Novel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroids

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dc.contributor.advisorBull, James Ren_ZA
dc.contributor.authorMountford, Pia Gailen_ZA
dc.date.accessioned2016-03-17T07:18:47Z
dc.date.available2016-03-17T07:18:47Z
dc.date.issued1995en_ZA
dc.descriptionIncludes bibliographical references.en_ZA
dc.description.abstractAn efficient synthetic strategy for the stereoselective introduction of a 14β-allyl group to estrone 3-methyl ether has been developed. The approach involves regio- and stereoselective Diets-Alder cycloaddition of acrolein to 3-methoxyestra-1,3,5(10),14,16- pentaen-17-yl acetate. Hydride reduction of the formyl group of the cycloadduct, followed by tosylation of the resultant primary hydroxy group, gave rise to a 17β-alkoxy 16¹-tosylate. Base-mediated Wharton fragmentation of the 1,3-removed diol derivative produced the 14β-allyl Δ¹⁵-17-ketone. Chemoselective conjugate reduction of the ring enone gave rise to 14-allyl-3-methoxy-14β-estra-1,3,5(10)-trien-17-one in 51% overall yield for five steps. Regioselective oxidation of the 14β-allyl group furnished precursors for intramolecular coupling reactions with the 17-oxo group, providing access to a series of 14β,17β-propanoestradiol and 'estriol' analogues. Wacker oxidation of the 14-allyl-3-methoxy-14β-estra-1,3,5(10),15-tetraen-17- one gave rise to both the 14β-acetonyl and 14β-formylethyl derivatives. The acetonyl enone underwent cerium(III)-mediated aldol condensation with the 17-oxo group to yield the 14β,17β-propano Δ¹⁵-estradiol analogue. This series of β-face propano bridged estradiols displayed no competitive binding affinity for the estradiol receptor. The enolisable 14β-acetonyl group was also shown to undergo smooth Michael addition to C(15). The product, 3-methoxy-3'H,l5αH-cyclopenta[14,15]-14β-estra-1,3,5(10)-triene- 4'(5'H),17-dione, was regioselectively deoxygenated and reduced to yield the 3,17- estradiol analogues. The 3,17β-estradiol displayed promising binding affinity for the estradiol receptor site, whereas the 17α-epimer was biologically inactive. The 14β-formylethyl enone underwent vinylogous reductive cyclisation with C(lS), to yield the 3'-hydroxy cyclopenta[14,15] 17-ketone. No regioselective coupling with the 17-oxo group was observed. Various attempts to homologate ring D of the 14β-allyl 17-ketone or its Δ¹⁵-analogue are described, none of which were successful. However, the silyl enol ether derivative of estrone 3-methyl ether underwent facile cyclopropanation of the Δ¹⁶-bond. Iron(III) chloride-mediated cleavage of the zero bridge of the resultant bicyclo[3.1.0] hexanoid intermediate gave rise to the D-homo Δ¹⁶-17a-ketone. Conversion of the en one into the derived 14,16-dienyl 17a-ketone furnished an intermediate for conjugate addition studies.en_ZA
dc.identifier.apacitationMountford, P. G. (1995). <i>Novel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroids</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/17901en_ZA
dc.identifier.chicagocitationMountford, Pia Gail. <i>"Novel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroids."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 1995. http://hdl.handle.net/11427/17901en_ZA
dc.identifier.citationMountford, P. 1995. Novel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroids. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Mountford, Pia Gail AB - An efficient synthetic strategy for the stereoselective introduction of a 14β-allyl group to estrone 3-methyl ether has been developed. The approach involves regio- and stereoselective Diets-Alder cycloaddition of acrolein to 3-methoxyestra-1,3,5(10),14,16- pentaen-17-yl acetate. Hydride reduction of the formyl group of the cycloadduct, followed by tosylation of the resultant primary hydroxy group, gave rise to a 17β-alkoxy 16¹-tosylate. Base-mediated Wharton fragmentation of the 1,3-removed diol derivative produced the 14β-allyl Δ¹⁵-17-ketone. Chemoselective conjugate reduction of the ring enone gave rise to 14-allyl-3-methoxy-14β-estra-1,3,5(10)-trien-17-one in 51% overall yield for five steps. Regioselective oxidation of the 14β-allyl group furnished precursors for intramolecular coupling reactions with the 17-oxo group, providing access to a series of 14β,17β-propanoestradiol and 'estriol' analogues. Wacker oxidation of the 14-allyl-3-methoxy-14β-estra-1,3,5(10),15-tetraen-17- one gave rise to both the 14β-acetonyl and 14β-formylethyl derivatives. The acetonyl enone underwent cerium(III)-mediated aldol condensation with the 17-oxo group to yield the 14β,17β-propano Δ¹⁵-estradiol analogue. This series of β-face propano bridged estradiols displayed no competitive binding affinity for the estradiol receptor. The enolisable 14β-acetonyl group was also shown to undergo smooth Michael addition to C(15). The product, 3-methoxy-3'H,l5αH-cyclopenta[14,15]-14β-estra-1,3,5(10)-triene- 4'(5'H),17-dione, was regioselectively deoxygenated and reduced to yield the 3,17- estradiol analogues. The 3,17β-estradiol displayed promising binding affinity for the estradiol receptor site, whereas the 17α-epimer was biologically inactive. The 14β-formylethyl enone underwent vinylogous reductive cyclisation with C(lS), to yield the 3'-hydroxy cyclopenta[14,15] 17-ketone. No regioselective coupling with the 17-oxo group was observed. Various attempts to homologate ring D of the 14β-allyl 17-ketone or its Δ¹⁵-analogue are described, none of which were successful. However, the silyl enol ether derivative of estrone 3-methyl ether underwent facile cyclopropanation of the Δ¹⁶-bond. Iron(III) chloride-mediated cleavage of the zero bridge of the resultant bicyclo[3.1.0] hexanoid intermediate gave rise to the D-homo Δ¹⁶-17a-ketone. Conversion of the en one into the derived 14,16-dienyl 17a-ketone furnished an intermediate for conjugate addition studies. DA - 1995 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 1995 T1 - Novel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroids TI - Novel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroids UR - http://hdl.handle.net/11427/17901 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/17901
dc.identifier.vancouvercitationMountford PG. Novel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroids. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 1995 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/17901en_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.titleNovel synthetic routes to 14β,17β-Propano and cyclopenta [14,15]19-norsteroidsen_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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