Methodology studies on the synthesis of chiral, non-racemic aza-quaternary centres

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dc.contributor.advisorHunter, Rogeren_ZA
dc.contributor.authorPetersen, Wade Franken_ZA
dc.date.accessioned2016-02-05T07:26:20Z
dc.date.available2016-02-05T07:26:20Z
dc.date.issued2015en_ZA
dc.descriptionIncludes bibliographical referencesen_ZA
dc.description.abstractThe synthesis of chiral, non-racemic aza-quaternary centres is one of the biggest challenges in current organic synthesis. Many natural products contain them and as a privileged biological motif they are of interest to medicinal chemistry. The structural complexities of these functionalities invites the development of new methodologies for their synthesis. The experimental part of the thesis appears in two Chapters. Chapter Two describes studies aimed at the enantioselective synthesis of chiral, non-racemic aza-quaternary centres via reagent -based approaches. In the first part studies are directed towards developing ephedrine -derived stoichiometric chiral aminating reagents in enantioselective nitrogen transfer, while in the second part of the Chapter the emphasis shifts to using an organocatalysis approach involving an ephedrine -hydrazide organocatalyst in conjunction with enantioselective amination methodology using an azodicarboxylate. Chapter Three shifts to a substrate -controlled approach based on using chiral malonate -imidazolidinones as a template for amination. Using KHMDS as base it has been shown that the enolate of α -substituted chiral malonate-imidazolidinones can be azidated with trisyl azide in excellent diastereoselectivity in yields > 92 % and dr ≥ 97:3 by chiral HPLC. The products were subsequently transformed to α,α-disubstituted α-serine derivatives by a series of chemoselective steps: reduction of azide with Zn / AcOH, removal of the chiral auxiliary with LiSEt followed by reduction of the resultant thioester with lithium-tri-tert-butoxyaluminium hydride in up to 75 % yield over 4 steps. The methodology opens up the way towards establishing a general methodology for synthesizing quaternized amino acids with a broad range of R groups, both natural and unnatural in type.en_ZA
dc.identifier.apacitationPetersen, W. F. (2015). <i>Methodology studies on the synthesis of chiral, non-racemic aza-quaternary centres</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/16792en_ZA
dc.identifier.chicagocitationPetersen, Wade Frank. <i>"Methodology studies on the synthesis of chiral, non-racemic aza-quaternary centres."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 2015. http://hdl.handle.net/11427/16792en_ZA
dc.identifier.citationPetersen, W. 2015. Methodology studies on the synthesis of chiral, non-racemic aza-quaternary centres. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Petersen, Wade Frank AB - The synthesis of chiral, non-racemic aza-quaternary centres is one of the biggest challenges in current organic synthesis. Many natural products contain them and as a privileged biological motif they are of interest to medicinal chemistry. The structural complexities of these functionalities invites the development of new methodologies for their synthesis. The experimental part of the thesis appears in two Chapters. Chapter Two describes studies aimed at the enantioselective synthesis of chiral, non-racemic aza-quaternary centres via reagent -based approaches. In the first part studies are directed towards developing ephedrine -derived stoichiometric chiral aminating reagents in enantioselective nitrogen transfer, while in the second part of the Chapter the emphasis shifts to using an organocatalysis approach involving an ephedrine -hydrazide organocatalyst in conjunction with enantioselective amination methodology using an azodicarboxylate. Chapter Three shifts to a substrate -controlled approach based on using chiral malonate -imidazolidinones as a template for amination. Using KHMDS as base it has been shown that the enolate of α -substituted chiral malonate-imidazolidinones can be azidated with trisyl azide in excellent diastereoselectivity in yields > 92 % and dr ≥ 97:3 by chiral HPLC. The products were subsequently transformed to α,α-disubstituted α-serine derivatives by a series of chemoselective steps: reduction of azide with Zn / AcOH, removal of the chiral auxiliary with LiSEt followed by reduction of the resultant thioester with lithium-tri-tert-butoxyaluminium hydride in up to 75 % yield over 4 steps. The methodology opens up the way towards establishing a general methodology for synthesizing quaternized amino acids with a broad range of R groups, both natural and unnatural in type. DA - 2015 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Methodology studies on the synthesis of chiral, non-racemic aza-quaternary centres TI - Methodology studies on the synthesis of chiral, non-racemic aza-quaternary centres UR - http://hdl.handle.net/11427/16792 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16792
dc.identifier.vancouvercitationPetersen WF. Methodology studies on the synthesis of chiral, non-racemic aza-quaternary centres. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 2015 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/16792en_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.titleMethodology studies on the synthesis of chiral, non-racemic aza-quaternary centresen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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