Dissertations / Theses: 'Total Synthesis, Antibiotics'

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Preece, Lewis. "Studies toward a total synthesis of Lactonamycin." Thesis, University of Sussex, 2012. http://sro.sussex.ac.uk/id/eprint/39607/.

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Work was undertaken towards the synthesis of the promising antibiotic lactonamycin (iii). Following the work of Parsons et al. it was proposed that cyclisation of the ene-diyne (i) would give access to advanced pentacyclic intermediate (ii) and that from this a total synthesis of lactonamycin would be achieved (scheme I). Scheme I : Proposed Parsons, Board, Waters cyclisation to form the pentacycle (iii)(For image refer to pdf). A synthesis towards the cyclisation precursor (i) was carried out and a route to the key tetrasubstituted phthalide (v) established. Further chemistry was proposed to complete the synthesis of lactonamycin (scheme II). Scheme II : Formation of a fully substituted benzolactone.(For image refer to pdf). During attempts to introduce the β-bromoallyl group of key intermediate (v) using a high temperature Claisen rearrangement it was established that the benzodioxin (vii) underwent thermolysis to generate the reactive quinone methide intermediate (viii) and that in the presence of a nucleophilic solvent the adduct (ix) was formed (scheme III). Model studies showed the reaction to be both general and high-yielding. Scheme III : Novel quinone methide methodology. (For image refer to pdf).

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Wohlrab, Aaron M. "The total synthesis of depsipeptide antibiotics." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3284214.

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Thesis (Ph. D.)--University of California, San Diego, 2007.
Title from first page of PDF file (viewed January 14, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.

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Lineswala, Jayana P. "Total synthesis of lavendamycin amides." Virtual Press, 1996. http://liblink.bsu.edu/uhtbin/catkey/1036197.

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The synthesis of 7-N-acetyldemethyllavendamycin butyl amide (47), 7-Nacetyldemethyllavendamycin isopropyl amide (48), 7-N-acetyldemethyllavendamycin amide of piperidine (49), 7-N-acetyldemethyllavendamycin amide of pyrrolidine (50), 7N-acetyldemethyllavendamycin amide of morpholine (51), demethyllavendamycin butyl amide (52), demethyllavendamycin amide of pyrrolidine (53), and demethyllavendamycin amide of morpholine (54) are described. Pictet Spengler condesation of 7-acetamido-2formylquinoline-5,8-dione (28) with tryptophan butyl amide (66), tryptophan isopropyl amide (67), tryptophan amide of piperidine (68), tryptophan amide of pyrrolidine (69), and tryptophan amide of morpholine (70) in an anisole - pyridine solution directly afforded the five lavendamycin amides 47-51. Compounds 52, 53, and 54 were obtained by hydrolysis of 47, 50, and 51 with 70% H2SO4-H20 solution.Aldehyde 28 was prepared according to the following general procedure.Nitration of 8-hydroxy-2-methylquinoline (30) yielded 8-hydroxy-2-methyl-5,7 dinitroquinoline (31). Compound 31 was then hydrogenated and acylated with acetic anhydride to yield 5,7-diacetamido-2-methyl-8-acetoxyquinoline (33). Compound 33 was oxidized by potassium dichromate to give 7-acetamido-2-methylquinoline-5,8-dione (27). Treatment of 27 with selenium dioxide in refluxing 1,4-dioxane afforded compound 28.Compounds 66, 67, 68, 69, and 70 were synthesized from compounds 61,62, 63, 64, and 65. These compounds were deprotected with ammonium formate in the presence of 10% Palladium on charcoal in methanol under an argon balloon at atmospheric pressure.Compounds 61, 62, 63, 64, and 65 were obtained from 58 with butylamine, isopropylamine, piperidine, pyrrolidine, and morpholine respectively in the presence of triethylamine under an argon balloon at atmospheric pressure.Compound 58 was synthesized by the reaction of N-carbobenzyloxytryptophan, with N-hydroxy succinimide, in the presence of N-dicyclohexylcarbodimide in dried and distilled dioxane under an argon balloon at atmospheric pressure.The structures of the novel compounds 58, 47, 48, 49, 50, 51, 52, 53, and 54 were confirmed by 1H NMR, IR, EIMS, and HRMS.The structures of protected and deprotected amides 61, 62, 63, 64, 65, 66, 67, 68, 69, and 70 were also confirmed by 1 H NMR and IR spectroscopy.
Department of Chemistry

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Martin, Bruce John. "A total synthesis of myxothiazol." Thesis, University of Nottingham, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283643.

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Glover, Christian. "Towards the total synthesis of thiopeptide antibiotics." Thesis, Cardiff University, 2006. http://orca.cf.ac.uk/56094/.

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The Bohlmann-Rahtz intermediates (aminodienones) have provided a viable route to 2,3,6- trisubstituted and 2,3,5,6-tetrasubstituted pyridines (a substitution partem hitherto unreported for Bohlmann-Rahtz intermediates), using new mild facile reaction conditions. These new methods provide the potential for both complimentary and independent pathways to access many of the thiopeptide antibiotics as well as other pyridine containing natural products. Degradation studies of thiopeptide antibiotics have led to the isolation of fragments that help in the structural elucidation of the parent molecules. Our efforts to synthesize degradation fragments from thiopeptide antibiotics have led to the total synthesis of the methyl sulfomycinate 39 in 9 steps from H-Thr-OMe and 15% overall yield, sulfomycinic amide 38, sulfomycinine 37 and the synthesis of saramycetic acid I 47, the latter in 9 steps and 11% overall yield. Furthermore progress towards the total synthesis of micrococcin Pi has demonstrated that enamine and alkynone precursors to the Bohlmann-Rahtz pyridine synthesis are viable intermediates en route to the core of micrococcin Pi.

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Karki, Rajesh. "Total synthesis of oxygenated lavendamycin analogs." Virtual Press, 1998. http://liblink.bsu.edu/uhtbin/catkey/1115420.

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The synthesis of 7-acetyl-11'-benzyloxylavendamycin methyl ester (47), 7acetyl-11'-hydroxylavendamycin methyl ester (48), 11'-hydroxylavendamycin methyl ester (49), 11'-benzyloxylavendamycin methyl ester (50), are described. Pictet-Spengler condensation of 7-N-acetyl-2-formylquinoline-5,8-dione (26) with 5-benzyloxytrytophan methyl ester (45) or 5-hydroxytryptophan methyl ester (46) in dry xylene or anisole directly afforded lavendamycin analogs 47 or 48. Compound 49 was obtained by hydrolysis of 48 with 70% H2SO4 - H2Osolution. Compound 50 was obtained by hydrolysis of 47 with sodium carbonate solution.Aldehyde 26 was prepared according to the following general procedure. Nitration of 8-hydroxy-2-methylquinoline (28) yielded 8-hydroxy-2-methyl5,7-dinitroquinoline (29). Compound 29 was then hydrogenated and acylated with acetic anhydride to yield 5,7-bis(diacetamido)-8-hydroxy-2methylquinoline (31). Compound 31 was oxidized to give 5,8- dione 25 by using potassium dichromate. Treatment of compound 25 with selenium dioxide in refluxing 1,4-dioxane yielded compound 26.3 (Isopropylaminoethylidene)-6,7-dimethoxyindole (39) was prepared via the following procedure. Acylation of vanillin (32) with acetic anhydride yielded acetylvanillin (33). Compound 33 was nitrated and hydrolyzed to give 2nitrovanillin (35). Compound 35 was then methylated using dimethyl sulfate to produce 2-nitroveratric aldehyde (36). Condensation of compound 36 with nitromethane yielded 3,4-dimethoxy-2-f3-nitrostyrene (37). Ammonium formate reductive cyclization of compound 37 in refluxing methanol in the presence of a catalytic amount of 10% palladium on charcoal yielded 6,7dimethoxyindole (38). Electrophilic substitution reaction of compound 38 with ethylideneisopropylamine (41) in dry toluene yielded compound 39.Methyl (2RS, 3SR)-2-amino-3-[3-(5-benzyloxyindolyl)]butanoate (45) and methyl (2RS, 3SR)-2-amino-3-[3-(5-hydroxyindolyl)]butanoate (46) were obtained following the procedure described below. Electrophilic substitutionreaction of 5-bezyloxyindole (40) with ethylideneisopropylamine (41) in dry toluene yielded 3-(isopropylaminoethylidene)-5-benzyloxyindole (42). Condensation of compound 42 with methyl nitroacetate (43) in dry toluene gave methyl 3-[3-(5-benzyloxyindolyl)]3-nitrobutanoate (44). Hydrogenation of compound 44 in the presence of Raney nickel and trifluoroacetic acid in ethanol yielded methyl (2RS, 3SR)-2-amino-3-[3-(5-benzyloxyindolyl)] butanoate (45). Hydrogenation of compound 44 in the presence of 10% palladium on charcoal and trifluoroacetic acid in ethanol yielded methyl (2RS, 3SR)-2-amino-3-[3-(5-hydroxyindolyl)] butanoate (46).The structures of the novel compounds were confirmed by 1H NMR, IR, and HRMS or elemental analysis.
Department of Chemistry

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Chen, Deqi. "Studies towards the total synthesis of aerocyanidin." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.240567.

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Ward, Richard Anthony. "A total synthesis of AI-77-B." Thesis, University of Salford, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315364.

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Stocksdale, Mark G. "Total synthesis of lavendamycin analogs." Virtual Press, 1992. http://liblink.bsu.edu/uhtbin/catkey/834647.

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The syntheses of 7-N-chloroacetyllavendamycin methyl ester (55), 7-N-butyryllavendamycin methyl ester (56), 7-N-chloroacetyldemethyllavendamycin octyl ester (57), 7-N-butyryldemethyllavendamycin octyl ester (58), 7-N-chloroacetyldemethyllavendamycin isoamyl ester (59), and 7-N-butyryldemethyllavendamycin isoamyl ester (61) are described. Incorporation of the Pictet-Spengler condensation of 7-chloroacetamido-2-formylquinoline-5,8-dione (62) or 7butyramido-2-formylquinoline-5,8-dione (63) with B - methyltryptophan methyl ester (11), L-tryptophan octyl ester (64), or L-tryptophan isoamyl ester (65) in xylene directly afforded six lavendamycin analogs.The aldehydes 62 and 63 were prepared according to the following general procedure. Nitration of 8-hydroxy-2methylquinoline (66) yielded 8-hydroxy-2-methyl-5,772, and 73 are also included. 1H NMR and IR are provided compounds 67, and 71, and 1H NMR is provided for compound dinitroquinoline (67). Compound 67 was then hydrogenated and acylated with chloroacetic anhydride (or butyric anhydride) to yield 5,7-bis(chloroacet4mido)-8-hydroxy-2-methylquinoline (69) (or 5,7-dibutyramido-8-butyroxy-2 methylquinoline (71)).Compound 69 (and 71) was oxidized by potassium dichromate to give the corresponding 5,8-dione 70 (and 72). Treatment of 70 (and 72) with selenium dioxide in refluxing 1,4-dioxane afforded compound 62 (and 63). It was also noted that 71 would hydrolyze to its 8-hydroxy derivative 73 in hot methanol-water.Compound 64 was prepared through the neutralization of Ltryptophan octyl ester hydrochloride with a 14 % ammonium hydroxide solution followed by extraction. Compound 65 was synthesized via a Fischer esterification of L-tryptophan with isoamyl alcohol saturated with hydrogen chloride. The synthesis of H-methyltryptophan (44) was accomplished with the method of Snyder and Matteson.The structures of the novel compounds 55, 56, 57, 58, 59, 60, 62, 63, 69, 70, 72 and 73 were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of 62, 63, 69, 70,for 44.
Department of Chemistry

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Chenault, Darrell Vincent. "Total synthesis of 6-chlorodemethyllavendamycin esters and amides." Virtual Press, 1998. http://liblink.bsu.edu/uhtbin/catkey/1115748.

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The synthesis of several 6-Chlorodemethyllavendamycin analogs and their chemistry are described. In this investigation the following compounds were prepared:6-Chlorodemethyllavendamycin methyl ester, 6-Chlorodemethyllavendamycin ethylester, 6-Chlorodemethyllavendamycin butyl ester, 6-Chlorodemethyllavendamycin isoamyl ester, 6-Chlorodemethyllavendamycin octyl ester, and 6-Chlorodemethyllavendamycin amide. Pictet Spengler condensation of 7-amino-6-chloro-2-formylquinoline-5,8-dione with tryptophan methyl ester, tryptophan ethyl ester, tryptophan butyl ester, tryptophan isoamyl ester, tryptophan octyl ester, and tryptophan amide in anisole afforded the compounds. 7-amino-6-chloro-2-formylquinoline-5,8-dione was prepared according to the following general procedures.The first step is the nitration of 8-Hydroxy-2-methylquinoline. 8-Hydroxy-2methylquinoline is reacted with 70% mixture of HNO3/H2SO4 to produce 5,7-dinitro-8hydroxy-2-methylquinoline. The next step requires hydrogenation and acylation. 5,7Dinitro-8-hydroxy-2-methylquinoline was reduced by H2/Pd-C in the presence of HCl and H20 filtered and then treated with sodium sulfite, sodium acetate and acetic anhydride to yield 5,7-diacetamido-8-acetoxy-2-methylquinoline. 5,7-Diacetamido-8-acetoxy-2methylquinoline was oxidized by potassium dichromate to produce 7-acetamido-2methylquinoline-5,8-dione. 7-Acetamido-2-methylquinoline-5,8-dione was chlorinated using hydrogen chloride gas in dry methanol producing 7-amino-6-chloro-2methylquinoline-5,8-dione. Treatment of 7-amino-6-chloro-2-methylquinoline-5,8-dione with selenium dioxide, under reflux in 1,4-dioxane produced 7-amino-6-chloro-2formylquinoline-5, 8-dione.All structures were confirmed by 'H NMR, IR, EIMS, and HRMS.
Department of Chemistry

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Freeman, Richard Neil Templar. "The total synthesis of non-beta-lactam antibiotics." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257963.

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Rawson, D. J. "A total synthesis of (+)-(9S)-dihydroerythronolide A." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317889.

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Olang, Fatemeh. "Total synthesis of lavendamycin analogs." Virtual Press, 1995. http://liblink.bsu.edu/uhtbin/catkey/958797.

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The synthesis of 7-N -furoyllavendamycin methyl ester (35), 7-N -furoyl demethyllavendamycin methyl ester (36), 7-N -furoyldemethyllavendamycin ethyl ester (37), 7-N -furoyldemethyllavendamycin propyl ester (38), 7-N -furoyl demethyl lavendamycin butyl ester (39), 7-N -furoyldemethyllavendamycin isoamyl ester (40),7-N -furoyldemethyllavendamycin cyclohexyl ester (41), 7-N -furoyldemethyl lavendamycin octyl ester (42), 7-N -furoyldecarboxydemethyllavendamycin (43), and demethyl lavendamycin isoamyl ester (44) are described. Pictet-Spengler condensation of 7-furoylamino-2-formylquinoline-5, 8-dione (55) with (3-methyltryptophan methyl ester (4), Ltryptophan methyl ester (56), L-tryptophan ethyl ester (57), L-tryptophan propyl ester (58), L-tryptophan butyl ester (59), L-tryptophan isoamyl ester (60), L-tryptophan cyclohexyl ester (61), L-tryptophan octyl ester (62), L-tryptamine (63), in xylene, or anisole afforded ten lavendamycin analogs.Aldehyde 55 was prepared according to the following general procedure.Nitration of 8-hydroxy-2-methylquinoline (30) gave 8-hydroxy-2-methyl-5,7dinitroquinoline (31). Compound 31 was then hydrogenated and acylated with 2-furoyl chloride (or acetic anhydride ) to yield 5,7-difuroylamino-8-hydroxy-2-methylquinoline (53) or 5,7-diacetamino-8-acetoxy-2-methyl- quinoline (33). Compounds 53 and 33 were oxidized by potassium dichromate to give the corresponding 5,8-diones 54, and 27. Treatment of 53, and 27 with selenium dioxide in refluxing wet dioxane afforded compounds 55 and 28.Compound 4 was previously prepared by other members of our group, compounds 56, 57, 59, and 62 were obtained through the neutralization of the corresponding Ltryptophan ester hydrochlorides with a 14% ammonium hydroxide solution followed by extraction. Compounds 58, 60, 61 were synthesized via a Fischer esterification of Ltryptophan with : propyl alcohol, isoamyl alcohol, and cyclohexyl alcohol saturated with hydrogen chloride.The structures of compounds 53, 54, 55, 35, 36, 37, 38, 39, 40, 41, 42, 43, and 44 were confirmed through 1H NMR, IR, EIMS, and HRMS. Elemental analyses of 53, 54, and 55 are also included.The structures of esters 56, 57, 58, 59, 60, 61, 62, and 63 were confirmed by 1H NMR.
Department of Chemistry

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Fellows, Ingrid Maria. "A formal synthesis of FR-900482 and studies toward the total synthesis of FR-900482 /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.

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He, Jing. "Studies towards the total synthesis of tetrodecamycin." Thesis, University of Oxford, 2007. http://ora.ox.ac.uk/objects/uuid:3a2ab5cb-2757-4e53-b8cf-c635aef99455.

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Tetrodecamycin (1) is a novel α-(γ-hydroxyacyl) tetronic acid based polyketide antibiotic isolated from the culture broth of Streptomyces nashvillensis MJ885-mF8 by Takeuchi et al. in 1994. Compound 1 shows potent inhibitory activity against Gram-positive bacteria including Bacillus anthracis and methicillin resistant Staphylococcus aureus (MRSA). It was proposed that an Aldol reaction of trans-decalin core 2 and tetronic acid derivative 3 followed by a face selective epoxidation and a subsequent epoxide-opening reaction would deliver the 6,6,7,5-skeleton of tetrodecamycm (1). To investigate this proposal, the silyl enol ether 5 was prepared from cycloheptene 4 in 7 steps. An unusual domino silyl enol ether reaction sequence was observed when the silyl enol ether 5 was submitted to a Diels-Alder reaction. It afforded cycloadduct 6, which was converted to the key intermediate 2 after another 3 steps (Scheme 1). Concurrently, double functionalisation of simple cyclic silyl enol ethers was investigated. Because of some difficulties in reproducing good overall yields to the cycloadduct 6, a second synthetic route was proposed. It was envisaged that a palladium-catalysed oxidative cyclisation or an organoselenium-mediated cyclisation reaction of compound 8 would construct the 6,6,7,5- skeleton 7, which would be converted to tetrodecamycin (1) via dihydroxylation followed by an introduction of the exo-methylene group. The intramolecular Diels-Alder reaction of trienal 11 afforded trans-decalin 10, which was converted to β-keto ester 9 in 2 steps. A Dieckmann-type cyclisation of 9 afforded compound 8 in good yield. However, so far transformation to compound 7 has not been achieved (Scheme 2).

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Li, Chengyong, and 李成永. "Total syntheses (-)-5-demethoxyfumagillol, (-)-fumagillol, (-)-RK-805,(-)-FR65814, and analogues." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B39793977.

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Basu, Shubhamita. "STUDIES TOWARDS THE TOTAL SYNTHESIS OF VANCOMYCIN AGLYCON." Case Western Reserve University School of Graduate Studies / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1183157258.

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Stansfield, Ian. "Synthetic and modelling studies on macrolide antibiotics : total synthesis of novel analogues of erythromycin A." Thesis, University of Cambridge, 1995. https://www.repository.cam.ac.uk/handle/1810/271994.

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Abou, Fayad Antoine. "Combining synthesis and biosynthesis to generate novel antibiotics." Thesis, University of St Andrews, 2014. http://hdl.handle.net/10023/6359.

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This thesis focuses upon pacidamycin, a member of the uridyl peptide antibiotics, a family of antibiotics which exhibit an, as yet, clinically unexploited mode of action, against MraY. The Goss group has previously demonstrated the ease of accessing N and C-termini analogues of pacidamycin utilizing precursor directed biosynthesis. The central diamino acid is key to pacidamycin's activity, yet little work has been carried out, to date, to investigate the SAR around this moiety. Particularly this thesis describes work toward generating pacidamycin analogues using the complementary tools of organic synthesis and biosynthesis. Chapter 1 introduces natural compounds and their importance in clinical use, provides a brief overview of the history of antibiotics and focuses on the urgent need for new antibiotics displaying new chemical architectures and possessing novel modes of action. This chapter also introduces uridyl peptide antibiotics and overviews the SAR studies around these unusual peptides, focusing on pacidamycin in particular. Diaminobutyric acid is central to these structures and a discussion of a selection of published methods to synthesis α, β-diaminobutyric acid (DABA) is also presented. Chapter 2 describes the synthesis of DABA and two analogues, in which the C-methyl moiety has been substituted by an ethyl or a cyclopropyl group. The mutasynthesis approach utilised in the attempt to generate novel pacidamycins and discussion around the results observes is also described. Chapter 3 demonstrates a three step one-pot reaction to access 1,3-disubstituted urea molecules. The chapter starts with a brief overview of previously established methods in the literature to access these useful molecules, and then moves towards a discussion about the reaction optimisation. The chapter also describes a family of analogues generated utilising this novel approach; and exploring the use of these analogues in the mutasynthesis of pacidamycin. In order to access the desired pacidamycin analogues with the modified diamino acid residue, it was determined that it is currently not possible to use a mutasynthesis approach, instead an approach of total synthesis needed to be employed. Chapter 4 describes this total synthesis. The C- terminal urea motif was generated using a novel 1-pot phosphine free route developed during this study. To access the central native (2S, 3S)- DABA, a variation of the route of Merino et al's via Garner's aldehyde was initially utilised. Subsequently, a shorter and more flexible approach from Soloshonok et al via a Ni (II) Schiff base complex of glycine was adopted. Unpublished results from the Goss group have shown that the 2',3'dihydroxy uridine analogues in pacidamycin conferred broader spectra of activity. Work towards the synthesis of these analogues has been conducted. The order of assembly of the peptide and the nucleoside fragments was in alignment with Boojamra et al's approach. If the de-protection chemistry had worked according to plan, this would have resulted with a synthesis that is at least 6 steps shorter and higher yielding then Boojamra's. The introduction in this chapter reports the various methods previously reported in the literature for the total synthesis of pacidamycin. A discussion about the current progress in the total synthesis highlighting the difficulties faced is also shown. Chapter 5 demonstrates utilising semi-synthesis as a useful tool to generate novel pacidamycins by applying a Pictet-Spengler reaction on pacidamycin 4. This chapter starts with an overview of this phosphate mediated Pictet-Spengler reaction. In addition, a discussion about the large-scale fermentation of Streptomyces coeruleorubidus, the wild type producer of pacidamycin, and the generation of pacidamycin analogues utilising a semi-synthesis approach is also presented. Chapter 6 describes the future work following on from this study building upon each of the above chapters.

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Vickers, Clare Frances. "A study concerning the total synthesis of the natural products abyssomicin C and stemofoline." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491851.

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Burnside, I. J. "Synthetic studies on macrolide antibiotics : the total synthesis of (+)-(6R)-Fluoro-6-deoxy-(9S)-dihydroerythronolide A." Thesis, University of Cambridge, 1996. https://www.repository.cam.ac.uk/handle/1810/273078.

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Glassford, Ian Michael. "Addressing Antibiotic Resistance: The Discovery of Novel Ketolide Antibiotics Through Structure Based Design and In Situ Click Chemistry." Diss., Temple University Libraries, 2016. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/410231.

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Chemistry
Ph.D.
Antibiotic resistance has become and will continue to be a major medical issue of the 21st century. If not addressed, the potential for a post-antibiotic era could become a reality, one that the world has not been familiar with since the early 1900’s. Multidrug-resistant hospital-acquired bacterial infections already account for close to 2 million cases and 23,000 deaths in the United States, along with 20 billion dollars of additional medical spending each year. The CDC released a report in 2013 regarding the seriousness of antibiotic resistance and providing a snapshot of costs and mortality rates of the most serious antibiotic resistant bacteria, which includes 17 drug resistant bacteria, such as carbapenem-resistant Enterobacteriaceae, vancomycin-resistant Enterococcus and Staphylococcus aureus, and multidrug-resistant Acinetobacter and Pseudomonas aeruginosa. The development of antibiotic resistance is part of bacteria’s normal evolutionary process and thus impossible to completely stop. To ensure a future where resistant bacteria do not run rampant throughout society, there is a great need for new antibiotics and accordingly, methods to facilitate their discovery Macrolides are a class of antibiotics that target the bacterial ribosome. Since their discovery in the 1950’s medicinal chemistry has created semi-synthetic analogues of natural product macrolides to address poor pharmacokinetics and resistance. Modern X-Ray crystallography has allowed the chemist access to high resolution images of the bacterial ribosome bound to antibiotics including macrolides which has ushered in an era of structure-based design of novel antibiotics. These crystal structures suggest that the C-4 methyl group of third generation ketolide antibiotic telithromycin can sterically clash with a mutated rRNA residue causing loss of binding and providing a structural basis for resistance. The Andrade lab hypothesized that the replacement of this methyl group with hydrogen would alleviate the steric clash and allow the antibiotic to retain activity. To this end, the Andrade lab set out on a synthetic program to synthesize four desmethyl analogues of telithromycin by total synthesis that would directly test the steric clash hypothesis and also provide structure-activity relationships about these methyl groups which have not been assessed in the past. Following will contain highlights of the total synthesis of (-)-4,8,10-didesmethyl telithromycin, (-)-4,10-didesmethyl telithromycin, and (-)-4,8-desmethyl telithromycin and my journey toward the total synthesis of (-)-4-desmethyl telithromycin Traditional combinatorial chemistry uses chemical synthesis to make all possible molecules from various fragments. These molecules then need to be purified, characterized, and tested against the biological target of interest. While high-throughput assay technologies (i.e., automation) has streamlined this process to some extent, the process remains expensive when considering the costs of labor, reagents, and solvent to synthesize, purify, and characterize all library members. Unlike traditional combinatorial chemistry, in situ click chemistry directly employs the macromolecular target to template and synthesize its own inhibitor. In situ click chemistry makes use of the Huisgen cycloaddition of alkyne and azides to form 1,2,3-triazoles, which normally reacts slowly at room temperature in the absence of a catalyst. If azide and alkyne pairs can come together in a target binding pocket the activation energy of the reaction can be lowered and products detected by LC-MS. Compounds found in this way generally show tighter binding than the individual fragments. Described in the second part of this dissertation is the development of the first in situ click methodology targeting the bacterial ribosome. Using the triazole containing third generation ketolide solithromycin as a template we were able to successfully show that in situ click chemistry was able to predict the tightest binding compounds.
Temple University--Theses

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O'Riordan, Timothy Jeremiah Cornelius. "Synthesis of the pyrrolidinone core of oxazolomycin A." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:298746d3-69df-47b9-8a83-7949df1c94dc.

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This thesis describes the development of synthetic strategies towards the densely functionalised pyrrolidinone core of the polyene β-lactone-γ-lactam antibiotic oxazolomycin A. Chapter 1 The oxazolomycins The oxazolomycins, a unique class of biologically active molecules containing a spiro-fused β-lactone-γ-lactam ring system are introduced. The isolation, structural elucidation and biological properties of the oxazolomycins as well as those of the structurally related inthomycins are reviewed. Chapter 2 Previous syntheses The two total syntheses of neooxazolomycin and the synthetic approaches to the pyrrolidinone core of oxazolomycin A and KSM-2690 B are evaluated. Chapter 3 Project aims An outline of the synthetic strategy employed in this project and details of the novel retrosynthesis of the pyrrolidinone core of oxazolomycin A are discussed. Chapter 4 Synthetic studies towards the pyrrolidinone core of oxazolomycin A The synthetic studies carried out towards the pyrrolidinone core of oxazolomycin A are described in detail. The preparation of an advanced intermediate containing the five chiral centres, four of which are contiguous, was achieved in twenty steps as a single diastereomer and as a single enantiomer. Chapter 5 Synthetic studies towards the middle fragment of oxazolomycin A A novel synthetic approach to the diene fragment contained in oxazolomycin A is reported. The formal synthesis of a dienyl iodide, in four fewer steps than previously reported was accomplished. Chapter 6 Conclusions and future work A summary of the synthetic work reported in this thesis and proposals for future study are presented. Chapter 7 Experimental Full experimental procedures and characterisation of compounds are reported. Chapter 8 References A complete list of citations employed in the previous seven chapters is provided.

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Wildermuth, Raphael [Verfasser], and Thomas [Akademischer Betreuer] Magauer. "A modular synthesis of tetracyclic meroterpenoid antibiotics : towards the total synthesis of cornexistin / Raphael Wildermuth ; Betreuer: Thomas Magauer." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2018. http://d-nb.info/1222908905/34.

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Baker, Simon. "Studies towards the total synthesis of BU-4794F and alkene metathesis in the synthesis of novel Î²-lactam antibiotics." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326162.

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Bułyszko, Ilona [Verfasser]. "Studies on ansamycin antibiotics : mutasynthetic approach towards new rifamycin derivatives and total synthesis of progeldanamycin derivatives / Ilona Bułyszko." Hannover : Technische Informationsbibliothek (TIB), 2016. http://d-nb.info/1126666726/34.

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Cascales, Jiménez Víctor. "Síntesis total de la Anfidinolida B(2)." Doctoral thesis, Universitat de Barcelona, 2021. http://hdl.handle.net/10803/673064.

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En esta Tesis doctoral se ha abordado la síntesis total de la Anfidinolida B2, un macrociclo de 25 miembros aislado por primera vez por Shimizu y colaboradores en 1994 en Brewer’s Bay, Santo Tomás, una de las Islas Vírgenes de los Estados Unidos de América. Posee una estructura compleja y una importante toxicidad. Aunque actualmente se acepta la propuesta de estructura de Carter (2013), esta no ha sido confirmada todavía, por lo que su síntesis total es un objetivo muy atractivo. Nuestra retrosíntesis se basa en la desconexión del macrólido en cuatro fragmentos más sencillos, cuya síntesis, optimización y unión son los objetivos de este trabajo. En el capítulo 2 se ha optimizado la preparación del Fragmento I, ya que la síntesis desarrollada anteriormente en el grupo presentaba ciertos inconvenientes. Por ello, decidimos optimizar la preparación de la cetona 10, un intermedio clave. Se investigaron seis rutas, concluyendo que más adecuada para preparar el Fragmento I transcurría en seis etapas a partir del metil-malonato de dietilo y con un rendimiento del 44%. En el capítulo 3 abordamos la optimización de la síntesis del Fragmento II. Inicialmente optimizamos una síntesis anterior, obteniendo el Fragmento II en 11 etapas y con un 17% de rendimiento a partir del (S)-lactato de metilo. Debido al elevado número de etapas de esta síntesis, exploramos dos alternativas. Pese a los prometedores resultados iniciales, ninguna de las dos rutas resultó factible. Una cuarta vía alternativa, no ha podido ser explorada por falta del material necesario. El Fragmento III se preparó en el capítulo 4 siguiendo una retrosíntesis anteriormente descrita en nuestro grupo. No obstante, obtuvimos resultados desalentadores en las transformaciones iniciales, por lo que se optó por modificar esta parte problemática de la ruta, preparando los mismos intermedios a partir de otros materiales de partida. De esta manera obtuvimos el Fragmento III en seis etapas y con un 52% de rendimiento a partir del butano-1,4-diol. Debido a que el Fragmento IV presenta ciertos grupos lábiles, en el capítulo 5 se estudió la preparación del Fragmento IV acortado, una versión más sencilla del fragmento inicial. Para ello se prosiguió una retrosíntesis anterior. Debido a que una etapa intermedia transcurría con rendimientos moderados y poco reproducibles, se estudió una aproximación alternativa. No obstante, los resultados eran peores que los de la ruta inicialmente propuesta, por lo que esta se descartó, preparando finalmente el Fragmento IV en tres etapas con un 44% de rendimiento a partir del 2,3-dibromopropeno. Una vez obtenidos los distintos Fragmentos, se procedió a su unión en el capítulo 6. En primer lugar, unimos el Fragmento I con el IV a través de un acoplamiento cruzado de Negishi. El compuesto obtenido se transformó en el yoduro correspondiente, que se sometió a un segundo acoplamiento de Negishi. Este transcurrió con rendimientos bajos y, además, era muy poco reproducible. Por ello, estudiamos una ruta alternativa que evitase esta transformación. Así pues, desarrollamos una nueva vía que promete ser una mejor alternativa que la originalmente propuesta. Solo se pudo llevar esta ruta a escala reducida, por lo que estos resultados aún no son concluyentes. El compuesto así obtenido, resultante de la unión de los Fragmentos I y IV, se sometió a la desprotección del hidroxilo terminal y se introdujo el grupo epoxialdehído deseado mediante una oxidación de Dess–Martin y una epoxidación de Jørgensen. Más tarde, se añadió el Fragmento III mediante una olefinación de Julia–Kocienski y se hidrolizó el éster con trimetilsilanoato de potasio. A continuación, una esterificación de Shiina permitió unir el último Fragmento, el Fragmento II. Estas etapas transcurrieron con rendimientos bajos, por lo que se optimizaron. Pese a nuestros intentos, solo se pudieron obtener rendimientos moderados. En estos momentos estamos llevando a cabo la siguiente etapa, la metátesis de cierre de anillo, y esperamos los resultados correspondientes.
In this Thesis we have undertaken the total synthesis of Amphidinolide B2, a 25-membered macrolide. It was first isolated by Shimizu and coworkers in 1994, from Brewer’s Bay, Saint Thomas, one of USA’s Virgin Islands. This molecule has a very interesting structure and an important cytotoxicity. Carter’s proposal of the structure of Amphidinolide B2 has yet to be confirmed, so that the total synthesis of this macrolide becomes an attractive goal. Our proposal for the synthesis of this molecule is based on the disconnection of the macrocycle into four, more simple, Fragments. In Chapter 2 the preparation of Fragment I was optimized, as the previously developed syntheses were relatively unsuccessful. Six different routes were studied for the preparation of ketone 10, a key intermediate in our synthesis. Finally, Fragment I was obtained in six steps, in a 44% yield starting from methyl-diethyl malonate. In Chapter 3 we approached the synthesis of Fragment II. Originally, we optimized a previous synthesis developed in group for this Fragment, obtaining the desired compound in 11 steps and a 17% yield starting from (S)-methyl lactate. Due to the high number of steps of this route, we explored two alternatives. However, both were unsuccessful. Fragment III was prepared in Chapter 4, following a retrosynthesis previously described in our group. However, discouraging results were obtained in the initial transformations, which made us search for a new route. In the end, Fragment III was obtained in six steps and in a 52% yield starting from butane-1,4-diol. The preparation of a shortened version of Fragment IV is described in Chapter 5, following a previous retrosynthesis. Because an intermediate step proved troublesome, a new approximation was studied, with no success. Finally, Fragment IV was prepared in three steps and in a 44% yield starting from 2,3-dibromopropene With the different Fragments in our hands, their coupling was investigated. Initially, we joined Fragment I with Fragment IV via a Negishi cross coupling. The obtained product was then transformed into the corresponding iodide, which was used in a second Negishi cross coupling. Despite our efforts, low yields were obtained in this transformation which also showed little reproducibility. Therefore, an alternative, promising route was investigated. After functional group manipulation, the desired epoxyaldehyde was prepared. Then, Fragment III was introduced via a Julia–Kocienski olefination. Hydrolysis of the ester, followed by a Shiina esterification was used to link Fragment II. At this moment, we are exploring the next step, the ring closing metathesis for the formation of the macrocycle.

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Hayes, J. F. "Studies towards the total asymmetric synthesis of macbecin." Thesis, University of Southampton, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374854.

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Chan, Tsui Fen. "Studies towards the total synthesis of ambruticin." Thesis, University of Salford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244865.

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Papillon, Julien Pierre Nicolas. "Studies towards the asymmetric total synthesis of oxazolomycin." Thesis, University of York, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288241.

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Dymock, Brian William. "A novel asymmetric [2+2] cycloaddition and its application to the total synthesis of 1233A." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388549.

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Ashcroft, Neil David. "Towards a total synthesis of the ansamycin antibiotic herbimycin A." Thesis, University of Reading, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294580.

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Pietsch, Inga-Marlene. "Studies towards the total synthesis of the ansamycin benzoquinone antibiotic herbimycin A." Thesis, University of Sussex, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.496799.

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Khatri, Hem Raj. "Synthesis of Complex ortho-Allyliodoarenes via Reductive Iodonio-Claisen Rearrangement and Total Synthesis of Antitumor Antibiotic Derhodinosylurdamycin A." University of Toledo / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1431342601.

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35

Guzman-Martinez, Aikomari. "Total synthesis of lysobactin a natural product antibiotic active against methicillin and vancomycin resistant bacteria /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3284164.

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Thesis (Ph. D.)--University of California, San Diego, 2007.
Title from first page of PDF file (viewed January 11, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.

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36

Hemmery, Hélène. "Étude de la synthèse totale de la ripostatine A." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112336/document.

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Cette thèse est consacrée à l’étude de la synthèse totale de la ripostatine A, un antibiotique inhibiteur de l’ARN polymérase des bactéries, isolé en 1995 à partir de la myxobactérie Sorangium cellulosum. La ripostatine A est caractérisée par une lactone à 14 chaînons et un lactol à 6 chaînons ; elle comporte trois doubles liaisons et trois centres stéréogènes. Les deux voies de synthèse envisagées de la ripostatine A comportaient comme étapes clés une cycloaddition 1,3-dipolaire d’oxyde de nitrile et une macrolactonisation. Des accès stéréocontrôlés à deux précurseurs importants comportant un motif 1,4-diène ont été développés, notamment à l’aide d’une carboalumination d’alcyne. Des β-hydroxycétones, précurseurs avancés dans la synthèse, ont été obtenues à partir de ces 1,4 diènes. Un couplage de Stille, entre un alcénylstannane qui a été synthétisé et un halogénure dérivé d’une des β-hydroxycétones préparées, reste à réaliser afin d’assembler le squelette de la ripostatine A
This thesis is dedicated to the study of the total synthesis of ripostatin A, an antibiotic which inhibits eubacterial RNA polymerase, isolated in 1995 from the myxobacteria Sorangium cellulosum. Ripostatin A is characterized by a 14 membered lactone and a 6 membered lactol, it contains three double bonds and three stereogenic centers. The two synthetic routes envisaged for ripostatin A included as key steps a nitrile oxide 1,3 dipolar cycloaddition and a macrolactonisation. Stereocontroled accesses to two important precursors containing a 1,4-diene moiety were developed, using in particular an alkyne carboalumination. Advanced precursors, β-hydroxyketones, were obtained from these 1,4 dienes. A Stille coupling between a synthesized stannane and an halide derived from one of the β-hydroxyketones, remains to be realized in order to assemble the skeleton of ripostatin A

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37

George, Nicolas. "Étude de la synthèse totale de tétrahydroisoquinoléines naturelles : quinocarcine, Tétrazomine et Lémonomycine. : rapide accés aux α-amidosulfures et leur utilisation en tant que précurseurs de N-acylimines dans la réaction de Friedel-Crafts." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00980348.

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La quinocarcine, la tétrazomine et la lémonomycine constituent une sous-famille appartenant à la famille des tétrahydroisquinoléines trisubstituées naturelles. Ce sont des puissants agents cytotoxiques et possèdent de nombreuses activités biologiques telles qu'antitumorales et antibiotiques. Leur complexité structurale, leurs intérêts biologiques ainsi que leur faible rendement d'extraction du milieu naturel font de ces molécules des cibles attrayantes pour les chimistes de synthèse.Ces trois molécules sont constituées d'une tétrahydroisoquinoléine différemment substitué fusionnée avec un diazabicycle[3.2.1]octane commun. Le but de ce projet était de mettre au point une stratégie commune à cette sous-famille et divergente grâce à la synthèse du diazabicyclooctane en premier. Une première stratégie faisant intervenir une aziridine n'a pas permis de construire le bicycle. Cet objectif a été réalisé grâce à une seconde stratégie. Elle repose sur une première cyclisation d'un hémiaminal puis d'une cyclisation par addition nucléophile d'un éther d'énol silylé sur un N-acylimmonium formé in situ au départ d'un N,S-acétal.Parallèlement à cette étude synthétique, nous avons mis au point une réaction multicomposant séquentielle qui permet l'accès rapide et général aux a-amidosulfures, comblant un manque dans la littérature. Ensuite nous avons étudié la réactivité de ces composés en tant que précurseurs simples de N-acylimines en conditions acides douces. Trois conditions réactionnelles, nous ont permis d'accéder à cette objectif : l'utilisation stœchiométrique d'acétate d'argent, catalytique d'acide phosphorique ainsi que le NIS en quantité stœchiométrique et catalytique. Cette dernière réaction est très attrayante. En effet, ce réactif doux et neutre permet l'élimination efficace du thiol formant la N-acylimine puis son activation pour se faire piéger in situ par un nucléophile. Les rendements atteints sont très hauts en moins de 5 minutes.

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Tun, Min Min. "Synthetic studies towards the total synthesis of renieramycin A (Antibiotics)." Thesis, 1988. http://hdl.handle.net/1911/13323.

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Formation of the skeleton of renieramycin A was achieved through sequential condensations of piperazinedione and substituted benzaldehydes. One of the key reactions of this synthesis, oxidation of benzylic position, produced hydroxylated compound 62 (see p. 22 in dissertation for illustration). Further elaboration of 62 has resulted in N-methyl 65 (p. 22), an important precursor to renieramycin A.

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39

Hecker, Evan Adam 1980. "Studies toward the total synthesis of (±)-chartelline C and (-)-platensimycin." 2008. http://hdl.handle.net/2152/17858.

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Herein is described our work towards the total synthesis of the marine natural product (±)-chartelline C and the potent antibiotic (-)-platensimycin. Part 1 relates the (±)-chartelline C project. The first chapter reviews (±)-chartelline C’s isolation, biogeneity, and previously reported studies relevant to the area. Chapter 2 tells of our contributions including the development of a convergent, regioselective assembly of an indole-imidazole compound en route to the natural product. Chapter 3 includes the experimental details of this work and the characterization of previously unreported compounds. Part 2 recounts the (-)-platensimycin research project. Chapter 4 discusses the importance of the natural product and the relevant previous research reported. Chapter 5 describes our efforts in this area, culminating in the stereoselective synthesis of an intermediate closely related to a known compound, which was converted to the natural product. Chapter 6 includes the experimental details of this work and the characterization of previously unreported compounds.
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40

Norbeck, Daniel Word. "Progress Toward the Total Synthesis of Polyether Ionophore Antibiotics." Thesis, 1985. https://thesis.library.caltech.edu/11444/2/Norbeck_DW_1985.pdf.

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Several subunits for the convergent synthesis of polyether ionophore antibiotics via the ester enolate Claisen rearrangement of furanoid and pyranoid carboxylic acids and glycals are prepared from carbohydrates. Key steps from D-fructose to the monensin spiroketal include the ester enolate Claisen rearrangement of a glycal propionate, expansion of a furanoid to a pyranoid ring, and the acid catalyzed equilibration of a bicyclic ketal to a spiroketal. An alternative approach, entailing the hetero-Diels-Alder condensation of a 2-methylenetetrahydropyran and acrolein is thwarted by facile isomerization to the endocyclic enol ether. The monensin bis-tetrahydrofuran is prepared from D-xylose and Dmannose. In the key step, in situ silylation of an ester enolate with a beta leaving group allows the tetrahydrofuran rings to be joined by Claisen rearrangement. The monensin tetrahydropyran is prepared from D-fructose and then joined to the bis-tetrahydrofuran by the ester enolate Claisen rearrangement. Methodology for the radical induced, reductive decarboxylation of the resulting acid via its phenyl selenoester is described. Anomeric stabilization of the intermediate tetrahydrofuran-2-yl radical is an important factor in the stereochemical outcome of this process. Reduction of 2,3-Q-(1-methylethylidene)furanosyl and pyranosyl chloride with lithium 4,4'-di-t-butylbiphenyl affords the corresponding glycals in high yield. The direct addition of nucleophilic reagents to crude Swern oxidation reaction mixtures circumvents the deleterious side reactions characteristic of highly reactive carbonyl compounds. Hexylglyoxal, produced by Swern oxidation of 1,2-octanediol, condenses with methyl (triphenylphosphoranylidene)acetate to give the γ-oxo-crotonate. Addition of methyl magnesiun bromide to an unstable 2-ketofuranoside delivers the branched chain carbohydrate derivative. The transient existence of monomeric trimethylsilyl formaldehyde, generated at -78°C by Swern oxidation of trimethylsilylmethanol, is established by isolation of a Wittig condensation product.

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41

Suttisintong, Khomson. "Studies toward the total synthesis of sanglifehrin A." Thesis, 2012. http://hdl.handle.net/1957/33199.

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Studies toward synthesis of subunits of sanglifehrin A, an immunosuppressant featuring a highly substituted [5,5]-spirolactam moiety as well as a 22-membered macrocycle are described. The macrolactone contains a peptidic backbone characterized by an unusual [beta]-substituted (S)-piperazic acid and (S)-m-hydroxyphenylalanine units. These studies resulted in the synthesis of advanced intermediate 358 which contains all of the carbon atoms of the C1-C25 macrolactone of sanglifehrin A, and 251 which bears the C31-C41 carbon skeleton of the [5,5]-spirolactam moiety of sanglifehrin A. A Masamune anti-aldol reaction of aldehyde 294 and ester 285 furnished alcohol 295 in a second generation approach to carboxylic acid 242, while a third generation route toward 242 improved the yield and required fewer synthetic steps. An asymmetric, catalytic phase-transfer method was used to introduce an [alpha]-amino function into 331 in the synthesis of (S)-m-hydroxyphenylalanine derivative 244. Assembly of 244, piperazic acid 113 and L-valine derivative 336 into tripeptide 241 using a racemization-free peptide coupling method is described. The synthesis of C31-C37 aldehyde 253 exploited double asymmetric crotylation to set in place the correct configuration of alternating hydroxyl and methyl groups at C33, 34, 35 and 36.
Graduation date: 2013

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42

O'Keefe, Brian Michael. "Synthetic studies on the pluramycin family of antitumor antibiotics : the total synthesis of isokidamycin." Thesis, 2010. http://hdl.handle.net/2152/ETD-UT-2010-12-2035.

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A total synthesis of the complex C-aryl glycoside isokidamycin was achieved during an effort to construct the natural product kidamycin, a member of the pluramycin family of antitumor antibiotics. The angolosamine carbohydrate was appended, along with annelation of a benzene ring by the implementation of the Martin group's silicon tether-directed, intramolecular aryne-furan cycloaddition strategy. The vancosamine-derived carbohydrate was then installed by an O -> C-glycoside rearrangement. A novel protocol for the carbonylative cross-coupling of ortho-disubstituted aryl iodides with aryl boronic acids and alkynyl zinc reagents was also discovered during efforts to introduce the pyranone ring of kidamycin. The reaction proved general, as a variety of electron-rich and electron-poor aryl iodides, boronic acids, and alkynyl-zinc reagents participated in the cross-coupling.
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43

Ghosh, Partha. "New methods and strategies towards total synthesis of (9S)-dihydroerythronolide A." 2008. http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.17316.

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Mahapatra, Subham. "Part I: Total synthesis of marine macrolide amphidinolide F and synthetic studies toward amphidinolide C; Part II: Computational study on proline sulfonamide-catalyzed aldol reaction." Thesis, 2013. http://hdl.handle.net/1957/37033.

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More than 30 members of the diverse amphidinolide family of biologically active macrolides have been isolated over last three decades. From this family, amphidinolides C and F stand among the most complex and densely functionalized affiliates. Recently, we have accomplished the first total synthesis of amphidinolide F. The all-carbon framework of amphidinolide C has been synthesized. During endeavor toward the total syntheses of amphidinolides F / C, we have uncovered a "hidden symmetry element" present in the northern and southern domains of amphidinolides F / C. The southern C₁-C₈ and northern C₁₈-C₂₅ tetrahydrofuran segments were derived from a common intermediate. A scalable silver-catalyzed isomerization / cyclization on propargyl-benzoate / diol furnished the common intermediate in multigram quantity. The common intermediate provided access to over half of carbon backbone of the macrocycle as well as majority of stereochemistry present in amphidinolides F / C. Two strategically different techniques have been developed for the C₉-C₁₁ diene preparation. A metal-catalyst free Weinreb amide-vinyl lithium coupling / methylenation sequence furnished the diene motif. Alternately, diastereoselective addition of a dienyl iodide derived 2-lithio-1,3-diene species to an α-oxy aldehyde installed the C₉-C₁₁ diene and secured the C₈ stereochemistry in single operation. The dienyl iodide was prepared via a regioselective hydrostannylation on an enyne. A challenging alkylation between an α-branched sulfone and an α-silyloxy iodide generated the all-carbon frameworks of amphidinolides F / C. An efficient oxidative desulfurization incorporated the carbonyl moiety at C₁₅. The protecting group on C₁₈ alcohol was found to have significant effect on the sulfone-iodide alkylation / oxidative desulfurization sequence. Installation of chelating ethoxyethyl ether on C₁₈ alcohol helped the successful incorporation of C₁₅ ketone and solved the deprotection problem in advanced stage of synthesis. A detailed analytical and computational study on proline sulfonamide-catalyzed aldol reactions has been performed. The pKa value of a proline sulfonamide catalyst was determined experimentally via NMR titration technique. Computational study revealed the origin of enhanced stereoselectivity by proline sulfonamide catalysts over parent proline. The non-classical hydrogen bonding interactions were found to be responsible for improved diastereoselectivity.
Graduation date: 2013

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45

Loong, David Tien Jack. "Stereoselective total syntheses of the macrolides (-)-cladospolide A and (+)-microcarpalide." Phd thesis, 2003. http://hdl.handle.net/1885/151275.

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46

Cvengroš, Ján. "Metal based strategies for the total synthesis of the antibiotics pestalone and patulin and structural analogues /." 2006. http://digitool.hbz-nrw.de:1801/webclient/DeliveryManager?pid=2225000&custom_att_2=simple_viewer.

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47

(6616715), Kwaku Kyei-Baffour. "DEVELOPMENT OF ARYL ISONITRILES AS ANTIMICROBIAL AGENTS, AND TOTAL SYNTHESIS OF 17-NOR-EXCELSINIDINE." Thesis, 2019.

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Infectious diseases caused by bacteria, fungi, and plasmodium parasites are a huge global health problem which ultimately leads to millions of deaths annually. The emergence of strains that exhibit resistance to nearly every class of antimicrobial agents, and the inability to keep up with these resistance trends has brought to the fore the need for new therapeutic agents (antibacterial, antifungal, and antimalarial) with novel scaffolds and functionalities capable of targeting microbial resistance. A novel class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically relevant strains of methicillin-resistant Staphylococcus aureus (MRSA). Synthesis, structure-activity relationship (SAR) studies, and biological investigations have led to lead molecules that exhibit anti-MRSA inhibitory activity as low as 1 – 2 µM. The most potent compounds have also been shown to have low toxicity against mammalian cells and exhibit in vivo efficacy in MRSA skin and thigh infection mouse models.

The novel aryl isonitriles have also been evaluated for antifungal activity. This study examines the SAR of aryl isonitrile compounds and showed the isonitriles as compounds that exhibit broad spectrum antifungal activity against species of Candida and Cryptococcus. The most potent derivatives are capable of inhibiting growth of these pathogens at concentrations as low as 0.5 µM. Notably, the most active compounds exhibit excellent safety profile and are non-toxic to mammalian cells up to 256 µM.

Beyond the antibacterial and antifungal activities, structure-antimalarial relationship analysis of over 40 novel aryl isonitrile compounds has established the importance of the isonitrile functionality as an important moiety for antimalarial activity. Of the many isonitrile compounds exhibiting potent antimalarial activity, two have emerged as leads with activity comparable to that of Artemisinin. The SAR details presented in this study will prove essential for the development new aryl isonitrile analogues to advance them to the next step in the antimalarial drug discovery process.

17-nor-Excelsinidine, a zwitterion monoterpene indole alkaloid isolated from Alstonia scholaris is a subject of synthetic scrutiny. This is primarily due to its intriguing chemical structure which includes a bridged bicyclic ammonium moiety, and its anti-adenovirus and anti-HSV activity. Herein we describe a six-step total synthesis of (±)-17-nor-Excelsinidine from tryptamine. Key to the success of this synthesis is the use of palladium-catalyzed carbonylative heck lactamization methodology which built the 6, 7-membered ring lactam in one step. The resulting pentacyclic product, beyond facilitating the easy access to (±)-17-nor-Excelsinidine, could also serve as a precursor to other related indole alkaloids.

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48

Morrison, Christopher F. "Efforts directed towards an asymmetric total synthesis of the antitumor antibiotic Fredericamycin A and a study of the Diels-Alder reactions of a carvone-derived diene /." 2001.

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49

Dorich, Stéphane. "Progrès vers la synthèse totale de la Pactamycine." Thèse, 2008. http://hdl.handle.net/1866/7818.

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50

Dorich, Stéphane. "Synthèse totale de la pactamycine et d’une sélection d’analogues, progrès vers la synthèse totale de la daphniglaucine C et brève étude d’une transposition allylique réductrice." Thèse, 2013. http://hdl.handle.net/1866/10129.

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Il y a plus de cinquante ans, la pactamycine a été isolée en tant qu’agent antitumoral potentiel. Il a été réalisé plus tard qu’il s’agissait en fait d’un agent antibactérien capable d’inhiber la synthèse de protéines lors du procédé de traduction. Récemment, il a même été démontré que certains de ses analogues possèdent des propriétés antiprotozoaires prometteuses. La présente thèse détaille la première synthèse totale de la pactamycine, entreprise au sein du groupe Hanessian, ainsi que la préparation d’une sélection d’analogues testés pour leurs propriétés biologiques. En outre, la daphniglaucine C appartient à une vaste famille de composés naturels isolés des feuilles du daphniphyllum au cours des dix dernières années. Bien que relativement peu d’information soit connue par rapport à l’activité biologique de la daphniglaucine C, la synthèse de celle-ci représente certainement un défi intéressant pour un chimiste organicien. Au passage, nos efforts vers la synthèse totale du composé cible auront permis d’explorer l’emploi de plusieurs méthodes en vue de la formation de centres quaternaires. De plus, un réarrangement réductif atypique, catalysé au palladium à partir d’alcools allyliques non-activés, a été étudié et employé afin de générer une sélection de pyrrolidines polysubstituées.
Although pactamycin was first isolated as a potential antitumoral drug, further studies highlighted its capacities in inhibiting protein synthesis, and thus its potency as an antibacterial agent. Furthermore, it was recently discovered that some of its analogs display promising antiprotozoal activity. The present thesis reports and details the first total synthesis of pactamycin, pursued in the Hanessian lab over the last few years, as well as the preparation of a selection of analogs thereby tested for their biological properties. Daphniglaucin C belongs to a large family of natural compounds isolated from the leaves of daphniphyllum over the last decade. Although relatively little is known as to the biological activity of daphniglaucin C, its synthesis poses an obvious and interesting challenge for organic chemists. En route towards its total synthesis, the use of several methods for the formation of quaternary centers was explored. Moreover, an atypical reductive allylic transposition, catalyzed by palladium from unactivated allylic alcohols, was studied and used to generate a variety of polysubstituted pyrrolidines.

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Dissertations / Theses on the topic 'Total Synthesis, Antibiotics'

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