract: 

A bisanthracene diester was synthesized in an effort to increase the rate of the anthracene photochemical dimerization. Preliminary reactions of the bisanthracene resulted in the formation of an intramolecular product that cyclizes across the 9, 10, 1’, 4’-position of the anthracenes. This results in an unsymmetrical dianthracene that possesses an isolated alkene group. The research in this thesis describes the photochromic properties of the bisanthracene, as well as studies into the reactivity of the isolated alkene. Different photochromic properties of the bisanthracene were investigated. The optimized conditions were found using a dilute solution in benzene while selectively exciting the bisanthracene. The addition of a peroxycarboxylic acid to the photoproduct resulted in the formation of an epoxide, which caused the intramolecular product to become more photochemically and thermally stable. This resulted in a locked state. Attempts to unlock this system by removal of the epoxide resulted in only low yields of the bisanthracene, but does represent a preliminary gated system for anthracene photochemical reaction.

Document type: 
Thesis
File(s): 
Senior supervisor: 
Vance Williams
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.