Browsing by Subject "Natural products"
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Item Biosynthesis of sulfur containing heterocycles in natural products(2016-12) Gengler, Jon Peter; Liu, Hung-wen, 1952-This thesis is a comprehensive review of the biosynthesis of sulfur containing heterocycles in natural metabolites. The review focuses on sulfur incorporation and cyclization of the moieties, with a lesser examination of the role these heterocycles play in the chemistry of their compound's activity.Item A carbolithiation approach toward the synthesis of 8-methyl-pyridoxatin(2011-05) Axelrod, Abram Joseph; Siegel, Dionicio R.; Magnus, Philip D.A stereoselective approach toward the synthesis of 8-methyl-pyridoxatin using an intramolecular carbolithiation strategy is discussed. Model studies have proven this approach is not feasible for the synthesis of 8-methyl-pyridoxatin.Item Development of multicomponent assembly processes and their application to the synthesis of novel heterocyclic scaffolds and the total synthesis of actinophyllic acid : application of an iminium ion mediated cascade(2013-08) Granger, Brett Adam; Martin, Stephen F.Several novel multicomponent assembly processes have been developed for the preparation of a diverse array of complex heterocyclic systems from relatively simple starting materials. These studies resulted in the discovery of a new quinazolone forming reaction, which was applied to the one-step synthesis of the quinazolinocarboline alkaloid rutaecarpine. Biological screening of these complex heterocycles culminated in the identification of a potent sigma-2 receptor ligand. A novel N-acyliminium ion mediated cascade reaction was employed for the concise synthesis of (±)-actinophyllic acid. The completion of the synthesis relied on the development of a reaction sequence that avoided a potentially detrimental fragmentation process. Furthermore, several anti-cancer compounds were identified through a diverted total synthesis approach.Item In vitro polyketide biocatalysis : triketide building-blocks and enzymology(2013-05) Harper, Andrew David; Keatinge-Clay, Adrian TristanPolyketide products are useful compounds to research and industry but can be difficult to access due to their richness in stereogenic centers. Type I polyketide synthases offer unique engineering opportunities to access natural stereocontrol and resultant complex compounds. The development of a controlled in vitro platform based around type I polyketide synthases is described. It has been used to produce a small library of polyketide fragments on an unprecedented and synthetically-relevant scale and explore polyketide synthase enzymology.Item Investigations into the biocatalytic potential of modular polyketide synthase ketoreductases(2013-08) Piasecki, Shawn Kristen; Keatinge-Clay, Adrian TristanThe production of new drugs as potential pharmaceutical targets is arguably one of the most important avenues of medicine, as existing diseases not only require treatment, but it is also certain that new diseases will appear in the future which will need treatment. Indeed, existing medicines such as antibiotics and immunosuppressants maintain their current activities in their respective realms, yet the molecular and stereochemical complexity of these compounds cause a burden on organic synthetic chemists that may prohibit the high yields required to manufacture a drug. The enzyme systems that naturally manufacture these compounds are incredibly efficient in doing so, and also do not use environmentally harmful solvents, chiral auxiliaries, or metals that are utilized in the current syntheses of these compounds; therefore utilizing these enzymes' machinery for the biocatalysis of new medicinally-relevant compounds, as researchers have in the past, is undeniably a rewarding endeavor. In order to harness these systems' biocatalytic potential, we must understand the processes which they operate. This work focuses on ketoreductase domains, since they are responsible for setting most of the stereocenters found within these complex secondary metabolites. We have supplied a library of substrates to multiple ketoreductases to test their limits of stereospecificity and found that, for the most part, they maintain their natural product stereospecificity seen in nature. We were even able to convert a previously nonstereospecific ketoreductase to a stereospecific catalyst. We have also developed a new technique to follow ketoreductase catalysis in real-time, which can also differentiate between which diastereomeric product is being produced. Finally, we have elucidated the structure of a ketoreductase that reduces non-canonically at the [alpha]- and [beta]- position, and functionally characterized its activities on shortened substrate analogs. With the knowledge gained from this dissertation we hope that the use of ketoreductases as biocatalysts in the biosynthesis of new natural product-based medicines is a much nearer reality than before.Item Model studies for the total synthesis of oscillatoxin A(Texas Tech University, 1988-12) Cunningham, Raymond ThomasThis account will describe the results of research on a model study for the total synthesis of oscillatoxin A. During the course of this work, major subunits of the target molecule were assembled and protecting group schemes were devised for use during the total synthesis. In addition, a new method for the selective benzylation of 1,2-diols was developed, and a new and highly efficient method for the synthesis of 3-deoxy-L-pentoses, compounds which are useful for the synthesis of nucleoside analogues, was discovered.Item Synthetic studies on a model system for the spirobicyclic ring system of oscillatoxin D(Texas Tech University, 1997-05) Jin, Xue-HuiThis thesis describes the development of some synthetic methodology applicable to the preparation of the spirobicyclic ring system of the marine natural product oscillatoxin D (1, Figure 1.1). Our goal was to find an efficient way to synthesize a major intermediate for the model compound (2) and thus to provide a guide for the subsequent synthesis of the natural product. Oscillatoxin D has shown some antileukemic activity and it might have undiscovered biological activity. It is a possible drug candidate.Item Synthetic studies on the pluramycin family of antitumor antibiotics : the total synthesis of isokidamycin(2010-12) O'Keefe, Brian Michael; Martin, Stephen F.; Krische, Michael J.; Bielawski, Christopher W.; Laude, David A.; Whitman, Christian P.A total synthesis of the complex C-aryl glycoside isokidamycin was achieved during an effort to construct the natural product kidamycin, a member of the pluramycin family of antitumor antibiotics. The angolosamine carbohydrate was appended, along with annelation of a benzene ring by the implementation of the Martin group's silicon tether-directed, intramolecular aryne-furan cycloaddition strategy. The vancosamine-derived carbohydrate was then installed by an O -> C-glycoside rearrangement. A novel protocol for the carbonylative cross-coupling of ortho-disubstituted aryl iodides with aryl boronic acids and alkynyl zinc reagents was also discovered during efforts to introduce the pyranone ring of kidamycin. The reaction proved general, as a variety of electron-rich and electron-poor aryl iodides, boronic acids, and alkynyl-zinc reagents participated in the cross-coupling.Item Total syntheses of the neuroregenerative natural products vinaxanthone and xanthofulvin and biosynthetic studies(2012-12) Axelrod, Abram Joseph; Siegel, Dionicio R.; Philip, Magnus D; Michael, Krische J; Keatinge-Clay, Adrian T; Pierce-Shimomura, JonathanTotal syntheses of the neuroregenerative natural products vinaxanthone and xanthofulvin have been accomplished. The synthetic routes to both molecules utilize a highly regioselective furan Diels-Alder cycloaddition - aromatization sequence to furnish the catechol fragment present in both natural products. The pentasubstituted catechol was elaborated to a vinylogous amide which was used twice in both syntheses, exploiting the pseudosymmetry found in vinaxanthone and xanthofulvin. This approach enabled the dimerization of 5,6-dehydropolivione forming vinaxanthone, lending significant evidence to a non-enzymatically driven formation of vinaxanthone in Nature. The total synthesis of vinaxanthone was accomplished in nine steps, the shortest synthesis to date, and an additional route was devised to access a set of analogs for biological study. The first total synthesis of xanthofulvin was accomplished in 18 steps and the convergent nature of the synthetic plan allows for analog synthesis. The sets of vinaxanthone and xanthofulvin analogs will be used to examine their inhibition of Semaphorin3A, a protein which inhibits neuronal regeneration, and is the biological target for both molecules.