Part I of this dissertation includes the chronological synthetic background of mandelalide A as well as the synthesis of the C1-C14 glycosylated southern subunit of mandelalide. A key aspect of the synthesis includes a novel silver-catalyzed cyclization (AgCC) of a propargylic benzoate to construct the substituted cis-pyran ring system present...
Sunscreen products are used worldwide to protect the skin from ultraviolet radiation. However, some of the ingredients used in sunscreen products are fatal to coral reefs especially in areas where tourism is a large part of the economy. In this study, we explored a synthetic route to produce 4-deoxygadusol, which...
The first part of this manuscript is about the total synthesis of the aspidosperma alkaloids leuconoxine, melodinine E and mersicarpine. Our synthetic strategy used a radical translocation-conjugate addition cascade to construct the core of the natural product. Specifically, a vinyl radical was generated from the homolysis of the C–I bond...
Substituted phenols are important substructures for pharmaceuticals, agrochemicals, natural products and biological probe molecules. The properties of phenolic molecules are substantially influenced by the substitution patterns of the phenolic ring. The chemical synthesis of phenols with various substitution patterns is an enduring challenge and multiple strategies have emerged. However, some...
In the past decades, femtosecond stimulated Raman spectroscopy (FSRS) has been gaining tremendous popularity in fundamental sciences stemming from chemistry to biology. It is capable of capturing both equilibrium and non-equilibrium structural information across a broad range of timescales with simultaneously high temporal and spectral resolutions. Femtosecond transient absorption spectroscopy...
Exploring bioactive natural products has contributed largely to clinically approved drugs we have been using over the last 100 years. Especially among the anti-infective drugs, around 70% of currently used antibiotics were discovered or derived from microbial secondary metabolites, among them compounds like vancomycin, chloramphenicol, and erythromycin. Facing the unavoidable...
Fungi have long been used for discovery of new chemical scaffolds. In the clinical setting, the fungal natural products penicillin, statins, and cyclosporine have revolutionized medicine to treat diseases and infections. In the environment, fungal natural products have been used as herbicides, fungicides, and insecticides to protect crops, livestock, and...
Dearomatization reactions exist broadly in biosynthesis and chemical synthesis. The highly functionalized atoms of arenes can be masked by it aromaticity, and upon dearomatization, those reactive atoms can be readily applied to bond formation and further manipulation. The total synthesis of (–)-cephalotaxine and (–)- homoharringtonine is described via an oxidative...
Mandelalide A has attracted considerable interest from the synthetic community due to its intriguing structure and important cytotoxic activity. Madeirolide A, a structurally related macrolide, shows promising antifungal activity but no appreciable anticancer activity. This dissertation describes synthetic studies toward mandelalide A, madeirolide A and their hybrid structures.
Part I...
The furanyl diterpenoid family of natural products has drawn the attention of both synthetic organic chemists and pharmacologists due to their complex structural architectures and diverse biological activity. Among them, wortmannin has been most extensively studied for biological activities. All these furanyl diterpenoids consist of a highly strained naptha[1,8-bc]furan core,...
This dissertation investigates the structure and topological properties of cyclicallypresented groups. First, a family of groups called groups of type Z is considered. Withfew exceptions, the finiteness, asphericity, fixed point, and 3-manifold spine problemsare solved. Most groups of type Z have a central element of infinite order fixed by theshift....
Lycopodium alkaloids have shown widespread and noteworthy biological activity, consisting of over 250 known natural products. Moreover, their structural complexity and diversity have attracted considerable attention from numerous laboratories including our own. Recently, we have developed a unified approach that would provides access to numerous, previously unprepared C₁₀-functionalized lycopodium alkaloids....
Carbon Nanotubes are a unique family of nanostructures that have shown remarkable promise for mechanical, electrical, and optical applications. Fundamentally similar to the earlier discovered Buckminsterfullerene (C₆₀), carbon nanotubes are hollow cylinders formed from a single sheet of carbon atoms. The research presented in this dissertation investigates several carbon nanotube...
The structural architecture present in marine toxin azaspiracid - 20 stereocenters, 9 rings, 3 separated spirocenters - has attracted considerable synthetic attention. Our efforts toward the synthesis of azaspiracid have led to the completion of both C₁-C₂₆ northern and C₂₇-C₄₀ southern halves. Herein, the
synthesis of southern FGHI ring system...
Three approaches toward the core of halichlorine and pinnaic acid are described. The first approach entails a racemic transannular nitrone-olefin [3+2] cycloaddition from nitrone 238. Construction of the nitrone 238 began with aldehyde 241. Another key feature in this route involved a ring-closing metathesis for the formation of a 14-membered...
This dissertation is separated into two parts according to the two major distinct research projects. In Part I, the full account of synthetic studies toward C10-functionalized lycopodium alkaloids is described. In Part II, the detailed discussion on the exploration of the Pummerer cyclization methodology and its application to the total...
Aminal radical intermediates were generated by the method of radical translocation and reacted in C-C bond forming reactions with electronically deficient alkenes (Schiedler et al. Org. Lett. 2012, 14, 6092). Aminal radical intermediates can participate in inter- and intra-molecular reactions using both Bu3SnH and (TMS)₃SiH as hydride donors. Carbon–carbon bonds...
Organic compounds which contain one or more nitrogen atoms are especially important as they are disproportionately represented among biologically active molecules. As a result, significant effort has been focused on the development of methods for the synthesis of nitrogenous molecules. We identified the aminal as an under-explored functional group. Despite...
More than 30 members of the diverse amphidinolide family of biologically active macrolides have been isolated over last three decades. From this family, amphidinolides C and F stand among the most complex and densely functionalized affiliates. Recently, we have accomplished the first total synthesis of amphidinolide F. The all-carbon framework...
Pharmaceuticals, molecular catalysts, and secondary metabolites often contain nitrogen. The problems faced synthesizing compounds which contain nitrogen was because of the Lewis base reactivity of nitrogen lone pairs, and the acidic protons of some nitrogenous functional groups. We developed two methods for the synthesis of nitrogeous compounds. Additionally, we successfully...
This thesis is separated into three distinct projects. First, synthetic studies towards the furanosteroid viridin shown in part I. Second, synthetic studies towards the diperene obtusanal shown in part II. Third, the analysis, characterization, and synthesis of coronene derivatives towards their application in organic batteries shown in part III. Significant...
Natural products from both terrestrial and marine sources represent a significant source of novel drug leads, and have previously been developed into clinically-approved agents for the treatment of various human diseases. This work represents the biological characterization of the mechanistic basis for activity of several natural product structures in models...
Complex organic transformations, such as the addition of pyrrole to ketene using planar chiral organocatalyst (*PPY), the four-component anhydride- Manniach reactions, and the site-selective desymmetrization of meso-1,2-diol, are remarkable synthetic reactions that provide high yield and high selectivity. However, the exact mechanism and origins of stereocontrol for theses synthetic organic...
This thesis describes the development of a new enantioselective synthetic method employing chiral cis-2,5-diaminobicyclo[2.2.2]octane-based organometallic catalysts. The significance of this new method to organic synthesis is illustrated with preparation of enantioenriched products that are transformed to important pharmaceutical agents. Chapter 1 provides a brief historical overview of asymmetric catalysis, especially...
The continued propagation of antibiotic resistance requires the development of new therapeutics. The lipopeptide antibiotic enduracidin has demonstrated high activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus. In addition to a lack of cross-resistance with existing antibiotic classes, enduracidin has no known transferrable resistance mechanism. The development of enduracidin as...
Azaspiracid-1, a novel marine toxin that contains 9 rings and 20 stereogenic centers, has drawn considerable attention from synthetic groups worldwide due to its structural complexity, which includes a unique trioxabisspiroketal fused to a tetrahydrofuran ring (ABCD rings), a piperidine-tetrahydrofuran spiroaminal system fused to a 2,9-dioxabicyclo[3.3.1]nonane system (FGHI rings), a...
Irradiation of a tryptamine linked through its side-chain nitrogen to an alkylidene malonate residue results in an intramolecular [2 + 2] cycloaddition to the indole 2,3-double bond. The resultant cyclobutane undergoes spontaneous retro-Mannich fission to produce a spiro[indoline-3,3-pyrrolenine] with relative configuration defined by the orientation of substituents in the transient...
Studies toward the total synthesis of (+)-providencin (1), a highly oxygenated cembranoid dipterpene with a unique bicyclo[12.2.0]hexadecane skeleton and pronounced biological activity, are described. These studies resulted in the synthesis of advanced intermediates 320 and 332 which contain all of the carbon atoms of 1. In a first generation approach...
Ion-selective polymeric optical sensors – ion optodes – are a promising alternative to ion-selective electrodes and fluorescent dyes for analytical and biological applications, e.g. extra- and intracellular measurements. They are non-toxic, highly selective robust probes for ionic fluxes monitoring.
A large-scale fabrication of ion optodes using a solvent displacement method...
A Diels-Alder approach to biaryls (DAB) has been applied towards the synthesis
of highly substituted, programmable biaryl templates. Tri- and tetra-ortho-substituted
biaryls can be produced in just three to four steps from commercially available materials
utilizing the Diels-Alder [4+2] cycloaddition. The methods described herein will
illustrate the ability of mono...
An expedient approach to the synthesis of a wide range of highly programmable biaryl templates has been accomplished. Utilizing the Diels-Alder [4+2] cycloaddition, a wide range of tri- and tetra-ortho-substituted biaryls have been synthesized in only three to four steps from commercially available materials. We have successfully synthesized entire classes...
Studies towards the total synthesis of (−)-kendomycin (1), a bacterial metabolite with
a unique molecular architecture and pronounced biological activity, are described. These
studies resulted in the synthesis of advanced intermediate 208, containing all of the
carbon atoms of 1.
A Dötz annulation between alkyne 122 and novel chromium carbenoid...
The total synthesis of a highly potent cytotoxic marine natural product, phorboxazole A, is described. Both a palladium(II)-mediated and a palladium(II)-catalyzed intramolecular alkoxycarbonylation were used as key steps for the preparation of the two cis-2,6-disubstituted tetrahydropyran rings (C22-C26 and C11-C15) of phorboxazole A.
The synthesis used a convergent approach involving...
Part 1: A Diels-Alder Approach to the Synthesis of Novel Analogues of the Natural
Product Siamenol
Due to the prevalence of biaryl motifs in natural product synthesis, the Carter
research group has been exploring the utility of a Diels-Alder approach to biaryl
synthesis. The Diels-Alder approach involves a [4+2] cycloaddition...
F1FO-ATP synthase targeting antimicrobials apoptolidin 1 (A1), (+)-erythromefloquine,
and oligomycin were tested in vitro for synergistic minimum inhibitory
concentrations against Staphylococcus aureus. Synergy was strictly defined as inhibition
by at most 25% the MIC of each participating drug. Ampicillin, with an MIC of 0.8
ug/mL, served as a negative control....
In this report, three studies are presented that aid in the development of drug discovery and their synthesis. In each, the importance of the marriage between computations and experiments is highlighted. Continued efforts in this vein are essential for future efforts towards improving human health.
The first case study investigated...
This dissertation describes the racemic and enantioselective synthesis cavicularin. Cavicularin is a macrocyclic bisbibenzyls family member natural product. It has been an attractive synthetic target due to its intriguing structure: the macrocyclic core imparts sufficient strain on the system to force one benzene rings to adopt a boat-shaped conformation, out...
Molecular chirality plays a critical role in chemistry, biology, and medicine. To study and better understand conformational chirality, it is necessary to obtain structurally interesting molecules that exhibit this form of chirality. Our lab utilizes total synthesis and methodological development to obtain conformationally chiral natural products of interest. We believe...
In this thesis, I present studies in the field of terahertz [THz] spectroscopy. It covers both the generation and detection of ultra-fast broadband THz pulses, as well as the transmission properties of vertically grown multi-walled carbon nanotube forests [MWCNTs]. We have found that these vertically grown MWCNTs respond strongly to...
Two improvements to the established procedures for synthesis and response detection of ion-selective optical sensors (optodes) were introduced.
The first improvement addresses the drawback of organic dye (optode-localized chromoionophore) photobleaching. This positively impacts fluorescence response and allows for (1) direct measurement of hydrogen ion activity upon binding with the dye,...
Effective methods for the enantiopure formation of substituted piperidine rings are significantly important due to their presence in alkaloid products. A valuable method to form these ring systems would be via an intramolecular heteroatom Michael addition from the corresponding enone or enal. Described herein is a methodolgy that has been...
Studies towards the total synthesis of (+)-Phomactin A (1), D (6), and G (9), fungal metabolites with unique molecular architecture and pronounced biological activity, are described. These studies resulted in the synthesis of advanced intermediates 354 and 356, which contain all of the carbon atoms of 1, 6 and 9....
Since the discovery of molecular chirality in 1848, this notion has had a substantial impact on medicine, biology, and chemistry. Extensive effort has been directed towards the construction of chiral molecules that contain sp³ hybridized stereogenic centers. In contrast, less effort has been dedicated to molecules that are chiral by...
Aromatic heterocycles are core structural motifs in natural products, pharmaceuticals and biological polymers. Indoles, in particular, represent a significant subclass of aromatic heterocycles, both in terms of sheer numbers, but also in biological and pharmaceutical relevance. As such, new methodologies for the synthesis of indoles represent an important and continually...
Oligotrophic bacteria are adapted to low nutrient concentrations. As most of the ocean is oligotrophic (low in nutrients), oligotrophic bacteria thrive in the ocean and make up the majority of planktonic cells. Because of this, oligotrophs are crucial to oceanic nutrient cycles. However, marine oligotrophic bacteria are dwarfed by their...
Let H be a cyclically-presented group on n generators with a single defining relator. Attempts have been made to classify such groups by their order, their status as a 3-manifold group, and the asphericity status of their presentations. For groups with a defining relator of length 3 these classifications are...
Small molecule drugs have been instrumental in our fight against diseases, beginning when some of the earliest ancient cultures used plant remedies to treat illnesses. More recently, the skill of isolating and characterizing the active ingredients within bioactive plants and microbial extracts has led to the isolation and design of...
Mensacarcin is a stereogenic complex polyketide with potent anti-tumor activity produced by a soil-dwelling Streptomyces bottropensis. The US National Cancer Institute (NCI) 60 human tumor cell line anticancer drug screen (NCI-60) reveals mensacarcin’s cytostatic properties in almost all tested cell lines and distinct cytotoxic properties specifically in eight melanoma cell...
Fungi have long been a prolific source of clinically approved drugs. The antibiotic penicillin, the cholesterol lowering statins, and the immunosuppressant cyclosporine have changed the treatment of human diseases in the last century. Recently, genome analysis of filamentous fungi has revealed that the biosynthetic potential for natural product expression is...
The first part of this manuscript is about the total synthesis of the Arundo donax bis(indole) natural products. The A. donax alkaloids were prepared using the first example of an ynindole Diels–Alder reaction. Each were then separated, isolated, and determined to have stable enantiomeric conformations at room temperature (Chen, J.;...
Pactamycin, first reported in 1962, is a potent antitumor antibiotic produced by the soil bacterium Streptomyces pactum. Structurally, it contains a cyclopentitol core unit, a 3-aminoacetophenone (3AAP), a 6-methylsalicylic acid (6-MSA), and a N,N-dimethyl urea. The aminocyclopentitol ring is derived from glucose, possibly via N-acetyl glucosamine (GlcNAc), the 3-aminoacetophenone (3AAP)...
Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. I hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Pregnant...
My work on computing complex catalyzed organic transformations reveals that only a few subtle chemical factors, e.g. non-classical hydrogen bonding, (hyper)conjugation and steric effects, common across different catalyst manifolds are critical for catalysis and selectivity. Rational manipulation and exploitation of these factors has led to improved catalyst designs, which has...
Lycopodium alkaloids have generated enormous amounts of interest from the scientific community, both as synthetic targets and for their medicinal properties. Herein is described work towards a unifying approach to large segments of the Lycopodium family. An organocatalyzed intramolecular heteroatom Michael reaction method, for the construction of piperidine and piperizine...
Studies toward synthesis of subunits of sanglifehrin A, an immunosuppressant featuring a highly substituted [5,5]-spirolactam moiety as well as a 22-membered macrocycle are described. The macrolactone contains a peptidic backbone characterized by an unusual [beta]-substituted (S)-piperazic acid and (S)-m-hydroxyphenylalanine units. These studies resulted in the synthesis of advanced intermediate 358...
Part I: Racemic and asymmetric syntheses of a new substance with prospective antidepressant properties were achieved. In vitro assays with synthetic racemates (±)-25 and (±)-26 suggested that the former is a relatively selective inhibitor of serotonin transporter whereas the latter is a more balanced inhibitor of both serotonin and norepinephrine...
In this thesis, I present studies in the field of terahertz (THz) spectroscopy. These studies are divided into three areas: Development of a narrowband THz source, the study of carrier transport in metal thin films, and the exploration of coherent dynamics of quasi-particles in semiconductor nanostructures with both broadband and...
Azaspiracid has generated an enormous amount of scientific interest in the fourteen years since its initial discovery. The structure contains a 6,5,6 bis-spiroketal, a [3.3.1] bicyclic ketal and a 6,5-spiroaminal linkage as key moieties. With 9 rings, 20 stereocenters and three alkenes, the azaspiracid immediately attracted the interest of the...
Studies toward the total syntheses of highly potent cytotoxic alkaloids
including the bromopyrrole alkaloids and indole alkaloids were conducted and are
described. Studies carried out in the course of this dissertation consist of five total syntheses of natural products that include bromopyrrole alkaloids nagelamide A, D and agelastatin D as...
The enantioselective total synthesis of quinolizidine-containing natural product cermizine D and formal syntheses of senepodine G and cermizine C has been achieved. These natural products are members of the lycopodium alkaloids, which have attracted significant attention due to their exciting biological activities and the diverse structural scaffolds. Key steps in...
This thesis consists of three papers which investigate marginal models, nonparametric approaches, generalized mixed effects models and variance components estimation in longitudinal data analysis. In the first paper, a new marginal approach is introduced for high-dimensional cell-cycle microarray data with no replicates. There are two kinds of correlation for cell-cycle...
Keeping FOSS developers motivated is a challenging problem, and their motivation levels can affect the team's productivity and satisfaction, leading to higher or lower productivity. Using reputation systems as a motivator has become the de-facto standard for many online communities, rewarding user's activity through badges of honor or achievement levels....
Two of the most powerful ways in which humans have altered ecosystems are by increasing productivity and changing the densities of important consumers. The bottom-up effects of productivity and the top-down effects of consumers have been identified as primary determinants of biological diversity, though the links between them remain unclear....
A total of 902 plasma samples from the Rambouillet, Targhee, Columbia, Lincoln, and Suffolk breeds of sheep were analyzed for transferrin type by disc electrophoresis. Six transferrin types, Tf[superscript A], Tf[superscript B], Tf[superscript C], Tf[superscript p], Tf[superscript E], and Tf[superscript P], were found in the Rambouillet, Targhee, and Columbia breeds...
Sustainability has become an unprecedented priority in global manufacturing due to the growing concerns over issues such as an aging workforce, environmental degradation, and public health. The simultaneous consideration of the economic, environmental, and social aspects – often referred to as the “three pillars of sustainability” – is crucial to...
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Karl R. Haapala
Sustainability has become an unprecedented priority in global manufacturing
Winegrapes are an important crop for Oregon agriculture, ranking amongst the top ten agricultural commodities based on farmgate value. The most widely planted winegrape cultivar in the state is ‘Pinot noir’ (Vitis vinifera L.), and the majority of acreage is produced in the Willamette Valley. Production of quality ‘Pinot noir’...
Drought and mandatory water restrictions are limiting the availability of irrigation water in many important blueberry growing regions and new strategies are needed to maintain yield and fruit quality with less water. Three potential options for reducing water use, including deficit irrigation, irrigation cut-offs, and crop thinning, were evaluated for...
The sudden and unexpected death of a seemingly healthy infant sets in motion a number of linked processes with potentially complex and far-reaching ramifications. While individuals, families and communities grapple with the shock and heartbreak associated with the loss of a young life, a chain of multidisciplinary investigative responsibilities is...
Vertically shoot positioned (VSP) training systems are common in Oregon's Willamette Valley, where deep fertile soils and high regional precipitation task growers with curbing vegetative vigor within this system. Management strategies, such as canopy hedging and cluster-zone leaf removal, are used to improve microclimate within the canopy and around the...
The purpose of this study was to document vegetation on "The Island", a
Research Natural Area at the confluence of the Crooked River and the Deschutes River in
central Oregon's Juniperus occidentalis Zone and to compare the results with an earlier
study reported in 1964 from 1960-'61 data. Present-day comparisons...
The marked increase in surface-to-volume ratio associated with microscale devices for hemodialysis leads to problems with hemocompatibility and blood flow distribution that are more challenging to manage than those encountered at the conventional scale. In this work, stable surface modifications with pendant polyethylene oxide (PEO) chains were produced on polycarbonate...
Striga, a genus of obligate parasitic weeds in the family Orobanchaceae, has been
identified as the most important biological factor limiting agricultural productivity in sub-Saharan Africa. Germination of Striga seeds is triggered by strigolactone root exudates
from host plants. Strigolactones also induce hyphal branching in arbuscular mycorrhizal
(AM) fungi, which...
The scale of pest and disease dispersal is often larger than the scale of individual farms. Therefore, an individual grower’s response to pests and diseases can affect and is affected by their surrounding growing region. Individual growers are also not isolated, and engage in various forms of information gathering, sharing,...
Single Point Incremental Forming (SPIF) is a forming process in which a fully clamped sheet is formed by a hemispherical ended tool that moves along a predefined 3D toolpath. The sheet is formed in a series of local deformations to reach its desired shape. Double Sided Incremental Forming (DSIF) includes...
The purpose of this case study was to describe the development
of an adult high school diploma program at Linn Benton Community
College, Specifically, the purposes of this study are: (1) the creation
of an instructional approach utilizing performance objectives as a
means of satisfying the minimum adult high school...
Using techniques that permit the direct observation of
fetuses in vivo, prenatal behavioral development was
compared among four species in the rodent family Muridae:
the Norway rat (Rattus norvegicus), Mongolian gerbil
(Meriones unguiculatus), cotton rat (Sigmodon hispidus), and
spiny mouse (Acomys cahirinus). Rattus and Meriones bear
altricial offspring, as do...
American meteorology was synonymous with subjective weather forecasting in the early twentieth century. Controlled by the Weather Bureau and with no academic programs of its own, the few hundred extant meteorologists had no standing in the scientific community. Until the American Meteorological Society was founded in 1919, meteorologists had no...
This research was designed to study the perinatal and
postweaning effects of the interaction between ethanol and low
dietary zinc during gestation and lactation in the rat.
Pregnant rats were fed liquid diets containing either 2 or 10
μg zinc/ml with or without 30% of kcal from ethanol throughout
gestation...
The continuous microreactor-assisted solution deposition (MASD) process was used for the deposition of CdS thin films on fluorine-doped tin oxide (FTO) glass. The MASD system, including a T-junction micromixer and a microchannel heat exchanger is capable of isolating the homogeneous particle precipitation from the heterogeneous surface reaction. The results show...
The primary goal of this thesis is to synthesize titanium dioxide nanorods using a continuous flow microreactor. Titania powder, one of the most important particulate materials is used for many purposes owing to its excellent optical properties of a high refractive index leading to high hiding power and whiteness of...
The various solution-based processes, spin coating, inkjet printing, microreactor assisted nanoparticle deposition (MANDTM) and spin-successive ionic layer absorption and reaction (Spin-SILAR) were used to demonstrate thin film electronics and anti-reflective coatings. Several aspects of thin film transistors (TFTs) were tested including a range of temperatures, annealing atmosphere, and deposition methods....
The earth is undergoing a “biodiversity crisis” characterized by loss of populations, species, genetic diversity, and ecosystem services. Part of this crisis consists of population declines, extinctions, and increased incidence of deformities in amphibians. It is unknown whether deformities contribute to these declines. Many cases of population declines in amphibians...
This research addresses sample process variance estimation on continuous domains and for non-probability samples in particular. The motivation for the research is a scenario in which a program has collected non-probability samples for which there is interest in characterizing how much an extrapolation to the domain would vary given similarly...