Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes

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dc.contributor.advisorBull, James Ren_ZA
dc.contributor.authorBorry, Joosten_ZA
dc.date.accessioned2016-09-28T19:09:00Z
dc.date.available2016-09-28T19:09:00Z
dc.date.issued1992en_ZA
dc.description.abstractAn 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.en_ZA
dc.identifier.apacitationBorry, J. (1992). <i>Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes</i>. (Thesis). University of Cape Town ,Faculty of Science ,Department of Chemistry. Retrieved from http://hdl.handle.net/11427/21999en_ZA
dc.identifier.chicagocitationBorry, Joost. <i>"Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes."</i> Thesis., University of Cape Town ,Faculty of Science ,Department of Chemistry, 1992. http://hdl.handle.net/11427/21999en_ZA
dc.identifier.citationBorry, J. 1992. Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Borry, Joost AB - 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. DA - 1992 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 1992 T1 - Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes TI - Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes UR - http://hdl.handle.net/11427/21999 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/21999
dc.identifier.vancouvercitationBorry J. Stereoselective synthesis of perhydrobenzo[4.5.6]cholestanes. [Thesis]. University of Cape Town ,Faculty of Science ,Department of Chemistry, 1992 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/21999en_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.titleStereoselective synthesis of perhydrobenzo[4.5.6]cholestanesen_ZA
dc.typeMaster Thesis
dc.type.qualificationlevelMasters
dc.type.qualificationnameMScen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceThesisen_ZA
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