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

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A concise and stereoselective synthesis of iminosugar alkaloidsfrom α-Chloroaldehydes

Date created: 
2012-12-04
Abstract: 

Iminosugars have generated much attention in recent years as targets for the potential therapeutic treatment of a wide range of illnesses (e.g. cancer, HIV, diabetes, liposomal storage disorders, etc). Not surprisingly, the development of new synthetic methods towards iminosugars is of great interest to synthetic chemists. Previous synthetic strategies rely on carbohydrate starting materials (e.g. chiral pool synthesis) and are limited in their ability to produce stereoisomers or analogues, limiting their application to target-specific syntheses. We propose it is more advantageous to develop a method such that many stereoisomers and analogues can be synthesized from a common intermediate. This thesis describes a general, concise, and stereoselective method for the preparation of iminosugar alkaloids from non-carbohydrate starting materials. The method reported herein involves the diastereoselective nucleophilic addition of propargylamines to α-chloroaldehydes, followed by a domino epoxidation-cyclization sequence providing 2,5-dihydropyrrole intermediates that upon dihydroxylation provides iminosugar natural products in good overall yield and optical purity.

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

Lipid interactions involved with pheromone binding protein function in Lymantria dispar

Author: 
Date created: 
2012-11-30
Abstract: 

The mechanism for insect olfaction is not fully understood. Pheromone-binding proteins (PBPs) are hypothesized to be critical for proper chemical signaling in insects. Using a pheromone-binding assay I have shown that endogenous fatty acids, which bind Lymantria dispar PBP1 and PBP2, cause increased affinity for pheromone. Using circular dichroism spectroscopy, I have shown that the structures of PBP1 and PBP2 are altered by the binding of endogenous ligands. I propose that the altered conformation and increased affinity are related. The large concentration of fatty acids found in the sensillar lymph, where PBP1 and PBP2 have access to these ligands, is well above the critical micellar concentration. With various analytical techniques, most importantly of which was mass spectrometry, I identified many lipid components found in L. dispar’s lipidome. Analysis has provided insight into lipid bilayer preservation in the presence of endogenous fatty acid micelles. This thesis work provides evidence that lipids play an integral role in PBP function and proposes that they may be critical for olfaction.

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

Studies towards the total synthesis of eleutherobin and other marine natural products

Date created: 
2012-10-05
Abstract: 

The primary focus of the research described in this document relates to the development and application of new synthetic methodologies relevant for the concise construction of four natural products. In Chapter 2, a discussion of our investigation of the total synthesis of eleutherobin (1) is disclosed. Eleutherobin (1), first isolated in 1997 from the rare soft coral Eleutherobia sp., is a member of a class of microtubule stabilising natural products. Although it displays potent cytotoxicity, its development as an anticancer drug has been hampered by the scarcity of material available from the natural source. In an effort to produce quantities of eleutherobin required for further biological testing, four conceptually unique approaches to eleutherobin were investigated which culminated in the development of an unprecedented palladium-catalysed α-arylation reaction/Friedel-Crafts cyclisation methodology for tetralone synthesis. This strategy permitted the production of multi-gram quantities of an advanced tetralone intermediate, and enabled the synthesis of a functionalised epoxyenone intermediate along our intended synthetic route. These investigations have provided a solid foundation for an eventual synthesis of eleutherobin that may also facilitate the evaluation of this natural product as an anticancer drug. In Chapter 3, the total synthesis of two potent anthelmintic oxylipid natural products, isolated from Notheia anomala, is discussed. Specifically, a silver-mediated cyclisation of two chlorodiols afforded two diastereomeric styryl-tetrahydrofurans, which were rapidly elaborated into the desired natural products. In addition, these syntheses featured a remarkable example of inverse-temperature dependence in the diastereoselective addition of Grignard reagents to tetrahydrofurfurals. Ultimately, these natural products were prepared in six synthetic transformations in excellent overall yield and efficiency. The last two topics presented in this thesis are contained in two separate appendices and highlight our interest in the synthesis of ecologically relevant natural products. In Appendix A, we report the synthesis and structure determination of the unknown banana volatile, (3R,2’S)-(2’-pentyl)-3-hydroxyhexanoate, and its olfactory recognition by the common fruit fly. The work presented in Appendix B focuses on the development of a scalable synthesis of mathuralure, the sex pheromone of the pink gypsy moth, Lymantria mathura, a potentially devastating invasive species.

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

Synthesis of heterocyclic natural products and analogues

Author: 
Date created: 
2012-09-18
Abstract: 

Organic compounds that contain rings composed of carbon and other atoms such as nitrogen, oxygen, sulfur or phosphorus are referred to as heterocyclic compounds. Compounds of this type are frequently encountered in natural products and a majority of all biologically-active molecules are heterocycles. This thesis concerns the synthesis of three distinct classes of heterocyclic natural products and analogues. Likonide B and smenochromene C are two structurally-related oxygen-containing heterocyclic marine natural products that feature a unique ansa-bridged farnesyl quinol moiety which is considered to be an interesting structural motif for synthetic studies. The total syntheses of these two natural products were completed in an efficient manner from commercially-available starting materials. The employment of a phenylboronic acid-mediated condensation reaction of phenols and a,b-unsaturated aldehydes, and a palladium-catalyzed O-allylation reaction constituted a potentially biomimetic total synthesis of these two natural products. Platensimycin, an oxygen-containing heterocyclic compound, is a new class of antibiotic. Its complex tetracyclic ketolide structure motif represents a considerable synthetic challenge. By manipulating the oxygenation pattern of this tetracyclic core, it was proposed that an asymmetric domino double Stetter reaction of an achiral molecule could be used to prepare the tricyclic skeleton of this compound with all the stereogenic centres correctly installed in a single synthetic transformation. After considerable experimentation, the key achiral compound was prepared in five steps from commercially-available starting materials. Preliminary studies were then undertaken to effect this key transformation. The synthesis and applications of 2,3-disubstituted pyrroles, a class of nitrogen-containing heterocycle, were also investigated. The ultimate-goal of this project was to develop an efficient synthesis of 7-phosphatryptophan, a synthetic analogue of the natural a-amino acid tryptophan that could exhibit different fluorescent properties to that of the natural substrate for biophysical studies. En route to the synthesis of 7-phosphatryptophan, a novel method to construct 2-chloro-3-carboxylate pyrrole was developed and optimized. It was also envisioned that this compound could serve as a central building block for the preparation of a series of potentially biologically-active heterocycles. In this regard, a series of pyrrole derivatives were synthesized via various palladium-catalyzed cross-coupling reactions for future biological activity studies.

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

A Dithienylethene that gates a spontaneous reaction and photolyzes with visible light and synthetic progress towards a corresponding hexatriene

Author: 
Date created: 
2012-08-22
Abstract: 

1,2-Dithienylethenes (DTEs) and the related ‘hexatriene’ derivative are a robust family of P-Type photochromes whose isomers may exhibit different degrees of reactivity due to the changes in structure and electronics that accompany the re-arrangement of their bonding frameworks. One approach to changing the reactivity is to control the precise localization of electrons in the π systems of the two isomers, which has previously been demonstrated to exert binary,“on/off” control over equilibria and endothermic reactions. In this work, a DTE derivative was shown to exert binary control over a spontaneous fragmentation reaction: after forming the active isomer using UV light, the desired fragmentation occurred. Contrary to expectations, the active isomer of the DTE did not revert to its inactive isomer but instead underwent the same fragmentation by photolysis with UV or visible light. A number of synthetic routes were attempted to form a ‘hexatriene’ counterpart activated by visible light directly, but none were ultimately successful. The reported DTE is thus a cage compound activated by visible light.

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

The use of upconverting nanoparticles to drive organic photoreactions

Date created: 
2012-08-27
Abstract: 

One of the primary disadvantages of organic photochemistry is the need for high-energy UV light, light that has many detrimental qualities. A viable solution to this problem is the use of upconverting nanoparticles (UCNP) that can locally convert near infrared (NIR) laser light into UV light or visible light of sufficient energy to drive organic photoreactions. In an initial study (Chapter 3), the use of UCNPs to drive both UV and visible light dependent photoreactions with NIR light was demonstrated using 1,2-dithienylethene (DTE) molecular switches functioning as probes. In this study the concept of NIR-to-visible ‘remote-control’ photorelease was also introduced. In a second study (Chapter 4), two multicolour UCNPs were developed. It was demonstrated that by only altering the power-density of the one wavelength NIR excitation source, the photochemistry of two DTE molecular switches could be selectively and bi-directionally driven along its two reaction pathways. In a third study (Chapter 5), fluorescence modulation bioimaging was demonstrated in vivo in C. elegans nematodes. The fluorescence modulation in aqueous medium was achieved by decorating the surface of an UCNP with polyethylene glycol functionalized DTE molecular switches by ‘click’ chemistry. In a fourth study (Chapter 6), multimodal fluorescence modulation of a multicolour UCNP by two DTE molecular switches decorated on the surface of the UCNP was demonstrated. Apart from a greater degree of control in this more advanced system, it is also capable of NIR-to-UV ‘remote-control’ photoswitching. In a fifth study (Chapter 8), the surface of an UCNP was decorated with 3’,5’-dialkoxybenzoin photocages and the concept of NIR-to-UV ‘remote-control’ photorelease for potential use in drug-delivery was demonstrated. In a sixth study (Chapter 9), a fully water dispersible drug-delivery system was synthesized. Unfortunately the system proved impractical due to the choice of both photorelease system and therapeutic payload. In a seventh study (Chapter 10), a donor-acceptor 4-dimethylamino-3’,5’-dimethoxybenzoin photocage with both red-shifted absorbance and a significantly enhanced molar absorbance coefficient was synthesized and its initial and unique photochemistry was studied.

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

Adenosine-induced elimination of redox intercalators from dsDNA-aptamer conformational switches

Author: 
Date created: 
2012-07-12
Abstract: 

Immobilization and electrochemical characterization of specially designed DNA-aptamer constructs (namely, “DNA conformational switches”) are of great importance for the development of versatile biosensorsand the fundamental understanding of DNA-ligand interactions. Wehave created andimmobilizedadsDNA-anti-adenosine aptamer construct on gold which is expected to undergo structural changes upon binding adenosine.In particular,methylene blue (MB), a solution-diffused redox marker, was used as a model system to probe the rather complex interaction modes between small redox molecules and surface-bound DNA switches. Besides intercalating with the double-stranded DNA stem, MB can stack with a single guaninebase in the relatively unstructured aptamer domain or electrostaticallybindtothe DNA backbone. The decreased surface density of MB after adenosine binding indicated that the ligand-gated structural change of the dsDNA-aptamer construct can eliminate MB molecules that were originally bound to the aptamer domain, but not those in the complementary stem.

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

Controlling luminescent and thermoresponsive materials with molecular photoswitching

Date created: 
2012-07-30
Abstract: 

Molecular switching motifs based on dithienylethenes provide a versatile framework for developing materials whose properties can be toggled between two states by alternately exposing them to ultraviolet and visible light. Materials with these features can then be selectively addressed and their properties manipulated even when present in complex mixtures, making them attractive for applications in controlled drug delivery, catalysis and imaging. Developing these materials nevertheless requires design strategies that couple light-induced changes in the dithienylethene architecture to desirable secondary events (e.g. changes in catalytic or biological activity, refractive index, or electrical resistance). This thesis describes analogous design strategies developed to control luminescent and thermoresponsive materials using optical cues. In the first system, quantum dot luminescence is reversibly quenched by photoisomerization of a cationic dithienylethene ligand. In the second, photoisomerization of a bicyclic dithienylfuran adduct is shown to gate the reversibility of the Diels-Alder reaction at elevated temperatures.

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

Partition, sorption & biodegradation of dialkoxybenzenes that modulate insect behavior

Date created: 
2012-07-20
Abstract: 

Plant protection is an important part of modern agriculture, in which high-yielding crop varieties are at risk of diseases and insect pest attacks. Dialkoxybenzenes are promising new insect control agents. Some of these compounds mimic naturally occurring odorants that modulate insect behavior. Before applying these compounds, however, their persistence and biodegradability at the application site and in the environment must be understood. In this study, the octanol-water partition coefficient, volatility and sorption on soil components (sand, clay and organic matter) of selected dialkoxybenzenes were investigated. In general, these compounds showed acceptable physical-chemical properties. Biodegradation experiments of 1-allyloxy-4-propoxybenzene with three strains of Pseudomonas putida. Two of the three strains of P. putida tested were able to metabolize 1-allyloxy-4-propoxybenzene. The first step in metabolizing by strain ATCC 17453 was dealkylation. In vitro tests with CYP101A1 (cytochrome P450cam, a camphor hydroxylase), revealed that the dealkylation is catalyzed by this enzyme.

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

Evaluating and optimizing the quality of silane-based self-assembled monolayers

Author: 
Date created: 
2012-06-22
Abstract: 

Self-assembled monolayers (SAMs) form spontaneously through the adsorption of surfactant molecules onto surfaces, forming ordered molecular assemblies due to a specific affinity of the molecule‘s headgroup to these surfaces. Monolayers are a simple means of modifying the properties of surfaces, which can be important to many fields. It is, however, still a challenge to achieve high quality SAMs using alkylsilane-based molecules. In this thesis, high quality monolayers of alkylsilanes are sought through the use of mono-reactive perfluoroalkylsilanes. Monolayers created by the deposition of monoreactive perfluoroalkylsilanes from toluene solutions were investigated to correlate the quality of these SAMs to changes in their processing conditions. Surface sensitive spectroscopic techniques were used to monitor and guide further improvements in the quality of these monolayers. Changes to the process conditions included altering the solution temperature, silane concentration, and reaction times. Initial work is also presented on the use of microwave processing to significantly decrease the time required to form monolayers from mono-reactive perfluoroalkylsilanes. As a demonstration of the potential utility of these SAMs, we analyzed the ability of the silane-modified surfaces to resist the non-specific adsorption of proteins. In this example, the non-specific adsorption of bovine serum albumin (BSA) was evaluated on surfaces coated with perfluoroalkylsilane monolayers.

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