Browsing by Subject "Methodology"

Now showing 1 - 11 of 11

2,5-Cyclohexadienones as a Useful Launching Point for the Synthesis of the Briarane Diterpenoids and A Hypervalent Iodine-Mediated Synthesis of Oxazolines
(2015-05) Moon, Nicholas
The briarane diterpenoids are a large class of natural products derived from gorgonians and other corals from throughout the world. Despite the extremely large number of briaranes that have been isolated, along with the potent and diverse range of biological activities that have been observed, the total synthesis of the briaranes remains underexplored. A facile synthetic route to the briarane diterpenoids will aid in the further exploration of these molecules. Herein, we will describe a number of synthetic approaches that were evaluated to access a key fragment of the briarane diterpenoids. A key feature of all routes involves the use of 2,5-cyclohexadienone substrates as a diverse platform for the launching of the synthesis. Chapter 1 will provide background information on 2,5-cyclohexadienones. Methods for their synthesis, a survey of their diverse reactivity, and selected examples of their use in natural product synthesis will all be described. Emphasis will be given to reactivity patterns which aided us in our research. Chapter 2 will provide a brief survey of the briarane diterpenoids as well as some of the major biologically active families. Previous synthetic efforts used to access these molecules will also be described. Chapter 3 will describe our efforts to synthesize a key fragment of the briarane diterpenoids (referred to as the briarane stereotetrad) utilizing intermediates containing a bicyclic lactone. Chapter 4 will describe our successful efforts to access the briarane stereotetrad using monocyclic intermediates. The important influence of torsional strain in key steps, as well as a successful route to access the briarane stereotetrad will be described. Chapter 5 will report the results of a separate research project in which an iodine(III) promoted cyclization of N-allylamides to form oxazolines was studied. The development of optimum reaction conditions and the evaluation of the substrate scope will be described. Key results that suggest novel mechanistic details for this electrophilic oxidative cyclization will also be described.
Accessibility and Behavior Impacts of Bus-Highway System Interactions
(Minnesota Department of Transportation, 2019-04) Carlson, Kristin; Owen, Andrew
This research presents a series of accessibility methodologies developed for bus-highway system interactions. Accessibility is defined as the collective number of jobs that can be reached by a particular mode of transportation within a given travel time period. The effects of managed lanes (ML), park-and-ride (PNR), and travel costs on walk-up transit accessibility are measured for the Minneapolis–Saint Paul (Twin Cities) region. Each methodology is introduced, supported by a literature review, and described in detail before scenario results are presented. The final analysis uses the ML and PNR methodologies to establish a comprehensive transit accessibility profile for the Twin Cities, which accounts for the dual impact of auxiliary transportation facilities.
Cyclic enaminones: methodology development, total synthesis, and library construction.
(2011-12) Seki, Hajime
The cyclic enaminone lies at the core of this entire doctoral work. It possesses exceptionally versatile reactivities, and can thus be utilized in the synthesis of various alkaloids. The first chiral-pool approach to synthesize enaminones was reported in 2006 from the Georg group. However, partial racemization was observed in some cases. Also, homologated amino acids were synthesized or purchased as a starting material. To address these issues a novel strategy, that retained the use of amino acids was sought. We found that enaminones can be synthesized using a ketene cyclization. In this approach, a pendant enamine moiety underwent a nucleophilic addition to a ketene generated by the Wolff rearrangement of a diazoketone. The diazoketone can be synthesized from α-amino acid in a one-pot procedure. Although this approach utilizes α-amino acids and provides enantiopure enaminones, the solubility of amino acids as well as the use of diazomethane to prepare diazoketone became major obstacles to the scalable synthesis of various enaminones. In this regard, alternative methods to synthesize the diazoketones were explored. We found that diazoketones could be obtained from three readily available components: a primary amine, an alkyne, and bromo diazoacetone. Although the incorporation of chirality was not achieved, a wide variety of enaminones were synthesized in two steps from commercially available compounds, providing a facile access to an enaminone library. Enantiospecific syntheses of (–)-(5S,8R,9S)-5-(3-furyl)-8-methyloctahydroindolizin and its C8-epimer were accomplished using our enaminone chemistry. The devised synthetic routes are conventional but reliable and scalable, providing access to Nuphar alkaloids in 9 steps from N-Boc-(L)-proline. This work led to the correction of multiple prior publications. We were able to disclose the bindings of the major isomer to the central nervous system receptors. Although phenanthropiperidines are promising anti-cancer agents due to their potency, their neurological toxicities thwart therapeutic use. Assuming that the side-effects are caused by the blood brain barrier permeation of phenanthropiperidines due to their extremely lipophilic nature, endeavors to prepare a polar phenanthropiperidine library were made. Specifically, the synthesis of hydroxylated phenanthroquinolizidines was attempted. However, most of those compounds were found to be unstable.
How the role of socialization affects blended learning methodologies for faculty working with teams in a healthcare setting.
(2010-07) Kenny, Kevin J.
When looking at healthcare education settings, one barrier to understanding the nature of socialization and its effect on teaching methodology design is the advent of blended learning formats used within education departments. The author utilized qualitative research using grounded theory with deductive, verification and inductive processes to help determine how the role of socialization influence these methodologies. The intent of this study was to learn how socialization considerations affect blended learning methodologies and formats for faculty working with teams in a healthcare setting. The research included analysis of case studies derived from interviews of a medical school educator, graduate school faculty member, clinical laboratory educator and professional developer working at Mayo Clinic and the University of Minnesota. Interviewees were key members in each of their respective areas and had varying levels of background using blended learning formats for groups/teams in their courses. The primary question posed to the interviewees was: how does the role of socialization affect blended learning methodologies for faculty working with teams in a healthcare setting? The author utilized NVivo software to code transcripts and to help with analyzing interviews and other data. Additionally, triangulation of the raw data was used with other researchers experienced in qualitative research. Results of the study are continually forthcoming but themes emerged centered around methodologies fostering three attributes of socialization for groups in healthcare classes: development of mutual respect in the blended format, developing a common ground for students, and understanding a student's purpose or vested interest in the group and class. Additionally, the study suggested the need for faculty awareness when designing blended learning formats to include methodology that bridges learning content with service aspects which are important in developing healthcare workers. Experienced faculty members/physicians/professional developers feel that with the large of amount of content available online, a sense of entitlement may occur with students who do not feel a need to build the socialization aspect of learning. This may shape long-term development of healthcare workers relative to patient care and overall quality. Implications of the study suggest the need for faculty development and organizational support that focuses on helping experienced healthcare teachers understand the socialization aspects of effective blended learning course design. Faculty working with groups in blended learning need to build confidence and skill levels when deciding the right balance of social interaction and technology use for the particular outcomes they are looking for in their courses.
Incorporation of Covariates in Bayesian Piecewise Growth Mixture Models
(2022-12) Lamm, Rik
The Bayesian Covariate Influenced Piecewise Growth Mixture Model (CI-PGMM) is an extension of the Piecewise Growth Mixture Model (PGMM, Lock et al., 2018) with the incorporation of covariates. This was done by using a piecewise nonlinear trajectory over time, meaning that the slope has a point where the trajectory changes, called a knot. Additionally, the outcome data belong to two or more latent classes with their own mean trajectories, referred to as a mixture model. Covariates were incorporated into the model in two ways. The first was influencing the outcome variable directly, explaining additional random error variance. The second is the influence of the covariates on the class membership directly with the use of multinomial logistic regression. Both uses of covariates can potentially influence the class memberships and along with that, the trajectories and locations of the knot(s). This additional explanation of class memberships and trajectories can provide information on how individuals change, who is likely to belong in certain unknown classes, and how these class memberships can affect when the rapid change of a knot will happen. The model is shown to be appropriate and effective using two steps. First, a real data application using the National Longitudinal Survey of Youth is used to show the motivation for the model. This dataset measures income over time each year for individuals following high school. Covariates of sex and dropout status were used in the class predictive logistic regression model. This resulted in a two-class solution showing effective use of the covariates with the logistic regression coefficients drastically affecting the class memberships. The second step is using a simulation after the motivating real data application. Pilot studies were used to show if the model was suitable for a full simulation using the coefficients from the real data example as a basis for the data generation. Four pilot studies were performed, and reasonable estimates were found for the full simulation. The conditions were set up with a two class model. One class containing one knot, and the second class as a linear slope. Two class predictive covariates and one outcome predictive covariate were used. A full simulation with 200 generated datasets was performed with manipulated conditions being error variance, sample size, model type, and class probability for a 3x3x3x2 model with 54 total conditions. Outcome measures of convergence, average relative bias, RMSE, and coverage rate were used to show suitability of the model. The simulation showed the use for the CI-PGMM was stable and accurate for multiple conditions. Sample size and model type were the most impactful predictors of appropriate model use. All outcome measures were worse for the small sample sizes and became more accurate when the sample sizes were larger. Also, the simpler models showed less bias and better convergence. However, these differences are smaller when the sample size is sufficiently large. These findings were supported with multi-factor ANOVA comparing simulation conditions. Use of the CI-PGMM in the real data example and the full simulation allowed for incorporation of covariates when appropriate. I show that model complexity can lead to issues of lower convergence, thus the model should only be used when appropriate and the sample size is sufficiently large. When used, however, the model can shed light on associations between covariates, class memberships, and locations of knots that were previously unavailable.
Interview codings of attachment style:using profile analysis to understand the patterns involved.
(2011-01) Swinburne Romine, Rebecca Esther
Attachment style is frequently discussed in terms of profiles of early childhood risk factors. Those using attachment interview methods use their ratings of these risk factors in developing an attachment style rating. In spite of this, profile analysis has yet to be used to model specific attachment styles. By using a multiple regression profile analysis to model attachment style in terms of coder's ratings of early risk factors, we can test empirically whether individual elements are relevant and how. The study of attachments began with Freud in the middle of the last century. Since that time attachment style has been studied first by John Bowlby and Mary Ainsworth, and since that time by many others. Early views of attachment, including the identification of specific attachment styles, and the investigation of its stability are discussed, as well as the limitations of the existing research. Specifically, the paper addresses the need for additional research to support or refute the theoretical models of attachment structure. Many methods have been developed to assess attachment style, most of which are closely tied to one particular theoretical view of attachment structure. Because the data for this paper are drawn from a study which utilized a four-prototype model of attachment as assessed for a coded semi-structured interview, the best way to understand the resultant codes is through a profile analysis. By using a two-step multiple regression profile analysis procedure, we can assess the unique contributions of both the level of risk, and the pattern of risk factors. The multiple regression methodology has the additional benefit of allowing for both continuous predictors and criterion variables; something that is not possible with other profile analysis methodologies. This allowed me to run the regressions with both dichotomous and semi-continuous criterion variables which enable the detection of different patterns. The results indicate that both the profile patterns and level can predict the criteria. The pattern component however is significantly more predictive of the criteria. While the derived patterns differ from the predicted patterns, they remain consistent with theory. Overall, environmental risk factors such as abuse, neglect, and parental rejection were not predictive of attachment style or score, while individual risk factors such as anger at parents and rebellion, and the interactive factor of role reversal were highly predictive. This leads us to conclude that profiles are a viable method of understanding attachment styles, and that it is the individual's responses to the risk factors present in the childhood environment rather than those factors themselves which determine attachment style.
Macrocyclization Through Ene-Yne Cross-Coupling/Alkyne Reduction Tandem Reaction And Its Application In Natural Product Synthesis
(2015-09) Li, Wei
Chapter 1 — Macrocyclization Through Copper-Catalyzed Castro–Stephens Coupling/Alkyne Reduction Tandem Reaction Macrocycles, incorporating conjugated polyene subunits within the ring, are structural features found in a number of natural products that exhibit diverse and potent biological activities. Existing methods for the construction of such structures are limited and in many cases inefficient. We discovered an unprecedented copper-mediated reductive ene–yne macrocyclization reaction during our pursuit of the total synthesis of oximidine II. The reaction selectively generates an endocyclic Z-double bond through an intramolecular coupling of a vinyl iodide and a terminal alkyne fragment followed by in situ alkyne reduction. We developed this transformation as a general method for the preparation of polyunsaturated macrocycles. The reaction conditions were optimized and the scope of the reaction was extensively explored. It was found that the alkyne reduction step is driven by the release of the ring strain. Thus, the reaction is particularly efficient for suitably strained 11- to 13-membered E,Z-1,3-diene macrocycles. A complementary stepwise procedure was employed for the synthesis of larger rings. Finally, a plausible reaction mechanism was proposed based on experimental findings. HASH(0x7f87dd8493f8) Chapter 2 — Formal Total Synthesis of Lactimidomycin Lactimidomycin is a macrocyclic natural product that possesses potent in vitro and in vivo anti-tumor activities. We accomplished a facile, 9-step synthesis of an advanced intermediate for the total synthesis of lactimidomycin. The crucial 12-membered polyene lactone core structure was constructed employing our newly developed Castro–Stephens coupling/alkyne reduction tandem reaction. The stereocenters were established via asymmetric a vinylogous aldol reaction and a Marshall’s propargylation reaction. Chapter 3 — Synthesis and Biological Evaluation of Oximidine II Analogues Oximidine II belongs to a family of benzolactone enamide natural products that exert their cytotoxic effects through inhibition of V-ATPases. Unlike other members of this family, the structure-activity relationship (SAR) of oximidines has not been extensively investigated. Guided by computational analysis and previous studies in our group, we designed and synthesized two oximidine II analogues with simplified scaffold. The simplified benzolactone core was accessed through a ring-closing metathesis (RCM) reaction and the enamide side chain was installed via a copper-mediated C–N coupling reaction. The analogues were evaluated for their biological activity. The results revealed that these molecules were weakly cytotoxic to a number of cancer cell lines.
Method Development and Degradation Studies to Verify the Stabilization of a Gallium Prodrug of Epinephrine
(2021-09) Livezey, Nicholas
Utilizing the unique and varied properties of metals, such as their redox activity, lability, and net charge, metal-based prodrugs can be designed and optimized for numerous applications. The most prominent usage of metal-based prodrugs has historically been anti-cancer agents, though there have been more recent efforts in the development of theranostic and antimicrobial agents as well. Gallium has promise for extending the scope of metal-based prodrugs, as it has been FDA approved for the treatment of tumors and hypercalcemia. Epinephrine is a compelling target for a gallium-based prodrug as conventional prodrugs are not suitable for the treatment of anaphylactic shock. This is because the prodrugs are inactive during their long half-lives. Additionally, as should mitigate drug degradation from high pH, light, and heat. The development of a novel gallium prodrug of epinephrine establishes the first prodrug treatment of anaphylactic shock, and extends the chemical space of metal-based prodrugs.
Minnesota Taconite Workers Health Study: Environmental Study of Airborne Particulate Matter in Mesabi Iron Range Communities and Taconite Processing Plants - Development of Standard Operating Procedures for Particulate Collection and Gravimetric Analysis
(University of Minnesota Duluth, 2019-12) Monson Geerts, Stephen D; Hudak, George J; Marple, Virgil; Lundgren, Dale; Olson, Bernard; Zanko, Lawrence M; Bandli, Bryan; Brecke, Devon M
The Minnesota Taconite Workers Health Study (MTWHS) was initiated in 2008 and included a multicomponent study to further understand taconite worker health issues on the Mesabi Iron Range (MIR) in northeastern Minnesota. Approximately $4.9 million funding was provided by the Minnesota Legislature to conduct five separate studies related to this initiative, including:  An Occupational Exposure Assessment, conducted by the University of Minnesota School of Public Health (SPH);  A Mortality (Cause of Death) study, conducted by the University of Minnesota SPH;  Incidence studies, conducted by the University of Minnesota SPH;  A Respiratory Survey of Taconite Workers and Spouses, conducted by the University of Minnesota SPH; and  An Environmental Study of Airborne Particulate Matter, conducted by the Natural Resources Research Institute (NRRI) at the University of Minnesota Duluth (UMD). NRRI’s “Environmental Study of Airborne Particulate Matter” comprises a multi-faceted characterization of size-fractionated airborne particulate matter (PM) from MIR community “rooftop” locations, background sites, and all taconite processing facilities active between 2008 and 2014. Characterization includes gravimetric determinations, chemical characterization, mineralogical characterization, and morphological characterization. This report discusses the standard operating procedures for particle collection and gravimetric analysis. The methodology and practices that have been developed and performed have been completed in conjunction with NRRI’s Science Advisory Board and in collaboration with aerosol scientists at the University of Minnesota Department of Mechanical Engineering and University of Florida-Gainesville. As well, this report outlines the development of the sampling methodology and the history of in-house experiments conducted throughout the project to strengthen the sampling design that ultimately resulted in the development of the standard operating procedures adopted by, and practiced in, this portion of the study. Definitions for specific terms used in this document are consistent with terminology described in Appendix G.
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.
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.

University Digital Conservancy

Browse by Subject

Browsing by Subject "Methodology"