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Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids
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...
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| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2016
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| _version_ | 1867613190126305280 |
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| access_status_str | Open Access |
| author | Loedolff, Michiel Christiaan |
| author2 | Bull, James R |
| author_browse | Bull, James R Loedolff, Michiel Christiaan |
| author_facet | Bull, James R Loedolff, Michiel Christiaan |
| author_sort | Loedolff, Michiel Christiaan |
| collection | Thesis |
| description | 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. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/18380 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:32:12.136Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2016 |
| publishDateRange | 2016 |
| publishDateSort | 2016 |
| publisher | Department of Chemistry |
| publisherStr | Department of Chemistry |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/18380 Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids Loedolff, Michiel Christiaan Bull, James R Chemistry 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. 2016-03-30T07:11:41Z 2016-03-30T07:11:41Z 1996 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/18380 eng application/pdf Department of Chemistry Faculty of Science University of Cape Town |
| spellingShingle | Chemistry Loedolff, Michiel Christiaan Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids |
| thesis_degree_str | Doctoral |
| title | Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids |
| title_full | Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids |
| title_fullStr | Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids |
| title_full_unstemmed | Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids |
| title_short | Synthesis and structure-activity relationships of ring D alkyl 19-norsteroids |
| title_sort | synthesis and structure activity relationships of ring d alkyl 19 norsteroids |
| topic | Chemistry |
| url | http://hdl.handle.net/11427/18380 |
| work_keys_str_mv | AT loedolffmichielchristiaan synthesisandstructureactivityrelationshipsofringdalkyl19norsteroids |