Mukund Sibi - Thesis Committee

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Synthesis of Precursors to Non-isocyanate Polyurethanes
(North Dakota State University, 2018) Wei, Manqing
Biobased diamines are excellent precursors for the synthesis of non-isocyanate polyurethanes (NIPUs). We have prepared several biobased diamines using three different reactions for their synthesis. In the first method, we have carried out chain elongation of cellulose-derived 2,5-diformylfuran by the Henry reaction followed by reduction of the nitroalkene. Yields of the key step: Hantzsch Ester reduction, were 70-80%. Method two involves the Friedel-Crafts alkylation of furfurylamine with different ketones under acidic conditions. Yields of large-scale alkylation reaction were 60-77%. In method three, we combined the Henry reaction and Friedel-Crafts alkylation techniques to access diamines from hemicellulose-derived furfural. These diamines can be reacted with carbonates to access hydroxyalkylcarbamates in good yields, around 80%. We have also developed a novel method for accessing biscarbamates directly from dialdehydes in good yields, 70-94%. The hydroxyalkylcarbamates and biscarbamates are valuable precursors to obtain polyurethanes via the phosgene-free route.
Achiral Templates in Asymmetric Catalysis: Applications in Construction of All Carbon Quaternary Centers
(North Dakota State University, 2018) Subramanian, Hariharaputhiran
Conjugated olefins are readily available and inexpensive starting materials and their functionalization offers a rapid access to many important building blocks for organic synthesis. The functionalization of these olefins by asymmetric catalytic methods for the formation of C-C and C-X bonds is an active area of research. Major advances in this field are not only triggered by the development of new catalysts but also by engineering of new acceptor olefins. In our lab we have successfully developed acceptor olefins appended to alkoxyimidazoles as a novel template. Using these templated acceptors, we demonstrated methodologies to construct all carbon-quaternary centers, one of the demanding tasks in synthetic methodology development. We have also made significant efforts towards understanding the solution structures of the intermediates involved in the catalytic asymmetric reactions developed in our lab. In chapter 1, the importance of templated acceptors in the field of chemical synthesis with special emphasis on acylimidazoles is reviewed. The versatility of the N-alkylimidazole templates is showcased by their utility in several organic transformations. In chapter 2, modes of activation of acceptor olefins by catalysts, need for templated acceptors and challenges associated with designing an asymmetric catalytic process is described. Our approach in designing novel acceptors based on imidazoles is also described. In chapter 3 the synthetic utility of these novel N-alkoxyimidazole based acceptors is shown by enantioselective construction all carbon quaternary centers by Lewis-acid catalysis. We also compare the effectiveness of other templates such as oxazolidinone and N-methylimidazoles in the Lewis-acidic catalyzed Friedel-Crafts alkylation reaction. The effect of various parameters such as Lewis acid, chiral ligands, temperature, additives and solvents on the conjugate addition of Friedel-Crafts nucleophiles are presented in this chapter. In chapter 4, our research efforts toward understanding solution structures of intermediates involved in catalytic asymmetric reactions are presented. A combination of Diffusion Ordered Spectroscopy (DOSY), heteronuclear NMR spectroscopy, mass spectrometry and X-ray crystallography has been used to study the solution structure of intermediates involved in asymmetric catalytic reactions. In chapter 5, a future outlook on templated chemistry developed in our laboratory is presented. Some preliminary results pertinent to future projects are presented.
Exploitation of Biomass for Applications in Sustainable Materials Science
(North Dakota State University, 2019) Serum, Eric Michael
Biorefinery may be defined as the process of accessing chemical commodities from living systems; consequently, biomass becomes the antecedent for renewable resources through biorefinery. Advantages to this process over petroleum refinery include: (1) increased potential for sustainable products, (2) increased diversity in chemical structure including heterocycles, and (3) potential for regional resource independence. Despite these clear advantages, adoption of biorefined commodities can be limited by the risk associated with small initial application portfolios and concomitant uncertainties. The strategies adopted by our dynamic and collaborative research team entail continuous engagement of those issues by: (1) preparing renewable polymers, (2) chemical diversification of biomass-derived platform chemicals, (3) direct modification of biopolymers, and (4) development of petroleum replacements. Battling the inveterate proclivity towards portents of gloom need not solely justify investigations into biorenewable feedstock chemicals; the ramifications of bioinspired molecular inquiry create opportunities to go beyond mere sustainability through innovation. This dissertation includes specific examples which illustrate utilization of three types of biomass: (1) oil seeds, (2) lignin, and (3) carbohydrates. Each class of biomass-derived materials offered unique advantages as well as challenges associated with their varied structures. The presentation has been divided into five sections: (1) biomass, sustainable chemistry and design thinking; (2) styrene replacements and their application in renewable vinyl ester thermosets; (3) catalyst-free lignin valorization by acetoacetylation; (4) chemical diversification of 5-(hydroxymethyl)furfural; (5) valorization of cellulose-derivable platform chemicals by cycloaddition with a potentially bioderivable reactive intermediate: benzyne.
Novel Synthetic Routes to Complex Amines: the Catalytic Hydroamination of Alkynes and Hydroimination of Allenes
(North Dakota State University, 2016) Moran, Erik John
Amines are valuable targets for synthesis in contexts of both research and industrial applications. This work proposes two atom-economical methods—hydroamination (HAM) and hydroimination (HIM)—as C-N bond formation strategies. A nickel-(N-heterocyclic carbene) catalyst system was developed to carry out HAM of internal, unactivated alkynes with aryl amines and cyclic secondary amines. It was demonstrated that the Ni-NHC catalyst was capable of promoting both HAM at room temperature and transfer hydrogenation to produce α-branched aryl amines. These two procedures were performed by the same catalyst to demonstrate an elegant 1-pot, multi-transformation protocol. Separately, optimization of a Rh-HIM catalyst system for the combination of monosubstituted allenes and aromatic N-H-ketimine was carried out to favor high conversion of substrates to the linear HIM product rather than [3+2] annulation. Both HAM and HIM C-N bond formation methods were found to be successful and capable of good conversion and selectivity for their respective products.
Late Transition Metal-Catalyst Development for Alkyne Coupling Reactions
(North Dakota State University, 2016) Manan, Rajith Singh
Alkynes are versatile and valuable synthetic precursors in a variety of organic transformations and have found tremendous applications in materials science and pharmaceutical chemistry. In recent years, there has been a tremendous growth in the development of transitionmetal catalyzed organic transformations by alkynes coupling reactions such as ring constructions (carbocycles and heterocycles), hydroarylation and hydroamination. This thesis describes the development of new transition metal catalyst for alkyne coupling reactions. The results are highlighted by chemoselective coupling between internal alkynes and N-H aromatic ketimines to synthesize indenamine, dihydroisoquinoline, and 2-aza-1,3-butadiene derivatives. Chapter 1 introduces background for alkyne coupling reactions towards hydrometalation, hydroarylation and hydroamination. Also this chapter provides new strategies developed towards C-H activation and hydroamination by using late transition metal catalysts. Chapter 2 describes catalytic development of rhodium catalyzed redox-neutral [4+2] annulation of N-H aromatic ketimines and alkynes to synthesize multi-substituted 3,4- dihydroisoquinolines (DHIQs) in high chemo-selectivity over competing annulation processes, exclusive cis-diastereoselectivity, and distinct regioselectivity for alkyne addition. Chapter 3 describes development of earth abundant metal nickel as the catalyst for the Nickel (0)/NHC-based catalyst system for alkyne hydroimination with aromatic N−H ketimines as N-nucleophiles. To demonstrate the potential of current method for practical synthesis, we also carried out a gram-scale alkyne hydroimination with benzophenone imine. Chapter 4 describes catalyst development for oxidative [4+2] imine/alkyne annulation with unconventional regioselectivity. Even though there are numerous methods towards the synthesis of isoquinoline derivative here in this chapter we proposed a different pathway for C-N bond formation compared to other reported methods. In spite of moderate yields for the unsymmetrical alkynes the regioselectivity is different from other reported isoquinoline products by oxidative [4+2] annulations. Chapter 5 describes about Ni/NHC catalyst development towards stereoselective semihydrogenation of alkynes by usig simple alcohol, isopropanol as the hydrogen source. Here we report new Ni-NHC complexes derived from Ni(0)-mediated facile C−H activation at the methyl position of IPr, one of the most commonly used NHC ligands in nickel catalysis. Results from stoichiometric transformations suggest that such cyclometalation provides a low-energy access to NHC-ligated Ni(II) hydride species that are envisioned as key reactive intermediates in many catalytic processes.
Photons in Action: Asymmetric Synthesis and Polymer Degradation
(North Dakota State University, 2016) Raghunathan, Ramya
Light is an environmentally benign and renewable source of energy that finds wide application in the field of science. This dissertation explores two areas of chemistry that utilizes light extensively viz., asymmetric phototransformations and photodegradation of polymers. Phototransformation is an elegant method to construct structurally complex and diverse organic scaffolds. However, controlling the excited state in phototransformation to manipulate its stereochemical outcome is a challenge. This dissertation discloses a unique method employing atropisomeric chromophore to tackle asymmetric induction from the excited state. Photodegradation is a safe method to breakdown polymers that pose huge environmental and ecological concerns. Apart from designing polymers with a phototrigger that initiates the breakdown in a programmed fashion, this thesis also demonstrates recovery and reuse of monomers making the strategy sustainable. Chapter 1 describes the importance of light and basic principles involved in organic phototransformations. In this section, principle differences between asymmetric thermal and photochemical transformations are introduced, methodologies developed in asymmetric phototransformations and the role of light in medicinal/biological system and material science is presented. Chapter 2 evaluates metal free, thiourea/urea organocatalyst in enantioselective 6π- photocyclization of acrylanilides. Preliminary investigations revealed that the asymmetric induction imparted by thiourea was low. Detailed photophysical analysis provided valuable information on the excited state interaction of the substrate with the catalyst, opening avenues for future development of this strategy. Chapter 3 demonstrates “axial-point chiral” strategy towards atropselective Paternò-Büchi reactions of oxoamides and chain length dependent [2+2] vs. [5+2]-photocycloaddition of atropisomeric maleimides. Axial chirality dictated high enantioselectivity (>97 %) in the photoproduct, while the solvent and substitution in the reactant controlled the diastereomeric ratio in photoproducts respectively. Chapters 4-5 report the photodegradation of bio-derived polymers using phototriggers. This method not only enabled us to deconstruct the polymers to its functional monomer(s) but also enabled a pathway to recover and recycle the monomer highlighting the sustainability of the strategy. In summary this thesis details the role of light in asymmetric phototransformations using organocatalyst and atropisomeric chromophores leading to chiral photoproducts. Further, it describes the photodegradation of biomass-derived polymers and its recoverability and reusability of the monomer as a sustainable approach.
Structural Studies of the Mechanism by Which BCL-2 and Beclin Proteins Regulate Autophagy and Apoptosis
(North Dakota State University, 2016) Su, Minfei
Autophagy and apoptosis are catabolic pathways essential for homeostasis in all eukaryotes. While autophagy usually promotes cell-survival by enabling degradation and recycling of damaged macromolecules, apoptosis is the canonical programmed cell death pathway. Dysfunction of autophagy and apoptosis is implicated in diseases like cancers, cardiac disease, and infectious disease. Beclin homologs are key for autophagy as they are core components of class III phosphatidylinositol 3-kinase autophagosome nucleation and maturation complexes. Anti-apoptotic Bcl-2s inhibit apoptosis through binding and antagonizing pro-apoptotic Bcl-2s. Anti-apoptotic Bcl-2s also down-regulate autophagy by binding to the Bcl-2 homology domain 3 (BH3D) of Beclin homologs, thereby enabling crosstalk between apoptosis and autophagy. The central goal of my doctoral research is to understand the structure-based mechanism of selected Bcl-2s and Beclin homologs in the regulation of autophagy and apoptosis. -Herpesviruses are common human pathogens that encode viral Bcl-2s to facilitate viral reactivation and oncogenic transformation. M11, a viral Bcl-2, and Bcl-XL, a cellular Bcl-2, bind with comparable affinities to the Beclin 1 BH3D. By assessing the impact of different Beclin 1 BH3D mutations on binding to M11 and Bcl-XL, we developed a cell-permeable inhibitory peptide that targets M11, but not Bcl-XL. The mechanism by which this peptide specifically binds to M11 was elucidated by determining the X-ray crystal structure of the peptide:M11 complex. Our attempts to investigate the role of other Bcl-2s in these pathways were unsuccessful. In one project, we were unable to express and purify BALF1, another viral Bcl-2. In another, no interaction was detected between purified samples of the anti-apoptotic Bcl-2 homolog Mcl-1, and the autophagy protein Atg12, that had previously been shown to bind. We also delineated the domain architecture of Beclin 2, a novel Beclin homolog and attempted to express and purify different Beclin 2 constructs for structural studies. We successfully purified and solved the X-ray crystal structure of the Beclin 2 coiled-coil domain (CCD), showing it is a curved, anti-parallel, meta-stable coiled-coil homodimer with seven pairs of non-ideal packing residues. In general, mutating the non-ideal packing residues to leucines enhanced Beclin 2 CCD homodimerization, but also weakened its binding to Atg14 CCD.
Polymers and Coatings Derived From Novel Bio-Based Vinyl Ether Monomers
(North Dakota State University, 2018) Kalita, Deep Jyoti
To fulfill the demand for household, industrial, light weight transportation, health, and cosmetic products etc., production of polymeric materials has been increasing every year. However, limited resource of fossil fuel is threatening the sustainability of the raw materials used to produce these products. These products have very low to no biodegradability, thereby staying in the ecosystem for long time causing serious threats. Increasing environmental concerns and strict regulations has made renewable based materials suitable for the development of environmental friendly polymers with sustainability. Novel plant oil based vinyl ether (POVE) monomers were derived from plant oil such as soybean, linseed and camelina oil. Polymers varying in molecular weight (MW) were derived from these monomers and studied for air-drying coatings. Study of the coating and free film properties showed that at a given MW, Tensile (Young’s modulus, and tensile strength), viscoelastic (Tg, XLD), physical (hardness, solvent resistance, and impact resistance) properties increased with increasing unsaturation in the parent PO. Polymers derived from distilled POVE monomers resulted essentially colorless poly(POVEs) which were evaluated as a binder for artist paint in comparison to linseed oil. Colorless poly(POVE)s showed significantly faster dry/cure along with dramatically lower yellowness than linseed oil. Novel, vinyl ether monomers, were also synthesized from cardanol (CEVE) and eugenol (EEVE) and coatings produced from their homopolymers and copolymers with cyclohexyl vinyl ether were studied in comparison to commercial alkyds. Glass transition temperatures of these homopolymers were increased with CHVE incorporation. However, incorporation of 25% CHVE resulted in cured coatings and free films with better mechanical, viscoelastic and physical properties than commercial alkyds. Incorporation of CHVE > 50wt.% in the copolymer resulted in low crosslinked networks with reduced properties such as percent elongation, chemical resistance and impact resistance. Epoxidized poly(EEVE) resins varying in percent epoxide (30%, 50% and 70%) were synthesized and studied for two component amine cured coatings in comparison to BPA based epoxy resin. Results obtained from high throughput experimentation showed the ability of Epoly(EEVE) resins with 50% or higher epoxide to form harder, higher crosslinked coatings with tunability based on type of curative than BPA based resin.
Stereospecific Phototransformations of Atropisomeric Chromophores
(North Dakota State University, 2014) Kumarasamy, Elango
Photochemical transformations are unique strategy in synthesis that enables us to access complex and structurally diverse organic scaffolds. However, the challenges in controlling the excited-state to perform stereoselective reactions left this method under-utilized. This dissertation describes a novel strategy that employs atropisomeric chromophores to perform stereospecific phototransformations. The success of this strategy is well established in thermal chemistry but not comprehensively investigated in photochemical transformations. This research largely relies on rotamer control in the ground state (NEER principle) wherein the axial chirality in the starting material was transferred to point chirality in the products upon excitation. The chapter 1 describes the principle differences between the asymmetric thermal and asymmetric photochemical reactions. Further, a survey of methodologies developed towards asymmetric phototransformations and their outcomes are described. A brief introduction about the atropisomeric systems in thermal chemistry and the preliminary investigations in phototransformations are also provided. In chapter 2, enantiospecific disrotatory 4π-ring closure of atropisomeric 2-pyridones were investigated. The differential axial chirality designed (sterics and H-bonding units) displayed distinct temperature and solvent dependency on the enantiospecificity of the reaction. Eyring plot was computed to calculate the differential activation enthalpy and entropy for the reaction. Also, the course of phototransformation was followed through single-crystal XRD to decipher the preferred mode of cyclization for a given isomer of 2-pyridones. The high-pressure racemization and photoreaction study revealed that pressure provided stable chiral axis even at elevated temperature resulting in higher enantiomeric excess (ee) in the photoproduct. The chapters 3-5 describe the [2+2]-photocycloaddition of atropisomeric enamide, maleimide and imine derivatives. The design features on these molecules allowed us to perform complementary reactions that are not observed in the literature. These modifications were significant improvement to “axial to point chiral” strategy that improves the versatility of the photoreactions. For example switching of the excited state in enamides, continuous flow visibleiv light photocatalysis of maleimides and unusual photocycloaddition of stabilized imines are notable features. This dissertation encompasses detailed studies on the mechanism, scope and photophysical studies on new atropisomeric chromophores such as 2-pyridones, enamides, maleimides and imine derivatives that provides excellent avenue to access chirally enriched building blocks.
Interactions of Light with Organic Chromophores: A Photochemical and Photophysical Investigation
(North Dakota State University, 2018) Clay, Anthony Marcel
Over the past century, light has emerged as a useful tool finding utility in various fields such as device fabrication, the medical field, as well as utility as an energy source. Chemist have adopted this abundant energy source to do work in material applications and to mediate simple chemical transformations. In regards to the latter, light utilized as a traceless benign reagent for organic transformations has proven fruitful and therefore unequalled in its ability to afford structural complexity from simple starting material(s). Photon absorption of the correct energy elevates organic molecules to a high energy excited state of “short” finite lifetime. In order to afford photoproducts of high selectivity or merely dictate the outcome of a desired photoreaction, control must exist during this short-lived excited state. This dissertation describes a complementary approach to already established photochemical methodologies by which excited state control can be employed in efforts to afford photoproducts of enhanced selectivity. By employing the NEER principle (Non-Equilibrating Excited State Rotamers) and exploiting axial chiral substrates and thereby implementing rotamer control in the excited state, photoproducts of high chemoselectivity, diastereoselectivity and enantioselectivity can be accessed. Additionally, by judicious choice of chromophore control over the excited state process can be gained affording materials of desired physical properties. It was determined that altering the functionality of bio-based feedstocks afforded photoresponsive molecules with altered photoreactivity. Photoacids and photoinitiators were synthesized and their photophysical properties were investigated. Photoinitiators were evaluated for their efficacy towards photochemical polymerization. This dissertation details synthesis, characterization and photophysical investigations of various organic chromophores in efforts to provide mechanistic rationale regarding atropisomeric photoreactions and utility of biobased photoresponsive molecules.
New Strategies for Ruthenium Catalyzed C-C Bond Formation
(North Dakota State University, 2014) Zhang, Jing
Transition metal-catalyzed C-H bond activation allows direct functionalization of the ubiquitous C-H bonds in organic molecules to increase the molecular complexity. Since Murai's pioneering work in ruthenium catalyzed regioselective arene-alkene coupling reaction, a number of transition metal catalysts have been developed for C-C bond formation via C-H bond activation. However, metal-catalyzed C-H functionalization faces a number of long-standing challenges such as the control over regio- and stereoselectivity and harsh reaction conditions. Presented herein is our research on the development of ruthenium(II)-based catalysts for new and improved methods in C-C bond formations by formal activation of sp2 C-H bonds and subsequent coupling with alkyne substrates. Chapter 1 introduces the background of alkyne hydroarylation initiated by transition metal-catalyzed C-H bond activation and the significance to develop new strategies to overcome the limitations of current methods. In Chapter 2 and Chapter 3, ruthenium(II)-N-heterocyclic carbene (NHC) catalyst systems were developed for efficient [3+2] carbocyclization between N-H aromatic ketimines or aromatic ketones and internal alkynes under very mild conditions. This process incorporates the ortho-directing imine and ketone groups for C-H bond activation into the overall transformation in a tandem manner and enables efficient access to indenyl amines and alcohols in high yields. Chapter 4 describes the development of bis-cyclometalated ruthenium(II) complexes with readily available N-H aromatic ketimine and ketone ligands as a new class of catalyst precursors for C-C coupling reactions. The catalytic activity of the bis(imine) complex is evaluated in several catalytic coupling reactions of alkene and alkyne substrates. The coupling reactions are proposed to proceed by Ru(II)/Ru(IV) catalytic cycles involving C-C bond formation by oxidative cyclization. Chapter 5 details the development of a decarboxylative alkyne hydroarylation process to synthesize arylalkenes with controlled and versatile regiochemistry of aromatic substituents. Following a tandem sequence of C-H bond activation and alkyne coupling, the subsequent decarboxylation is facilitated by the newly installed ortho-alkenyl moiety and is compatible with various aromatic substituents at para-, meta- and ortho-positions. This new decarboxylation strategy eliminates the prerequisite of substrate activation by ortho-substitution and allows a broad scope of substituted benzoic acids to serve as aromatic building blocks for alkyne hydroarylation.
Stereospecific Photochemical Transformations Involving Axially Chiral Acrylanilides and a-Oxoamides
(North Dakota State University, 2013) Ayitou, Anoklase Jean-Luc
Asymmetric photochemical transformations have been under-explored due to the ineffectiveness of conventional methodologies/reagents/catalysts (point chiral auxiliaries and inductors) that were generally employed for thermal reactions. This limitation to use point chiral auxiliaries for asymmetric photochemistry is partly due to the asynchronous behavior of photo-excitation and chiral transfer/induction processes. This dissertation describes a complementary approach to conventional methodologies involving light induced chirality transfer from atropisomeric viz axially chiral molecular reactants (acrylanilides and α-oxoamides) to enantiopure product(s) with point chirality. The study has revealed the importance of rotamers control in the ground state and how it can impact the stereospecificity during light induced excited state reactions leading to enantiopure product(s). Con-rotatory 6π-photocyclization of axially chiral acrylanilides was explored under various reaction conditions. For example, α,β-unsaturated acrylanilides gave the expected 3,4-dihydroquinolin-2- one photoproduct(s) with enantiomeric excess (ee) values > 90% in both direct and triplet sensitized irradiations. On the other hand, the solution phase direct irradiations of α-substituted acrylanilides yielded racemic photoproduct(s) whereas the triplet sensitized reactions led to ee values > 90% in the expected photoproduct(s). By changing the reaction medium from isotropic media to solid state, α-substituted acrylanilides gave photoproducts with ee values as high as 70%. In addition to the effect of the reaction medium and the reactive spin state on the enantioselectivity, preliminary evaluation of the role of Lewis acid(s) and heavy cations (Na+, K+ and Cs+) were explored. The initial observations were quite promising with ee values up to 90% in the photoproducts upon direct irradiation in isotropic media. The photochemical γ-hydrogen abstraction reaction involving axially chiral α-oxoamides leading to β-Lactam photoproducts was investigated. The enantiomeric ratio (e.r.) > 90:10 in the expected β- Lactam photoproducts was found to be dependent on the temperature under which the irradiation was performed. Furthermore, elevated pressure was employed to counter the effect of elevated temperature and slow the rotation around N-C(aryl) chiral axis leading enantioenriched β-Lactam photoproducts. This dissertation details the overall mechanistic rationales and photophysical control studies during the photochemical transformations of atropisomeric acrylanilides and α-oxoamides leading to chirally enriched products.
Synthesis and Antioxidant, Anticancer, and Antimicrobial Activities of Palmityl Ester Derivative of Carnosic Acid
(North Dakota State University, 2013) Prasad, Asharani
Carnosic acid (CA) along with carnosol (CAR) is the strongest phenolic diterpene antioxidants (PDAs) present in rosemary plant. However, CA has low antioxidant activity in emulsion-type food system due to its polar nature. The identification and characterization of the anticancer and antimicrobial properties of natural products and their semisynthetic derivative such as that of CA and CAR have received significant interest over the years. The goals of this research were to synthesize lipophilic palmityl derivative (PE) of CA and study its antioxidant activity in bulk and emulsified corn oil. Anticancer properties against CCRF-CEM, K-562 and P388D1 leukemia cell lines and antimicrobial activity against Staphylococcus auerus (S. auerus), Bacillus cereus (B. cereus), Salmonella enterica, and Escherichia coli (E. coli) O157:H7 bacteria were also tested. A four steps synthetic route was designed. In the first step CAR was converted into a benzyloxy protected benzyl ester of CA (yield 78%). Reduction of the benzyl ester to a primary alcohol (yield 63%) followed by esterification with palmitoyl chloride gave the palmityl ester derivative (yield 97%). Finally, double bond reduction followed by deprotection of benzyloxy group gave PE (yield 99%). Overall yield for the route was 47%. The modification of CA affected functionality. PE had improved antioxidant activity in emulsified corn oil compared to bulk corn oil than the CA. However, CA was more effective in bulk oil. Compounds with hydroxyl groups were found to have cytotoxicity against three cell lines CCRF-CEM, P388D1 and K-562. Among compounds tested, CAR was found to be the most potent anticancer agent against all three cell lines. The study also indicated structure dependent activities for the compounds that had hydroxy group at the C-20 position. CA and CAR had antimicrobial activity against S. auerus, B. cereus, Salmonella, and E. coli O157:H7. S. auerus, B. cereus were more sensitive to CA and CAR than Salmonella, and E. coli O157:H7. Other compounds, without hydroxyl groups, did not have antimicrobial activity. Study also indicated that antimicrobial activity varied depending on functional group present at C-20 position. Compound PE did improve antioxidant activity in emulsion but did not improve antimicrobial activity.
Attempted Total Syntheses of a Novel Lycopodine-Class Alkaloid and (R)-Myricanol, Compounds for the Treatment of Alzheimer's Disease
(North Dakota State University, 2013) Ostlund, Anthony John
Alzheimer's Disease (AD) is a significant challenge to both the pharmaceutical world as well as the synthetic organic chemistry world. One of the most important problems in this field is the lack of a unified approach to the most biologically active class of natural products for the treatment of AD, the lycopodine alkaloids. Presented herein is an attempt at the total synthesis of a novel member of this family. The synthesis spans three complete generations of retrosynthesis and forward progress. In the ultimate effort, the carbon backbone of the entire lycopodine class was successfully synthesized using a 6 step process in 44% overall yield. Features of this synthesis are the formation of an intermediate aldehyde by tandem Horner-Wadsworth-Emmons olefination/Baylis-Hillman reaction, quantitative reduction resulting in a monoprotected diol, cationic Au(I) O-vinylation, and microwave assisted Claisen rearrangement. The final step towards the backbone was realized using a hydrozirconation/transmetalation sequence with addition to the aldehyde to make the penultimate allylic alcohol in 54% yield. Final studies on the elimation of the allylic alcohol to create the desired 1,3-diene functionality show limited access to this important precursor. Simultaneous model system studies have shown that an intramolecular, cationic Rh(I)-catalyzed ynamide Diels-Alder reaction is feasible to set the B and D rings of the final lycopodine core, although the reaction requires optimization. Model systems for the unique intramolecular allylation proposed in the retrosynthesis also show feasibility, however the intramolecular variant has not been fully explored. Additional studies towards the total synthesis (R)-myricanol are also presented as a continuance of efforts towards general approaches to AD combative compounds. Featured are straightforward methods to the two main segments of the natural product, including a three-step process to synthesize the southern half. Finally, a successful 2-step synthesis of (R)-convolutamydine E is used to showcase an In(0)-mediated allylation methodology.
Developing Platform Chemicals from Renewable Resources
(North Dakota State University, 2013) Wojciechowski, Kristin Lynn
The Department of Energy has listed 5-hydroxymethylfurfural (HMF) and 2,5-furandicarboxylic acid (FDCA) as two of the twelve building blocks derived from cellulosic biomass. HMF can serve as a renewable platform for the production of fuels and chemicals. Our research goal is to develop novel methods for the conversion of renewable resources to feedstock chemicals for polymer synthesis. The Diels-Alder reaction, the cycloaddition of alkenes and dienes, has become one of the most important synthetic methods used in organic chemistry. We were interested in carrying out Diels-Alder reactions with derivatives of HMF. Naphthalene analogs of terephthalic acid were synthesized by reacting HMF derivatives with benzyne which could lead to the formation of bio-based polyethylene terephthalate (PET) analogs.
Lung Mucosal Response to Repeated Inhalational Insults with Immunomodulatory Agents in a Murine Model of Fungal Asthma: Airway Epithelium Takes the Center Stage
(North Dakota State University, 2013) Pandey, Sumali
Asthma is a debilitating disease of the lungs affecting 235 million people worldwide. Fungus-associated asthma leads to a particularly severe type of disease, and exposure to environmental fungi and their products is unavoidable due to the ubiquitous nature of fungal species. Besides being allergenic, fungi are opportunistic pathogens, and anti-fungal and/or allergic pathways may be modified through repeated inhalation of immunomodulatory agents, affecting the outcome of fungus-induced asthma. Our aim in this project was to investigate the extent to which repeated inhalation of immunomodulatory agents influence the lung mucosal responses in a naïve murine host or in one that had been sensitized to fungal proteins (allergic). The immunomodulatory substances chosen hold relevance to human inhalational exposure, and included live or irradiation-killed Aspergillus fumigatus (a fungi) spores, deoxyxnivalenol (a mycotoxin), and fluticasone propionate (an inhalationally administered corticosteroid, commonly prescribed for allergic asthma). In a naïve host, inhalation of live A. fumigatus spores showed pathological features of fungal asthma. However, in an allergen-sensitized lung, both dead and live A. fumigatus spores established fungal airway disease, albeit to different extents. Next, we tested the effect of deoxynivalenol in an allergic host and found that its repeated inhalation did not affect pulmonary disease pathology, but did lead to a dose- and time- dependent increase in mucosal and systemic total IgA. Finally, we tested the effect of fluticasone propionate, and found that it did not influence the development of fungal airway disease, but did induce dynamic changes in lung physiology and antibody titers. Besides mimicking human inhalational exposures, inhalation ensures direct interaction of the inhaled substances with airway epithelium, which plays an important role in defense against inhaled substances and in asthma pathophysiology. By analyzing various mechanisms involved in murine lung-mucosal response to the inhaled substances, a critical involvement of airway epithelium as an orchestrator of immune responses is highlighted, and this would inform mechanism-based future studies. In conclusion, this project is likely to aid in establishing evidence based standards for fungus-related exposures and in making informed therapeutic decisions for fungus-associated diseases.
Highly Functionalized Thermosets from Renewables for Composites and Coatings Applications
(North Dakota State University, 2017) Yu, Arvin
Renewable sources have attracted attention due to their affordable cost and wide availability. Vegetable oils are renewable sources that have been extensively studied as potential replacement for petroleum derived chemicals. However, vegetable oils tend to produce soft materials with modest properties due to their chemical structure. Consequently, their modifications have been studied to develop high performance materials with improved properties. One of the modifications involves substituting the glycerol core with sucrose to increase the functionality per molecule. Another approach is converting the less reactive internal carbon-carbon double bonds with the more reactive epoxy groups, which permits access to a variety of crosslinking pathways. Epoxidized sucrose soyate (ESS) is a sucrose ester fatty acid (SEFA), which was epoxidized via the Prilezhaev reaction. ESS has a rigid sucrose core and epoxy functionalized fatty acid side chains. The high functionality of ESS was exploited and it was converted to methacrylated and carbonated resins. The methacrylated resins were applied in producing themosets by free-radical polymerizations while the carbonated resins were studied in step-growth polymerizations. Several studies were done to exploit the high functionality of the methacrylated resins: reduction of the viscosity while increasing crosslinkable moieties, introduction of ductility, structure-property relationships, and investigation of resin versatility in photocurable systems. Meanwhile, the carbonated resins were used to form non-isocyanate polyurethane (NIPU) coatings via cyclic carbonate-amine reactions. Overall, the highly functionalized bio-based thermosets showed very promising properties for composites and coatings applications.
Stereoselective Carbon-Carbon Bond Construction Using Indium and Bismuth: New Methods in Green Chemistry
(North Dakota State University, 2012) Balasubramanian, Narayanaganesh
Selective chemical reactions that can be accomplished with minimal waste using non-toxic catalysts and reagents will allow for new greener chemical processes for future environmentally sustainable technologies. This work will present an account on enantioselective nucleophilic addition to carbon-nitrogen and carbon-oxygen double bonds mediated by the environmentally benign indium and bismuth metals. The dissertation entitled “ Stereoselective carbon-carbon bond construction using indium and bismuth: new methods in green chemistry” is divided into three chapters Chapter one outlines a few concepts in green chemistry and background information on the vital role of indium and bismuth in present day organic synthesis. The development of a procedure for using allylic alcohol derivatives for ümpolung type allylation of chiral hydrazones is described in chapter two. This procedure affords homo allylic amines in good yields and excellent diastereoselectivity. An interesting study with respect to the mechanism of the reaction has been conducted. Switching gears towards the end of this chapter, ultrasound-promoted indium-mediated Reformatsky reaction of chiral hydrazones is described. This chapter describes a potential green chemical method for making β-amino acids. In chapter three, indium mediated enantioselective allylation of α-ketoamides is described. The developed procedure is applied in the allylation of linear and cyclic α- ketoamides. Overall, an operationally simple and environmentally benign stratergy development has been explained. The later section of this chapter discusses the Reformatsky reaction in isatin series using the same protocol applied for imines. To fully explore any organometallic reaction, it is important to understand the mechanism with which they operate at molecular level. Chapter three outlines some of our attempts to understand the enantioselective indium and bismuth mediated allylation and the nature of chiral- indium and bismuth Lewis acids. A postive non-linear effect has been observed and studied in bismuth-mediated allylation. Key findings obtained in each chapter and their implications to the future of our research is also discussed in each chapter. The chapters also details on what we understood about the potentials of organoindium and organobismuth chemistry towards developing new green chemical methods.
Visible Light Photocatalysis of N-N Bond Based Compounds
(North Dakota State University, 2016) Iyer, Akila
The well-established principles of organic photochemistry, offer chemists the fundamental understanding and tools for studying light induced chemical transformations. Employing visible light for photocatalysis, one can design and develop benign routes for the synthesis of new organic materials. In our present investigation, we have developed novel N-N bond based compounds for visible light mediated phototransformations. We have presented synthesis for targeting achiral/chiral N-N bond based compounds and their study for various light driven applications. To name a few applications, these compounds have shown to react smoothly under visible light, metal-free conditions for classical photoreactions, chloromethylation, asymmetric photocyclization and photopolymerization. A diverse range of compounds has shown to react smoothly to afford products in high yields. The scope of this methodology has been evaluated for both intermolecular and intramolecular reactions. Our work benefits from the ability of these compounds to undergo desired phototransformation in both solution and in crystalline media. We have provided photochemical and photophysical details that corroborates our experimental findings and highlights the role of excited state reactivity of the novel N-N bond based compounds. This thesis will be an effort to make chemists familiarize with potential of these compounds in light induced reactions.
High Performance Bio-Based Thermosets for Composites and Coatings
(North Dakota State University, 2016) Ambeg Paramarta, Adlina
In the recent decade, there has been increasing interest in using renewable feedstocks as chemical commodities for composites and coatings application. Vegetable oils are promising renewable resources due to their wide availability with affordable cost. In fact, the utilization of vegetable oils to produce composite and coatings products has been around for centuries; linseed oil was widely used for wide variety of paints. However, due to its chemical structure, the application of vegetable oils for high-performance materials is limited; and thus chemical modification is necessary. One of the modification approaches is by substituting the glycerol core in the triglycerides with sucrose to form sucrose esters of vegetable oil fatty acids, in which this resin possesses a higher number of functional group per molecule and a more rigid core. In this research, thermosets of highly functionalized sucrose esters of vegetable oils were developed. Two crosslinking methods of epoxidized surcrose soyate (ESS) resins were explored: direct polymerization with anhydride moieties for composite applications and Michael-addition reaction of acrylated-epoxidized sucrose soyate (AESS) for coatings applications. In the first project, it was shown that the reaction kinetics, thermal and mechanical properties of the materials can be tuned by varying the molar ratio between the epoxide and anhydride, plus the type and amount of catalyst. Furthermore, the toughness properties of the ESS-based thermosets can be improved by changing the type of anhydride crosslinkers and incorporating secondary phase rubbers. Then, in the second system, the epoxy functionality in the ESS was converted into acrylate group, which then crosslinked with amine groups through the Michael-addition reaction to produce coatings systems. The high number of functional groups and the fast reactivity of the crosslinker results in coatings that can be cured at ambient temperature, yet still possess moderately high glass transition temperatures.

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