{"id":{"repo_id":"cape-town","oai_identifier":"oai:open.uct.ac.za:11427/18380"},"canonical_url":"https://search.dev.ndltd.org/etd/cape-town/oai:open.uct.ac.za:11427/18380","repository":{"repo_id":"cape-town","name":"University of Cape Town","base_url":"https://open.uct.ac.za/oai/request"},"display":{"title":"Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids","abstract":"Studies have been conducted in synthesising ring D alkyl 19- norsteroids. The aim was to investigate methods for the stereoselective introduction of alkyl groups at C(14) and C(15), for eventual conversion of the intermediates into 14- and 15-alkyl analogues of estradiol hormones. In the first phase of this investigation, 17β-tert-butyldimethylsilyloxyestra-1,3,5(10),14-tetraen-l6-one was synthesised as starting material for alkylation experiments. Estrone 3-methyl ether was converted into the derived 17β-hydroxy 16-ketone by standard methods. This conversion involved the introduction of a 16α-hydroxyl group by bromination-hydrolysis, followed by base-mediated rearrangement of the hydroxy ketone to the thermodynamically preferred 16-ketone. Protection of the 17β-hydroxyl group as a TBS ether, followed by palladium acetate-mediated dehydrosilylation of the derived ∆¹⁵-16-trimethylsilyloxy enol ether gave the ∆¹⁴-16-ketone.The 17β-silyloxy ∆¹⁴-16-ketone resisted conjugate addition reactions, leading only to products of 1,2-alkylation. Stereoselective introduction of a 16-allyl group gave the corresponding ∆¹⁴-16-allyl 16-alcohols, but these compounds showed no sigmatropic reactivity and failed to undergo anionic oxy-Cope rearrangement. Hydride reduction of the 16-oxo group gave the corresponding At4-16-alcohols. The stereoselectivity was dependant on the choice of reagent. The ∆¹⁴-l6α-alcohol underwent ·stereodirected cyclopropanation to give 17β-tert-butyldimethylsilyloxy-14,15α-methyleneestra-1,3,5(10)-trien-16α-ol. Oxidation of this compound gave the corresponding 14α,15α methylene16-ketone, dissolving metal reduction of which furnished the 16β-alcohol. Routine deprotection of the epimeric pair of methylene 16-alcohols gave the derived estriol analogues, which were subjected to biological evaluation. Treatment of the 14α,15α methylene16-ketone with lithium in liquid ammonia gave 17β-tert-butyldimethylsilyloxy-14-methylestra-l,3,5(10)-trien-16-one. Stereoselective reduction of the 16-oxo group gave the epimeric 14α-methyl 16-alcohols. Deprotection of these compounds at C(3) gave a second pair of estriol analogues, which were also assayed for receptor binding affinity.","abstract_html":"Studies have been conducted in synthesising ring D alkyl 19- norsteroids. The aim was to investigate methods for the stereoselective introduction of alkyl groups at C(14) and C(15), for eventual conversion of the intermediates into 14- and 15-alkyl analogues of estradiol hormones. In the first phase of this investigation, 17β-tert-butyldimethylsilyloxyestra-1,3,5(10),14-tetraen-l6-one was synthesised as starting material for alkylation experiments. Estrone 3-methyl ether was converted into the derived 17β-hydroxy 16-ketone by standard methods. This conversion involved the introduction of a 16α-hydroxyl group by bromination-hydrolysis, followed by base-mediated rearrangement of the hydroxy ketone to the thermodynamically preferred 16-ketone. Protection of the 17β-hydroxyl group as a TBS ether, followed by palladium acetate-mediated dehydrosilylation of the derived ∆¹⁵-16-trimethylsilyloxy enol ether gave the ∆¹⁴-16-ketone.The 17β-silyloxy ∆¹⁴-16-ketone resisted conjugate addition reactions, leading only to products of 1,2-alkylation. Stereoselective introduction of a 16-allyl group gave the corresponding ∆¹⁴-16-allyl 16-alcohols, but these compounds showed no sigmatropic reactivity and failed to undergo anionic oxy-Cope rearrangement. Hydride reduction of the 16-oxo group gave the corresponding At4-16-alcohols. The stereoselectivity was dependant on the choice of reagent. The ∆¹⁴-l6α-alcohol underwent ·stereodirected cyclopropanation to give 17β-tert-butyldimethylsilyloxy-14,15α-methyleneestra-1,3,5(10)-trien-16α-ol. Oxidation of this compound gave the corresponding 14α,15α methylene16-ketone, dissolving metal reduction of which furnished the 16β-alcohol. Routine deprotection of the epimeric pair of methylene 16-alcohols gave the derived estriol analogues, which were subjected to biological evaluation. Treatment of the 14α,15α methylene16-ketone with lithium in liquid ammonia gave 17β-tert-butyldimethylsilyloxy-14-methylestra-l,3,5(10)-trien-16-one. Stereoselective reduction of the 16-oxo group gave the epimeric 14α-methyl 16-alcohols. Deprotection of these compounds at C(3) gave a second pair of estriol analogues, which were also assayed for receptor binding affinity.","abstract_has_math":false,"creators":["Loedolff, Michiel Christiaan"],"institution":"Department of Chemistry","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Bull, James R"],"committee_chairs":[],"committee_members":[],"year":1996,"date_issued":"1996","date_published":"1996","updated_at":"2026-07-22T22:22:47Z","subjects":[],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/11427/18380","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Bull, James R"]},{"key":"dc:creator","label":"Author","values":["Loedolff, Michiel Christiaan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2016-03-30T07:11:41Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2016-03-30T07:11:41Z"]},{"key":"dc:date.issued","label":"Date","values":["1996"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Department of Chemistry"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cape Town"]},{"key":"dc:type","label":"Dc Type","values":["Doctoral Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/11427/18380"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Studies have been conducted in synthesising ring D alkyl 19- norsteroids. The aim was to investigate methods for the stereoselective introduction of alkyl groups at C(14) and C(15), for eventual conversion of the intermediates into 14- and 15-alkyl analogues of estradiol hormones. In the first phase of this investigation, 17β-tert-butyldimethylsilyloxyestra-1,3,5(10),14-tetraen-l6-one was synthesised as starting material for alkylation experiments. Estrone 3-methyl ether was converted into the derived 17β-hydroxy 16-ketone by standard methods. This conversion involved the introduction of a 16α-hydroxyl group by bromination-hydrolysis, followed by base-mediated rearrangement of the hydroxy ketone to the thermodynamically preferred 16-ketone. Protection of the 17β-hydroxyl group as a TBS ether, followed by palladium acetate-mediated dehydrosilylation of the derived ∆¹⁵-16-trimethylsilyloxy enol ether gave the ∆¹⁴-16-ketone.The 17β-silyloxy ∆¹⁴-16-ketone resisted conjugate addition reactions, leading only to products of 1,2-alkylation. Stereoselective introduction of a 16-allyl group gave the corresponding ∆¹⁴-16-allyl 16-alcohols, but these compounds showed no sigmatropic reactivity and failed to undergo anionic oxy-Cope rearrangement. Hydride reduction of the 16-oxo group gave the corresponding At4-16-alcohols. The stereoselectivity was dependant on the choice of reagent. The ∆¹⁴-l6α-alcohol underwent ·stereodirected cyclopropanation to give 17β-tert-butyldimethylsilyloxy-14,15α-methyleneestra-1,3,5(10)-trien-16α-ol. Oxidation of this compound gave the corresponding 14α,15α methylene16-ketone, dissolving metal reduction of which furnished the 16β-alcohol. Routine deprotection of the epimeric pair of methylene 16-alcohols gave the derived estriol analogues, which were subjected to biological evaluation. Treatment of the 14α,15α methylene16-ketone with lithium in liquid ammonia gave 17β-tert-butyldimethylsilyloxy-14-methylestra-l,3,5(10)-trien-16-one. Stereoselective reduction of the 16-oxo group gave the epimeric 14α-methyl 16-alcohols. Deprotection of these compounds at C(3) gave a second pair of estriol analogues, which were also assayed for receptor binding affinity."]},{"key":"dc:title","label":"Title","values":["Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids"]}]}],"canonical_facts":{"dc:contributor.advisor":["Bull, James R"],"dc:creator":["Loedolff, Michiel Christiaan"],"dc:date.accessioned":["2016-03-30T07:11:41Z"],"dc:date.available":["2016-03-30T07:11:41Z"],"dc:date.issued":["1996"],"dc:description.abstract":["Studies have been conducted in synthesising ring D alkyl 19- norsteroids. The aim was to investigate methods for the stereoselective introduction of alkyl groups at C(14) and C(15), for eventual conversion of the intermediates into 14- and 15-alkyl analogues of estradiol hormones. In the first phase of this investigation, 17β-tert-butyldimethylsilyloxyestra-1,3,5(10),14-tetraen-l6-one was synthesised as starting material for alkylation experiments. Estrone 3-methyl ether was converted into the derived 17β-hydroxy 16-ketone by standard methods. This conversion involved the introduction of a 16α-hydroxyl group by bromination-hydrolysis, followed by base-mediated rearrangement of the hydroxy ketone to the thermodynamically preferred 16-ketone. Protection of the 17β-hydroxyl group as a TBS ether, followed by palladium acetate-mediated dehydrosilylation of the derived ∆¹⁵-16-trimethylsilyloxy enol ether gave the ∆¹⁴-16-ketone.The 17β-silyloxy ∆¹⁴-16-ketone resisted conjugate addition reactions, leading only to products of 1,2-alkylation. Stereoselective introduction of a 16-allyl group gave the corresponding ∆¹⁴-16-allyl 16-alcohols, but these compounds showed no sigmatropic reactivity and failed to undergo anionic oxy-Cope rearrangement. Hydride reduction of the 16-oxo group gave the corresponding At4-16-alcohols. The stereoselectivity was dependant on the choice of reagent. The ∆¹⁴-l6α-alcohol underwent ·stereodirected cyclopropanation to give 17β-tert-butyldimethylsilyloxy-14,15α-methyleneestra-1,3,5(10)-trien-16α-ol. Oxidation of this compound gave the corresponding 14α,15α methylene16-ketone, dissolving metal reduction of which furnished the 16β-alcohol. Routine deprotection of the epimeric pair of methylene 16-alcohols gave the derived estriol analogues, which were subjected to biological evaluation. Treatment of the 14α,15α methylene16-ketone with lithium in liquid ammonia gave 17β-tert-butyldimethylsilyloxy-14-methylestra-l,3,5(10)-trien-16-one. Stereoselective reduction of the 16-oxo group gave the epimeric 14α-methyl 16-alcohols. Deprotection of these compounds at C(3) gave a second pair of estriol analogues, which were also assayed for receptor binding affinity."],"dc:identifier.uri":["http://hdl.handle.net/11427/18380"],"dc:language.iso":["eng"],"dc:publisher.department":["Department of Chemistry"],"dc:publisher.institution":["University of Cape Town"],"dc:title":["Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids"],"dc:type":["Doctoral Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["PhD"]},"updated_at":"2026-07-22T22:22:47Z"}