Development of an alternative synthesis of 2-acetamido-2-deoxy-L-altruronic acid: an unusual sugar found in the O-specific polysaccharide of Shigella sonnei

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dc.contributor.advisorGammon, David Wen_ZA
dc.contributor.advisorRavenscroft, Neilen_ZA
dc.contributor.authorAnderson, Kirstin P Cen_ZA
dc.date.accessioned2017-06-01T10:14:08Z
dc.date.available2017-06-01T10:14:08Z
dc.date.issued2017en_ZA
dc.description.abstractA new synthetic route has been explored for the preparation of derivatives of 2-acetamido-2-deoxy-L-altruronic acid (L-AltNAcA). This is a rare sugar found together with 2-acetamido-4-amino-2,4-dideoxy-D-fucose(D-FucNAc4N) in the repeating unit of Shigella sonnei. Derivatives are needed inter alia for chemical and spectroscopic calibration standards, and as building blocks for preparing oligomeric subunits of the O-polysaccharide antigen for possible incorporation into a synthetic glycoconjugate vaccine. Two synthetic routes were investigated. The first route successfully repeated a published four step sequence converting diacetone-D-glucose to 1,6-anhydro--L-idopyranose in a 38% yield overall, and a further selective benzylation at O-3. Attempts to discriminate between O-2, O-3 and O-4 using low temperature acylation or alkylation conditions were unsuccessful, but modest selectivity for the 4-benzoate was observed in a Bu₂SnO-mediated benzoylation, although this product could not be easily separated from other mono-benzoates. The second route started from N-acetyl-D-glucosamine which was successfully converted in the first step to 2-methyl-(1,2-dideoxyl-5,6-O-isopropylidene-α-D-glucofurano)-[2,1-d]-2-oxazoline. The oxazoline and dioxolane units could be selectively manipulated in a series of steps to afford 2-acetamido-2-deoxy-3-O-benzyl-6-O-t-butyldimethylsilyl-α-D-glucofuranosyl acetate in a 41% yield over four steps. This is a key synthetic intermediate in which the 5-OH is available for the required inversion step. During this study, an unusual minor side-product, 1,6-anhydro-2-acetamido-O-acetyl-2-deoxy-3-O-benzyl-α-D-glucofuranose, was isolated. While this was also a potentially useful intermediate, having only the 5-OH unprotected, it proved not possible to find conditions for optimizing this product. Inversion of configuration at C-5 in the 6-O-silylated glucofuranose was attempted via the 5-O-triflate and 5-O-mesylate: the triflate formed but was displaced in situ by the solvent pyridine to give an unusual 5-pyridinium derivative, while the mesylate was stable but unreactive towards subsequent SN2 inversion. These outcomes were attributed to the steric congestion imposed by the combination of the 3,4-cis-disubstitution of the furanose ring and the very bulky silyl substituent at O-6. While the goal of preparing L-AltNAcA was not achieved via these approaches, useful insights have been contributed towards the ongoing study.en_ZA
dc.identifier.apacitationAnderson, K. P. C. (2017). <i>Development of an alternative synthesis of 2-acetamido-2-deoxy-L-altruronic acid: an unusual sugar found in the O-specific polysaccharide of Shigella sonnei</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/24464en_ZA
dc.identifier.chicagocitationAnderson, Kirstin P C. <i>"Development of an alternative synthesis of 2-acetamido-2-deoxy-L-altruronic acid: an unusual sugar found in the O-specific polysaccharide of Shigella sonnei."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2017. http://hdl.handle.net/11427/24464en_ZA
dc.identifier.citationAnderson, K. 2017. Development of an alternative synthesis of 2-acetamido-2-deoxy-L-altruronic acid: an unusual sugar found in the O-specific polysaccharide of Shigella sonnei. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Anderson, Kirstin P C AB - A new synthetic route has been explored for the preparation of derivatives of 2-acetamido-2-deoxy-L-altruronic acid (L-AltNAcA). This is a rare sugar found together with 2-acetamido-4-amino-2,4-dideoxy-D-fucose(D-FucNAc4N) in the repeating unit of Shigella sonnei. Derivatives are needed inter alia for chemical and spectroscopic calibration standards, and as building blocks for preparing oligomeric subunits of the O-polysaccharide antigen for possible incorporation into a synthetic glycoconjugate vaccine. Two synthetic routes were investigated. The first route successfully repeated a published four step sequence converting diacetone-D-glucose to 1,6-anhydro--L-idopyranose in a 38% yield overall, and a further selective benzylation at O-3. Attempts to discriminate between O-2, O-3 and O-4 using low temperature acylation or alkylation conditions were unsuccessful, but modest selectivity for the 4-benzoate was observed in a Bu₂SnO-mediated benzoylation, although this product could not be easily separated from other mono-benzoates. The second route started from N-acetyl-D-glucosamine which was successfully converted in the first step to 2-methyl-(1,2-dideoxyl-5,6-O-isopropylidene-α-D-glucofurano)-[2,1-d]-2-oxazoline. The oxazoline and dioxolane units could be selectively manipulated in a series of steps to afford 2-acetamido-2-deoxy-3-O-benzyl-6-O-t-butyldimethylsilyl-α-D-glucofuranosyl acetate in a 41% yield over four steps. This is a key synthetic intermediate in which the 5-OH is available for the required inversion step. During this study, an unusual minor side-product, 1,6-anhydro-2-acetamido-O-acetyl-2-deoxy-3-O-benzyl-α-D-glucofuranose, was isolated. While this was also a potentially useful intermediate, having only the 5-OH unprotected, it proved not possible to find conditions for optimizing this product. Inversion of configuration at C-5 in the 6-O-silylated glucofuranose was attempted via the 5-O-triflate and 5-O-mesylate: the triflate formed but was displaced in situ by the solvent pyridine to give an unusual 5-pyridinium derivative, while the mesylate was stable but unreactive towards subsequent SN2 inversion. These outcomes were attributed to the steric congestion imposed by the combination of the 3,4-cis-disubstitution of the furanose ring and the very bulky silyl substituent at O-6. While the goal of preparing L-AltNAcA was not achieved via these approaches, useful insights have been contributed towards the ongoing study. DA - 2017 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2017 T1 - Development of an alternative synthesis of 2-acetamido-2-deoxy-L-altruronic acid: an unusual sugar found in the O-specific polysaccharide of Shigella sonnei TI - Development of an alternative synthesis of 2-acetamido-2-deoxy-L-altruronic acid: an unusual sugar found in the O-specific polysaccharide of Shigella sonnei UR - http://hdl.handle.net/11427/24464 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/24464
dc.identifier.vancouvercitationAnderson KPC. Development of an alternative synthesis of 2-acetamido-2-deoxy-L-altruronic acid: an unusual sugar found in the O-specific polysaccharide of Shigella sonnei. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2017 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/24464en_ZA
dc.language.isoengen_ZA
dc.publisher.departmentDepartment of Chemistryen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherChemistryen_ZA
dc.titleDevelopment of an alternative synthesis of 2-acetamido-2-deoxy-L-altruronic acid: an unusual sugar found in the O-specific polysaccharide of Shigella sonneien_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMScen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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