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Handley, Paul Newton. "The chemistry of some Australian natural products /." [St. Lucia, Qld.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16940.pdf.
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Heaviside, Elizabeth Anne. "Analogues of antibacterial natural products." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:6b5bd771-515b-49d0-8ec9-cee115d3aebf.
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Analogues of Antibacterial Natural Products Elizabeth Anne Heaviside, St Catherine’s College, University of Oxford DPhil Thesis, Trinity Term 2012 This thesis is concerned with the synthesis and biological evaluation of structural mimics for the natural products 16-methyloxazolomycin and lemonomycin which display potent biological activity including antibacterial and antitumour activity. Chapter 1 explores methods and approaches to the discovery of new antibacterial drugs and the challenges faced in this respect. It also gives an overview of the properties of the natural products investigated in the following chapters and summarises previous synthetic approaches to these molecules published in the scientific literature. Chapter 2 describes the work carried out towards the synthesis of the diazabicyclo[3.2.1]octane unit of the tetrahydroisoquinoline antitumour antibiotic lemonomycin. The intended retrosynthesis of the natural product led to a 2,5-disubstituted pyrrolidine bearing a 1ʹ-amino functional group; a series of routes were explored for the synthesis of this unit. Using (S)-pyroglutamic acid, strategies using Eschenmoser and thiolactim ether coupling reactions were investigated. A sequence based on the formation of a pyrrolidine ring from the cyclisation of an appropriately substituted oxime ether derived from L-phenylalanine was then implemented but a competing Beckmann rearrangement/Grob fragmentation prevented access to the desired heterocycle. Preliminary investigations were also carried out on the modification of cyclic imines derived from oxime ethers which did not undergo Beckmann rearrangement. Chapter 3 describes the synthesis of a library of densely functionalised tetramic acid and pyroglutamate mimics for the right-hand fragment of 16-methyloxazolomycin, and their coupling with a gem-dimethylamide unit mimicking the middle fragment of the natural product. Tetramates were accessed through the Dieckmann cyclisation of N-acyloxazolidines and were derivatised with various alkyl halides. The pyroglutamates were accessed via the highly diastereoselective aldol cyclisation of N-acyloxazolidines formed by the amide coupling of a threonine derived oxazolidine and β-keto-acids. A series of β-keto-acids were synthesised through the acylation and subsequent ring-opening/decarboxylation reaction of Meldrum’s acid. The formation of right-hand/middle fragment adducts was explored using cycloaddition, alkylation and Sonogashira chemistry before a Wittig protocol led to the formation of adducts (E)- and (Z)- 402 and 403. Biological evaluation of the compounds synthesised in this chapter was carried out using both broth and hole-plate bioassays and active compounds were identified. Of particular note was that the Wittig adducts displayed a higher level of activity against Gram-negative E. coli than either the pyroglutamate or amide motifs alone.
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Anderson, Margaret Marie. "Cytotoxic and antimalarial natural products." Thesis, University College London (University of London), 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320404.
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van, der Sar Sonia. "Studies in the chemistry of fungal natural products." Thesis, University of Canterbury. Chemistry, 2006. http://hdl.handle.net/10092/1333.
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Natural products as sources of novel therapeutic agents experienced a steady increase from around the turn of the twentieth century until it peaked in the 1970s and 1980s. However since this time pharmaceutical research in natural products has experienced a decline. Despite this trend the natural products industry now seems to be experiencing a revival of sorts. This thesis represents a continuation of the work on the isolation and structure elucidation of potential drug leads from terrestrial fungal sources that the natural products group at the University of Canterbury is engaged in. The known compound, pseurotin A (2.7) and two novel diastereomers, pseurotin A2 (2.8) and pseurotin A3 (2.9) were isolated from the extract of a Penicillium sp. of fungus collected from the foreshore of a beach in Vancouver, Canada. The absolute stereochemistry of pseurotin A2 and proposed absolute stereochemistry for A3 were elucidated using a combination of X-ray crystallography (A2 only), circular dichrosim, oxidative cleavage reactions, and J2-resoved 2D NMR experiments. The extract of an as yet unidentified endophytic fungus has yielded eight novel compounds related to the spirobisnaphthalene class of compounds. These eight compounds fall into to distinct groupings. The spiro-mamakones, distinguished by a structurally unprecedented oxygenated spiro-nonene skeleton, comprise five compounds, spiro-mamakones A-E (3.11, 3.15-3.18). In addition to these naturally occurring compounds, the semi-synthetic compounds, 4-oxo-spiro-mamakone A (3.12) and O-acetyl-spiro-mamakone A (3.21), were also synthesised. spiro-Mamakone A was found to be racemic, while X-ray crystallography and optical rotation revealed spiro-mamakone C (3.15) to be present as an enantiomeric mixture (4S*, 5S*, 9R*). Unfortunately the enantiomeric excess was unable to be elucidated. NOE experiments revealed spiro-mamakone B (3.16) to have the relative stereochemistry 4S*, 5S*, 9S*. The relative stereochemistry of spiro-mamakones D (3.17) (4S*, 5S*, 8S*, 9S*) and E (3.18) (4S*, 5S*, 8S*, 9R*) was proposed from comparison of coupling constant calculations from energy-minimised models with those of the experimentally determined values. The second group, comprising three novel compounds named the mamakunoic acids, mamakunoic acid A-C (3.8, 3.7, 3.10), are characterised by their acid substituted dihydro benzofuran system. The low yield obtained of these compounds, unfortunately prevented their stereochemical elucidation. In addition to structure elucidation, biosynthetic studies on spiro-mamakone A and mamakunoic acid B were also carried out. Analysis of the NMR spectra derived from spiro-mamakone A, labelled with isotopic acetate, revealed a situation complicated by the presence of isotopomers and racemisation, resulting in NMR spectra that were somewhat anomalous in appearance. These irregularities however, were resolved leading to the proposal that spiro-mamakone A was derived from a dihydroxynaphthalene (DHN) intermediate, which proceeds through to spiro-mamakone via an epoxide intermediate. Despite problems with purity and low yields of isotopically labelled mamakunoic acid B, it was proposed that like spiro-mamakone A, it proceeded via a DHN intermediate. The extract derived from a Malaysian Scleroderma sp. was found to contain a new dichlorinated pulvinic acid derivative, methyl-3',5'-dichloro-4,4'-di-O-methylatromentate (4.14), the structure of which was confirmed by X-ray crystallography. In addition three previously reported compounds, 4,4'-dimethoxyvulpinic acid (4.11), methyl-3'-chloro-4,4'-di-O-methylatromentate (4.12) and methyl-4,4'-dimethoxyvulpinate (4.13), were also isolated. The extract of another, as yet unidentified endophytic fungus was found to contain the new acetogenin, 1,5-dihydroxy-6-(2-hydroxyethyl)-3-methoxyacetophenone (5.7), differing from the known compound, 2,4-dihydroxy-6-(2-hydroxyethyl)-3-methoxyacetophenone (5.8) only by virtue of the substitution pattern. The structure of 5.7 was confirmed by X-ray crystallography. The implementation of efficient dereplication procedures is paramount for those working in the field of natural products. The recent advances that have been made in the dereplication process in the natural products group at the University of Canterbury are given using examples from this research and where necessary from other group members.
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Hickford, Sarah Jane Herbison. "Studies in the Chemistry of Marine Natural Products." Thesis, University of Canterbury. Chemistry, 2007. http://hdl.handle.net/10092/1429.
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Compounds from the marine environment exhibit a wide variety of biological activities, and thus hold much promise as potential drugs. The halichondrins, isolated from the Kaikoura sponge Lissodendoryx sp. are no exception to this, demonstrating potent anticancer activity. Novel cytotoxic compounds have also been isolated from the Chatham Rise sponge Lamellomorpha strongylata. Knowledge of the cellular origins of such compounds is desirable, in order to establish if the sponge or associated micro-organisms are producing the compounds of interest. Siderophores are also important molecules, which are produced on demand by bacteria in order to obtain sufficient iron necessary for their growth. Knowledge of the biosynthesis of these compounds has potential for the control of undesirable bacteria, such as the anthrax-causing pathogen Bacillus anthracis. Cell separation studies have been carried out on Lamellomorpha strongylata, locating a swinholide in sponge-associated filamentous bacteria and theonellapeptolides in sponge-associated unicellular bacteria. A microscopic analysis of dissociated cells from Lissodendoryx sp. was also undertaken. The structures of four new halichondrins (3.13 - 3.16), isolated from Lissodendoryx sp., have been determined from spectral data. All of these compounds are very similar to known B series halichondrins, with differences occurring only beyond carbon 44. As biological activity has been shown to be derived from the portion of the molecule between carbons 1 and 35, they all retain good activity in the P388 assay as expected. A new siderophore, petrobactin sulfonate (4.2), was characterised, along with three cyclic imide siderophore derivatives (4.3 - 4.5). Petrobactin sulfonate is the first marine siderophore containing a sulfonated 3,4-dihydroxy aromatic ring. The structures were elucidated from spectral data, resulting in a revision of the NMR assignments of petrobactin.
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施麗琼 and Lai-king Sy. "Structure elucidation and oxidation chemistry of natural products." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1998. http://hub.hku.hk/bib/B3123768X.
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Jabbar, Abdul. "The chemistry of natural products of the Rutaceae." Thesis, University of Aberdeen, 1987. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU498401.
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Obligately anaerobic bacteria of the genus Bacteroides are important and abundant inhabitants of the rumen and hind gut of mammals. They are the most numerous group in the rumen and play a major role in fibre degradation with the rumen. They are phylogenetically remote from the better studied groups of facultatively anaerobic gut bacteria (eg. enterobacteria), but are closely related to the colonic Bacteroides. Interstrain conjugal transfer of a plasmid, pRRI4 (coding for tetracycline (Tc) resistance), from the multiple plasmid bearing B.ruminicola strain 223/M2/7 to F101, a rifampicin resistant mutant of B.ruminicola B 14, was demonstrated. pRRI4 was demonstrated to be self transmissible and carried the genes coding for TcR in B.ruminicola. Transformation of B.ruminicola F101 to TcR with pRRI4 was achieved using electroporation at frequencies up to 106 per mug DNA. Four other B.ruminicola strains were not transformed with this plasmid nor was a strain of B.uniformis. Similar procedures gave transformation of B.uniformis strains, but not B.ruminicola strains, with the E.coli:Bacteroides shuttle vectors pDP1 and pE5-2 at frequencies up to 107 per mug DNA. A nuclease assay was developed to determine the nuclease activity of a number of rumen bacteria and high nuclease activity in all B.succinogenes and five B.ruminicola strains was demonstrated. E.coli and B.uniformis strains were also transformed using electroporation by the shuttle vector, pRRI207, which has been constructed from a cryptic B.ruminicola plasmid (pRRI2, 3.4kbp) cut with EcoRI* , an E.coli vector plasmid (pHG165, 3.37kbp) carrying the pUC8 multiple cloning site, and the 4.2kbp Cc-EmRTc R* EcoRI region of pDP1. pRRI207 is capable of transforming B.uniformis, B.distasonis and B.ruminicola to clindamycin (Cc) resistance and E.coli to TcR (only expressed aerobically), and was the only construct from eleven different constructs obtained based on pRRI2 able to do so.
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Sy, Lai-king. "Structure elucidation and oxidation chemistry of natural products /." Hong Kong : University of Hong Kong, 1998. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19737300.
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Blasiak, Leah Cameron. "Crystallographic studies on enzymatic halogenation of natural products." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/42914.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2008.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Vita.
Includes bibliographical references.
Halogenated natural products are common and serve roles as hormones, pesticides, antibiotics, and anti-tumor agents. The incorporation of a halogen atom into an organic scaffold can tune the molecule's potency and selectivity, making halogenation an important tailoring reaction. To understand the mechanisms of enzymatic halogenation of natural products, X-ray crystallography was used to solve structures of enzymes from two classes of halogenases, the flavin-dependent halogenases and the non-heme iron dependent halogenases. Structures of the flavin-dependent tryptophan 7-halogenase RebH from Lechevalieria aerocolonigenes, involved in rebeccamycin biosynthesis, were solved by molecular replacement. These structures show distant flavin and L-Trp binding sites and identify the conserved residue Lys79 as a likely candidate for covalent modification to produce an enzyme-bound lysine chloramine intermediate. A lysine chloramine at this position would direct the chlorination reaction to the correct site on the substrate, which could account for the halogenase's observed regioselectivity. Crystal structures of the non-heme iron-dependent threonine 4-halogenase SyrB2 from Pseudomonas syringae, involved in syringomycin biosynthesis, were solved using selenomethionine labeling and single wavelength anomalous dispersion (SAD) techniques. These structures show an overall cupin or [beta]-sandwich fold and a novel iron binding motif containing a naturally occurring iron-chloride bond. The carboxylate ligand typically found in non-heme iron dependent hydroxylases is replaced by an alanine residue in the halogenases, opening a coordination site for the halide and suggesting a mechanism by which these enzymes accomplish halogenation instead of hydroxylation.
(cont)The final chapter of this thesis reviews the known classes of halogenating enzymes and examines questions of halide binding and selectivity from the perspective of protein structure.
by Leah Cameron Blasiak.
Ph.D.
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Mahaney, Paige E. (Paige Erin). "Efforts toward the synthesis of taxane natural products." Thesis, Massachusetts Institute of Technology, 1996. http://hdl.handle.net/1721.1/38760.
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McAulay, Kirsten. "The total synthesis of furanocembrane natural products." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8448/.
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The furanocembranes are a family of marine diterpenoids isolated from octocoral invertebrates. These macrocyclic natural products possess interesting molecular structures including a furan ring at C3-C6 and a butenolide moiety encompassing C10-C12. As well as their unique structures, family members have shown promising biological activities, and thus they represent attractive synthetic targets. This thesis describes the synthetic efforts towards two of these family members: pukalide and 7-acetylsinumaxmol B. In particular, focus has been directed towards the investigation of different synthetic strategies and the synthesis of key fragments; culminating in the total synthesis of 7-epi-pukalide and 7-acetylsinumaximol B. The key synthetic approach undertaken was designed to take advantage of new methodology developed by our group for the synthesis of highly functionalised furans, including epoxy-furans, in which tetrahydrothiophene (THT) was used as an organocatalyst. The reaction promotes the formation of both a furan and an epoxide in one step from a Knoevenagel condensation product. In the first approach described herein, an intramolecular Knoevenagel condensation strategy for macrocycle formation was explored. The C12-C14/C1-C4 and C5-C11 were initially coupled through esterification; however, after further functionalisation, macrocyclisation could not be effected under Knovenagel conditions. The second approach focused on the use of an intermolecular Knoevenagel condensation reaction for fragment coupling. Although fragment coupling was successful further functionalisation proved to be difficult because of the reactive nature of the ynenone intermediates. The third and final approach investigated the development of a one-pot condensation and furan formation; combining the Knoevenagel condensation with organocatalytic tetrahydrothiophene to produce the furan directly from two separate fragments. This approach was successful, allowing completion of the full skeleton to be effected through macrolactonisation and ring-closing metathesis. Following this strategy both 7-epi-pukalide and 7-acetylsinumaximol B were accessed in 16 steps from the chiral pool starting material (R)-perillyl alcohol.
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Pasqua, Adele Elisa. "Total synthesis of enamide-containing natural products." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4088/.
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Enamides are an important class of functional group commonly present in natural products and drug candidates. In particular, enamides and dienamides are common in many anti-parasitic and anti-cancer natural products and pharmaceutical drug leads. The enamide moiety is strictly related to the biological activity of such compounds as it is directly involved in their mode of action. Due to the great importance of the enamide moiety in biological and medicinal chemistry, a deep interest has risen in the synthetic community in the past two decades and a wide variety of methodologies for the preparation of enamides have been developed so far. However, current methods suffer from poor efficiency and stereocontrol, in particular in the case of the thermodynamically unfavoured (Z)-enamides. The work reported herein details the development of a new methodology for the stereoselective synthesis of β-halo-enamides and β,β-dihalo-enamides from which it is possible to synthesise, via Pd-mediated cross-coupling reactions, more complex structures, such as β-yn-enamides, stereodefined (E,Z)-dienamides and branched products. In addition, oxazoles can be achieved via basic treatment of β-halo-enamides. The methodology has been successfully applied to the total syntheses of simple enamide-containing natural products, such as lansiumamide A, lansiumamide B and alatamide. The total synthesis of a more complex family of enamide-containing natural products, such as the antifungal, antibiotic and cytotoxic crocacins, was also explored. The attention was focused firstly on (+)-crocacin C that is the primary amide and can be envisioned as the synthetic precursor of the other crocacins, and secondly on (+)-crocacin D, that is the most active and promising of the family. Two novel syntheses of (+)-crocacin C and (+)-crocacin D are therefore reported. The synthesis of simplified unnatural analogues with some promising insecticidal activity is also described.
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Dengada, Amrapali Harishkumar. "Isolation and Structural Elucidation of Compounds from Natural Products." Thesis, Virginia Tech, 2014. http://hdl.handle.net/10919/64303.
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Isolation and Structural Elucidation of Compounds from Natural Products
Amrapali H. Dengada
In continuation of the Kingston group's work to identify new compounds from natural products as a part of the International Cooperative Biodiversity Group (ICBG) program and in collaboration with the Institute for Hepatitis and Virus Research (IHVR), the two plants Neoharmsia baronii and Lopholaena cneorifolia were studied to identify their chemical components. Structural elucidation and characterization of the compounds were done using mass spectrometry, 1D and 2D NMR spectroscopy techniques.
A systematic study of the ethanol extract of the plant Neoharmsia baronii Drake from the Madagascar forest led to the isolation of seven compounds, characterized as isoflavones and pterocarpans. The structures of the compounds were characterized by using 1D NMR and 2D NMR spectra, mass spectroscopy and in one case, x-ray crystallography. The HSQC and HMBC data along with comparison of these data with reported literature values confirmed the structures. The aforementioned isoflavones and pterocarpans showed varying cytotoxicity to ovarian cancer cell lines, with the isoflavone vogelin E being the most active compound.
The extract of Lopholaena cneorifolia was studied as a part of a cooperative project with the IHVR to identify its chemical composition. Fractionation of this extract led to the isolation of three compounds which were characterized as stilbenes. Their structures were elucidated by using 1D NMR and 2D NMR spectra and mass spectroscopic data.Master of Science
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Hou, Yanpeng. "Antiproliferative Natural Products from the Madagascar Rainforest." Diss., Virginia Tech, 2009. http://hdl.handle.net/10919/39467.
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As part of an International Cooperative Biodiversity Groups (ICBG) program and a continuing search for anticancer natural products from the Madagascar rainforest, twenty extracts from Madagascar were selected for investigation based on their antiproliferative activity. Bioassay-guided fractionation of five of the extracts yielded sixteen new compounds, and their structures were determined using a combination of 1D and 2D NMR experiments, including COSY, HSQC/HMQC, HMBC, and ROESY/NOESY sequences, mass spectrometry, and chemical conversion. In addition, ten known compounds were obtained from five of the extracts. Studies on the remaining extracts were suspended due to various reasons. A multi-step synthesis of the sesquiterpenoid, (7R*)-opposite-4(15)-ene-1beta,7-diol, was also described.
The first chapter of this dissertation reviews the new compounds isolated from Malagasy plants and marine organism in the last two decades. Chapters II to VI discuss the isolation, structure elucidation and bioactivities of new compounds from Scutia myrtina, Cordyla madagascariensis ssp. madagascariensis, Elaeodendron alluaudianum, Cassipourea lanceolata, and Sclerocarya birrea subsp. caffra. Chapter VII describes the synthesis and bioactivity of the sesquiterpenoid,(7R*)-opposite-4(15)-ene-1beta,7-diol. The isolation of known compounds is discussed briefly in the last chapter.Ph. D.
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Hans, Renate Hazel. "Novel Antimalarial and Antitubercular Agents Based on Natural Products." Doctoral thesis, University of Cape Town, 2009. http://hdl.handle.net/11427/6311.
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Malaria and tuberculosis are listed among the major infectious diseases. They are responsible for severe morbidity and mortality especially in resource-poor settings where control interventions are inaccessible, unaffordable and plagued by widespread resistance. According to current estimates, malaria afflicts over 40% of the worldâs population and claims the lives of 1-3 million annually. The epidemiology of tuberculosis is just as grim. About one third of the world population is reported to be infected with Mycobacterium tuberculosis and it is responsible for 2-3 million deaths annually. Of particular interest to this project, is the fact that natural products have always been on the frontline in the battle against these diseases, that is, most of the clinically used drugs in antimalarial and antitubercular chemotherapy are of natural product-origin. In this project we therefore focussed on the design, synthesis, characterization and biological evaluation of novel antimalarial and antitubercular agents obtained by synthetically hybridizing and decorating scaffolds based on natural products or derivatives - with a history in the aforementioned disease models. Scaffolds selected include the thiolactone ring system, a key intermediate of the natural product thiolactomycin, the non-peptidic natural product isatin and the chalcone scaffold. In this way a series of hybrids were constructed which can be subdivided into three main groups: (i) thiolactone-isatin hybrids, (ii) -amino alcohol thiolactone-chalcone and isatin-chalcone hybrids, and (iii) dihydroartemisinin-isatin, dihydroartemisinin-chalcones and other miscellaneous hybrids. These were evaluated for antiplasmodial activity against the chloroquine resistant (W2) and chloroquine sensitive (D10) strains of Plasmodium falciparum as well as for inhibitory activity against cysteine proteases. Evaluation of antimycobacterial activity of the synthesized compounds against the drug sensitive H37Rv strain of M. tuberculosis was also undertaken. (i) For the first group of hybrids we used the C-4 hydroxyl group of the thiolactone ring as a handle for functionalization by attaching it via a variable, non-hydrolyzable alkyl linker to the isatin scaffold. Most striking, is the operational simplicity of the synthesis methodology employed and how it led to the discovery of a novel tetracyclic ring system. Identified from the latter is the compound 3.8p which is the most active antimalarial from this series with an IC50 of 6.92 μM in the W2 strain. Some of the hybrids (3.7 and 3.8) were more active than the monomers and the parent drug thiolactomycin, thus demonstrating the potential of hybridization as a drug discovery tool. Antimalarial structure activity relationships for the novel tetracycles 3.8 revealed the importance of substitution at C-5 of the isatin scaffold and vi the need for increased lipophilicity. Although the antitubercular activity of the hybrids was inferior compared to the control drugs, a number of advanced intermediates were identified which displayed promising activity against both fast growing and slow-growing, persistent forms of M. tuberculosis. (ii) The second group of hybrids consisted of a 36-member library obtained by the covalent linkage of methoxylated chalcones with the thiolactone ring and the isatin scaffold. Incorporated in their design is the -amino alcohol moiety, a known bioactiphore. For the synthesis of these hybrids we employed the copper-catalyzed Huisgen 1,3-dipolar cycloaddition reaction (also know as âclickâ chemistry) which in addition to expediting structure activity relationship studies yielded the 1,2,3-triazole ring system. The antiplasmodial results showed that the thiolactone-chalcones, with IC50s ranging from 0.68 to 6.08 μM, were more active against the W2 strain than the isatin-chalcones (IC50 = 2.09 - 14.90 μM). More so, structure activity relationships delineated for the former indicated the preference for triOMe substitution on ring A of the chalcone scaffold. The most active compound for this series 4.14f [IC50 = 0.68 μM (W2)] is 10-fold less active than chloroquine but has a greater efficacy than the parent natural product thiolactomycin. Results obtained for cysteine protease activity showed that the isatin-chalcone hybrids inhibited falcipain-2 activity, whereas the thiolactone-chalcone hybrids were devoid of enzyme inhibitory activity. With regard to antitubercular activity, the advanced intermediates were more active than the hybrid constructs. The most promising antitubercular agent identified is the acetylenic chalcone 4.10f (MIC = 13.1 μM) which is 2-fold more active than one of the controls, moxifloxacin (MIC = 31.1 μM) against the slow-growing persistent forms of M. tuberculosis. (iii) The final group of compounds is a limited series of semi-synthetic artemisinin analogues obtained by hybridizing the first generation analogue, dihydroartemisinin with previously mentioned scaffolds (isatin, chalcones, thiolactone) and other biologically relevant scaffolds such as the 4-aminoquinoline unit and azidovudine (AZT). As with the previous series we utilized the âclickâ reaction to effect the synthesis of these hybrids. The most active compound identified is the intermediate 5.4 [IC50 = 6.13 nM (W2)] which is more active than the parent natural product artemisinin [IC50 = 10.84 nM (W2)], 16 times more active than chloroquine and 2-times less active than dihydroartemisinin. The lack of antitubercular activity of compounds in this series moreover confirmed the antimalarial specificity of artemisinin analogues.
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Clark, J. Stephen. "Approaches to the synthesis of oxocane natural products." Thesis, University of Cambridge, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293810.
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Newman, Nicola Ann. "Cyclisation strategies towards the synthesis of natural products." Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342637.
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Blunt, Christoper Edward. "The synthesis of benzisothiazole and benzothiazole natural products." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/49541/.
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Chapter 1 gives an introduction to benzisothiazole and benzothiazole natural products. It explores the scope of natural products that are known within these families and discusses what they are used for, how they have been made and how they may have been biosynthesised. Chapter 1 provides a review of each family of natural products in turn. Chapter 2 describes the total synthesis of the benzisothiazole natural products aulosirazole and pronqodine A, and a series of unnatural analogues. The Chapter begins with a short discussion on the use of the Diels-Alder reaction for the formation of naphthoquinones, then illustrates this strategy for the first synthesis of aulosirazole. The chapter continues with the synthesis of pronqodine A, a structurally similar natural product. The Chapter ends with an evaluation of these compounds as inhibitors of indoleamine-2,3-dioxygenase. Chapter 3 contains work towards the synthesis of the benzothiazole containing natural product erythrazole A. The first half of the Chapter focuses on the formation of the heterocyclic core, originally attempting to use a biomimetic strategy but switching to an approach utilising the oxidative cyclisation of thioamides. The second half of the Chapter discusses many routes to synthesise and introduce the terpene derived side chain. Chapter 4 contains experimental detail for the work carried out.
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Kostiuk, Sarah Louise. "The total synthesis of macrocyclic bisbibenzyl natural products." Thesis, University of Southampton, 2009. https://eprints.soton.ac.uk/193731/.
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This thesis is concerned with the total synthesis of two related macrocyclic natural products, cavicularin and riccardin C. Cavicularin is particularly noteworthy owing to its interesting structure: its 14-membered macrocyclic core imparts sufficient strain on the system to force one of the arenes in this paracycophane to adopt a boat-shaped conformation, deviating from planarity. The natural product also exhibits optical activity despite containing no chiral centres, this being due to axial and planar chirality in the molecule. Herein, routes to these two natural products are presented. Key steps include a highly chemoselective hydrogenation and a Wittig macrocyclisation and, in the case of cavicularin, regioselective halogenation and radical induced transannular ring contraction. This work also furnished a number of highly strained macrocycles as precursors to the natural products. These structures were found to contain boat-shaped aromatic rings, in addition to twisted olefin functionalities. A discussion of these features is presented in Chapter 6, with full crystallographic data provided in the Appendix. A review of these and related bisbibenzyl natural products is presented in Chapter 1, including their isolation, characterisation, an overview of their biological activity and previous synthetic work. Experimental procedures and characterisation data are provided in Chapter 7
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Nolan, William Peter. "Synthesis of indolo[2,3-A]carbazole natural products." Thesis, University of Cambridge, 1990. https://www.repository.cam.ac.uk/handle/1810/272982.
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Leslie, Pauline. "Studies towards the synthesis of chlorinated natural products." Thesis, University of Bristol, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.268989.
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Dexter, Hannah. "Towards the synthesis of heterocycle containing natural products." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/40735/.
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Chapter 1 gives an introduction to ribosomally synthesised and post-translationally modified peptides. The different classes of this group of natural products are described. Examples of linear azol(in)e-containing peptides and cyanobactins are given, along with more detail about these classes of peptides and examples of their chemical synthesis. Chapter 2 explains the importance of the natural product goadsporin 64, along with the retrosynthesis and a review of methods to synthese oxazoles, thiazoles and dehydroalanines. The first total synthesis of goadsporin 64 is then reported, demonstrating the use of rhodium catalysis to construct the four oxazole rings. Synthesis of the N-terminal fragment 78 validated methods for incorporating the sensitive enamide functionality, and removal of the necessary protecting group. These methods were then applied to the full structure to complete the total synthesis. Chapter 3 describes work carried out towards the total synthesis of the wewakazole natural products, again using rhodium catalysis methodology. The structures of wewakazole A 65 and wewakazole B 66 share a largely peptidic fragment 267, differing only by the bis-oxazole fragments 266 and 268, allowing the synthesis of two natural products via three main fragments. Reported herein is the synthesis of the bis-oxazole fragments 266 and 268 of wewakazole A 65 and B 66.
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Hariprakasha, H. K. "Synthesis Of Natural Products Based On Cyclohexadienes." Thesis, Indian Institute of Science, 1996. http://hdl.handle.net/2005/118.
Full textAbstract:
The thesis entitled "Synthesis of Natural Products Based on Cyclohexadienes" consists of two chapters.
Chapter 1 is divided into two parts. Part I gives a brief introduction to the structure, synthesis, biosynthesis and biological activities of some naturally occurring phthalides (eg. mycophenolic acid 1, zinniol2, phthalides 3 & 4). A general strategy for the preparation of highly substituted phthalides is also described. Cycloaddition of 1,s-dimethoxycoclohexa-1, 4-diene with dimethylacetylenedicarboxylate(DMAD) followed by an Alder-Rickert reaction gave the diester 5 which upon hydrolysis with KOH and refluxing with acetic anhydride gave the phthalic anhydride 6. Regioselective reductions of the anhydride 6 gave the phthalides 7 and 8. Using a similar strategy the phthalides 11 & 12 were prepared from 2,6dimethoxytoluene through the intermediates 9 & 10. The aromatic ethers 13 & 14 upon Birch reduction followed by Diels-Alder reaction with maleic anhydride gave the bicyclic anhydrides 15 & 16 respectively. Attempts to dehydrogenate 15 using variety of conditions failed. But refluxing 15 in nitrobenzene gave a poor yield of 17 which is an important intermediate in the synthesis of mycophenolic acid. Part II describes the first total synthesis of zinniol 2, phthalide-1 3 & phthalide-2 4. Thus the diene 18, obtained from 2-methylcyclohexane-1,3dione, upon Diels-Alder and Alder-Rickert with DMAD gave the diester 19. Prenylation of 19 afforded the diester 20 which was convened into 21 upon hydrolysis and DCC treatment. DIBAL reduction of 20 gave Zinniol 2 which on oxidation provided the phthalides 3 & 4 (7:3 ratio respectively). The anhydride 21, on selective reduction, gave the same phthalides in 2:8 ratio which could be readily separated and characterized.
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Fisher, Michelle H. (Michelle Harriette). "Efforts towards the synthesis of stelliferin natural products : a thesis." Thesis, Massachusetts Institute of Technology, 1997. http://hdl.handle.net/1721.1/43440.
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Carazza, Rebecca J. (Rebecca Johnson) 1971. "Efforts toward the synthesis of natural products : a thesis presented." Thesis, Massachusetts Institute of Technology, 1998. http://hdl.handle.net/1721.1/47480.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1998.Includes bibliographical references.
by Rebecca J. Carazza.
Pt. A. Paeoniflorin -- pt. B. (+)- Taxusin.
Ph.D.
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Leroy, Vincent. "Studies relevant to the synthesis of nitrogen-containing natural products /." The Ohio State University, 1995. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487864485229217.
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Kondakal, Vishnu. "The attempted synthesis of indolizidine and pyrrolizidine natural products." Thesis, University of Huddersfield, 2013. http://eprints.hud.ac.uk/id/eprint/19281/.
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Aza-sugars are naturally occurring polyhydroxylated alkaloids in which the ring oxygen is replaced by nitrogen. They are reported to have a wide range of biological properties, most importantly as glycosidase inhibitors; these glycosidases play a key role in various diseases like HIV, cancer and lysosomal storage disorders. This thesis will describe an approach to the synthesis of analogues and precursors of azasugar natural products in the indolizidine (for example castanospermine) and pyrrolizidine (for example hyacinthacine) using cyclopropenones and cyclic imines as key intermediates. This thesis contains work that is an extension of the work pioneered by Eicher and Heimgartner and followed by our group for the reaction of cyclic imines with diphenylcyclopropenone. The methodology was extended towards the synthesis of more complex bicyclic heterocycles like indolizidine and pyrrolizidine aza-sugars and is summarised by the following Scheme. In this thesis, cyclopropenones other than diphenylcyclopropenone were used. This work also extended the range of cyclic imines that can be reacted by using for the first time, the parent aldimines, polyhydroxylated cyclic aldimines synthesised from sugars and other substituted cyclic imines. The reactions gave bicyclic products but always with an extra oxygen at the bridge head postion (X= OH) via aerial oxidation of the initial product (X= H).
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Berger, Raphaëlle. "The enantioselective total syntheses of eight cladiellin natural products." Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2565/.
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The cladiellins (also known as eunicellins) are oxygen-bridged 2,11–cyclised cembranoids, isolated from gorgonian octocorals and soft corals. They present an unusual oxatricyclic ring system composed of a hydroisobenzofuran and an oxonene unit. The natural role of these cembranoids is proposed to involve predatation deterrence, and biologically they have been shown to exhibit in vitro cytotoxicity against various cancer cell lines, anti inflammatory properties antimicrobial activities. The Clark group has been interested in the synthesis of cladiellins for some time, and in 2007 Clark and co-workers reported the total synthesis of vigulariol. This thesis describes the investigation of the synthesis of both E- and Z-cladiellins using our general strategy. The key transformations in the synthetic route are ring formation reactions. Firstly, a SmI2-mediated reductive cyclisation forms the tetrahydropyran ring, then a tandem oxonium ylide formation [2,3]-sigmatropic rearrangement constructs the oxabicyclo[6.2.1]undecenone bicyclic core. Finally, a Diels-Alder cycloaddition reaction forms the third ring of the tricyclic core of the cladiellins. Particular interest was given to the tandem oxonium ylide formation [2,3]-sigmatropic rearrangement reaction. This transformation was studied in order to develop conditions allowing the selective formation of the E-oxonene ring needed for the synthesis of the E-cladiellin tricyclic core. Herein, is presented work towards the synthesis of ophirin B, a cladiellin bearing a Z-oxonene alkene, as well as the enantioselective total synthesis of eight cladiellins obtained from an E-cladiellin tricyclic core: (−)-cladiella-6,11-dien-3-ol, (−)-cladiell-11-ene-3,6,7-triol, (−)-3-acetoxycladiella-6,11-diene, 3-acetoxy-cladiellin-11-ene-6,7-diol, (−)-sclerophytin A, (−)-sclerophytin B, (+)-deacetylpolyanthellin A and (+)-polyanthellin A in 20 to 24 steps from our allylic alcohol precursor.
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Wootton, R. C. R. "Synthetic approaches to polyoxygenated chromone and chromanome natural products." Thesis, University of Salford, 2000. http://usir.salford.ac.uk/2171/.
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The work described in this thesis is concerned with the chemistry of polymethoxylated aromatic carbonyl compounds bearing a 2,6-dioxygenated substitution pattern, with particular regard to establishing synthetic routes to biologically active chromone and chromanone systems. Syntheses of key intermediates in the approaches to the natural products stigmatellin, baicalein and LL-D253(x) (and related products) were undertaken. In chapter one the reactions of nucleophiles at the carbonyl moieties of 2,6- dioxygenated benzene carbonyl compounds are reviewed. This type of process can present special difficulties and was to prove particularly significant at various stages of the work described in subsequent chapters. Chapter two is a review of the provenance, abundance, biosynthesis, and previous syntheses of the natural products stigmatellin, baicalein and LL-D253(x), these being the targets of the synthetic work undertaken in the course of the project. Chapter three is concerned with an approach to a fragment of the stigmatellin molecule (referred to as stigmatellin fragment A) using the Vilsmeier formylation reaction, while chapter four is concerned with an alternative approach to stigmatellin fragment A using Friedel-Crafts acylation methodology. The strategies and the results obtained are described and analysed in detail. In chapter five a strategy for the synthesis of baicalein trimethyl ether is described and the results obtained are discussed.
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Brooks, Steven Halton. "Studies in methodology toward the synthesis of natural products." Thesis, University of Reading, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385612.
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Chau, Yasmin-Pei(Yasmin-Pei Kamal). "Biosynthesis and medicinal chemistry of therapeutically promising plant natural products." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/122839.
Full textAbstract:
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2019Cataloged from PDF version of thesis.
Includes bibliographical references.
Modern molecular biology, biochemical, and chemical techniques have made it possible to identify individual natural products that possess pharmacological activity from medicinal plants. While approximately 50% of all new FDA-approved small molecule therapeutics in the past 40 years were natural products or natural product analogs, challenges including limited natural resources and the difficulty of solving the total synthesis or semi-synthesis of natural products has limited our ability to harness the full diversity of chemical structures provided by nature to treat human diseases. One solution to these challenges is the elucidation of plant specialized metabolite biosynthetic pathways. Identifying and characterizing the enzymes involved in specialized metabolite biosynthesis will provide insight into the evolution of enzymes performing interesting chemistries and provide new tools for the enzymatic production of therapeutically promising natural products. The goal of this dissertation is to explore the aspects of both medicinal chemistry and the elucidation of biosynthetic pathways that can contribute to the development of novel therapeutics. First, we analyzed the structure-activity relationship of analogs of the the flavonoid icariin and identified analogs with improved potency in inhibiting human phosphodiesterase-5. We subsequently identified and characterized a novel flavonoid prenyltransferase and O-methyltransferase from the medicinal herb Epimedium sagittatum that is known to produce many bioactive prenylated and methylated flavonoids.
by Yasmin-Pei Chau.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biological Engineering
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Carter, Catherine Frances. "The application of flow chemistry to natural product synthesis." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610524.
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Khatri, Buddha Bahadur. "Photocycloaddition of Conjugated Enynes and its Application in Natural Products Synthesis." Diss., Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/374648.
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ChemistryPh.D.
Aromatic 2-pyridones and 2-pyrones are known to undergo a facile [4+4] photocycloaddition with themselves and other conjugated molecules. The unifying objective of this work is to explore the potential of conjugated enynes as a photocycloaddition partner with a variety of unsaturated systems and establish it as a path for the synthesis of valuable natural products and molecular scaffolds. With a 1,3-enyne as a reactant, the immediate photocycloadduct, a highly strained cyclic allene, was stabilized and functionalized to give advanced intermediates in natural product synthesis. Participation of substituted benzenes in higher order photocycloaddition with 2-pyridones was also discovered. Intramolecular enyne-pyridone [4+4] photocycloaddition led to the formation of cyclic, strained allenic products that undergo rapid dimerization through various modes leading to complex mixtures. Such allene-allene dimerization was suppressed by introducing steric shielding. With reactive tethered functional group present, the intermediate allene can undergo a secondary cycloaddition with either the proximal or distal double bond, depending on the tether length. In the absence of such functional groups, the allene can isomerize to a 1,3-diene. Oxidation of the allene led to a cyclopropanone, a bicyclo-[5.1.0]-octane, which was transformed into pseudoguaiane-like 7-5 ring systems. Participation of enynes in the photocycloaddition of other unsaturated systems was also investigated. Anthracene, naphthalene derivatives and 2-pyrones were all found to undergo quantitative photocycloaddition with an enyne. During this investigation, a low temperature Cope rearrangement was also discovered. In addition, meta-substituted benzenes were reluctant partners in [4+4] photocycloaddition with enynes but underwent efficient [4+4] photocycloaddition with 2-pyridones. The synthetic utility of enyne photocycloaddition was applied in the synthesis of the cyclooctanoid containing natural product, (+)-dactylol. The intramolecular enyne – 2-pyrone [4+4] photocycloaddition-isomerization gave a lactone bridged-cyclooctanoid product which serves as an advanced intermediate for sesquiterpene synthesis.
Temple University--Theses
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Murphy, Brian Thacher. "Isolation and Structure Elucidation of Antiproliferative Natural Products from Madagascar." Diss., Virginia Tech, 2007. http://hdl.handle.net/10919/29599.
Full textAbstract:
As part of an ongoing search for bioactive natural products from the endemic rainforests and surrounding ocean in Madagascar, a total of four extracts were comprehensively studied and were found to contain novel and/or bioactive compounds. The following dissertation discusses the isolation, structure elucidation, and bioactivity studies of these isolates.
The following compounds from plants of Madagascar's rainforest are discussed in the order they were studied: flavonoids and long-chain compounds from Schizolaena hystrix, a cyclohexene derivative and butenolides from Artabotrys madagascariensis, and limonoids from Malleastrum sp. From the Malagasy marine ascidian Trididemnum sp. collected in the Indian Ocean, the identification as well as the potential biosynthetic origin of polyketide derived bistramides is reported.
n an attempt to explore other facets of natural products chemistry, the second part of this dissertation discusses the process of designing potential anticancer agents based on the scaffold of a natural product. The biomolecular target of these studies is an enzyme that is overexpressed in tumor cells, namely Cdc25B, whose inhibition catalyzes cell cycle arrest at the G2/M transition of the cell cycle. Several analogs of a potent Cdc25B inhibitor were synthesized and tested in the enzyme-based assay.Ph. D.
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Fabiano, E. "Synthesis and reactions of amino compounds relating to natural products." Thesis, University of Newcastle Upon Tyne, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.373890.
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Cameron, J. F. "Approaches towards macrocyclic natural products using #pi#-allylnickel halide complexes." Thesis, University of Strathclyde, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382251.
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Sigerson, Ralph Clark. "Formal synthesis of the asbestinin family of marine natural products." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3835/.
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The asbestinins are a sub-class of the ether bridged 2,11-cyclised cembranoid family of marine natural products that have been isolated from octocoral species Briareum Asbestinum. They exhibit high structural complexity and a diverse range of bioactivities that include cytotoxicity against tumour cell lines, potent anti-bacterial properties and antagonism of both histamine and acetylcholine. This report presents the continued efforts in developing an efficient synthetic route to the asbestinins which will be general enough to enable the synthesis of virtually every member of this family of compounds. The key synthetic steps include; a samarium diiodide reductive cyclisation to generate 2,6-syn-5,6-anti tetrahydropyranol motif, oxonium ylide formation with subsequent [2,3]-sigmatropic rearrangement of a functionalised diazoketone and an intramolecular Diels-Alder cycloaddition to construct the cyclohexyl ring. Many studies have been carried out on other sub-classes within the ether bridged 2,11-cyclised cembranoid family of natural products, of particular interest have been the sarcodictyins and cladiellins, the latter of which has been extensively investigated within the Clark group.
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Robinson, Anthony R. "Approaches to the synthesis of oxocane and oxonane natural products." Thesis, University of Cambridge, 1994. https://www.repository.cam.ac.uk/handle/1810/273010.
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Marx, Leo. "Studies towards and total synthesis of pyrrolidinone containing natural products." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:84ac3159-3c5e-4826-89d1-4b293935ed53.
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Chapters 1 and 2 of this thesis focus on the application manganese(III) and copper(II)-mediated oxidative radical cyclisation of alkenyl amidomalonates to the formation of pyrrolidinone-lactones and their subsequent use in the total syntheses of highly bioactive natural products. A novel concise total synthesis of (-)-salinosporamide A based on the oxidative cyclisation previously developed in the group is presented in chapter 1. The second chapter discusses the work towards the pyrrolidinone core of the oxazolomycin. Each chapter contains its own introduction to set in context the presented results, which discusses the isolation and the biological activity of the two families of natural products. Previous synthetic work toward salinosporamide A and the oxazolomycin family achieved in the group and reported in the literature is also described in the introduction of each chapter. The third chapter of the thesis succinctly presents the extension of the scope of the manganese(III) and copper(II)-mediated oxidative radical cyclisation reaction. The optimisation, development and scope of the rapid access to fused THF-lactones via the cyclisation of alkenyl oxymalonates is described. Preliminary synthetic manipulations of the resultant bicyclic products to study the application possibilities of the new reaction in future complex molecules syntheses are also presented. The final conclusion gives a summary of the results obtained and introduces the proposed future work that may arise from these three areas.
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Angell, Scott Edward. "Genomic and metagenomic approaches to natural product chemistry." [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-2671.
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Almaliti, Jehad S. "Natural Products-Inspired Synthesis and Biological Evaluation of Bioactive Agents." University of Toledo Health Science Campus / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384555204.
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Sirasani, Gopal. "Development of Novel Methods and Applications in Total Synthesis of Natural Products." Diss., Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/213117.
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ChemistryPh.D.
The olefin cross metathesis reaction has been sequenced with four common organic transformations in a one-pot manner to rapidly access useful building blocks. Those reactions are: (1) phosphorus-based olefination (e.g., Wittig and Horner- Wadsworth-Emmons); (2) hydride reduction; (3) Evans propionate aldol reaction; and (4) Brown allyl- and Roush crotylboration. The products of these reactions include stereodefined 2,4-dienoates, trans allylic alcohols, syn-propionate aldols and chiral non- racemic homoallylic alcohols, respectively, which can be carried further in the context of chemical synthesis. Two approaches toward the total synthesis of cytotoxic polyketide natural product (+)-crocacin C have been accomplished. The first-generation approach used a Crimmins aldol reaction and reagent-controlled double asymmetric crotylboration (Brown and Roush) reaction, which was not selective. The first-generation approach was replaced altogether with a second that afforded (+)-crocacin C in 10 steps from commercially available Evans' chiral propionimide (5% overall yield). The key reactions in the second-generation approach included an Evans dipropionamide aldol reaction, 1,3-anti reduction and a vinylogous Horner-Wadsworth- Emmons olefination. No protecting groups were utilized in the total synthesis of (+)- crocacin C. A novel method to access the ABCE tetracyclic framework of the Strychnos alkaloids has been developed. Five different strategies were utilized toward this goal, out of which the first four were unsuccessful. The fifth-generation strategy featured a novel sequential one-pot bis-cyclization method. Specifically, the AgOTf-mediated spirocyclization of an appropriately functionalized indole 3-carbinamide afforded a stable spiroindolenine intermediate; subsequent addition of DBU to the reaction mixture effected an unprecedented intramolecular aza-Baylis-Hillman reaction, delivering tetracyclic product in 70% isolated yield. The bis-cyclization was showcased in concise racemic total syntheses of akuammicine and strychnine in six and thirteen operations, respectively. Key steps include (1) the vinylogous Mannich reaction; (2) our sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction; and (3) a Heck cyclization. The synthesis of strychnine proceeded via the Wieland-Gumlich aldehyde. We have also utilized our method to prepare other biologically active Strychnos alkaloids (-)- akuammicine, (-)-leuconicines A and B, (-)-norfluorocurarine, (-)-dehydrotubifoline, (-)- dihydroakuammicine, (-)-tubifoline and (-)-valparicine in a concise, asymmetric manner.
Temple University--Theses
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Kulyk, Svitlana. "PYRIDONE PHOTOCYCLOADDITION IN SYNTHESIS OF DIVERSE NATURAL AND UNNATURAL PRODUCTS." Diss., Temple University Libraries, 2014. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/250995.
Full textAbstract:
ChemistryPh.D.
2-Pyridones are known to undergo a facile [4+4] photocycloaddition with themselves and other conjugated molecules. These transformations provide an access to complex molecular structures such as highly substituted cyclooctanoid derivatives, which normally represent a significant synthetic challenge. Moreover, the 2-pyridone photoadducts can be further elaborated into various biologically relevant products. The work presented here broadens the horizons of the [4+4] photocycloaddition in two distinct directions: 1) by utilizing [4+4] photocycloaddition in a total synthesis of crinipellin natural products possessing antibiotic and antitumor activity and 2) by developing a novel type of [4+4] photocycloaddition that employs a conjugated enyne as a partner of 2- pyridone. Our approach to the tetraquinane core of the crinipellins features intramolecular [4+4] photocycloaddition of a tethered furan-pyridone molecule followed by a four-step transannular ring closure. The sequence allows for a rapid assembly of a molecular framework by installing 19 of the 20 required carbon atoms and all but two stereogenic centers. The described synthesis represents an interesting new approach to these polycyclic molecules and a way to access crinipellin analogues. The enyne-pyridone [4+4] photocycloaddition led to formation of intriguing 1,2,5-cyclooctatriene-based products. Presence of the allene functionality was used as a lever in exploring the possibilities for derivatization of these photoadducts. Our investigations of enyne-pyridone photocycloaddition have come a long way: from the first proof-of-concept intermolecular trials producing complex mixtures, through the initial investigations of the intramolecular variant that taught us how to direct the reaction to the necessary mode ([2+2] vs. [4+4] photocycloaddition), and eventually to the controlled formation of stable allenic photoadducts and their further transformation into a diverse set of functionalized molecular scaffolds. We found that the inherent kinetic instability of 1,2,5-cyclooctatrienes facilitates several pathways of strain relief: allene-allene [2+2] dimerization, photooxidative decarbonylation when the irradiation is conducted in presence of air, isomerization of the 1,2-diene fragment into a 1,3-diene and the acid-promoted Cope rearrangement. Additionally, enyne-pyridone photoadducts can undergo transannular ring closure when treated with bromine and also be transformed into valuable bicyclo [5.1.0] octane structures that incorporate a rare example of a stable cyclopropanone by a fast and selective epoxidation-rearrangement process. Several important goals were achieved in the described research study. First, strategic incorporation of [4+4] photocycloaddition as one of the key steps in targeted synthesis of natural products has demonstrated the potential of this powerful reaction. Second, an efficient new approach to a tetraquinane skeleton was developed and successfully executed. Third, the fundamental basis for the novel photochemical transformation (enyne-pyridone cycloaddition) was set and major trends for this reaction were established resulting in obtaining stable allenic photoadducts. Finally, chemical properties and reactivity of stabilized amide-bridged 1,2,5-cyclooctatriene photoproducts were investigated breaking the ground for future involvement of these intermediates in synthetic strategies towards biologically active natural products and their analogues.
Temple University--Theses
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Turkut, Engin. "Chemoenzymatic Synthesis Of Biologically Active Natural Products." Master's thesis, METU, 2004. http://etd.lib.metu.edu.tr/upload/12604854/index.pdf.
Full textAbstract:
Racemic metyhl 3-cyclohexene-1-carboxylate was resolved via enzymatic hydrolysis to afford the enantiomerically enriched 3-cyclohexene-1-carboxylic acid with PLE (S-configuration), HLE (S-configuration), CCL (S-configuration) and PPL (R-configuration) . The nucleoside�
s precursor, 5-(hydroxymethyl)-2-cyclohexen-1-ol (19), was synthesized by iodolactonization, followed by iodine elimination and the reduction of the lactone. In connection with this work, alpha,beta-unsaturated and saturated cyclic ketones were selectively oxidized on alpha'
- and alpha-positions using Mn(OAc)3 and Pb(OAc)4, respectively. The resultant racemic alpha'
- and alpha-acetoxylated substrates were resolved into corresponding enantiomerically enriched alpha'
- and alpha-hydroxylated and acetoxylated compounds via PLE hydrolysis.
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Hancock, William Stephen. "Study of the chemistry of natural products: collected reprints 1970-1992." 1992, 1992. http://hdl.handle.net/2440/38509.
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Hancock, William Stephen. "Study of the chemistry of natural products: collected reprints 1970-1992." Thesis, 1992, 1992. http://hdl.handle.net/2440/38509.
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Persichini, Phillip John. "The chemistry and use of pyrroline ring systems in the synthesis of natural products." Master's thesis, This resource online, 1994. http://scholar.lib.vt.edu/theses/available/etd-03302010-020511/.
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Wu, Boshen. "Synthesis of taurospongin A and other biologically active natural products." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:37a34bc4-efb4-4a6b-9d44-a3ad1c8ae0be.
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This thesis firstly describes a synthesis of the natural product taurospongin A, a potent DNA polymerase beta inhibitor. Sharpless asymmetric dihydroxylation on olefin E-1.60 followed by selective deoxygenation at C(2) via Barton‒McCombie reaction delivers the desired C(1)–C(10) carboxylic acid core. Subsequent esterification of the C(1)–C(10) fragment with C(1′)–C(25′) fatty acid furnishes the natural product in 13.5% yield. The structure of an unnamed natural product 2.14 isolated in 1974 is proven to be misassigned by previous studies within the Robertson group. As described in this thesis, two proposed structures A and B are obtained via total synthesis in order to reveal the identity of the natural product. A synthesis of key intermediate spirocycles 2.148 and 2.158 with desired trans- diol moiety is described by a dihydroxylation reaction on an electron deficient gamma-keto unsaturated acid with subsequent spirocyclisation reaction. Finally, methodology for generating high-value synthetic intermediates by an asymmetric, one-pot enzymatic di/polycarbonyl reduction is described. The concept of such methodology is first proven by the synthesis of (3R)-hydroxybutyl (3R)-hydroxybutanoate 3.20. This thesis then describes substrate scope studies and corresponding stereochemical proof to provide more information about this methodology.
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Stefinovic, Marijan. "Novel synthetic and mechanistic metholologies for the construction of natural products." Thesis, University of Reading, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385614.
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Romiti, Filippo. "Total synthesis of members of the amphidinolide family of natural products." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6445/.
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The amphidinolides are macrolide natural products isolated from marine dinoflagellates of the genus Amphidinium and most of them display potent cytotoxic activities in vitro. Amphidinolides C-C3, F and T1-5 represent attractive synthetic targets due to a combination of potent bioactivity and complex molecular architecture. This thesis describes the total syntheses of amphidinolides T1, T3 and T4, and the preparation of the C1-C17 fragment of amphidinolides C and F. Concise and high-yielding total syntheses of amphidinolides T1, T3, and T4 have been completed using an alkynyl macrolactone as a common late-stage intermediate. The α-hydroxy ketone motif was installed by sequential alkyne hydrosilylation, epoxidation, and Fleming–Tamao oxidation. A tandem oxonium ylide formation [2,3]-sigmatropic rearrangement reaction was used to construct the trisubstituted tetrahydrofuran core found within the natural products. The C1-C17 fragment of amphidinolides C, C2, C3 and F was synthesised employing [2,3]-sigmatropic rearrangement of an oxonium ylide generated by decomposition of 1-sulfonyl-triazole to construct the trisubstituted tetrahydrofuran ring found in the natural products. The two main segments were conjoined using a Stille cross-coupling reaction that allowed simultaneous installation of the isomerization-prone 1,3-diene unit.