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

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Synthesis of Heterocyclic Natural Products Jaspine B and (-)-Swainsonine

Author: 
File(s): 
Date created: 
2013-05-15
Supervisor(s): 
Robert Britton
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.
Abstract: 

Tetrahydrofurans and pyrrolidines are important structural motifs that are found in a variety of natural products that exhibit useful biological properties. Owing to their abundance in nature and both varied and potentially useful biological activity, numerous synthetic methods and strategies have been developed for the preparation of substituted tetrahydrofurans and pyrrolidines. The research work presented in this thesis describes the use of α-chloroaldehydes in the synthesis of the tetrahydrofuran-containing natural product pachastrissamine, as well as the development of new methods that provides rapid access to hydroxyalkyldihydropyrroles and iminosugars such as (-)-swainsonine.Pachastrissamine (also known as jaspine B), is a naturally-occurring anhydrophytosphingosine isolated in 2002 from two different marine sponges Pachatrissa sp. and Jaspis sp., and displays potent activity against numerous cancer cell lines. A total synthesis of this natural product was achieved in 8 steps that included an α-chloroaldehyde aldol reaction and novel thermal cyclization of the aldol adduct as the key steps. The second part of the thesis details the development of a concise and stereoselective strategy for the synthesis of hydroxyalkyldihydropyrroles. This study involves the nucleophilic addition of protected propargyl amines to α-chloroaldehydes, followed by Lindlar reduction of resultant chlorohydrin and an epoxide formation/cyclization sequence. This methodology was further demonstrated in the synthesis of unnatural iminosugars and in a formal synthesis of natural product (-)-swainsonine, a potent lysosomal α-mannosidase inhibitor.

Document type: 
Thesis

The borneol cycle of cytochrome P450cam and evolution of the enzyme for new applications

Author: 
File(s): 
Date created: 
2013-04-10
Supervisor(s): 
Erika Plettner
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) Ph.D.
Abstract: 

Cytochrome P450cam isolated from the soil bacterium Pseudomonas putida catalyses the hydroxylation of camphor to 5-exo-hydroxy camphor and further to 5-ketocamphor. Unexpectedly, we have also observed the formation of the reduction product, borneol in our enzymatic assays performed under shunt conditions using meta-chloro perbenzoic acid (m-CPBA) or with the complete P450 system under low O2 conditions. Under shunt conditions using m-CPBA, borneol was the major product. To further demonstrate the origin of Hexo in borneol, we monitored the bioconversion of camphor in deuterated buffer (pD = 7.4) under shunt conditions using m-CPBA as the oxidant and mono-deuterated borneol at C-2 was detected. We demonstrate that the source of electrons for this reduction reaction is water and not the nicotinamide cofactor. When 17O labeled buffer was used in the reaction mixture, labeled hydrogen peroxide (H217O2) formed. We propose a novel reduction mechanism for P450cam, discuss its generality and also the ecological implications of this reaction for P. putida and E. coli. To accommodate unnatural substrates in the active site, a mutant library of P450cam was constructed by Sequence Saturation Mutagenesis (SeSaM). With an objective to identify mutants from SeSaM library that would dehalogenate the chlorinated pesticide endosulfan, the library was screened with 3-chloroindole as a substrate and the active clone(s) were identified by isatin/indigo formation. The mutant (E156G/V247F/V253G/F256S) was the most active in the conversion of 3-chloroindole to isatin, (KM = 250 µM) compared to the WT enzyme (which did not accept 3-chloroindole). The mutant also degrades endosulfan and endosulfan diol to pthalaldialdehyde under shunt conditions using m-CPBA. We propose a mechanism for the dechlorination of endosulfan and the formation of pthalaldialdehyde with mutant (E156G/V247F/V253G/F256S) of P450cam.

Document type: 
Thesis

Nanoscale Phenomena in Ultrathin Catalyst Layers of PEM Fuel Cells: Insights from Molecular Dynamics

File(s): 
Date created: 
2013-05-09
Supervisor(s): 
Michael H Eikerling
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.
Abstract: 

Ionomer-free ultrathin catalyst layers have shown promise to enhance the performance and reduce the platinum loading of catalyst layers in polymer electrolyte fuel cell. The nanostructure of a catalyst layer affects the distribution and diffusion of reactants, and consequently its effectiveness factor. We employed classical molecular dynamics to simulate a catalyst layer pore as a water-filled channel with faceted walls, and investigated the effect of channel geometry and charging on hydronium ion and water distribution and diffusion in the channel.Equilibrium hydronium ion distribution profiles on the catalyst channel were obtained to calculate the effect of channel structure on the electrostatic effectiveness factor of the channel. Furthermore, we calculated the self-diffusion coefficient and interfacial water structure in the model channel. Results on proton concentration, diffusion and kinetics are discussed in view of catalyst layer performance.

Document type: 
Thesis

A chip-based "bipolar" DNA switch modulated by intermolecular interactions

Author: 
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Date created: 
2013-03-15
Supervisor(s): 
Hua-Zhong Yu
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.
Abstract: 

Herein, we report a unique “bipolar” DNA switch that integrates an anti-adenosine aptamer (a 12-base mismatch loop) in the middle of a complementary DNA double helix. The electrochemical signal change of methylene blue attached to the distal end of the DNA switch upon ligand binding is dependent on the DNA surface density. At high surface density, it switches on by increasing the peak current; at low surface density, it switches on by decreasing the peak current. No significant change of either the integrated charge (peak area) or the electron transfer rate is observed; only the shape of the reduction peak changes. Rather than by removal of perturbations or by change of surface accessibility, the switching is caused by a change of intermolecular interactions. The high specificity, reusability and stability of the DNA switch suggest the possibility of designing a new class of biosensors in which analyte binding produces large changes in intermolecular interactions.

Document type: 
Thesis

An Investigation into Polybenzimidazoles as Anion Exchange Membranes

File(s): 
Date created: 
2013-03-01
Supervisor(s): 
Steven Holdcroft
Department: 
Science: Department of Chemistry
Thesis type: 
(Thesis) M.Sc.
Abstract: 

A study was done into three sets of polybenzimidazoles (PBIs). The first set is a quaternized PBI known as poly(1,3-dimethyl benzimidazolium) (P(DMBI)) that was shown to have anion exchange properties. The second set is a novel quarternized PBI that had additional methylation on the phenyl ring known as mesitylene-poly(1,3-dimethyl benzimidazolium) (Mes-P(DMBI)) which also had anion exchange properties. The last set is a series of blend membranes of PBI and Mes-P(DMBI)-OH-, which showed that it was possible to synthesize a stable, hydroxide-conducting polymer. The P(DMBI) membranes were synthesized with various counter-anions (I-, Cl-, Br-, NO3-, HCO3- and OH-) and they were mostly found to have low water uptake at high ion exchange capacities (IECs) and good conductivity values. They were also found to be thermally stable up to approximately 150°C. The hydroxide membrane was unstable due to membrane degradation, which provided the impetus to synthesize the second and third sets of PBIs mentioned above. Mes-P(DMBI) is a novel polymer that was synthesized in order to attempt to create a stable hydroxide-conducting polymer. It was also synthesized with various counter-anions (I-, Cl-, Br-, OH-), and they were found to have much higher water uptake than their P(DMBI) counterparts. The hydroxide membrane was stable, but water-soluble, rendering it unusable as anion exchange membranes (AEMs). The stability of the aforementioned Mes-P(DMBI)-OH- prompted the synthesis of a series of blend membranes of PBI and Mes-P(DMBI)-OH- with different IECs. This utilized the cross-linking and mechanical stability properties of PBI, combined with the hydroxide-conducting property of Mes-P(DMBI)-OH- to make a stable, hydroxide-conducting membrane. The blend membranes were found to conduct hydroxide and to be stable in concentrated (2 M) KOH(aq) at 60°C over the period of a week, showing great promise for use in AEM fuel cells.

Document type: 
Thesis

Studies related to heteroatom analogues of D-Galactofuranose and its Alditol

Author: 
File(s): 
Date created: 
2005
Department: 
Department of Chemistry - Simon Fraser University
Thesis type: 
Thesis (Ph.D.)
Abstract: 

This thesis describes the heteroatom analogues of the monosaccharide Dgalactofuranose and its alditol, a mild Pummerer-like reaction of seleno-and thio-ethers, and the synthesis of the first seleno sugar derivative. D-Galactofuranose (Galj) is present in the cell walls of mycobacteria and other microorganisms such as protozoa and fungi. These microorganisms are responsible for a variety of life-threatening diseases, and Galf is known to be crucial for their survival, pathogenicity, or infectivity. The syntheses of potential inhibitors of the enzymes UDPgalactopyranose mutase and UDP-galactofuranosyltransferase that are responsible for the formation and incorporation of Galf, respectively, in cell walls of microorganisms are described. The compounds were intended to mimic the oxacarbenium ion transition state in the enzyme-catalyzed reactions. Two ammonium salts of 1,4-dideoxy- 1 ,4-imino-Dgalactitol, a known inhibitor of the enzyme UDP-galactopyranose mutase, as well as their selenonium analogues, derived from 1,4-dideoxy- 1 ,4-seleno-D-galactitol were synthesized. Both series of compounds contained a pendant polyhydroxylated alkyl chain with a sulfate counterion. Progress towards the synthesis of the 4-thio-analogue of UDPgalactofuranose, a potential inhibitor or substrate for the enzyme UDP-Galp mutase, is also described. The Pummerer rearrangements of carbohydrate-based heterocycles containing sulfur and selenium were investigated. Ozonization of 1,4 anhydro-D- galactitol or 1,5 anhydroxylitol derivatives containing sulfur or selenium as the ring heteroatom gave unstable intermediates, that were attributed to ozonides. These intermediates decomposed upon warming to give selenoxides or sulfoxides. Addition of acetic anhydride at low temperature to the ozonization reaction mixtures gave Pummerer-rearrangement-products after warming to ambient temperature, in contrast to the much higher reaction temperatures required for rearrangement of the isolated selenoxides or sulfoxides. The mechanism of the rearrangement, probed by trapping experiments with rubrene, and electron paramagnetic resonance (EPR) studies with the radical trap 5,5-dimethy-1- pyrroline N-oxide (DMPO), is consistent with the intermediacy of radical species in the rearrangement. Finally, the synthesis of the hitherto unknown 4-seleno-D-galactofuranose is described. The synthesis represents the first of a selenosugar. A preliminary study of 4- seleno-D-galactofuranosyl derivatives as glycosyl donors is also described.

Document type: 
Thesis

Total synthesis of the xyloketal natural products and alboatrin

File(s): 
Date created: 
2006
Department: 
Department of Chemistry - Simon Fraser University
Thesis type: 
Thesis (Ph.D.)
Abstract: 

The isolation and structural characterization of seven closely related natural products, the xyloketals, from a mangrove fungus of the Xylaria species have been reported recently by Lin and co-workers. Of these natural products, all of which incorporate identical chiral nonracemic 5,6-bicyclic acetal moieties, xyloketal A has a unique and aesthetically pleasing C3-symmetric molecular structure that was elucidated by detailed spectroscopic studies and by X-ray crystallography. Xyloketal A, B, C and D have also been shown to be potent inhibitors of acetylcholine esterase and so represent important lead compounds for the treatment of neurological diseases. In addition, xyloketal A, B and F have been shown to have L-calcium channel blocking activity. Thus, the total synthesis of these natural products, and structural analogues thereof, is of notable significance. Towards these ends, a series of novel synthetic routes to prepare these compounds were developed. The initial route, in which the key synthetic transformation involved an inverse electron demand hetero Diels-Alder reaction between appropriately substituted ortho-quinone methides and dihydrofurans, afforded (±)-, (+)- and (–)-xyloketal D. In addition, demethyl analogues of xyloketal A and D were prepared. However, the application of this synthetic route to prepare the more structurally complex xyloketals was unsuccessful. A second route, utilizing a phenylboronic acid-mediated condensation reaction as the key synthetic transformation, afforded a series of novel tris-2H-chromenes that represent structural analogues of the natural product xyloketal A. However, due to the instability of a key reaction intermediate, the total synthesis of xyloketal A was not completed by this route. A third route was also investigated that featured a boron trifluoride diethyl etherate-promoted electrophilic aromatic substitution reaction as a key step. This synthetic route was used to complete total syntheses of xyloketal A, B, D, E, F and G. Moreover, demethyl analogues of xyloketal A, B, C, D, E and G were also prepared. The application of the electrophilic aromatic substitution reaction towards the total synthesis of the structurally related and biologically active natural product alboatrin was also investigated. This led to the first asymmetric total synthesis of this natural product as well as a demethyl analogue.

Document type: 
Thesis

Unusual degradation pathway of pheromone odorants in gypsy moth

Author: 
File(s): 
Date created: 
2005
Department: 
Department of Chemistry - Simon Fraser University
Thesis type: 
Thesis (M.Sc.)
Abstract: 

Gypsy moth is a major pest in Europe and North America. The closely related species, nun moth, is also a destructive pest in Europe. Both species use the pheromone cis 7(R), 8(5')-2-methyl-7, 8-epoxyoctadecane, (+)-disparlure, for sexual communication. The alkene precursor of disparlure, 2-methyl-7(Z)-octadecene, and (-)-disparlure are also of biological importance in both species. In this thesis I describe the metabolic fate of 2-methyl-7(Z)-octadecene, (+)- disparlure and (-)-disparlure in the gypsy moth. Unexpectedly, I found that the incubation these odorants with moth extracts stimulates the formation of methyl and ethyl esters of linoleic and oleic acid. I hypothesize that the incubated compounds are degraded into smaller unit s and t hese units a re t hen inc orporated int o t he b iosynthesis o f o leic and linoleic acids. These fatty acids are then mterified into their corresponding fatty esters. The formation of these fatty esters fiom the incubated substrates is NADPH and FAD dependent.

Document type: 
Thesis

Characterization of membrane protein primary structure and protein covalent modification by MALDI-TOF-MS

Author: 
File(s): 
Date created: 
2005
Department: 
Department of Chemistry - Simon Fraser University
Thesis type: 
Thesis (M.Sc.)
Abstract: 

The subjects of this thesis were to illustrate membrane protein primary structure determination, protein covalent modification and protein-protein interaction by using matrix assisted laser desorptiodionization time-of-flight mass spectrometry (MALDITOF- MS). First, in one mode of sample preparation referred to as wall-less sample preparation, an increase in sequence coverage of a model membrane protein, bacteriorhodopsin, increased from 8 1 % using traditional sample methodology to 89%. Second, chemical modification sites of proteins, pheromone binding protein 2 (PBP2) and cytochrome P45OCam (P45OCam), were characterized by MALDI-MS. This finding contributed to further studies of protein-ligand interaction of PBP2, and also provided information about native conformation of P45OC,,. Third, co-imrnunoprecipitation and MALDI-MS was used to identify the interaction of synapse-associated protein (SAP97) with potassium voltage-gated ion channel Kv1.5. This study provided the first direct mass spectral evidence to support their protein-protein interaction. In addition, to better understand one of MALDI ionization pathways, a simple two-plate method was used to examine the MALDI gas-phase cationization.

Document type: 
Thesis

Studies toward the total synthesis of artocarpol A, D, E and structurally related analogues

Author: 
File(s): 
Date created: 
2006
Department: 
Department of Chemistry - Simon Fraser University
Thesis type: 
Thesis (Ph.D.)
Abstract: 

The work described in this thesis concerns studies toward the total synthesis of artocarpol A, D and E as well as the synthesis of structurally related analogues. The artocarpol family of natural products was isolated from the root bark of a breadfruit tree, Artocarpus rigida (Moraceae). Notably, artocarpol A has a particularly interesting molecular structure as well as potent anti-inflammatory activity and so it represents an important target for total synthesis. Artocarpol A, C, D, E, F, G and I share a common structural feature, a functionalized dibenz[b,f]oxepin ring system. Moreover, in the case of artocarpol A the dibenz[b,f]oxepin moiety is fused to a tricyclic system (a condensed 4, 5,6-polycyclic system that features four contiguous stereogenic centres at the ring-junctions). Based on retrosynthetic analysis of this target compound, a novel synthetic route was devised and model studies were undertaken. The known 11H-dibenzo[b,f]oxepin-10-one was efficiently synthesized in five steps in order to test the validity of the two key steps in the proposed route. The first key step involved a cross-aldol condensation reaction between the unsubstituted oxepinone and citral that was coupled to a subsequent electrocyclization reaction. The second key step, involved an intramolecular [2+2] photocycloaddition reaction that resulted in the construction of the complete polycyclic ring system of artocarpol A and installed the four stereogenic centres in the correct relative sense. The structure of this complex polycyclic artocarpol A analogue was elucidated by detailed NMR studies and by X-ray crystallography. A series of related 2H-chromenes and pyrans were also pre pared by modification of a known synthetic procedure and were employed as additional substrates for this photocycloaddition reaction. An analogue of artocarpol D was also prepared from senecialdehyde. An alternative strategy was also developed for the synthesis of analogues of artocarpol A, D and E that employed alkylation reactions of the parent oxepinone with geranyl and prenyl bromide as key steps. The synthesis of a dimethoxy-substituted dibenzo[b,f]oxepinone was also completed. However, this appropriately functionalized substrate proved to be unsuitable for the proposed total syntheses. Thus, the corresponding dinitro-substituted oxepinone was identified as an alternative substrate for synthesis and preliminary investigations were undertaken.

Document type: 
Thesis