Synthesis and structure-activity studies of skeletally modified estradiol analogues

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dc.contributor.advisorBull, James Ren_ZA
dc.contributor.authorDe Koning, Pieter Daviden_ZA
dc.date.accessioned2017-01-25T14:40:22Z
dc.date.available2017-01-25T14:40:22Z
dc.date.issued1997en_ZA
dc.date.updated2016-11-22T09:22:04Z
dc.description.abstractIn the first phase of this investigation, synthetic approaches to skeletally modified variants of 14,17α-ethanoestra-l,3,5(10)-triene-3,17β-diol were examined, with the purpose of determining the influence of configurational inversion at C-8, C-9 or C-13 upon the high oral estrogenicity associated with introduction of a 14, 17-ethano bridge into the estradiol skeleton. 3-Methoxyestra-1,3,5(10)-trien-17-one was converted conventionally into the 13α-isomer, which underwent sequential silyl enol ether formation and dehydrosilylation into 3-methoxy-13α-estra-1,3,5(10), 15-tetraen-17-one, which failed to undergo conversion into the corresponding 3-methoxy-13α-estra-1,3 ,5( 10), 14, 16-pentaen-17-yl acetate required for cycloaddition studies. Hydrogenation of 3-methoxyestra-1,3,5( 10),8, 14-pentaen-17β-yl acetate afforded 3-methoxy-8α-estra-1,3 ,5(10)-trien-17β-yl acetate, which was converted into 3-methoxy-8α-estra-1,3 ,5(10), 14, 16-pentaen-17-yl acetate. Cycloaddition with phenyl vinyl sulfone gave a mixture of products, which was converted into the desired 14,17α-ethano-8α-estra- 1,3,5(10)-triene-3, 17β-diol, by a hydrogenation, desulfonylation, deprotection reaction sequence. The unexpectedly complex result for the cycloaddition reaction was interpreted with the assistance of other cycloaddition reactions of the Δ¹⁴,¹⁶-dienyl acetate. 17,17-Ethylenedioxy-3-methoxy-9β-estra-l ,3,5(10)-trien-11-one was readily prepared from estrone using conventional methodology. Deoxygenation followed by standard functional group manipulation afforded 3-methoxy-9β-estra-1 ,3 ,5(10)-trien-17-one. As a result of the poor overall yield, the optimisation of a number of steps in this reaction sequence was investigated. Despite some improvement in the yields, subsequent conversion into the target, 14, 17a-ethano-9β-estra-1,3 ,5(10)-triene-3, 17β-diol was not synthetically useful. However, dehydrogenation of 14, 17α-ethanoestra-1,3,5(10)-triene-3, 17β-diol followed by standard functional group modification gave 14, 17 a-ethanoestra-1,3 ,5(10),9(11)-tetraene- 3, 17β-diyl diacetate, hydrogenation of which afforded 14, 17α-ethano-9β-estra-1 ,3,5(10)triene-3, 17β-diol, after conventional deprotection, in moderate yield.en_ZA
dc.identifier.apacitationDe Koning, P. D. (1997). <i>Synthesis and structure-activity studies of skeletally modified estradiol analogues</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/23105en_ZA
dc.identifier.chicagocitationDe Koning, Pieter David. <i>"Synthesis and structure-activity studies of skeletally modified estradiol analogues."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 1997. http://hdl.handle.net/11427/23105en_ZA
dc.identifier.citationDe Koning, P. 1997. Synthesis and structure-activity studies of skeletally modified estradiol analogues. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - De Koning, Pieter David AB - In the first phase of this investigation, synthetic approaches to skeletally modified variants of 14,17α-ethanoestra-l,3,5(10)-triene-3,17β-diol were examined, with the purpose of determining the influence of configurational inversion at C-8, C-9 or C-13 upon the high oral estrogenicity associated with introduction of a 14, 17-ethano bridge into the estradiol skeleton. 3-Methoxyestra-1,3,5(10)-trien-17-one was converted conventionally into the 13α-isomer, which underwent sequential silyl enol ether formation and dehydrosilylation into 3-methoxy-13α-estra-1,3,5(10), 15-tetraen-17-one, which failed to undergo conversion into the corresponding 3-methoxy-13α-estra-1,3 ,5( 10), 14, 16-pentaen-17-yl acetate required for cycloaddition studies. Hydrogenation of 3-methoxyestra-1,3,5( 10),8, 14-pentaen-17β-yl acetate afforded 3-methoxy-8α-estra-1,3 ,5(10)-trien-17β-yl acetate, which was converted into 3-methoxy-8α-estra-1,3 ,5(10), 14, 16-pentaen-17-yl acetate. Cycloaddition with phenyl vinyl sulfone gave a mixture of products, which was converted into the desired 14,17α-ethano-8α-estra- 1,3,5(10)-triene-3, 17β-diol, by a hydrogenation, desulfonylation, deprotection reaction sequence. The unexpectedly complex result for the cycloaddition reaction was interpreted with the assistance of other cycloaddition reactions of the Δ¹⁴,¹⁶-dienyl acetate. 17,17-Ethylenedioxy-3-methoxy-9β-estra-l ,3,5(10)-trien-11-one was readily prepared from estrone using conventional methodology. Deoxygenation followed by standard functional group manipulation afforded 3-methoxy-9β-estra-1 ,3 ,5(10)-trien-17-one. As a result of the poor overall yield, the optimisation of a number of steps in this reaction sequence was investigated. Despite some improvement in the yields, subsequent conversion into the target, 14, 17a-ethano-9β-estra-1,3 ,5(10)-triene-3, 17β-diol was not synthetically useful. However, dehydrogenation of 14, 17α-ethanoestra-1,3,5(10)-triene-3, 17β-diol followed by standard functional group modification gave 14, 17 a-ethanoestra-1,3 ,5(10),9(11)-tetraene- 3, 17β-diyl diacetate, hydrogenation of which afforded 14, 17α-ethano-9β-estra-1 ,3,5(10)triene-3, 17β-diol, after conventional deprotection, in moderate yield. DA - 1997 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 1997 T1 - Synthesis and structure-activity studies of skeletally modified estradiol analogues TI - Synthesis and structure-activity studies of skeletally modified estradiol analogues UR - http://hdl.handle.net/11427/23105 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/23105
dc.identifier.vancouvercitationDe Koning PD. Synthesis and structure-activity studies of skeletally modified estradiol analogues. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 1997 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/23105en_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.titleSynthesis and structure-activity studies of skeletally modified estradiol analoguesen_ZA
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhDen_ZA
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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