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Oxocarbenium Ion and Alkene Metathesis Strategies for the Synthesis of Complex Cyclohexanes
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ABSTRACT Oxocarbenium Ion and Alkene Metathesis Strategies for the Synthesis of Complex Cyclohexanes. by Clayton Mattis Mentor: Professor David R. Mootoo Highly oxygenated cyclohexanes comprise the structures of a number of pharmacologically interesting molecules, including potently bioactive natural products and carbapyranosides. The latter, which are unnatural analogues of carbohydrates in which the ring oxygen of the parent sugar is replaced with a methylene group, have attracted interest as hydrolytically stable mimetics of their parent O-glycosides. This research reports the development of two general methodologies for the synthesis of highly oxygenated cyclohexanes: (1) Oxocarbenium Ion Cyclization (OCC) and (2) Ring Closing Metathasis (RCM). Chapter one gives a review of the literature on the synthesis for highly oxygenated cyclohexanes. Previous results from this laboratory have shown that OCCs on cyclic oxocarbeniums derived from 1-thio-1,2-O-isopropylidene precursotrs are highly stereoselective for cyclohexanes and tetrahydropyrans with cis 3,4-diols. To expand the scope of the OCC methodology, the goal was to evaluate the OCCs on non-cyclic oxocarbenium ions derived from mixed thioacetal precursors. Chapter two describes reactions with alkene nucleophiles. In particular, the OCC on an alkene-mixed thioacetal precursor aimed at the cyclohexane core of the immunosuppressive agent FR65814, was examined. This study revealed that OCCs on non-cyclic oxocarbenium ions could deliver cyclohexanes with trans 3,4-diols in high stereoselectivety. As for the previous observations on OCCs with cyclic oxocarbenium ions, these results can be explained in terms of conformational arguments. Chapter three discusses OCCs for non-cyclic oxocarbenium ions and enol-ether nucleophiles. These reactions were expected to give highly oxygenated cyclic enol ether precursors for carba- and C- pyranosides with trans 3,4-diols. However, in all cases, complex mixtures of products that suggested multiple deleterious pathways from the initial formed cyclization intermediates, was observed. This result contrasts to the successful OCCs involving cyclic oxocarbenium ions and enol ethers, and suggests that conformational rigidity is an important requirement for OCCs involving enol ether nucleophiles. Therefore, the OCC strategy appears to be limited to the synthesis of carba- and C- pyranosides with cis-3,4-vicinal diols. Chapter four describes a more general synthesis of carbapyranosides, which is based on the RCM of an enol ether - alkene substrate. This reaction delivers a six-membered cyclic enol ether in which the enol ether oxygen is exocyclic, and contrasts with a related cyclization from the Postema group that provides C-1-substituted glycals, i.e. cyclic enol ethers with an endocyclic enol ether oxygen. This RCM strategy for carbapyranosides was applied to the carba-arabinose and carba-xylose analogues of the sugar residues in the potent antitumor steroidal glycoside OSW-1.
The Development Of New Organocatalysts and New Organocatalytic Cascade Reactions
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Organocatalysis is the use of small organic molecules to catalyze chemical reactions. They are generally cheaper, less toxic, and easier to handle on a laboratory and industrial scale than more traditional metal-based catalysts. This dissertation discusses the development of new organocatalysts and organocatalytic methods for the asymmetric synthesis of useful small molecules. The research conducted has specifically focused on the use of chiral diarylprolinol silyl ether organocatlysts and their ability to catalyze a variety of useful cascade reactions through iminium and enamine catalysis. Cascade reactions are useful in that a great deal of molecular complexity may be generated in a one-pot process using simple, readily available building blocks. Herein, is provided a comprehensive background on the use of diarylprolinol silyl ethers in the catalysis of iminium-initiated cascade reactions. The research conducted has focused on three main topics: 1.) The development of a novel class of bifunctional bissulfonamide organocatalysts for the asymmetric conjugate addition of dicarbonyls to nitroolefins. 2.) The use of diarylprolinol silyl ether organocatalysts to catalyze a novel Michael-Michael cascade reaction which generates fused carbocycles. 3.) The discovery and development of a novel organocascade kinetic resolution reaction using diarylprolinol silyl ether organocatalysts, which can be used for the synthesis of chiral 2,6-disubstituted tetrahydropyrans and chiral 2,5-disubstituted tetrahydrofurans.
SPECIATION OF TECHNETIUM-99 INCORPORATED INTO METAL OXIDE MATRICES: A MOLECULAR LEVEL UNDERSTANDING OF Tc-99 REDUCTION AND ITS COMPLEXATION INTO POLYOXOMETALATES
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Technetium-99 (99Tc) is a long-lived (T1/2 = 2.13 x 105 years) β-emitting (Emax = 294 KeV) radionuclide formed during the fission of 235U and fallout from nuclear weapons testing. It exists in relatively high concentrations in nuclear waste tanks, and the pertechnetate (TcO4-) anion has been shown to leach into surrounding subsurface soils and groundwaters. Due to its long half-life and the high mobility of the pertechnetate (TcO4-) anion, 99) Tc management is an issue for both waste characterization and long-term storage. A better understanding of both its extensive redox chemistry and the parameters that affect the speciation and coordination environment of Tc will promote the development of more appropriate methods for the separation of Tc from nuclear waste tanks as well as more fitting mediums for storage. Polyoxometalates (POMs) are early transition metal oxide clusters that are chemically robust. They have homogeneous crystalline structures and are known to be good model systems for metal oxide solid-state materials such as the glasses and ceramics used to house nuclear waste. The synthesis of pure 99Tc-POM compounds, however, is complicated by both the unwanted hydrolysis of the Tc(V) starting material and difficulties with the separation of the free POM ligand from the desired 99Tc-POM complex. We have developed methods for the clean synthesis of the 99Tc - (α1-P2W17O61)10-) and (α2-P2W17O61)10-) Wells-Dawson POM compounds (as both organic and aqueous soluble complexes) and characterized them using various spectroscopic techniques. POMs also have unique, tunable, electron transfer abilities and can be reduced, both electrochemically and photochemically in the presence of a sacrificial electron donor, by multiple electrons while maintaining their structural integrity. To this end we have investigated a number of POMs; Keggin ions, (XW12O40n-), X=P, n=3; Si, n=4; Al, n=5), the Wells-Dawson lacunary isomer (α2-P2W17O61) 10-), and a "wheel" POM, P8W48O18440-), for their ability to reduce pertechnetate and sequester low valent 99Tc. The resulting low valent Tc species have been characterized by physical methods including multinuclear NMR and electrochemistry.
Studies Toward a General Synthesis of Poly-Substituted Alpha-Hydroxytropolones
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ABSTRACT Studies Toward a General Synthesis of Poly-Substituted Alpha-Hydroxytropolones by Christine Meck Advisor: Prof. Ryan P. Murelli, Ph.D. Chapter 1: This chapter gives a brief history of α-hydroxytropolones, how they were discovered and unique properties of these substrates. Included is a background on the bioactivity of these substrates in cellular targets such as bacteria, fungi, parasites, tumors and toxicity, as well as their ability to inhibit various metallo-based enzymes. Structure activity relationships studies are reviewed on important metalloenzymes HIV-Reverse Transcriptase (RT) and Inositol monophosphatase (IMPase). Finally the chapter finishes with a synthetic overview of α-hydroxytropolones including natural product targets such as puberulic acid, puberulonic acid, β-thujaplicinol, and α-hydroxytropolone. Chapter 2: A brief review on β-hydroxy-γ-pyrone based oxidopyrylium cycloadditions will be presented as well as important oxidopyrylium cycloaddition/ring opening procedures to yield natural tropolone products. Research from the Murelli laboratory will be highlighted. This chapter will discuss a new synthetic route toward functionalized α-hydroxytropolones. A β-hydroxy-γ-pyrone intermolecular oxidopyrylium cycloaddition with a range of alkynes that was optimized to an efficient and high yielding process will be discussed. Next two ring catalyzed ring openings will be discussed; one that utilizes boron trichloride that attains α-hydroxytropolones and 7-methoxytropolones, and a triflic acid mediated sequence that yields exclusive 7-methoyxtropolones and furans. Finally, a new reaction with the oxidopyrylium species will be highlighted that shows the exchange of alcohols in these reactive species. Chapter 3: Chapter three describes the background on three specific medicinal targets: ANT (2”)-Ia, HIV RT RNase H, and HBV RT RNaseH and preliminary structure activity relationship studies with α-hydroxytropolones synthesized in this research are outlined.
Benzophenone photoprobes for chemical proteomics and drug target identification
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Benzophenone photoprobes are widely used in photoaffinity-labeling studies, especially for the characterization of ligand-receptor interaction. Photolabeling studies using benzophenone, however, are by no means routine experiments. It is not uncommon that carefully designed photoligands fail to label target proteins. In order to get insights into the important factors that affect the photolabeling efficiency, we conducted a structure-activity relationship study (SAR) on adenine-benzophenone photoligands. The study suggested that conformational flexibility was the determining factor that controls the photolabeling efficiency by benzophenone photoprobes. In theory, photoaffinity-labeling can also be used for target identification of small molecules. However, the complexity of proteins in biological samples, such as cell lysate, tissue homogenates and serum samples, limits the use of benzophenone photoprobes in drug target identification and chemical proteomics. By using so called "blocking strategy" we were able to systematically classify the list of proteins identified from photoaffinity-labeling studies using benzophenone. The findings of this study enabled us to refine the experimental protocol for drug target identification and chemical proteomics using benzophenone photoprobes. During the affinity purification of phochemically biotinylated proteins, we discovered that monomeric avidin resin can selectively enrich heat shock proteins (Hsps) from complex proteomes. Although such serum Hsps or circulating Hsps, has been linked to various diseases, including cancer and cardiovascular diseases, their characterization have been hampered be the abundant proteins in serum such as albumin and immunoglobulings. The development of simple and reproducible method for Hsp enrichment opens a new opportunity to define the roles of circulating Hsps in various diseases.
Chiral Sulfurization For Synthesis Of Antisense Oligonucleotides
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Chapter 1: Antisense and RNA interference (RNAi) reagents are two of the most widely studied oligonucleotide-based therapeutics. Phosphorothioate oligonucleotide, an antisense reagent, has a stereogenic center at the phosphorothioate linkage and in the absence of enantioselective synthesis, a mixture of diastereomers results. Stereodefined phosphorothioates have shown greater antisense activity; however, only a few research groups have successfully designed methods for enantioselective synthesis of phosphorothioates with >98% de, albeit in low yields. This dissertation presents a conceptually different method for enantioselective synthesis of phosphorothioate oligonucleotides via a Curtin-Hammett system that requires epimerization of the phosphite triester on the reaction time scale and selective sulfurization of one of the equilibrating epimers with a chiral sulfurizing reagent. Chapter 2: 2-Cyanoethyl[5'-O-acetyl-2'-deoxythymylyl]-(3',5')-3'-O-(acetyl)-2'-deoxythymidine phosphite triester was found to invert at 150 ºC with &DELTA;G = 33.0 ± 0.2 kcal/mol. Separation of the two diastereomers of the phosphite triester was successfully achieved via its 2-cyanoethyl[5'-O-(p,p'-dimethoxytrityl)-2'-deoxythymylyl]-(3',5')-3'-O-(tert-butyldimethylsilyl)-2'-deoxythymidine boranophosphate analogue. For the inversion study the p,p'-dimethoxytrityl and tert-butyldimethylsilyl groups were substituted with acetyl groups to reduce decomposition during heating. Attempts to induce inversion at lower temperature with acidic and radical species failed. Chapter 3: Chiral analogues of phenylacetyl disulfide (PADS) and 5-methyl-3H-1,2,4-dithiazol-3-one (MEDITH) were synthesized from the same α-alkylated carboxylic acids to give products with enantiomeric purities of 99.0 to >99.9% and 86.1-99.4%, respectively. X-ray diffraction results for one pair of enantiomers unequivocally establish the absolute configurations of two disulfides, and density functional theory (DFT) calculations suggest that the observed high specific rotations could be due to preferred retention of helicity about the S-S bond in solution. Chapter 4: Phosphite triesters with varying degrees of steric hindrance around the phosphorus atom (β-cyanoethyl, TMS, TBDMS, and TPS derivatives) were screened against chiral analogues of PADS and MEDITH. The RPS:SPS diastereomeric ratios of the resulting phosphite sulfides or phosphorothioates were determined by reverse-phase HPLC, and a numerical procedure was developed to express the diastereoselectivity of the reactions. The best selectivities to give RPS enriched and SPS enriched phosphorothioates were achieved with MEDITH analogues (S)-6d (naproxen derivative) (14.7% de) and (S)-6c (isopropyl group at the α position) (-7.9% de), respectively, when reacted with the phosphite triester bearing the TMS group.
SYNTHESIS, CHARACTERIZATION, RAMAN, AND SURFACE ENHANCED RAMAN STUDIES OF SEMICONDUCTOR QUANTUM DOTS
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The major contributions and discoveries of the dissertation include: (1) Homogeneous nucleation processes for the formation of nanocrystals can occur at low temperature and do not need to proceed at high temperature to overcome a high energy barrier. Monodisperse PbS quantum dots (QDs) obtained with nucleation and growth at 45°C support this finding. (2) Monodisperse single elemental Se QDs can be produced by simple solution crystallization from TDE (1-tetradecene) or ODE (1-octadecene). (3) TDE is a better non-coordinating solvent compare to ODE. STDE (S dissolved in TDE) and SeTDE (Se dissolved in TDE) are stable reagents with long storage time. They can be used as universal precursors for S-containing and Se-containing QDs. (4) QDs synthesis can be carried out at low temperature and relatively short reaction time using the simple, non-injection, one-pot synthetic method. (5) The one-pot method can be extended for the synthesis of QDs and graphene oxide nanocomposites and metal and graphene oxide nanocomposites. (6) PbCl2-OLA (oleylamine) is a universal system for the synthesis of Pb-chaclogenides QDs. (7) Surface enhanced Raman spectroscopy (SERS) is used to probe both size and wave length dependent quantum confinement effects (QCEs) of PbS QDs. (8) Raman spectroscopy is a powerful tool to elucidate crystal structure of Se nanoclusters with size of 1-2 nm. Semiconductor QDs have attracted considerable attention due to their potential for energy-efficient materials in optoelectronic and solar cell applications. When the radius of a QD is decreased to that of the exciton Bohr radius, the valence and conduction bands are known to split into narrower bands due to QCEs. QCEs are both size and wave length dependent. We have developed, synthesized and characterized a series of Pb-chaclogenide QDs, which all the sizes of the QDs are monodisperse and smaller than their respective exciton Bohr radius, to study the QCEs of these QDs. SERS is used as a crucial tool to investigate these QCEs. The QCEs are due to any of the following three resonances or a combination among them: interband resonance, molecular state resonance, and charge-transfer resonance.
Applications of Bionanotechnology
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The aim of nanotechnology is to devise technologies at the crossroads of chemistry, physics and biology to shape matter at the atomic scale to form nanosized functional objects and to arrange them into intricate assemblies to elaborate new devices. Today, its biological aspect is largely emphasized to tackle biomedical issues such as pathogen identification, disease diagnosis and treatment. In this respect, interdigitated electrodes were employed to monitor the presence of harmful bacteria, then to attempt to detect human PC3 carcinoma prostate cells as well as the size variation of stimulus-responsive hydrogel beads designed for drug delivery. Our second project aimed at demonstrating the potential use of TiO2-labeled antibodies as substitute for horse-radish peroxidase-labeled antibodies for Enzyme-Linked ImmunoSorbent Assays (ELISA). Our last project revolved around harnessing the enzymatic activity of urease to grow silver-sulfide nanoparticles.
FACTORS AFFECTING THE REMOVAL OF AMMONIA FROM AIR ON CARBONACEOUS ADSORBENTS: INVESTIGATION OF REACTIVE ADSORPTION MECHANISM
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Air pollution related to the release of industrial toxic gases, represents one of the main concerns of our modern world owing to its detrimental effect on the environment. To tackle this growing issue, efficient ways to reduce/control the release of pollutants are required. Adsorption of gases on porous materials appears as a potential solution. However, the physisorption of small molecules of gases such as ammonia is limited at ambient conditions. For their removal, adsorbents providing strong adsorption forces must be used/developed. In this study, new carbon-based materials are prepared and tested for ammonia adsorption at ambient conditions. Characterization of the adsorbents' texture and surface chemistry is performed before and after exposure to ammonia to identify the features responsible for high adsorption capacity and for controlling the mechanisms of retention. The characterization techniques include: nitrogen adsorption, thermal analysis, potentiometric titration, FT-IR spectroscopy, X-ray diffraction, Energy Dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy and Electron Microscopy. The results obtained indicate that ammonia removal is governed by the adsorbent's surface chemistry. On the contrary, porosity (and thus physisorption) plays a secondary role in this process, unless strong dispersive forces are provided by the adsorbent. The surface chemistry features responsible for the enhanced ammonia adsorption include the presence of oxygen- (carboxyl, hydroxyl, epoxy) and sulfur- (sulfonic) containing groups. Metallic species improve the breakthrough capacity as well as they lead to the formation of Lewis acid-base interactions, hydrogen-bonding or complexation. In addition to the latter three mechanisms, ammonia is retained on the adsorbent surface via Brønsted acid-base interactions or via specific reactions with the adsorbent's functionalities leading to the incorporation of ammonia into the adsorbent's matrix. Another mechanism involves dissolution of ammonia in water when moisture is present in the system. Even though this process increases the breakthrough capacity of a material, it provides rather weak retention forces since ammonia dissolved in water is easily desorbed from the adsorbent's surface.
PEPTIDE NANOTUBES AND THE EXPERIMENTAL DESIGN INTEGRATING NANOPARTICLES FOR USE IN NANOELECTRONICS
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Scientists have just begun to explore the world of nanotechnology, as instruments become more sophisticated areas previously unable to be seen or probed can now be studied. Peptide nanotubes are often used in experiments since they are extremely versatile. They are nontoxic, self-assembled, they have available functional groups in order to bind to other compounds and the tubule structure allows for the exclusivity of inside or outside binding. The ability of the peptide tubes to bind to other compounds permits biomineralization and additionally creates an atmosphere of selective binding to desired locations. The importance in using peptide nanotubes for study becomes the ability to rely on consistency of the shape and size. Ph factors can regulate whether a tubule or sheet is formed in solution, while controlling the diameter has been achieved through the use of various membranes, such as polycarbonate and alumina oxide. One of the main goals in nanotechnology is the ability to create functional machines of decreased size, improved storage capacity and faster cooler electrical components, therefore, making peptide nanotubes with electrical properties is of extreme interest. This dissertation takes a look at the properties of peptides coated with FePt and Pt.