Browsing by Subject "Synthesis"

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Bimetallic Cooperativity of Nickel and Cobalt–Group 13 Pincer Complexes via Polarized Metal–Metal Bonds
(2022-06) Graziano, Brendan
The underpinnings of modern industrial chemistry necessitate the use of transition metals to catalyze a wide variety of challenging chemical transformations. Precious metals, such as platinum, palladium, rhodium, and iridium are an essential component to many of these processes and have dominated due to the high catalytic activity and predictable two-electron redox. In the area of homogenous catalysis, precious metals have been an indispensable tool in many industrial processes. The scarcity of these metals and their high environmental impact have prompted a more recent focus on earth-abundant 3d metals. Earth-abundant transition metals are a critical component in many difficult biological transformation and offer untapped potential for homogenous catalysis. However, unlike precious metals, base metal catalysis tends to suffer from unproductive one-electron pathways which often hinder performance.Metal-ligand cooperativity has emerged as a premier strategy to perform catalysis with base metals. Cooperative ligand supports promote two-electron chemistry with base metal by working in concert during catalysis. Main group metalloligand scaffolds have shown promise in enhancing and turning on new types of reactivity at transition metals. Among these, Lewis acidic group 13 metals have garnered much attention due to their ability to act as strong σ-acceptors and potential for ambiphilic character. In this regard, rational ligand design was used to synthesize group 13 pincer-type ligands aimed towards cooperative bond activations involving first-row transition metals. Two new bimetallic systems have been developed with an open ligand framework that allows direct access to the M−group 13 interaction and exhibit a diverse array of cooperative σ-bond activations. Specifically, the group 13 support embedded in the pincer framework functions to bind substrate, stabilize low-valent metal states, and stabilize intermediates during reactivity. This strategy enabled two-site C–H, C–X, and H–H cleavage in which both metal ions participate. A key finding of this study is the unique bond polarization towards the transition metal which is induced by the electropositive group 13 element. A Ni–alane moiety is isolated which undergoes a reversible transformation between a Z and X-type ligand via aryl group transfer between the two metals. Mechanistic investigations identify that the Ni−Al bond is formed or broken as necessary during metal-ligand cooperativity. Additionally, by systematically varying the ligand frameworks and group 13 element, structure property relationships are found, highlighting important principles in the design of pincer-type group 13 metalloligands. A pair of isostructural Co–Al and Co–Ga pincer complexes are isolated which feature an X-type aluminyl or gallyl ligands. The isostructural nature of this pair allows for direct comparison of the effects of the supporting metal for reactivity. Further investigation of the duo reveals disparate reactivity with a much more active Al ion compared to Ga. Collectively, experimental and theoretical results show that the Lewis acidic metalloligand is key to the observed reactivity
Catalytic desymmetrization of cyclohexadienones
(2014-05) Kalstabakken, Kyle A.
2,5 Cyclohexadienones are versatile synthetic building blocks that are currently underutilized in natural product synthesis. The desymmetrization of symmetrically substituted cyclohexadienones is a strategy for the asymmetric synthesis of complex frameworks that has been rapidly gaining popularity. Two desymmetrization methodologies developed by our group are described herein.The first is a phase-transfer catalyzed intramolecular Michael addition of malonate-tethered cyclohexadienones mediated by Cinchona alkaloid-derived ammonium salts. Under these conditions, bicyclic lactones are formed in enantiomeric ratios of up to 91:9. For unsymmetrically substituted substrates, the regioselectivity of the reaction is governed by a combination of steric and electronic affects: cyclization occurs away from sterically bulky substituents and towards electron-withdrawing substituents. In the case of brominated substrates, unique tricyclic cyclopropanes are obtained.The second methodology is a Pd-catalyzed intramolecular enyne reaction of alkyne-tethered cyclohexadienones. This cyclization occurs with enantiomeric ratios of up to 81:19 in the presence of bipyridine-based chiral ligands. Substituents on the cyclohexadienone core were found to have a great influence on the both the selectivity and the efficiency of the reaction, which can likely be attributed to steric effects.Finally, the use of the phase-transfer catalysis methodology in the total synthesis of the briarane family of natural products was explored. In the pursuit of a key intermediate containing the briarane core, it was discovered that the enolates of the bicyclic lactone products are particularly unstable, and are not amenable to functionalization. Further studies toward this goal are underway.
Characterization and synthetic studies of Okundoperoxide and synthetic studies of Scyphostatin.
(2009-09) Nelson, Dorian P.
The research presented in this thesis comprises two main projects: the structural characterization and synthetic studies of okundoperoxide (Chapter 4) and synthetic studies of scyphostatin (Chapter 3). In Chapter 4, I describe the characterization of a new antimalarial natural product. I also outline our biosynthetic hypothesis, which motivated us to launch a synthetic project to investigate these ideas. In Chapter 3, I describe work leading to a concise synthesis of the polar core of (+)-scyphostatin. This work included the study of a rare transformation, the vinylogous Payne rearrangement. Also, this rearrangement was found to be useful in a dynamic kinetic resolution to resolve a pair of pseudoenantiomers. Two smaller projects are discussed in the first two chapters. In Chapter 1, I discuss synthetic work directed towards preparation of an analog of kendomycin. In Chapter 2, I present reactions of various phenols with a nitrogen-based electrophile, N-phenyl-1,2,4-triazolinedione.
Construction of the hasubanan alkaloid core through an oxidative dearomatization/lewis acid catalyzed cyclization
(2014-07) Beckman, Karen L.
Access to novel opioid receptor binding ligands is important as chronic pain continues to be a pervasive problem in healthcare. The hasubanan (HB) alkaloids have been identified as potential candidates for selective opioid receptor binding. These alkaloids are a family of compounds, primarily isolated from the flowering plants of the sp Stephania, which have been used for centuries in traditional medicinal remedies. While morphine and HB alkaloids share several structural features, the natural occurring HB alkaloids have a configuration opposite to that of morphine. The unnatural antipodes of the HB alkaloids have a similar spatial orientation to morphine, making then increasingly attractive as potential analgesic therapeutics. Based on these observations we were inspired to develop a synthetic strategy that allows access to both the natural and unnatural enantiomers for several of the HB alkaloid family members.
Design and synthesis of new ligand saffolds and transition metal complexes for small molecule activation
(2013-08) Miller, Deanna Lynn
The objective of this thesis is to explore the synthesis of new ligand scaffolds designed to support late first row transition metals and to study their potential for small molecule activation. Many researchers have utilized sterically encumbered ligands to protect reactive metal centers. In the second chapter, the design and synthesis of novel cage ligands featuring a hydrophobic cavity to provide protection to reactive metal centers will be explored. Ideally, the cavity will effectively prevent bimolecular decomposition reactions that often plague small molecule activation. The synthesis and characterization of two cage ligands, a trianionic tri(amido)amine and a neutral tri(amino)amine variant, will be presented. Additionally, the preparation and characterization of the zinc(II) complex of the tri(amido)amine cage ligand will be discussed and its uptake of small molecules explored. In addition to employing protection of reactive metal centers in ligand design, a bio-inspired ligand design will be explored. The biological cofactor dihydronicotinamide adenine dinucleotide (NADH) can efficiently reduce and oxidize substrates through the transfer of a hydride (or a proton and two electrons). The third chapter explores the design and synthesis of a NADH-type ligand scaffold. The systems presented herein have three NADH-like moieties built into the ligand, designed to reduce substrates via either hydride transfer or proton coupled electron transfer. Having three NADH moieties allows for the possibility of multi-electron redox chemistry. The synthesis and characterization of zinc(II) and cobalt(II) complexes will be discussed. Additionally, the reaction of both the NADH ligand and the zinc(II) complex with known hydride acceptors will be explored. Finally, in chapter four, the synthesis and characterization of a family of diiron and iron cobalt bimetallic complexes with a third type of ligand design will be presented. Previous work in the Connie Lu group has shown reactivity toward small molecules using heterobimetallic complexes supported by a tripodal phosphine amide ligand scaffold. Herein, the same ligand scaffold is applied to late transition metals to explore their synthesis, reactivity toward small molecules, and electronic and magnetic properties to allow for a better understanding of metal-metal bonding interactions.
Directed synthesis and characterization of zeolite nanoparticles
(2013-10) Zhang, Xueyi
Zeolites are a class of materials with ordered micropores (smaller than 2 nm), that can be used for gas separation, catalysis, and adsorption. Structurally, zeolites are composed of SiO₄ tetrahedra sharing corners in an ordered manner. The numerous arrangements of these SiO₄ tetrahedra give zeolites micropores in the forms of channels and cages. Although the applications of each zeolite depends on the spatial arrangements and the sizes of these micropores, size and morphology of zeolite particles are equally important. By preparing zeolite nanoparticles, diffusion paths of zeolite particles can be shortened, total surface area of zeolite particles can be increased, which are beneficial to reducing energy consumption in gas separation, reducing deactivation in catalytic reactions, and increasing adsorption capacities. This dissertation introduces various methods to prepare zeolite nanoparticles. Zeolite nanoparticles prepared with the help of mesoporous carbon templates (hard template) are firstly introduced where the shape and size of zeolite particles are imprinted from the templates. In addition to hard templates, the use of bifunctional surfactant (soft templates) to prepare ultra-small zeolite nanoparticles and lamellar zeolite membrane is also introduced. With only one structure-directing agent that is less intuitive than hard or soft templates, the preparation of hierarchical lamellar zeolite with 2 nm lamellae, the self-pillard pentasil (SPP) zeolite, is introduced, where the intrinsic growth patterns of the crystal played an important role. Finally, template-free synthesis of zeolite nanoparticles, where zeolite formation is totally driven by the intrinsic growth patterns, is introduced. In addition to the preparation methods, a series of computational methods to determine and study the structures of zeolite nanoparticles are also introduced.
Formal Techniques for Realizability Checking and Synthesis of Infinite-State Reactive Systems
(2020-07) Katis, Andreas
Reactive systems are fundamental building blocks in the development of critical safety systems. The are called "reactive" due to the necessity of them interacting with (or against) an unpredictable and uncontrollable environment, for an indefinite amount of time. As a consequence, the verification of a critical system more often than not in- volves the process of writing requirements, modeling, implementing and testing reactive subcomponents. Research in formal verification for reactive systems attempts to solve fundamental problems in each of these processes, with an emphasis given on the cre- ation of mathematical proofs regarding the system's safety. More importantly, it has been shown that such proofs can lead to significant savings both in development time as well as overall production cost. This dissertation explores the problem of reactive synthesis, where the goal is the development of decision procedures that are able to (dis)prove the realizability of reactive system specifications, as well as produce artifacts that essentially serve as witnesses to the decision. Reactive synthesis is a problem closely related to formal verification, as it requires the development of precise, mathematical proofs of realizability. The overwhelming majority of research conducted in this area has so far been focused in its application to propositional specification, where only operations over the Boolean domain can be performed. For the first part of this thesis, we propose novel, efficient reactive synthesis algorithms that extend the support for propositional specification to also generate implementations when the requirements involve the use of richer theories, such as integer and real arithmetic. We discuss the advantages and disadvantages of each algorithm, and accompany their implementation with a formal proof of soundness. In the second part of this dissertation, we delve into an unexplored sub-problem in reactive iv synthesis, where we present the first attempt ever to synthesize witnesses for infinite-state problems in which the implementation behaves in a random, diverse manner. While the product of synthesis is typically expected to be a deterministic witness, we argue that randomness can still be valuable in practice. To that end, we evaluate the application of randomly-behaving solutions to problems related to fuzz testing and robot motion planning, demonstrating how reactive synthesis can be used in an innovative way in software engineering concepts that have not been considered before.
Metallocenium Incorporated Lewis and Brønsted Acid Catalysts: Synthetic Routes and Catalytic Applications
(2023-04) Blechschmidt, Daniel
Lewis acids are some of the most widely used reagents for organic transformations. They are prized for their reactivity but are often sensitive to air and water. The metallocenium scaffold offers many advantages to the improvement of both robust homogeneous Lewis acids and asymmetric catalysts. Chirality is vitally important to natural systems including for the development of pharmaceuticals and agrochemicals. In this document, I first describe the development of air and moisture tolerant, reactive metallocenium Lewis acid catalysts, and their use in Friedel-Crafts alkylation and Diels-Alder cycloaddition reactions. Furthermore, I combined these active substituents with the organocatalytic thiourea scaffold in a model study to determine catalytic activity in acid catalyzed reactions. Finally, I developed a general procedure which combines aminocobaltocenium hexafluorophosphate with a variety of chiral isothiocyanates and explored the selectivity of these species in the Friedel-Crafts reaction of indole and trans- β-nitrostyrene.
A Novel Synthesis of Benzoxazolone and Derivatives via a Ring Expansion and Reduction Approach
(2022-07) DeLong, Mark
Benzoxazolone is a heterocyclic aromatic molecule whose structure can be found in a wide range of biologically active molecules including but not limited to antibacterial, anticancer, analgesic, and anti-HIV, in addition to having some applications in material science. A well-established approach for synthesizing this class of compounds is by cyclization of aminophenol derivatives. We present an alternative route of synthesis of this class of compounds from readily available isatin derivatives through an oxidative ring expansion and ring reduction approach. Various optimization studies and a range of derivatives synthesized will be presented.
Pantomeshes: kinematics, synthesis, and applications of closed pantograph-style linkage systems.
(2010-12) Larson, Blake Timothy
This research describes the kinematics, analysis, and synthesis of a pantomesh. A pantomesh is a patchwork assembly of pantograph elements (known elsewhere as scissor pairs or duplets) that obey certain mobility requirements. A pantomesh, as described in this thesis, has scissor-like elements connected to one another by spherical joints to allow a wide variety of motions. Previous pantograph-style linkages, such as the Hoberman Sphere, use special geometry restrictions and have elements joined with gussets, thereby limiting the variety of shapes possible. The thesis begins with examining the kinematics of pantomeshes and their constituent parts. First, the kinematics of the individual pantograph elements are detailed for further use. The mobility of a closed pantomesh is ensured by the mobility of its constituent pantopatches, two-wide by two-high sub-assemblies of pantograph elements that must be mobile themselves for the entire pantomesh to be mobile. A new method for mobility of spatial linkages is presented relating the use of polygonal elements. Next, two methods for pantomesh synthesis are presented. A graphical method is presented to use a computer-aided design system to create a mobile pantomesh that meets specified requirements. A computational method for synthesis is also presented, using a numerical optimization method to create pantomeshes to certain specifications. Practical considerations of manufacturing are considered in the discussion of multi-link spherical joints, including past work and new approaches. The new approaches include a compliant multi-link spherical joint and a crossed-tendon system that acts a a spherical joint. Finally, an application is presented: a new linkage which provides radial pressure for the purpose of stabilizing a human breast during cancer-related diagnosis and treatment procedures.
Selective Chemistry to Improve Organic Chemistry and Drug Discovery
(2018-08) Buonomo, Joseph
Selectivity in both organic and medicinal chemistries represents the pinnacle of these scientific fields. The ability to do exactly as one intends in the most efficient manner facilitates a limited negative impact technology may impart in the environments in which it acts. As such, during these dissertation studies, I have endeavored to design new selective reactions to enable the most streamlined synthesis of organic molecules that may impart a variety of functions while simultaneously working to rationally create new drug substances that limit side effects in the patient, while also protecting the molecule from the harsh environment of an organism. To briefly summarize the material contained herein, the first chapter comprises of the technologies I have developed for better enabled organic synthesis. These reactions can improve green chemistry initiatives to limit the negative impact on the environment, only possible because of the highly selective nature of these reactions. I expect these technologies should enable chemists who design molecules with many intended purposes, although they were designed with the intent of empowering medicinal chemists. The second chapter of this work covers highly collaborative efforts to design improved chemotherapeutics in an effort to eradicate Tuberculosis, the leading cause of infectious disease mortality worldwide. These molecules range from selective pro-drugs that are released at the site of action by utilizing a selective targeting pro-moiety to rationally designed agents to take advantage of biological mechanism knowledge. These molecules can potentially be drugs in themselves while they certainly inform future endeavors to make new drug materials to combat Tuberculosis.
Solid Source Metal-Organic Molecular Beam Epitaxy Toward All-Epitaxial Ferroelectric Capacitors
(2021-07) Nunn, William
Great strides have been made in the area of thin film synthesis of complex materials. Among these, perovskite oxides have been identified as an immensely important multi-functional class due to exhibiting a large variety of materials properties, including ferroelectricity. Much progress has been made in the development of ferroelectric perovskite oxides but, unfortunately, the model electrode materials desired for many devices mostly contain difficult to work with or “stubborn” elements due to their ultra-low vapor pressures, in evaporation techniques, or low oxidation potentials, in general. Despite the construction of ferroelectric-metal heterostructures having a large impact on device fabrication, deposition of these electrode materials with atomic precision remains challenging in techniques like molecular beam epitaxy (MBE) and has not progressed much past using electron-beam evaporation.To deposit metals and metal oxides in a simpler, more cost-effective, and safer manner, a modification of MBE is developed for the first time here in this work and henceforth referred to as solid source metal-organic MBE. The growth of the simple metal Pt, binary oxide RuO2, and complex perovskite oxide SrRuO3 are shown using metal-organic source temperatures less than 100°C. Furthermore, the metals in these solid metal-organic precursors are in a pre-oxidized state, come bonded with an additional source of oxygen, are air stable, non-toxic, and can be used directly in-vacuum instead of requiring complicated external gas inlets. The growth results from this novel technique introduce it as another advancement in the long history of MBE. Additionally, with regards to the ferroelectric material, control over complex oxide stoichiometry has remained one of the largest issues within oxide MBE synthesis. Here, a different but rapidly expanding metal-organic-based MBE approach, hybrid MBE, is employed for the growth of ferroelectric and dielectric perovskite oxides with great control over the cation stoichiometry and, therefore, the structure and properties. The prototypical ferroelectric BaTiO3 is studied as well as the consequence of substituting Sn for Ti in the growth of the complete BaTiO3 – BaSnO3 alloy system for the first time in MBE. Together, these two approaches are utilized and developed for the goal of creating all-epitaxial in-situ-grown ferroelectric capacitors.
Spontaneity to serendipity: from an enediyne core biosynthetic hypothesis to the hexadehydro-Diels-Alder reaction
(2014-08) Woods, Brian Patrick
Enediyne containing natural products have promising potential as cancer therapeutics due to their unique molecular architecture. The (Z)-1,5-diyn-3-ene subunit in the enediyne core can undergo cycloaromatization to yield a diradical capable of scission of the DNA double helix. While the biological mechanism of action is well established, almost nothing is known about the biosynthesis of the enediyne core. Specifically, researchers have been unable to identify a cyclase enzyme capable of ring-closing acyclic precursors. In the case of 9-membered enediynes, we propose that the bicyclic enediyne core is formed biosynthetically via spontaneous (i.e. non-enzymatic) cyclization from an acyclic precursor. In the course of examining this hypothesis, we serendipitously encountered a [4+2] cyclization between a diyne and an alkyne. The product of such a cycloaddition is one of the oldest and most interesting reactive intermediates in organic chemistry, o-benzyne. This process, which we have termed a hexadehydro-Diels-Alder (HDDA) reaction, has remained almost entirely unexploited until now. The strategy unites an entirely atom-economical, thermal generation of arynes with their in situ elaboration into a diverse set of polysubstituted benzenoids. HDDA precursor triynes cycloisomerize in a very exergonic fashion to produce complex benzyne intermediates, which are trapped with a variety of inter- and intra-molecular functionalities in an efficient and selective manner. The byproduct-free environment in which the benzynes are generated allows for new trapping reactions to be discovered and for mechanistic pathways to be interrogated and elucidated.
Studies of Intramolecular Cyanoamidation with Alkenes and Application Toward the Total Synthesis of Natural Products
(2017-10) Otte, Sadie
Chapter One. A brief discussion of the relevant background in intramolecular cyanoamidation. Examples from successive methodology studies are given. The proposed mechanism and published mechanistic experiments are presented, along with its applications in the synthesis of complex molecules. Chapter Two. A summary of the design, discovery, and optimization of the diastereoselective intramolecular cyanoamidation reaction is presented. Significant findings are discussed along with a preliminary substrate scope. A detailed description of our attempts to cleave the chiral directing group is given. Chapter Three. An overview of the Aspidosperma alkaloid family with an emphasis on quebrachamine is presented. A discussion is given of the isolation, biological activity, and previous total syntheses of quebrachamine. Strategies for the synthesis of the all–carbon quaternary center and formation of the nine–membered ring are specified. Chapter Four. A novel strategy for the total synthesis of quebrachamine via intramolecular cyanoamidation is proposed. Three routes to the key cyanoformamide intermediate are presented. Optimization of the intramolecular cyanoamidation is described along with reproducibility studies. Progress toward the final ring closure between indole and nitrile groups via one– and two–step methods is discussed, along with future work. Chapter Five. The application of a serendipitously discovered Bischler–Napieralski-type reaction toward the total synthesis of eburnamonine is proposed. Optimization of the reaction is discussed along with attempts to grow high-quality crystals of the product. Subsequent efforts to hydrogenate the iminium ion product are presented.
Survival of the Fittest Controller
(2020-05) Samson, Edward
This thesis presents computational approaches to controller tuning. It addresses the hypothesis that standard hard disk drive track following control designs do not take full advantage of actuator capability. In the ﬁrst experiment a controller is synthesized with Matlab’s hinfstruct for H∞ robust optimal performance on a training set modeled on real drive actuator response data. Compared to standard robust synthesis the sensitivity bandwidth of the closed loop system increases, at the expense of robustness to hardware uncertainty. In the second experiment the scalar parameters of a classical control law are tuned with Matlab’s fmincon to increase the simulated closed loop bandwidth of the drives in a training set. The results of both experiments support the hypothesis while providing avenues along which these modiﬁcation can be developed and applied to other applications.
Synthesis of Photoresponsive Nucleosides and Their Incorporation into Oligonucleotides: Targeting Androgen Receptor and NF-κB Transcription Factors
(2016-02) Struntz, Nicholas
The sequencing of the human genome suggests that transcription factors (TFs) make up one of the largest classes of human proteins, revealing that there are over 2000 genes that code for transcription factors. The pivotal roles of TFs in cell biology become quite apparent when one or more of these regulatory mechanisms becomes mutated or altered. For example, the androgen receptor (AR) transcription factor plays a pivotal role in prostate carcinogenesis and progression. Additionally, the inflammatory response of the NF-κB transcription factor proteins results in the transcription of many genes, which play pivotal roles in carcinogenesis. There are several approaches to modulate and study transcription factor activity and biochemistry. Utilizing cis element DNA decoys to sequester TFs is one approach to directly modulate transcription factors. Introducing these synthetic double-stranded DNA decoys containing TF binding sites into cells effectively sequesters TFs and inhibits their target gene expression. Over the past couple of decades, numerous reports have validated utilizing this approach. For example, a phosphorthioate STAT3 DNA decoy has entered the “first-in-human” Phase 0 clinical trials for the treatment of head and neck squamous cancer. STAT3 expression and cell viability was reduced in the head and neck cancers injected with the decoy compared to the saline control. Combining the spatial and temporal resolution of caging technology with the DNA decoy strategy for the inhibition of transcription factor activity can yield an approach for the very precise ability to photochemically regulate gene expression, which has potential as a therapeutic agent and tool for probing biological pathways. This thesis will focus on efforts to develop several novel DNA-based and small molecule-based probes to investigate the biochemistry of TFs and their signaling pathways. Chapter 2 discusses the synthesis and characterization of caged DNA decoys that target the Androgen Receptor (AR). Caged DNA decoys successfully captured AR in LNCaP lysate when irradiated with light. Chapter 3 introduces the complement to caging technology, which is catch and release DNA decoys (CRDDs). CRDDs capture transcription factors, by binding and sequestering them, and then a pulse of light photochemically destroys the CRDD, permitting release of the TF. Several 7-nitroindole (7-NI, 1.47) nucleobase mimics were incorporated into NF-κB-directed DNA decoys, which still allowed the capture of the p50-p65 NF-κB proteins. Irradiation with 350 nm light drives the release of the p50-p65 NF-κB. The capture and photochemical release of an endogenous transcription factor is demonstrated for the first time. Chapter 4 continues the work of Chapter 3 by developing second-generation nucleobase mimics for use in CRDDs. Addition of molecular recognition properties on a photo-responsive monomer is hypothesized to increase binding affinity to capture endogenous TFs. 8-Nitroguanosine contains this added molecular recognition, is more stable within duplex DNA, and also displayed similar photochemical depurination properties. Chapter 5 outlines work developing photoswitchable nucleobases that transpose their hybridization properties upon photolysis. Chapter 6 highlights work to determine the mechanistic NF-κB inhibitory properties of several Cryptocaryone analogues, which were found to inhibit the NF-κB translocation to the nucleus. Appendix A focuses on the characterization of the enantioselectivity of guanosine monophosphate synthetase (GMPS), a crucial enzyme in nucleotide biosynthesis.
Synthetic Control and Characterization of NU-1000
(2019-12) Webber, Tom
The production and release of greenhouse gasses has become a major issue in today’s society. Methane is a powerful greenhouse gas and is the main component of natural gas. Natural gas is often collected and transported to be used as a fuel, but leaks result in release of some of that methane into the atmosphere. Work is underway to develop an efficient catalyst capable of selective oxidation of methane to methanol. Metal-organic frameworks have become popular candidates for catalysts and catalyst scaffolds. The Zr-based metal-organic framework NU-1000 is a robust, mesoporous material that can be used in a variety of applications, including catalysis, sensing, gas separation and storage, and scaffolds. It can be synthesized by combining a solution of hexazirconium nodes ([Zr6O16H16]8+) and organic acid modulator in N,N-dimethylformamide with a solution of linker (1,3,6,8-tetrakis(p-benzoic acid)pyrene) and aging at elevated temperature. The typical product is 1-3 μm crystals that are primarily composed of NU-1000 but that contain domains of an impurity phase called NU-901 that is a polymorph of NU-1000. The ideal NU-1000 synthesis will yield phase-pure particles and enable control over crystal size. The structural differences between NU-1000 and NU-901 lead to a hypothesis that changing the organic acid modulator from benzoic acid to a larger and more rigid carboxylic acid might lead to steric interactions between the modulator coordinating on the node and linkers bound to nodes, inhibiting growth of the more dense NU-901-like material and resulting in phase-pure NU-1000. Side-by-side reactions comparing the products of synthesis using benzoic acid or biphenyl-4-carboxylic acid as organic acid modulator produce structurally heterogeneous crystals and phase-pure NU-1000 crystals, respectively. NU-1000 particles synthesized in the range of 1-3 μm, while useful for many applications, are not large enough for single-crystal X-ray diffraction and are not small enough for nanomaterial applications like drug delivery. The synthesis of NU-1000 provides a variety of experimental handles that can be tuned to produce a wide range of particle sizes. For example, the rate of nucleation and growth is closely tied to the concentration of modulator. This is because NU-1000 is formed via a competitive reaction between modulator and linker molecules for the binding sites on the hexa-Zr nodes. By changing the concentration of the linker, modulator, and any additives, the nucleation and growth rates can be altered to produce the desired particle size. The choice of Zr precursor between ZrOCl2 • 8 H2O and ZrCl4 also plays a significant role in determining the resulting particle size. People acquire a wide range of data like crystal size and morphology, crystallographic information, and elemental quantification and distribution using techniques like transmission electron microscopy and energy-dispersive X-ray spectroscopy. The characterization of size, size distribution, crystallinity, and chemical composition are critical to studying the catalytic properties of product materials. However, due to the delicate nature of MOFs, gathering this data can be very challenging. MOFs commonly undergo radiation damage under a focused electron beam causing a loss of crystallinity. While various techniques can circumvent this damage like cryogenic transmission electron microscopy and low-dose electron microscopy, this dissertation focuses on analyzing the damage and ensuring the data collected remains reliable.
Synthetic efforts toward a total synthesis of (+)-Pelorusdie A.
(2009-06) Kopel, Lucas C.
This thesis has been divided into six chapters that describe synthetic efforts toward the cytotoxic marine macrolide (+)-peloruside A, isolated by Northcote and coworkers from the New Zealand marine sponge Mycale hentscheli. Chapter 1 discusses the background of peloruside A and published literature studies relating to its biological activity. Chapter 2 conveys a detailed report of the synthetic efforts by others that have resulted in three total syntheses and multiple efforts toward the total synthesis of peloruside A. Chapter 3 describes the previous synthetic efforts by Hoye group members toward peloruside A. Two different strategies for synthesizing the C13-C20 fragment of (+)-peloruside A have been established using ring-closing metathesis. Synthesis of the C1-C9 fragment of (+)-peloruside A was accomplished using a kinetic lactonization strategy. Chapter 4 reports on my efforts at scaling-up and optimizing the synthesis of the C1-C9 fragment of (+)-peloruside A and modifications to the previous route. Chapter 5 describes the new progress toward synthesizing (+)-peloruside A that was achieved. These efforts culminated in the synthesis of a C1-C11 fragment of (+)-peloruside A along with studies investigating the coupling of late stage segments via a 1,5-anti boron-mediated aldol. Chapter 6 highlights the key features of my synthetic efforts toward (+)-peloruside A.
Targeting Two Late-Stage Enzymes of the Mycobacterium tuberculosis Biotin Biosynthetic Pathway
(2018-09) Bockman, Matthew
Mycobacterium tuberculosis (Mtb), responsible for both latent and symptomatic tuberculosis (TB), remains the leading cause of mortality among infectious diseases worldwide. The rise and propagation of drug-resistant TB remains a global health crisis and has prompted researchers to investigate novel mechanisms of action for the development of antitubercular agents. Chapter 1 discusses the biotin biosynthetic pathway as a target for the development of antibiotics targeting Mtb, providing both chemical and genetic validation evidence of inhibiting this pathway in Mtb infections. This chapter thoroughly examines each enzyme in the biotin biosynthetic pathway by reviewing: the reaction it catalyzes, its mechanism of action, structural and sequence analysis, and catalogue of inhibitors known for each enzyme. The late-stage biotin synthase (BioB) and biotin protein ligase (BPL) proteins are elaborated on and will be the focus of this thesis. Mycobacterial biotin protein ligase (MtBPL) is an essential enzyme in Mtb and regulates lipid metabolism through the post-translational biotinylation of acyl coenzyme A carboxylases. Chapter 2 reports the synthesis and evaluation of a systematic series of potent nucleoside-based bisubstrate inhibitors of MtBPL that contain modifications to the ribofuranosyl ring of the nucleoside. All compounds were characterized by isothermal titration calorimetry (ITC) and shown to bind potently with KDs ≤ 2 nM. Additionally, this chapter discusses the structural interactions between the inhibitors and MtBPL using the highly-resolved x-ray co-crystal structures. Despite relatively uniform biochemical potency, the whole-cell Mtb activity varied greatly with minimum inhibitory concentrations (MICs) ranging from 0.78 to >100 uM. Cellular accumulation studies showed a nearly ten-fold enhancement in accumulation of a C-2′-a-fluoro analogue over the corresponding C-2′-b-fluoro analogue, consistent with their differential whole-cell activity. The parent compound, Bio-AMS, was also evaluated for its pharmacokinetic (PK) parameters, and although it shows stability toward plasma and liver microsomes, Bio-AMS is rapidly cleared form CD-1 mice. From chapter 2, the potent compound Bio-AMS was shown to possess selective activity against MtBPL. However, Mtb develops spontaneous resistance to Bio-AMS with a frequency of resistance (FOR) of at least 1 x 10-7 by overexpression of Rv3406, a type II sulfatase that enzymatically inactivates Bio-AMS. In an effort to circumvent this resistance mechanism, chapter 3 describes the strategic modification of the Bio-AMS at the 5’-position to prevent enzymatic inactivation. The new analogues retain subnanomolar potency to MtBPL, and the 5′R-C-methyl derivative exhibited identical antimycobacterial activity toward: Mtb H37Rv, MtBPL overexpression, and an isogenic Rv3406 overexpression strain (MIC = 1.56 uM). Moreover, this compound was not metabolized by recombinant Rv3406 and resistant mutants to this compound could not be isolated (FOR < 1.4 x 10-10) demonstrating it successfully overcame Rv3406-mediated resistance. The natural product acidomycin, discovered in 1952 and isolated from Streptomyces spp., was originally shown to have selective antibiotic activity against Mtb grown in the absence of biotin, implying it is an antimetabolite of the biotin biosynthetic pathway. Chapter 4 fully investigates the mechanism of action and selectivity of acidomycin. Acidomycin was evaluated against an array of drug susceptible and drug resistant Mtb strains, as well as a panel of gram-positive and gram-negative pathogens, and showed remarkable selectivity to Mtb with MICs ranging from 0.096 – 6.2 uM for the Mtb strains and >100 M for the other microorganisms. Acidomycin was also shown to be a reversible, competitive inhibitor of E. coli biotin synthase (EcBioB), with a Ki of 1.5 uM, and a homology model shows substantial sequence alignment in the mycobacterial enzyme (MtBioB). The selectivity of acidomycin against E. coli versus Mtb is due to differential levels of cellular accumulation, with a 30-fold increase in the amount of acidomycin accumulated in Mtb over E. coli. In vivo, acidomycin was shown to be rapidly eliminated from CD-1 mice, is a half-life of 9.6 min, but exhibited remarkable plasma and microsomal stability. A brief series of acidomycin analogues showed a very tight SAR window for modifications, with the primary amide analogue being the best analogue with an MIC less than two-fold of acidomycin.
Transforming Community: Transitway Impacts Research Program - Research Synthesis
(Center for Transportation Studies, University of Minnesota, 2013-09)
This synthesis pulls together seven years of Transit Impacts Research Program (TIRP) research as well as findings from two related projects conducted by University of Minnesota researchers. It summarizes the actual and projected impacts of transitways on the Twin Cities region, offering lessons learned to help guide the build-out of the rest of the network most effectively. It concludes with a set of implications for policymakers.

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