Some Aspects of the Partial Synthesis of Cortisone

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

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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

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