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Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes
An intramolecular Michael-aldol reaction sequence has been developed for the stereocontrolled synthesis of pentacyclic steroids! with the new six-membered ring attached to the C(4) and C(6) positions. Cholesterol was converted into 3β-hydroxycholest-4-en-6-one by standard methods, and the correspond...
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| Format: | Thesis |
| Language: | English |
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Department of Chemistry
2016
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| _version_ | 1867613246027988992 |
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| access_status_str | Open Access |
| author | Borry, Joost |
| author2 | Bull, James R |
| author_browse | Borry, Joost Bull, James R |
| author_facet | Bull, James R Borry, Joost |
| author_sort | Borry, Joost |
| collection | Thesis |
| description | An intramolecular Michael-aldol reaction sequence has been developed for the stereocontrolled synthesis of pentacyclic steroids! with the new six-membered ring attached to the C(4) and C(6) positions. Cholesterol was converted into 3β-hydroxycholest-4-en-6-one by standard methods, and the corresponding 3α-isomer was obtained through Mitsunobu inversion. Acetoacetylation of the 3-alcohols afforded the corresponding 3β- and 3α-acetoacetoxycholest-4-en-6-ones, which served as substrates for an investigation of intramolecular condensation routes to the target ring systems. Base treatment of the 3β-ester resulted in an efficient and stereocontrolled intramolecular Michael addition to give (2R)-2-(3β-hydroxy- 6-oxo-5β-cholestan-4β-yl)-3-oxobutanoic acid 1,3'-lactone, and reaction conditions were developed to achieve sequential lactone cleavage, decarboxylation, and aldol closure, leading to 3β,6-dihydroxy- 4α,4',5β,6β-tetrahydrobenzo[4.5.6]cholestan-5'(6'H)-one. Although this product resisted base-mediated B-elimination, acid treatment resulted in dehydration to give the corresponding Δ⁶-compound. which underwent double bond isomerisation and 5-epimerisation. to give 3β-hydroxy- 4α,5α-dihydrobenzo[4.5.6]cholestan-5'(6'H)-one. A similar series of reactions was performed on the 3α-acetoacetate, leading finally to formation of 3α-hydroxy-4β,5α-dihydrobenzo[4.5.6]cholestan-5'(6'H)-one. Modification of foregoing reaction conditions, resulted in the design of a tandem Michael-aldol sequence, in which the 3-acetoacetates could be converted directly into the corresponding pentacyclic enones. These products were interrelated via base-mediated equ1llbration of their respective 3,6-diketones, leading to the thermodynamically favoured 4β,5α-isomer. Preliminary investigations into the stereoselective reduction of the olefinic bond in the 4α.5α-isomer, resulted in the formation of a new class of. hexahydrobenzo[4.5.6]cholestane derivatives. The structural and conformational properties of the condensation products were studied with the aid of ¹H NMR, ¹³C NMR, and IR spectroscopy. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/21999 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:33:05.164Z |
| 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:11427/21999 Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes Borry, Joost Bull, James R Chemistry An intramolecular Michael-aldol reaction sequence has been developed for the stereocontrolled synthesis of pentacyclic steroids! with the new six-membered ring attached to the C(4) and C(6) positions. Cholesterol was converted into 3β-hydroxycholest-4-en-6-one by standard methods, and the corresponding 3α-isomer was obtained through Mitsunobu inversion. Acetoacetylation of the 3-alcohols afforded the corresponding 3β- and 3α-acetoacetoxycholest-4-en-6-ones, which served as substrates for an investigation of intramolecular condensation routes to the target ring systems. Base treatment of the 3β-ester resulted in an efficient and stereocontrolled intramolecular Michael addition to give (2R)-2-(3β-hydroxy- 6-oxo-5β-cholestan-4β-yl)-3-oxobutanoic acid 1,3'-lactone, and reaction conditions were developed to achieve sequential lactone cleavage, decarboxylation, and aldol closure, leading to 3β,6-dihydroxy- 4α,4',5β,6β-tetrahydrobenzo[4.5.6]cholestan-5'(6'H)-one. Although this product resisted base-mediated B-elimination, acid treatment resulted in dehydration to give the corresponding Δ⁶-compound. which underwent double bond isomerisation and 5-epimerisation. to give 3β-hydroxy- 4α,5α-dihydrobenzo[4.5.6]cholestan-5'(6'H)-one. A similar series of reactions was performed on the 3α-acetoacetate, leading finally to formation of 3α-hydroxy-4β,5α-dihydrobenzo[4.5.6]cholestan-5'(6'H)-one. Modification of foregoing reaction conditions, resulted in the design of a tandem Michael-aldol sequence, in which the 3-acetoacetates could be converted directly into the corresponding pentacyclic enones. These products were interrelated via base-mediated equ1llbration of their respective 3,6-diketones, leading to the thermodynamically favoured 4β,5α-isomer. Preliminary investigations into the stereoselective reduction of the olefinic bond in the 4α.5α-isomer, resulted in the formation of a new class of. hexahydrobenzo[4.5.6]cholestane derivatives. The structural and conformational properties of the condensation products were studied with the aid of ¹H NMR, ¹³C NMR, and IR spectroscopy. 2016-09-28T19:09:00Z 2016-09-28T19:09:00Z 1992 Master Thesis Masters MSc http://hdl.handle.net/11427/21999 eng application/pdf Department of Chemistry Faculty of Science University of Cape Town |
| spellingShingle | Chemistry Borry, Joost Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes |
| thesis_degree_str | Master's |
| title | Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes |
| title_full | Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes |
| title_fullStr | Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes |
| title_full_unstemmed | Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes |
| title_short | Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes |
| title_sort | stereoselective synthesis of perhydrobenzo 4 5 6 cholestanes |
| topic | Chemistry |
| url | http://hdl.handle.net/11427/21999 |
| work_keys_str_mv | AT borryjoost stereoselectivesynthesisofperhydrobenzo456cholestanes |