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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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Wallace, Stephen. "A cascade approach towards the gephyrotoxins." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:1f7b55ec-0346-498c-be03-81f3b9fde2f5.
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The aim of this project was to develop a cascade approach towards perhydropyrrolo-[1,2-a]-quinolines and to apply this to the asymmetric synthesis of the gephyrotoxin alkoids. Chapters Two and Three outline the development of a synthetic route towards a range of cascade precursors, whilst Chapter Four outlines investigations into the enamine-Michael cascade. Central to understanding the cascade process was the discovery that the major product of the enamine-Michael cascade was the unusual tricyclic hydroquinium salt. This can subsequently be engaged in a diastereoselective inter- or intramolecular reduction to afford either a trans-perhydro-[1,2-a]-quinoline or a tetracyclic aminal in high overall yield depending on the C1 oxygen substituent.
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Källström, Jan Eddy Adolf. "Synthesis studies towards daphlongeranine B." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:638685a8-da64-488b-b65d-ba9a2111d4fb.
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This thesis describes the development of a synthetic route towards daphlongeranine B, an alkaloid isolated from the fruits of Daphniphyllum longeracemosum, by utilising an intramolecular Michael addition to form its unique tricyclic core. Chapter 1 gives a general introduction to the family of Daphniphyllum alkaloids together with some recent examples, from the literature, illustrating some synthetic attempts towards structurally similar alkaloids. This chapter also features our retrosynthetic analysis of daphlongeranine B. Chapter 2 details the synthesis of the model spirocyclic enone 72 which was the vital building block needed to investigate the key intramolecular Michael addition. This key reaction was then successfully validated and access to the unique tricyclic core 64 of daphlongeranine B was made possible. Chapter 3 expands the scope of the key intramolecular Michael addition step. This chapter first describes a synthetic route to the Î2-substituted spirocyclic enone 112 and subsequently validates the key intramolecular Michael addition step to give the tricyclic core 138 of daphlongeranine B. Chapter 4 details a synthetic route towards the spirocyclic fragment 141 by utilising a Baker's yeast reduction and a tandem addition/cyclisation reaction.
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Dyson, Bryony Sara. "Determining the structures of halogenated marine natural products by total synthesis." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:31737a99-a13c-4110-b36d-1c043b66565b.
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Elatenyne, a brominated C15 acetogenin isolated from the red Laurencia elata marine algae, was originally assigned a pyranopyran structure. Previous total synthesis of the pyranopyran structure has found this assignment to be incorrect. During this work the revised 2,2’-bifuranyl skeleton of elatenyne was suggested, but this skeleton has 32 possible diastereomers. The most likely diastereomer of elatenyne was predicted using computational 13C NMR chemical shift calculation in combination with the possible stereochemical outcomes from the proposed biosynthesis. Chapter 1 introduces the structural misassignment of natural products and describes the misassignment of elatenyne as well as a related chloro enyne. The use of computational methods and biosynthetic postulates to aid structure elucidation are also discussed. Chapter 2 describes the first generation synthesis of cross metathesis coupling partners required for the synthesis of elatenyne from D-mannitol. Chapter 3 describes the completed total synthesis of elatenyne, along with three derivatives and the (E)-isomer of elatenyne; itself a natural product. A comparison of the synthetic data with the isolation data for the natural products is presented, as well as comparison with the synthetic material of Kim and co-workers whose concurrent biomimetic total synthesis is also presented. Chapter 4 describes the modular nature of the devised synthetic route to access any diastereomer of elatenyne and its application to related 2,2’-bifuranyl natural products.
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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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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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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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Tan, Song Wei Benjamin. "Natural product inspired organic synthesis : enantiopure heterocycles modelled on pramanicin." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:2368dca6-7fe5-46b7-a913-6fecbaa21bf0.
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This thesis is concerned with the synthesis of chiral pyrrolidinone scaffolds as mimics of the natural product pramanicin, and the evaluation of their antibacterial properties for use towards the development of potential novel antibacterial lead compounds. Chapter 1 discusses the urgency of the antibiotic resistance problem as well as the current lack of new antibiotics in the drug pipeline. This dearth of new antibacterials is partly attributed to the combinatorial libraries used in the screening process which occupies a limited chemical space. By applying the natural product-inspired paradigm, it is hypothesised that a drug discovery process with a starting point based on a natural product, possessing intrinsic antibacterial properties, may provide insights to a novel class of antibacterials. Chapter 2 describes the synthesis of three different scaffolds of oxygenated pyrrolidinones via a common bicyclic intermediate synthesised from L-pyroglutamic acid. The use of a mild and facile epoxidation condition utilising H2O2/tertiary amine afforded the epoxypyrrolidinones. α-Hydroxylation with “Davis oxaziridine” and a Ru-mediated dihydroxylation gave 2-hydroxypyrrolidinones and 2,3-dihydroxypyrrolidinones respectively. In all cases, a pendant Weinreb amide was used to introduce a variety of side-chains onto the parent pyrrolidinones. The enantioselective oxygenation of these scaffolds was accomplished as a result of the chiral [3.3.0] bicyclic intermediate. Chapter 3 describes the attempted synthesis of oxygenated pyrrolidinones via tetramic acids. Although progress was thwarted by synthetic challenges discussed therein, a series of tetramic acids was synthesised. A synthetic sequence to install a 3-acyl moiety onto the parent tetramic acid core was accomplished via an O-acyl/C-acyl rearrangement using a series of carboxylic acids in the presence of excess DMAP. The use of a 3-acyltetramic acid with a pendant phosphorane permits a general synthetic route, compatible with a wide range of aldehydes, towards 3-enoyltetramic acids via Horner-Wadsworth-Emmons olefination. These tetramic acids are mimics of another class of bactericidal natural products which nonetheless allows the natural product-inspired paradigm to be investigated. Finally, an analysis of the antibacterial properties of the synthesised compounds is discussed in Chapter 4. A cellular hole-plate bioassay with E. coli and S. aureus was chosen to provide a rapid assessment for active compounds. A correlation between the physicochemical properties and the observed activities of these active compounds suggested possible chemical modifications which could be undertaken in the future to improve their activities.
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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.
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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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Elbert, Bryony L. "The synthesis and applications of cyclic alkenylsiloxanes." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:a332365e-22f2-4449-b517-3fd8a62ea8a3.
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This thesis describes the development of robust methodology to access cyclic alkenylsiloxanes, and their subsequent application in Hiyama-Denmark cross couplings. An early chapter shows the identification of Lindlar reduction conditions capable of generating cyclic alkenylsiloxanes from alkynylsiloxanes in high yields. The use of such species in Hiyama-Denmark cross coupling is then examined, with particular emphasis on the development of fluoride-free conditions, previously unreported for this class of organosilane. A ring-size dependent orthogonality is revealed, where 5-membered cyclic alkenylsiloxanes cross couple under basic conditions, while 6-membered analogues are inert. The origins of this effect are investigated experimentally and theoretically, leading to the proposal of detailed mechanisms for coupling. In the final chapter, the methodology that has been developed is applied to total synthesis. The great potential of the orthogonality uncovered is demonstrated with the highly convergent construction of anti-inflammatory natural product resolvin D3 by sequential, one-pot, orthogonal cross couplings.
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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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Medeiros, Edna Faria de. "The use of pyrylium salts in natural product synthesis." Thesis, University of Essex, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.334742.
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Aldred, Gregory. "Studies towards the total synthesis and structural elucidation of leiodolide A." Thesis, University of St Andrews, 2015. http://hdl.handle.net/10023/6657.
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In 2006, the secondary metabolite leiodolide A was isolated from a newly discovered deep-sea sponge of the genus Leiodermatium. The 19-membered macrolide represented a new class of mixed polyketide, nonribosomal, peptide synthetase natural products. A total synthesis of leiodolide A is yet to be achieved and is of specific interest, not only for its complex structure and undefined stereochemistry, but also the potent cytotoxic properties it possesses, particularly towards leukaemia, non-small cell lung and ovarian cancers. A synthetic strategy for leiodolide A must be flexible to overcome the currently unresolved stereochemistry and a convergent route towards the synthesis of the molecule required three subunits. Following the earlier synthesis of the C21-C25 vinyl stannane fragment, this work describes the synthesis of the C1-C10 subunit in the both possible diastereomeric forms. The synthesis of the two required C13 epimers of the C11-C20 subunit is also detailed accompanied by an investigation into potential fragment coupling, in preparation for total synthesis.
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Tatton, Matthew R. "New methods for the synthesis of aromatic compounds." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:52a95189-d8ea-432f-aefd-4f9ae7ef996a.
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Introduction The introduction describes the importance of arylamine compounds to society and provides a brief overview of the methods available for their synthesis. The application of metathesis catalysis to the de novo synthesis of heteroaromatic compounds is also described. Results and discussion The first section describes efforts towards the de novo synthesis of arylamines using a cross metathesis/oxidation protocol to form a 1,5-unsaturated dicarbonyl followed by an amine mediated cyclisation. The scope with respect to the 1,5-unsaturated dicarbonyl and amine is covered as well as the utility of some of the products. The section concludes with a modification of the Bohlmann Rahtz pyridine synthesis to furnish arylamines. The next section describes the applications of our methodology to the synthesis of naphthylamines, specifically using the palladium catalysed α-arylation reaction. A discussion of the α-arylation reaction is included as well as our efforts to explore the scope of the reaction. The third section follows our efforts to apply this methodologyy to the synthesis of five benzo[c]phenanthridine alkaloids including the first reported synthesis of maclekarpine B and C. The final section concludes with a discussion of our efforts towards the de novo synthesis of furans bearing a benzylic stereocentre.
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Giampa, Geoffrey. "Investigations Into Carbon Nanotube And Natural Product Synthesis." ScholarWorks @ UVM, 2016. http://scholarworks.uvm.edu/graddis/552.
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This dissertation describes research into the synthesis of carbon nanotubes using traditional organic synthetic methods, as well as work on the fragmentation of β-hydroxy-α-diazoesters with a γ-hetero group and applications of their reactivity towards natural product synthesis.
Carbon nanotubes are unique structures that can exhibit different electronic properties based on their chiral vector, and are a potential future source of semiconductors. Current methods of synthesis are unable to be adapted to commercial synthesis, providing the opportunity for the application of organic synthetic methods to generate them more uniformly and on a larger scale.
The generation of tethered aldehyde ynoates and their utilization in 1,3-dipolar cycloadditions has been well developed by the Brewer group. Traditionally they have been generated from γ-siloxy-β-hydroxy-α-diazoesters, herein we explore utilizing an amino group as the fragmentation initializer. Additionally, application of the tethered aldehyde ynoate towards the synthesis of the natural products Demissidine and Aspidospermine are discussed.
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Nimkar, Sandeep Krishnaji. "Studies in asymmetric synthesis: Development of new synthetic methods for syntheses of natural products." Diss., The University of Arizona, 1993. http://hdl.handle.net/10150/186538.
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The research, to be discussed in three chapters, involves the development of new synthetic methods which are applicable to the total synthesis of many natural products. Chapter 1: As a part of a program to synthesize new auxiliary agents for asymmetric synthesis, we have prepared a structurally rigid acetal from norbornene in three chemical steps. This enantiomerically pure acetal has been used for resolution of racemic α-hydroxy esters and might be applied as a chiral auxiliary for diastereoselective reactions. Chapter 2: The Calicheamicin and Esperamicin antibiotics have shown remarkable biological activity as site-specific cleaving agents of double stranded DNA. The oligosaccharide portion of these molecules plays an important role in the site specificity. We have developed synthetic methodologies that allow synthesis of the deoxyaminosugar components of these antibiotics and can be extended to synthesize unnatural amino sugars for structure-activity studies. Chapter 3: Enantiomerically pure cyclopropyl ketones, which are available via chiral ketals, are very useful for syntheses and diastereoselective manipulations of common and large rings. This method has been extended to introduce up to four contiguous chiral centers in a common ring. This extension could be useful for the syntheses of complex natural products.
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Cordonnier, Marie-Caroline A. "Palladium-catalysed cascade cyclisation of alkynyl silanes and studies towards rubriflordilactone A." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:24302e85-de80-4562-a98e-ee0e6ba93862.
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In this work, a new methodology for the synthesis of a number of silylated bicyclic dienes has been reported. These bicyclic dienes allowed access to a variety of enones and phenols in 2 further steps. The stabilities and reactivities of different dialkylisopropoxy silanes have been evaluated,revealing relative instability of the dimethylisopropoxy silyl group towards chromatography. When using the analogous diethylisopropoxy silyl group instead, the products showed greater stability towards chromatography, however a higher temperature was necessary to oxidise the more sterically hindered silyl group to the desired hydroxyl moiety. A powerful cascade cyclisation for the synthesis of the CDE-core of rubriflordilactone A was then demonstrated and was successfully used for the synthesis of two systems, 284 and 333. The phenolic oxygen has been successfully installed by oxidation of a dialkylisopropoxy silane. The synthesis of these ring systems provides a solid foundation for the completion of the total synthesis of rubriflordilactone A. Finally the synthesis of suitable diynes 405 for the synthesis of the acyclic precursor of the cyclisation has been achieved. The stabilities of theses silanes towards a range of reaction have been demonstrated.
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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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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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Rathi, Akshat Hemant. "Studies towards the synthesis of complex amino acids derived from microsclerodermins." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:ca121a22-aee7-4da5-bd0d-dc7ee6e53bea.
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This thesis describes the studies towards the synthesis of β-amino acids found in the microsclerodermins, a family of complex macrocyclic hexapeptides. These β-amino acids have four or five contiguous stereocentres and an aliphatic side-chain. The synthetic route utilised an aminohydroxylation reaction to install the most challenging moiety in the structure - the 1,2- amino alcohol. The work aimed to construct the core structure (five contiguous stereocentres) of the β-amino acids and install the side-chain later to enable the synthesis of multiple members (A, B, F, G, H and I) of the microsclerodermin family. The synthesis started with Roche ester, which contained the first methyl stereocentre. It was converted to the diene precursor in four high yielding steps. The next two stereocentres were installed via a Sharpless asymmetric dihydroxylation. With the appropriate protecting groups in place, the remaining two stereocentres were to be installed via a Sharpless asymmetric aminohydroxylation. Various reported reagents and conditions were used to effect the transformation, but the attempts were unsuccessful. This forced us to alter our synthetic plans, and the revised synthetic route involved the use of the tethered aminohydroxylation (TA) reaction developed by the Donohoe group. After the development of an efficient protocol to prepare the TA-precursor, the alkene, with three stereocentres already in place, was successfully converted to the desired stereopentad via the TA-reaction (10 steps, 11% overall yield). With the stereopentad in hand, installation of the side-chain of the β-amino acids through an alkenyl or alkyl linkage was investigated. For alkenyl-linked side-chains, the appropriate aldehyde was synthesised, but attempts to effect the transformation via a Horner-Wadsworth- Emmons reaction or a Witting reaction failed. With lessons learnt from those, we then focused our efforts on installing an alkyl-linked side-chain. In this case, we were able to install a side- chain via a copper-mediated displacement reaction, which gave us a protected form of the precursor of the β-amino acid of microsclerodermin B. Finally, various efforts to study the reactivity of the stereopentad and the investigations into finding the most effective set of protecting groups have been used to propose a synthetic route for the incorporation of the β- amino acid into the macrocycle.
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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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Larsson, Michael. "Natural products from nonracemie building blocks : synthesis of pine sawfly pheromones." Doctoral thesis, KTH, Kemi, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-128.
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This thesis describes a number of synthetic approaches for obtaining chiral, enantiomerically pure natural products, in particular some semiochemicals. This has been accomplished by using various strategies; by starting from compounds from the chiral pool, by using chiral auxiliaries, via enzymatic resolutions or by chemical asymmetric synthesis. Hence, the sexual pheromone of Microdiprion pallipes, a propanoate ester of one or several isomers of 3,7,11-trimethyltridecan-2-ol, was synthesised, both as a mixture of all isomers and as the sixteen pure, individual stereoisomers. These compounds were obtained by joining different enantiopure building blocks stemming from the chiral pool. When compared with some synthetic blends, both the propanoate esters of the stereoisomeric erythro-3,7,11-trimethyltridecan-2-ols originally found in the extract from the female of M. pallipes, surprisingly, showed lower activities in biological studies. Indeed, the propanoates of two threo-isomers gave significantly higher responses in biological tests, than did the propanoates of the two natural erythro-ones. Because the synthetic strategy used earlier was not very efficient for the preparation of the threo-isomers of 3,7,11-trimethyltridecan-2-ol, we were encouraged to look for alternative synthetic approaches. The new synthetic strategy chosen led us to two key synthetic building blocks, an O-protected derivative of (2S,3S)-3-methyl-4-(phenylsulfonyl)butan-2-ol butanol and (3R,7R)-1-iodo-3,7-dimethylnonane. Deprotonation of the former followed by alkylation with the latter should give a compound with the desired carbon skeleton. For efficient preparation of the first building block, we developed a new diastereoselective addition reaction of dialkylzincs to some chiral aldehydes, the products of which were diastereomerically enriched 1,2-dialkyl-alkanols. Using this method, each enantiomer of the desired building block was obtained via efficient diastereoselective addition of dimethylzinc to each enantiomer of a 2-methylaldehyde. The resulting product, a diastereomerically and enantiomerically highly enriched 3-methyl-2-alkanol was further purified by enzyme catalysed acylation followed by some functional group interconversions. The second building block was prepared via convergent multistep synthesis, starting from a single, enantiomerically pure compound, (R)-2-methylsuccinic acid 4-t-butyl ester, derived from the chiral pool. The two enantiomerically pure building blocks, so obtained, were coupled together. Some additional functional group manipulations of the product produced furnished the desired isomer, which had shown the highest activity in field tests of the M. pallipes, namely the propanoate ester of (2S,3R,7R,11R)-3,7,11-trimethyltridecan-2-ol. This thesis describes a number of synthetic approaches for obtaining chiral, enantiomerically pure natural products, in particular some semiochemicals. This has been accomplished by using various strategies; by starting from compounds from the chiral pool, by using chiral auxiliaries, via enzymatic resolutions or by chemical asymmetric synthesis. Hence, the sexual pheromone of Microdiprion pallipes, a propanoate ester of one or several isomers of 3,7,11-trimethyltridecan-2-ol, was synthesised, both as a mixture of all isomers and as the sixteen pure, individual stereoisomers. These compounds were obtained by joining different enantiopure building blocks stemming from the chiral pool. When compared with some synthetic blends, both the propanoate esters of the stereoisomeric erythro-3,7,11-trimethyltridecan-2-ols originally found in the extract from the female of M. pallipes, surprisingly, showed lower activities in biological studies. Indeed, the propanoates of two threo-isomers gave significantly higher responses in biological tests, than did the propanoates of the two natural erythro-ones. Because the synthetic strategy used earlier was not very efficient for the preparation of the threo-isomers of 3,7,11-trimethyltridecan-2-ol, we were encouraged to look for alternative synthetic approaches. The new synthetic strategy chosen led us to two key synthetic building blocks, an O-protected derivative of (2S,3S)-3-methyl-4-(phenylsulfonyl)butan-2-ol butanol and (3R,7R)-1-iodo-3,7-dimethylnonane. Deprotonation of the former followed by alkylation with the latter should give a compound with the desired carbon skeleton. For efficient preparation of the first building block, we developed a new diastereoselective addition reaction of dialkylzincs to some chiral aldehydes, the products of which were diastereomerically enriched 1,2-dialkyl-alkanols. Using this method, each enantiomer of the desired building block was obtained via efficient diastereoselective addition of dimethylzinc to each enantiomer of a 2-methylaldehyde. The resulting product, a diastereomerically and enantiomerically highly enriched 3-methyl-2-alkanol was further purified by enzyme catalysed acylation followed by some functional group interconversions. The second building block was prepared via convergent multistep synthesis, starting from a single, enantiomerically pure compound, (R)-2-methylsuccinic acid 4-t-butyl ester, derived from the chiral pool. The two enantiomerically pure building blocks, so obtained, were coupled together. Some additional functional group manipulations of the product produced furnished the desired isomer, which had shown the highest activity in field tests of the M. pallipes, namely the propanoate ester of (2S,3R,7R,11R)-3,7,11-trimethyltridecan-2-ol. This thesis describes a number of synthetic approaches for obtaining chiral, enantiomerically pure natural products, in particular some semiochemicals. This has been accomplished by using various strategies; by starting from compounds from the chiral pool, by using chiral auxiliaries, via enzymatic resolutions or by chemical asymmetric synthesis. Hence, the sexual pheromone of Microdiprion pallipes, a propanoate ester of one or several isomers of 3,7,11-trimethyltridecan-2-ol, was synthesised, both as a mixture of all isomers and as the sixteen pure, individual stereoisomers. These compounds were obtained by joining different enantiopure building blocks stemming from the chiral pool. When compared with some synthetic blends, both the propanoate esters of the stereoisomeric erythro-3,7,11-trimethyltridecan-2-ols originally found in the extract from the female of M. pallipes, surprisingly, showed lower activities in biological studies. Indeed, the propanoates of two threo-isomers gave significantly higher responses in biological tests, than did the propanoates of the two natural erythro-ones. Because the synthetic strategy used earlier was not very efficient for the preparation of the threo-isomers of 3,7,11-trimethyltridecan-2-ol, we were encouraged to look for alternative synthetic approaches. The new synthetic strategy chosen led us to two key synthetic building blocks, an O-protected derivative of (2S,3S)-3-methyl-4-(phenylsulfonyl)butan-2-ol butanol and (3R,7R)-1-iodo-3,7-dimethylnonane. Deprotonation of the former followed by alkylation with the latter should give a compound with the desired carbon skeleton. For efficient preparation of the first building block, we developed a new diastereoselective addition reaction of dialkylzincs to some chiral aldehydes, the products of which were diastereomerically enriched 1,2-dialkyl-alkanols. Using this method, each enantiomer of the desired building block was obtained via efficient diastereoselective addition of dimethylzinc to each enantiomer of a 2-methylaldehyde. The resulting product, a diastereomerically and enantiomerically highly enriched 3-methyl-2-alkanol was further purified by enzyme catalysed acylation followed by some functional group interconversions. The second building block was prepared via convergent multistep synthesis, starting from a single, enantiomerically pure compound, (R)-2-methylsuccinic acid 4-t-butyl ester, derived from the chiral pool. The two enantiomerically pure building blocks, so obtained, were coupled together. Some additional functional group manipulations of the product produced furnished the desired isomer, which had shown the highest activity in field tests of the M. pallipes, namely the propanoate ester of (2S,3R,7R,11R)-3,7,11-trimethyltridecan-2-ol.QC 20101026
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Baron, James Andrew 1971. "Preparation of tricyclic enones as templates for stereocontrolled natural product synthesis." Diss., The University of Arizona, 1998. http://hdl.handle.net/10150/282796.
Full textAbstract:
Small cycloalkanones with adjacent fused cyclopropane rings are excellent substrates for highly diastereoselective (α'-alkylations of enolates derived from these systems. Diastereoselectivity can be attributed to steric interactions between the cyclopropane endo methylene hydrogen and the incoming electrophile, since this atom shields the face of the enolate cis to the cyclopropane. Monoalkylation of enolates derived from bicyclo[3.1.0]hexan-2-one, bicyclo[4.1.0]heptan-2-one and bicyclo[5.1.0]octan-2-one with general electrophiles resulted in the corresponding 3-alkylated cyclopropyl ketone derivatives in synthetically useful yields. Diastereoselectivities for these systems ranged from 4:1 for six-membered cyclopropyl ketones to >20:1 for five- and seven-membered cyclopropyl ketones. Enolates derived from these 3-alkylated cyclopropyl ketones exhibited similar diastereoselectivities and yields to give the corresponding 3,3-dialkylated derivatives when alkylated with similar electrophiles. The relative stereochemistry of alkylation was determined to be trans to the cyclopropane through analysis of anisotropic shielding interactions between alkyl side chains containing phenyl rings and the endo protons on the cyclopropane carbon. This relative stereochemistry can be controlled by the sequence of alkylation, since reversal in the alkylative steps results in an inversion at the newly formed quaternary center. Synthesis of tricyclic enones was carried out through application of this (α'-alkylation methodology using electrophiles that could later be modified to give the corresponding 1,3- and 1,4-cyclopropyl diketones. Cyclization of these diketone intermediates through intramolecular aldol condensations resulted in a series of tricyclic enones whose ring junction relative stereochemistry is controlled through correct ordering of electrophiles in the alkylation steps. The result is a broadly applicable toolbox of annulated materials that can be applied towards the synthesis of natural products containing fused five- and six-membered rings with a defined stereochemistry at the ring junction.
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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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Cumaranatunga-Ilangasinghe, P. Kamani. "Stereocontrolled diversity oriented synthesis of 2H-benzopyran-based natural product-like polycyclics." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/29208.
Full textAbstract:
Over the years, it has been shown that natural products that act as highly specific modulators of protein function are complex in nature, highly functionalized and contain few stereogenic centers. There are several examples in literature, where benzopyran-based natural products have been utilized as small molecule chemical probes in understanding protein function. Inspired by the "privileged benzopyrans", the studies reported in this thesis are centred on the development of a novel method leading to the synthesis of functionalized benzopyran-derived scaffolds. Further, several attempts have been made to obtain natural product-like polycyclic compounds as derivatives of these scaffolds. Our approach has been to develop the synthetic methods initially by solution synthesis. In one case, a partial solid phase synthesis has been achieved that could further be extended to library generation.
The synthetic efforts to obtain several benzopyran-based analogs are reported. These include the development of a novel, stereoselective synthetic route to obtain functionalized benzopyran templates (71a,b) and further extensions leading to diverse tricyclic derivatives having medium sized rings with few asymmetric diversity sites. An intramolecular Mitsunobu-based approach was explored to obtain benzopyran-derived tricyclic derivatives having a cis- and trans-fused lactone moiety ( 72, 73). Although we were successful in making the amino acid conjugates (387, 392, 395), we were not successful in making their tricyclic derivatives. Several ring closing metathesis (RCM)-based approaches were also developed to obtain benzopyran-based tricyclic derivatives having functionalized 6- and 8-membered rings, and were successful in making the polyethers ( 74, 75). Also reported in this chapter is the preliminary work on solid phase synthesis in which benzopyran-based tricyclic compounds with 6- and 8-membered rings were obtained by a RCM approach (541a,b).
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Welch, Rosemary. "The development of new synthetic methods towards the synthesis of biologically active natural products." Thesis, University of Portsmouth, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.292089.
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Yip, Adam Christopher Loy. "Studies towards the total synthesis of madeirolide A." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/284918.
Full textAbstract:
Madeirolide A (1) is a structurally novel polyketide natural product first isolated from the deep-sea sponge Leiodermatium sp. by Wright in 2009. Initial biological investigations of madeirolide A revealed potent inhibition of the fungal pathogen Candida albicans but failed to determine any appreciable cytotoxicity when tested against a limited range of cancer cell lines. The unusual bioactivity of madeirolide A coupled with uncertainty over the true stereostructure of the natural product makes it a compelling target for synthesis. This thesis discloses synthetic efforts towards the total synthesis of madeirolide A with an emphasis on the construction of the all-cis C21 - C27 eastern tetrahydropyran. Chapters 1 and 2 provide an introduction to the importance of natural products in drug discovery and outline the context of this project with details of the isolation and biological activity of madeirolide A. Previous synthetic efforts are also reviewed including those from within the group which formed the basis of the present studies. Chapter 3 describes the synthesis of a fully elaborated C1 - C11 fragment, building upon previously published work in the group. Specifically, it details the successful completion of a modified approach designed to avoid some of the major challenges previously encountered such as undesired migration of protecting groups and challenges in selectively installing an (E)-vinyl iodide. Chapter 4 discusses ongoing efforts towards the challenging C12 - C27 fragment of madeirolide A. The stereocontrolled synthesis of several linear C19 - C27 precursors is outlined, followed by details of screening reactions conducted to affect the desired oxy- Michael cyclisation. Additionally, extensive computational studies have been undertaken in an attempt to rationalise the frustrating lack of reactivity observed with the goal of developing a substrate suitably elaborated to cyclise. Finally, the asymmetric synthesis of the C13 - C17 subfragment is outlined, which will provide eventual access to the eastern tetrahydrofuran. Chapter 5 summarises the synthetic work carried out thus far and explores potential strategies for the future completion of the natural product with a focus on alternative disconnections of the eastern tetrahydropyran.
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Jeffery, Stephen. "The use of thian-4-one derivatives in cyclopentenone natural product synthesis." Thesis, University of East Anglia, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.280401.
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Talbot, Eric Philippe Andre. "Towards the synthesis of anthecularin and anthecotulides." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:372f2e3c-dd56-4c63-b89d-66dfd4b2ab02.
Full textAbstract:
The work presented in this thesis mainly describes the discovery and development of methodology for the synthesis of anthecularin and anthecotulides, a family of unusual sesquiterpene lactones. Firstly, two 1,3-dipolar cycloaddition approaches toward anthecularin have been evaluated, using either oxidopyrylium ylide chemistry (Path A) or carbonyl ylides, generated by rhodium-catalysed decomposition of diazo ketones (Path B). Synthesis of the key precursor for the diazo strategy was achieved but unfortunately no desired cycloadduct was isolated. Secondly, an experimentally straightforward method to stereoselectively synthesise β-hydroxymethyl-α-methylene-γ-butyrolactones was developed using chromium or zinc. The synthetic utility of this methodology was demonstrated in syntheses of (±)-methylenolactocin, (±)-hydroxymatairesinol and, ultimately, (±)-hydroxyanthecotulide using a gold-catalysed Meyer-Schuster rearrangement. Finally, the first asymmetric synthesis of (+)-anthecotulide has been achieved, in 6 steps from commercially available materials. During this synthesis the absolute configuration was established. Furthermore, a novel rhodium-catalysed enantioselective ene-yne cycloisomerisation was used to form the α-methylene-γ-butyrolactone core.
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Jordan, Stuart Ian. "The Stille reaction in natural product synthesis : the total synthesis of 14,15-anhydrovirginiamycin M2." Thesis, University of Nottingham, 1997. http://eprints.nottingham.ac.uk/12387/.
Full textAbstract:
The thesis describes synthetic studies directed towards the total synthesis of 14,15-anhydrovirginiamycin M2, a streptogramin antibiotic of the virginiamycin family. This novel natural product shows pronounced antibacterial activity against a wide range of potentially lethal bacteria. The Introduction summarises the main therapeutic uses, isolation, structural determination, biosynthesis, and mode of action of the virginiamycins. Also included is a review of synthetic approaches which have been described to access these and similar streptogramin antibiotics by other research groups. A review of the intramolecular Stille coupling reaction within organic synthesis incorporating the most prominent examples of its use over the past ten years in the synthesis of natural products is also presented. The Discussion part of the thesis contains details of our synthetic studies on suitable model systems, including: a study of conjugated triene formation via Stille chemistry; peptidic bond formation; and special reference to the problems involved in the synthesis of the 2,4-disubstituted oxazole contained within the virginiamycins. The studies culminate with a description of the first total synthesis of 14,15- anhydrovirginiamycin M2, which proved identical to the natural product obtained from a Streptomyces fermentation process. A full description of the experimental work carried out, and spectroscopic data for all compounds synthesised, is contained in an Experimental section.
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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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Docherty, Paul Henry. "Diastereocontrolled synthesis of hetero- and carbocycles via manganese(III) and copper(II) : towards a novel prostaglandin total synthesis." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:6ca5556a-3d2d-454a-abbd-0a3a269c5724.
Full textAbstract:
The prostaglandins are a unique family of natural products found in all mammalian life, including humans. Their biological significance is profound, and they are responsible for a vast array of bodily functions. This importance, coupled with their low concentration in vivo, has made them attractive targets for total chemical synthesis. The work herein describes synthetic efforts towards their synthesis using an oxidative radical cyclisation to construct the key [3.3.0]-bridged bicyclic lactone, from which the prostaglandin skeleton may be derived. Key to this was the development of manganese(III) acetate and copper(II) triflate as optimal reagents for this cyclisation of unsaturated malonate/malonic acid derivatives. To study this, several model substrates for this crucial cyclisation were synthesised, and their cyclisation analysed. Chapter 5 describes the design and synthesis of several model substrates containing malonate groups for the oxidative radical cyclisation. The results of the cyclisation with manganese(III) and various copper(II) salts influenced the design of the substrates, and led to the use of malonic acids as more effective substrates for the formation of [3.3.0]-bicyclic lactones. A catalytic process, in which atmospheric oxygen is the terminal oxidant was also developed. Chapter 6 describes the studies towards a total synthesis of the prostaglandin family. Two potential routes are followed, the first of which used a key asymmetric epoxidation to install asymmetry. A Suzuki coupling was used to deliver the desired diene required for the cyclisation substrate, which was successfully cyclised using manganese(III) acetate and copper(II) triflate, creating the desired [3.3.0]-bicyclic lactone in good yield and with excellent diastereomeric control. A second, shorter route to the same lactone was also developed, using a novel asymmetric deconjugative aldol condensation to establish asymmetry. Cyclisation of this analogous substrate was also successful, delivering the same lactone after olefin metathesis.
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Phillips, Andrew. "Studies towards the total synthesis of patellazole B." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269364.
Full textAbstract:
The patellazoles are a family of marine polyketide natural products first isolated from Lissoclinum patella in 1988 by both the Moore and Ireland groups. They exhibit significant cytotoxicity against the HCT 116 human colon tumour cells. To date however, their full 3D stereostructure have yet to be elucidated, which has hindered their development as potential drugs, and hampered full investigation into their biological mechanism of action and has deterred total synthesis efforts. This thesis describes synthetic efforts towards Patellazole B, which exhibits the highest potency of the three main congeners. To fully elucidate the structure and renew interest in the patellazoles as anticancer compounds, we have developed a flexible and modular synthesis that aims to define the unknown stereocentres within the pertinent region and allow for rapid fragment union. Compound 36 has been chosen as an initial target for NMR comparison studies. The synthesis of all eight diastereomers of this macrocycle should aid determination of the four unknown stereocentres. Chapter 2 describes the synthesis of the C1–C12 fragment, focusing on the configuring of the C5 methyl stereocentre and the construction of the C7-C10 stereotetrad via a boron-mediated anti aldol with an in-situ reduction. In the third chapter, the synthesis of the C13-C19 fragment is outlined. A boron-mediated glycolate aldol has been used to install the C16-C17 anti stereochemistry and a substrate-controlled reduction at C15 delivered the hydroxyl with high diastereoselectivity. Studies into the C¬17¬ methylation are also described. Chapter 4 describes the synthesis of one possible diastereomer of the C20-C25 fragment, as a template for the preparation of the other 7 possible diastereomers. The route therefore employs only catalyst based control methods to install the three stereocentres, utilising a Sharpless asymmetric epoxidation and Evans aldol to construct the stereotriad. The 22R, 23S, 24S diastereomer has been initially chosen to investigate the later chemistry. Chapter 5 contains discussion of the ongoing work investigating fragment union and formation of the macrocycle. A Heck coupling reaction has been employed to construct the C19-C20 bond and a Suzuki coupling reaction has been developed to facilitate the C12-C13 bond formation. These two cross couplings have delivered the C1 - C25 fragment, 360, the final compound reported in this thesis, which is three steps away from the completed macrocycle and six from compound 36. The experimental procedures and spectroscopic characterisation of the synthesised intermediates can be found in Chapter 6 and the Appendix.
38
Mears, Paul. "Approaches towards the synthesis of the 20-deoxybryostatins and their 20,20-difluorinated analogues." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/approaches-towards-the-synthesis-of-the-20deoxybryostatins-and-their-2020difluorinated-analogues(82de5040-e32f-45fb-9537-8a5eaed7c67b).html.
Full textAbstract:
This thesis describes approaches towards the synthesis of 20-deoxybryostatins and 20,20-difluorobryostatins. Towards the 20-deoxybryostatins, a route previously developed within the group was followed with a protecting group change designed to prevent problems encountered with a late-stage deprotection. To this end, (R)-pantolactone was transformed through to dimethyl (4S,6R,8R)-[4-(para-methoxybenzyloxy)-10-hydroxy-6,8-O-isopropylidine-3,3-dimethyl-2-one] phosphonate which was subsequently subjected to a Horner-Wadworth-Emmons condensation with (5R,E)-6-(4-methoxybenzyloxy)-5-triethylsilyloxy-3-(2’-triisopropylsilyloxyethylidene)hexanal. The reactions of the resulting enone through to the advanced intermediate allyl [(4R,6R)-6-((S)-2’-(4-methoxybenzyl)oxy-5-{(2’’S,6’’R)-6’’-(4-methoxybenzyloxymethyl)-4’’-[2-triisopropylsilyloxyeth-(Z)-ylidene]-tetrahydropyran-2’’-yl}-3,3-dimethyl-4’-oxopentyl)-2,2-dimethyl-1,3-dioxan-4-yl]-acetate are described, and this compound corresponds to a C1-C16 northern bryostatin fragment. A synthetic route to 20,20-difluorobryostatins was begun by the synthesis of three 3,3-difluoro-2-hydroxytetrahydro-4H-pyrans which started from an indium-mediated coupling of 3-bromo-3,3-difluoro-1-propene with an aldehyde. A strategy was employed which culminated in the preparation of 3,3-difluoro-2-hydroxy-2-(3-methylbut-1-en-3-yl)-4-(E)-methoxycarbonylmethylenetetrahydro-4H-pyran which corresponds to a C16-C23 20,20-difluorobryostatin southern fragment. Of particular interest is the selectivity observed in the reaction of α,α-difluoroketones with a stabilised Wittig reagent. The indium-mediated coupling was extended to include the first example of the coupling of a 2-alkyl substituted bromide.
39
Stevens, Kiri. "Methodology for the synthesis of NP25302 and other bioactive natural products." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:ae18879e-d75e-4280-ba55-1ae08e64034f.
Full textAbstract:
Total synthesis of the pyrrolizidine alkaloid NP25302: (+)-NP25302 is an unusual vinylogous urea containing pyrrolizidine alkaloid shown to exhibit cell adhesion inhibition. It was envisaged that this natural product could be accessed by a novel 5-endo-dig cyclisation to construct the pyrrolizidine core, and a Curtius rearrangement to install the vinylogous urea motif. This methodology was first tested on a model system, furnishing nor-NP25302 from L-proline in 12 steps and 9% overall yield. The total synthesis of (±)-NP25302 was completed in 9 steps and 26% overall yield from ethyl 2-nitropropionate using similar methodology. Studies into the stereospecificity of the Au(I)-catalysed cyclisation of monoallylic diols: During the synthesis of (+)-isoaltholactone in the Robertson group, the key Au(I)-catalysed cyclisation was observed to occur with some stereospecificity. Further investigations were therefore conducted into the stereochemical outcome of this reaction using stereodefined allylic alcohols, and from the combined results a mnemonic was proposed to predict the stereochemistry of the products of this reaction. Studies into the total synthesis of ascospiroketals A and B: Investigations were conducted into the total synthesis of the recently isolated natural products ascospiroketals A and B. A second generation synthesis was used to construct advanced intermediates 1 and 2.
40
Shah, Rushabh Surendra. "Total syntheses of the nakinadine alkaloids." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:c022e538-9ff8-4914-8c17-dc0b3ed1fbae.
Full textAbstract:
This thesis is concerned with the development of methodology for the asymmetric syntheses of the nakinadine family of marine alkaloids and through these synthetic endeavours, seeks to confirm the structure and assign the relative and absolute configurations of these alkaloids for the first time.
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Woodard, John Lewis IV. "SYNTHESIS AND STRUCTURAL OPTIMIZATION OF THE NATURAL PRODUCTS SILVESTROL AND PHYLLANTHUSMIN C." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1424384284.
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Torssell, Staffan. "Stereoselective Synthesis of Amino Alcohols : Applications to Natural Product Synthesis." Doctoral thesis, Stockholm : Kemi, Kungliga Tekniska högskolan, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-4472.
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Rali, T. "Approaches to the synthesis of 5- and 6-membered nitrogen containing heterocyclic natural products." Thesis, University of East Anglia, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.370395.
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Rahman, S. S. "Generation of ketenes by photolysis of cyclobutanones : A versatile route to natural product synthesis." Thesis, University of Salford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384092.
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McFarland, Heather Lynn. "An intramolecular Diels-Alder approach towards the total synthesis of the natural product phorbol." Thesis, University of Liverpool, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337143.
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Cox, Glen Adam. "THE ASYMMETRIC HYDROVINYLATION REACTION: APPLICATIONS IN THE SYNTHESIS OF PSEUDOPTEROGORGIA ELISABETHAE NATURAL PRODUCTS." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1332433731.
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Campbell, Erica L. "Total Synthesis of Lucilactaene and Efforts Towards the Total Synthesis of Ceratamines A and B." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1218650229.
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Williamson, Emily R. "Organic Synthesis of Kaurenoic Acid." Kent State University Honors College / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ksuhonors158832460424579.
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Figuccia, Aude L. A. "Total asymmetric syntheses of iminosugars." Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:7075b45f-e3e1-4ae6-a544-4d6e54d4714e.
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This thesis is concerned with the development of ring-closing iodoamination and ringexpansion methodology and its subsequent application to the asymmetric syntheses of pyrrolidine and piperidine iminosugars. Chapter 1 highlights the remarkable biological properties displayed by iminosugars and introduces methods for the formation of the pyrrolidine and piperidine sub-classes. Chapter 2 describes investigations into the ring-closing iodoamination of bishomoallylic amines which occurs with concomitant N-debenzylation to give an iodomethyl pyrrolidine scaffold. Conversion to the corresponding aziridinium species followed by its regioselective intermolecular ring-opening by H2O enabled the synthesis of (+)-2,5-dideoxy-2,5-imino-Dglucitol (DGDP). A protocol for the preparation of its 1-deoxy-1-amino analogue (+)-ADGDP was also developed. Chapter 3 details studies into the ring-expansion of iodomethyl pyrrolidine scaffolds via the trapping of CO2 (from NaHCO3) to produce cyclic carbonates as single diastereoisomers. Subsequent deprotection of these piperidines allowed the syntheses of (−)-1-deoxymannojirimycin (DMJ) and (+)-1-deoxyallonojirimycin (DANJ) to be completed. Chapter 4 delineates investigations into the trapping of alternative “X=C=Y” electrophiles, via the ring-expansion methodology developed in Chapter 3, initially utilising a model system. These studies culminated in the development of the trapping of p-TsNCO and the application of this methodology in the total asymmetric syntheses of (−)-ADMJ and (+)-ADANJ, the 2-deoxy-2-amino analogues of (−)-DMJ and (+)-DANJ, respectively. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.
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Allwein, Shawn Paul. "Iterative strategies toward the synthesis of fused ether ring systems and the synthesis of fused ether containing natural products." Diss., The University of Arizona, 2001. http://hdl.handle.net/10150/280230.
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A highly efficient and general approach to fused ether ring systems has been presented. The approach couples stereoselective C-glycoside forming reactions with subsequent annulations. C-glycosides were formed from glycals through an oxidation and carbon-carbon bond forming sequence. Annulations involving a two step methylenation/enol ether-olefin ring closing metathesis or a single flask, acid mediated cyclization/elimination proved to be efficient tribenzyl- D-glucal (95), [4.4.0] and [4.5.0] bicyclic enol ethers (194, 200, 204) were stereoselectively generated in 2-4 steps in good overall yields (53%, 57%, and 39% respectively). Iteration resulted in the stereoselective formation of tricylic enol ethers (240, 241). In addition, our C-glycoside approach was applied to the synthesis of fused ether containing natural products. A formal synthesis of (±)-hemibrevetoxin B (2) was achieved by intercepting Mori's intermediate ( 278) in 21 steps and 3.8% overall yield. The C-glycoside approach to fused ethers was also demonstrated in the synthesis of halichondrin B's model compounds, bicycle 374 and tricycle 383. Subsequent fragmentation of 383 resulted in bicyclic alcohol 384 which correlates to the C,23-C,38 subunit of halichondrin B (8).