Some Aspects of the Partial Synthesis of Cortisone

Stevenson, Robert (1952) Some Aspects of the Partial Synthesis of Cortisone. PhD thesis, University of Glasgow.

Abstract

The elaboration of the cortisone sidechain, the conversion of ergosterol into 11-oxygenated derivatives, and the degradation of the bile acid sidechain have been investigated. 3beta-Hydroxypregna-5 :17-diene-21-carboxylic acid and 3beta-acetoxypregna-5:17-dien-21-al, both useful intermediates in the synthesis of compounds possessing the characteristic cortisone sidechain, have been prepared by a new route with greater facility. Treatment of dehydroandrosterone acetate with ethoxyethynylmagnesium bromide gave 3beta-acetoxy- 21-ethoxypregn-5-en-20-yn-17beta-ol, which on acid rearrangement followed by hydrolysis yielded 3beta-hydroxypregna-5:17-dien-21-carboxylic acid, identical with a specimen prepared by a previously established route. 3beta-Acetoxy-21-ethoxypregna-5:20-dien-17beta-ol and 3beta-acetoxy- 21-ethoxypregn-5-en-17beta-ol were obtained by catalytic hydrogenation of 3beta-acetoxy-21-ethoxypregn-5-en-20-yn-17beta-ol. Acid rearrangement of the former compound, followed by acetylation gave 3beta-acetoxypregna-5:17-dien-21-al. Degradation of ethyl 3beta-acetoxypregna-5:17-diene-21-carboxylate to dehydroandrosterone acetate semicarbazone proved that the reactions had proceeded without D-ring enlargement. Ergesterol has been converted by various procedures into 11alpha-hydroxy and 11-ketosteroids. The action of oxidising agents on ergosteryl-D acetate has been investigated; treatment with one mol. of performic acid giving 3beta-acetoxyergosta-9(11):22-dien-7-one, with two mols. of performic acid giving B-acetoxy-9alpha:11alpha-epoxyergoet-22-en-7-one, with chromic acid giving 3beta-acetoxyergosta-8: 22-dien-7-one, and with perbenzoic acid giving 9alpha:11alpha-epoxyergosta-7:22-dien-3beta-yl acetate. 3beta:11alpha-Diacetoxy-ergosta-8:22-dien-7-one was obtained by mild alkaline treatment, and 7:11-diketoergost-22-en-3beta-yl acetate was obtained by strong alkaline treatment, of 3beta-acetoxy-9alpha:11alpha-epoxyergost-22-en-7-one. Treatment of 5-dihydroergoateryl acetate with bromine gave a tetrabromoergostenyl acetate, treatment of which with sodium iodide gave ergosteryl-D acetate 22: 23-dibromide and with zinc gave ergosteryl-D acetate. Oxidation of ergosteryl-D acetate 22:23-dibromide with peracetic or performic acids gave 3beta-acetoxy-22:23-dibromo-9alpha:11alpha-epoxyergostan-7-one, which yielded 3beta:11alpha-diaoetoxy-22:23-dibromoergost-8-en-7-one on mild alkaline hydrolysis followed by acetylation and 3beta-acetoxy-22:23-dibromo-llo(hydroxyergost-8-en-7-one on filtration of a benzene solution through alumina. Chromic acid oxidation of the latter compound gave 22 : 23-dibromo-7:11-diketoergost-8-en-3beta-yl acetate, and hydrogenation of 3beta:11alpha-diaeetoxy-22s 23-dibromoergost-8-en-7-one in ethanolic potassium hydroxide solution with platinum catalyst gave 3beta:11alpha-dihydroxyergost- 22-en-7-one. In projected degradations of the bile acid sidechain, the oxidation of 3alpha:12alpha(-diacetoxy-24:24-diphenylchol-23-ene by selenium dioxide, N-bromosuccinimide, and tertiary-butyl chromate was investigated. The action of the last reagent on cholesteryl acetate to give 7-ketocholesteryl acetate was also studied. Bromination of 3a:12a-diacetoxy-norcholanyl phenyl ketone gave both diastereoisomeric forms of 3alpha:12alpha-diacetoxy-23-bromonorcholanyl phenyl ketone. This compound was not successfully dehydrobrominated. Treatment with sodium alkoxides followed by re-acetylation gave two isomeric compounds, C36H50O7, one of which has been identified as 3alpha:12alpha23-triacetoxynorcholanyl phenyl ketone by comparison with a sample prepared by an unambiguous route, and the other is believed to be 3alpha:12alpha:24-triacetoxy-23-keto-24-phenylcholane. Two forms of 3alpha-acetoxy-23-bromo-11-ketonorcholanyl phenyl ketone were also isolated on monobromination of 3alpha-acetoxy-11-ketonorcholanyl phenyl ketone.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Organic chemistry
• Date of Award: 1952
• Depositing User: Enlighten Team
• Unique ID: glathesis:1952-78921
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 28 Feb 2020 12:09
• Last Modified: 28 Feb 2020 12:09
• URI: https://theses.gla.ac.uk/id/eprint/78921