Alumni Dissertations and Theses

 
 

Alumni Dissertations and Theses

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  • Strategies Towards Modular Syntheses of Fluorocarbons

    Author:
    Rakesh Kumar
    Year of Dissertation:
    2012
    Program:
    Chemistry
    Advisor:
    Rakesh Kumar
    Abstract:

    Synthesis of TMS-protected fluoropropargyl benzothiazolyl sulfone, a bifunctional fluoro-Julia-Kocienski reagent, was achieved by metalation-electrophilic fluorination of benzothiazolyl propargyl sulfone. Reactions of the fluoro-Julia-Kocienski reagent with carbonyl compounds produced fluoroenynes in high yields and with high E-selectivity. Olefinations proceeded with LHMDS, or the milder base, DBU. A one-pot deprotection-copper-catalyzed azide alkyne cycloaddition (CuAAC) to the alkyne moiety in the Julia-Kocienski reagent provided a new class of triazole-derived fluorinated and unfluorinated Julia-Kocienski reagents. Competitive experiments showed higher reactivity of the fluorinated reagent in the CuAAC than the protio analog. Computational analysis of electron densities in fluoro and protio propargyl sulfones showed that fluorine lowers electron density at the terminal alkynyl carbon, which can contribute to its higher reactivity. These triazole-derived "second generation" Julia-Kocienski reagents reacted smoothly with aldehydes and ketones, and olefinations could be tuned towards E- or Z-stereoselectivity by change in reaction conditions. The CuAAC-Julia olefination sequence was also used for the synthesis of triazole-derived analogs of biologically relevant combretastatin A-4. Biological testing of these compounds against HeLa cancer cell lines showed that two analogs displayed modest activity. Putative fjord region dihydrodiol and diol epoxide metabolites of 5-fluorobenzo[c]phenanthrene (5-FBcPh), arising by the oxidation of the angular ring remote to the fluorinated ring, were synthesized. A key step in the chemistry was fluoro-Julia-Kocienski olefination, followed by photocyclization. Deoxyadenosine adducts of the (+)-series 2 diol epoxide of 5-FBcPh were synthesized. Trans opening of this epoxide by azide, followed by reduction, furnished (+)-aminotriol. SNAr reaction of the aminotriol with silyl protected 6-fluoro-9-(2'-deoxy-β-D-ribofuranosyl)purine gave two diastereomeric deoxyadenosine adducts. Unequivocal stereochemical assignment to the individual adduct diastereomers came via conversion of the racemic trans dihydrodiol to the bis(-)-menthoxy acetate ester, and chromatographic separation of the diastereomers. Resolved enantiomers were converted to bis-p-(N,N)-dimethylaminobenzoates of a trans tetrahydrodiol. Absolute configuration was determined by CD spectroscopy. R,R-dihydrodiol enantiomer was converted to the R,S,S,R diol epoxide of 5-FBcPh, which was used for the synthesis of a single diastereomer of the 2'-deoxyadenosine adduct, whose CD spectrum and optical rotation were recorded. This allowed configurational assignment to the adenosine adducts, obtained from the racemic diol epoxides.

  • Synthesis of Analogs of Sphingophospholipids, Glycolipids, and Plasmalogen

    Author:
    Ravi Lankalapalli
    Year of Dissertation:
    2009
    Program:
    Chemistry
    Advisor:
    Robert Bittman
    Abstract:

    This dissertation presents the asymmetric syntheses of naturally occurring sphingoid bases and novel sphingolipid analogs, including (a) an unnatural sphingomyelin with a Δ4-cis double bond in the long-chain base (cis-SM), (b) L-threo-β-glucosyl and galactosyl-ceramides, (c) a photoactivatable analog of β-galactosyl sphingosine (psychosine), and (d) caged sphingosine 1-phosphate and ceramide 1-phosphate analogs. Also included in this dissertation is a novel synthesis of an unnatural analog of the glycerophospholipid plasmalogen with a trans-O-vinyl ether linkage at the sn-1 position of the glycerol backbone.

  • SYNTHESIS AND STRUCTURAL MODIFICATION OF THE MDMA ANTAGONIST NANTENINE: A NATURALLY OCCURRING APORPHINE ALKALOID

    Author:
    Onica Le Gendre
    Year of Dissertation:
    2010
    Program:
    Chemistry
    Advisor:
    Wayne Harding
    Abstract:

    MDMA ("Ecstasy") is a synthetic phenethylamine stimulant which is known to affect the re-uptake of serotonin, dopamine and nor-epinephrine in the brain. Adverse effects of "Ecstasy" in humans include development of hyperthermia, hallucinations, organ failure and in extreme cases, death. There is evidence that the behavioral and physiological effects of MDMA are mediated by α1-adrenergic and 5-HT2A receptors. Nantenine is a naturally occurring aporphine alkaloid which has been shown to block and reverse behavioral and physiological effects of MDMA in mice via antagonism of the aforementioned receptors. However, the relative role of these receptors in mediating the MDMA antagonizing effects of nantenine in vivo is unknown. The goal of this project is to explore different methods of synthesizing nantenine and nantenine derivatives. These compounds were subjected to in vitro testing for antagonistic activity at α1-adrenergic and 5-HT2A receptors and their ability to block/reverse MDMA-induced effects in mice through in vivo drug discrimination assays. This work provided insight into the relative role of these receptors in mediating the antagonistic activity of nantenine. Moreover, the results may provide the foundation for the design and development of potent and selective MDMA antagonists in the future. Here we present our synthetic studies as well as the results of biological evaluations of nantenine and analogues.

  • PHARMACOLOGICAL STUDIES OF OCTANAL RECOGNITION BY MAMMALIAN ODORANT RECEPTORS

    Author:
    Yadi Li
    Year of Dissertation:
    2013
    Program:
    Chemistry
    Advisor:
    Kevin Ryan
    Abstract:

    The sense of smell is initiated when small molecule odorants bind and activate specific subsets of olfactory receptors (ORs) expressed by olfactory sensory neurons (OSNs). The mammalian nose is able to distinguish thousands of chemical structures through these receptors. The molecular recognition strategies that ORs use to bind and distinguish among different odorants are poorly understood. Here we use drug design techniques to probe olfactory molecular recognition using a model odorant-receptor pair in vivo. Specifically, octanal analogs were designed and synthesized to probe the steric and electronic requirements of octanal recognition by the aldehyde-specific rat OR-I7 in OSNs. The testing of conformationally restricted octanal analogs (Chapter 1) indicates that OR-I7 distinguishes among aliphatic aldehydes according to their length and carbon chain conformation. A gauche conformation between C4 and C5 is proposed to be necessary to fill a small hydrophobic binding pocket 7 to 8 Å from the receptor-bound aldehyde with octanal's hydrophobic tail. In addition, small cycloalkyl groups at the tail enhance activation potency, leading to one analog that is more potent than octanal. Several pairs of stereoisomers and analogs derived from cyclohexylacetaldehyde (Chapter 2) were also designed and synthesized to study the active conformation of octanal at C4-C5 and C6-C7 positions. To study the possibility that OR-I7 and other aldehyde-specific olfactory receptors recognize, not the aldehyde, but its gem-diol hydrate, difluorooctanal, dimethyloctanal, octanol and octanal and were screened against more than 1,000 OSNs in vivo. 87 octanal-responsive OSNs were found. The response profiles of these cells support the hypothesis that for some ORs aldehydes function, by analogy to prodrugs, as pro-odorants, or "prodorants." The volatility of the aldehyde allows delivery to nasal mucous, where the aldehyde form is in equilibrium with the gem-diol, a form that has much richer H-bonding capacity. Through these studies, some molecular recognition details of octanal by ORs were obtained, which could contribute to the understanding of general odorant-receptor recognition strategy.

  • Synthetic Studies of Bioactive Nature Products: Azaspiracid-1 and Angelmicins

    Author:
    Jialiang Li
    Year of Dissertation:
    2013
    Program:
    Chemistry
    Advisor:
    David Mootoo
    Abstract:

    The trioxadispiroketal residue in the marine biotoxin azaspiracid-1, which exists in a configuration capable of a double anomeric effect, is believed to be the thermodynamically most stable bis-acetal diastereomer. In order to get insight into how structural factors affect this equilibrium, a simplified ABC trioxadispiroketal analog of azaspiracid-1 was synthesized and subjected to equilbration and computational studies. These results suggest that while a double anomeric effect may play a major role in the stability of the trioxadispiroketal configuration in the more complex natural product, the substituion pattern of the C ring is also a contributing factor. Angelmicins B (hibarimicin B) was first isolated from Microbispora rosea by Uehara and co-workers in 1993. It is a potent v-Src protein tyrosine kinase (PTK) inhibitor (IC50=23 μM), and also shows growth inhibiting and differentiation inducing activity on human myeloid leukemia (HL-60) cell lines (IC50=57 nM). The work reported in this part of the thesis presents a divergent synthetic strategy for the angelimicin family of anthraquinoid natural products, involving conversion of a central highly oxygenated decalin intermediate to the AB and A'B' subunits. The strategy centers on an intramolecular Diels-Alder (IMDA) reaction on a triene to provide the complex highly oxygenated decalin, which is elaborated to tricyclic AB and bicyclic A'B' subunits. The differentiating tact in the two syntheses is control of the Suárez radical fragmentation of lactol precursors by modulation of the structural rigidity of the substrate. A more flexible lactol gave the AB tricyclic framework, whereas a more rigid substrate led to the A'B' bicyclic precursor, presumably through divergent pathways from the radical produced in the initial fragmentation step. Given the symmetry with respect to the biaryl bond of HMP-Y1 (hibarimicin-mutant product Y1, a biosynthesis precursor of angelmicin B), a bi-directional synthesis is attempted. The bi-directional donors for Hauser annulation and Michael-Dieckmann condensation were synthesized from known 2,3,5-trimethoxytoluene in 27% and 42% yield, respectively. When they are applied to the annulation with cyclohex-2-enone, the Hauser annulation was unsuccessful while Michael-Dieckmann condensation gave 40% yield. However, the subsequent required aromatization of Michael-Dieckmann condensation product was unsuccessful.

  • Atomic and Molecular Low-n Rydberg States in Supercritical Fluids

    Author:
    Luxi Li
    Year of Dissertation:
    2009
    Program:
    Chemistry
    Advisor:
    Cherice Evans
    Abstract:

    The structure of low-n Rydberg states doped into supercritical fluids represents an important probe to investigate solvation effects, especially near the solvent (or perturber) critical point. We have investigated the solvation of excited atomic and molecular dopants in various perturbing fluids (both atomic and molecular). This systematic study was performed from low perturber number densities to the density of the triple point liquid, at both non-critical temperatures and on an isotherm near the critical isotherm. Dopant low-n Rydberg states were investigated using vacuum ultraviolet photoabsorption spectroscopy. The absorption spectra of these states were then simulated using a semi-classical statistical line shape function. With accurate line shape simulations, the perturber induced energy shift of the primary transition was obtained using a standard moment analysis. The moment analysis indicated that the dopant low-n Rydberg state energy blue shifts as a function of perturber number density without a significant temperature effect (except near the critical isotherm). A significant critical point effect was observed in all dopant/pertuber systems investigated here. This critical point effect is caused by a large increase in the dopant/perturber radial distribution function near the critical temperature of the perturber. Since the first perturber solvent shell shields the cationic core, the binding energy of the optical electron decreases. This acts to increase the dopant low-n Rydberg state excitation energy. However, the overall blue shift and critical point effect varies from atomic to molecular perturber systems due to the structure of the perturber. These differences are also discussed in more detail in this work.

  • A theoretical study of ionic liquids using analytical theory and molecular dynamics simulation

    Author:
    Hualin Li
    Year of Dissertation:
    2011
    Program:
    Chemistry
    Advisor:
    Mark Kobrak
    Abstract:

    In a series of theoretical analyses and simulation studies, we explore the relationship between ionic structure and liquid dynamics in room-temperature ionic liquids (ILs). As a framework, we define an ionic property we call the Charge Lever Moment (CLM) based on earlier theoretical work. We use the CLM to investigate ionic liquid dynamics and demonstrate a correlation between the CLM and IL viscosity. We extend this analysis using molecular dynamics simulation of a series of model molten salts with different intra-ionic charge distributions. These simulation clarify the relationship between charge distribution and ionic motion. We extend the analysis further with a thorough study using an instantaneous normal mode analysis in the model ILs, with the goal of investigating the roles of translational and rotational motion in IL dynamics.

  • Development of Mesoporous Silicas, Responsive Polymer Microgels, and Related Nanocomposites

    Author:
    Yingyu Li
    Year of Dissertation:
    2014
    Program:
    Chemistry
    Advisor:
    Michal Kruk
    Abstract:

    This dissertation covers research on polymer-templated nanoporous materials and functional soft materials, and it consists of four major parts. The first part is on introduction. The next part (Chapters 2-3) describes the research work on the synthesis of silicas with spherical mesopores. Chapter 2 is focused on the synthesis of large-pore FDU-12 silicas at room temperature by using surfactants with large hydrophilic blocks and relatively small hydrophobic blocks (such as Pluronic F108 (EO132PO50EO132)) as the template. Chapter 3 discusses an interesting mesopore structure, which is the hollow silica nanosphere (HSN). The single-micelle-templating strategy provides a general approach for the synthesis of HSNs at room temperature, and the judicious choice of the framework precursor and synthesis conditions allows for the synthesis of HSNs with pore void diameter tunable from ~ 10 nm to ~ 44 nm. In addition, the one-pot room-temperature synthetic approach can be employed to the construction of hybrid organic/inorganic hollow spheres. The third part involved the preparation of glucose-responsive polymer microgels (Chapter 4-6). In Chapter 4 and 5, two kinds of dye-composited microgel sensors have been developed, and they exhibited good stability, high selectivity, and good reproducibility for detection of glucose. In Chapter 6, a glucose responsive core-shell structured microgel was designed and developed for insulin release at proper physiologically needed glucose levels. The last part of this dissertation (Chapter 7, 8) was about the synthesis of inorganic particle/polymer hybrid materials. In Chapter 7, the stimuli-responsive polymer brushes were successfully grafted from the surface of hollow silica nanospheres via surface-initiated atom transfer radical polymerization with activators regenerated by electron transfer (SI-ARGET ATRP), and the polymer loading was well controlled. Besides, the core-shell-structured nanocomposites were successfully fabricated in Chapter 8. Magnetite nanoparticles were adopted as the core, and the multifunctional polymer layer was coated on their surface. They demonstrated significant adsorption capacity towards cobalt ions, and suitability for magnetic separation, making it an excellent absorbent for waste water treatment.

  • A theoretical study of ionic liquids using analytical theory and molecular dynamics simulation

    Author:
    Hualin Li
    Year of Dissertation:
    2011
    Program:
    Chemistry
    Advisor:
    Mark Kobrak
    Abstract:

    In a series of theoretical analyses and simulation studies, we explore the relationship between ionic structure and liquid dynamics in room-temperature ionic liquids (ILs). As a framework, we define an ionic property we call the Charge Lever Moment (CLM) based on earlier theoretical work. We use the CLM to investigate ionic liquid dynamics and demonstrate a correlation between the CLM and IL viscosity. We extend this analysis using molecular dynamics simulation of a series of model molten salts with different intra-ionic charge distributions. These simulation clarify the relationship between charge distribution and ionic motion. We extend the analysis further with a thorough study using an instantaneous normal mode analysis in the model ILs, with the goal of investigating the roles of translational and rotational motion in IL dynamics.

  • Two Types of Protein Salt Bridges Studied by Quantum Calculation

    Author:
    Sing Liao
    Year of Dissertation:
    2009
    Program:
    Chemistry
    Advisor:
    Michael Green
    Abstract:

    Abstract Two types of protein salt bridges in an aqueous environment, the arginine-acid salt bridge and the lysine-acid salt bridge, are studied here. The former is modeled by propionic acid and ethylguanidine, the latter by propionic acid and propyl amine. Both have been investigated by quantum calculations for the purpose of obtaining improved salt bridge potentials in an aqueous environment with constraints on the distances between the two functional groups, which are defined as the bridge lengths in this report, designed for applications to molecular dynamics simulations of ion channels. For the arginine-acid salt bridge, we perform optimization calculations on 13 molecular clusters corresponding to the salt bridge with 0 to 12 water molecules. For the lysine-acid salt bridge, we perform optimization calculations on 2 molecular clusters for the salt bridge with 0 or 1 water molecule. To each of the model systems, after obtaining its optimized geometry, we slowly vary the bridge lengths and bridge angles in three dimensions, and subsequently we perform COSMO, frequency and NBO calculations on the contracted and expanded model systems. COSMO calculations give the dielectric constant dependence, and the frequency provides the thermodynamic properties of the system while the NBO provides the electronic distributions and bonding information. We found: (1) there is a fill-in mechanism for water molecules to enter into the salt bridge systems; such a fill-in order may have periodicity in energy, as a function of number of water molecules. (2) we show that the salt bridge systems have both hydrophilic and hydrophobic properties; (3) we look into the proton ionization process from several new aspects in terms of comparison between potentials in two different salt bridge systems and the rates of Wiberg bond order change; (4) we have an in-depth look at effects that can cause large variations to system potentials, and we take note of effects that resulted from environments of limited amounts of local waters and that may have been missed by classical treatments; (5) we look into a new aspect in the applications of Wiberg bond order that are closely associated with the electron density in predicting the formation and disruption of bonding in the systems; (6) in regard to applications to simulations of ion channels, we discuss a possible method to formulate system potentials in specific environments.