Partial Synthesis and Regioselective Reduction of Steroidal 11,12-Seco-Dioic Anhydrides

Hassan, Hassan Abbas (1987) Partial Synthesis and Regioselective Reduction of Steroidal 11,12-Seco-Dioic Anhydrides. PhD thesis, University of Glasgow.

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12-seco-5beta-cholane-11,12,24-trioic acid in 42% yield, along with two other compounds identified as 3alpha-hydroxy-11,12-seco-12-nor-5beta-cholane-11,24-dioic acid (25%) and 3alpha, 13-dihydroxy-11,12-seco-12-nor-5beta-cholane-11,24-dioic acid (32%). Ozonolysis of methyl 3alpha-ethoxycarbonyloxy-5beta-chol-11-enoate afforded the3alpha-ethoxycarbonyloxy-11,12-seco- 5beta -cholane-11,12,24-trioic acid 24-methyl ester, in 25% yield, which was converted to the desired 11,12-seco-dioic anhydride by treatment with acetic anhydride. Reduction of the obtained anhydride with NaBH4 in THF gave in total regioselectivity the 3alpha-ethoxycarbonvloxv-11,12-seco-12-hvdroxy-5beta-cholane-11,24-dioic acid 24-methyl ester. Treatment of the hydroxy-acid with acetic anhydride led to the corresponding acetoxy-acid, 3alpha-ethoxycarbonyioxy-11,12-seco-12-acetoxy-5beta-cholane-11,24-dioic acid 24-methyl ester. Oxidation of methyl 12beta-hydroxy-11-oxo-5beta-cholanoate with NaIO4/CrO3 afforded the corresponding 11,12-seco-dioic acid in good yield. Treatment with acetic anhydride led to the desired 11,12-seco-5beta-cholane-11,12,24-trioic acid-11,12-anhydride 24-methyl ester. Reduction of the anhydride with NaBH4 in THF gave exclusively the 11,12-seco-12-hvdroxv-5beta-cholane-11,24-dioic acid 24-methyl ester. Treatment of the latter with acetic anhydride afforded the corresponding lactone, methyl 12-oxa-C-homo-11-oxo-5beta-cholanoate, in only 6% yield and the acetoxy-acid, 11,12-seco-12-acetoxy-5beta-cholane-11,24-dioic acid 24-methyl ester, as the major product. In the 5a-series, hecogenin was chosen as the starting material. The corresponding 3beta-acetoxy- and 3beta-benzoyloxy-12-hydroxy-11-ones derivatives were prepared through the corresponding bromo-ketones. Oxidation of these ketols with NaIO4 /CrO3 gave the corresponding 11,12-seco-dioic acids which led, upon treatment with acetic anhydride, to the desired 11,12-seco-dioic anhydrides. Reduction of the obtained 3beta-acetoxy-11,12-secotigogenin-11,12-dioic anhydride with NaBH4 in THF gave in total selectivity the corresponding hydroxy-acid, 3alpha-acetoxy-11,12-secotigogenin-12- hydroxy-11-oic acid. Treatment of the latter with acetic anhydride afforded in a quantitative yield the corresponding 11,12-seco-12-acetoxy-11-oic acid derivative. When the hydroxy acid was treated with p-toluenesulphonic acid in xylene, 5% of the corresponding lactone was obtained. Treatment of the hydroxy-acid with 2,2-dipyridyl disulphide in dry benzene afforded 14% of the corresponding lactone. Gas chromatography technique has been used for qualitative and quantitative analysis. Detailed GLC data of bile acid and hecogenin derivatives, which have been studied in this work, are given in tables 1,4,5,6,7,10,11,12a, and 12b. Mass spectrometry has been also very useful for the identification of different compounds. Interpretations of mass spectral data of all new compounds are given in figures at the appropriate places in Chapter 2. Detailed mass spectral data of most of the investigated derivatives are listed in tables in the Appendix. In conclusion, 11,12-seco-dioic anhydrides, in both 5a- and 5beta-series, having different substituents at C-3 have been prepared. Treatment of those anhydrides with NaBH4 has led to the reduction in total regioselectivity at C-12. Neither the substituents at C-3 nor the type of A/B ring fusion seem to have an effect on the course of regioselectivity. A rationalisation for this selectivity, in the hydride reduction of these anhydrides, is offered in 2.16. It has also been observed that the products from the reduction process are the corresponding hydroxy-acids. These hydroxy-acids have proved to resist attempts for cyclisation to the corresponding lactones.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1987
Depositing User: Enlighten Team
Unique ID: glathesis:1987-77443
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 14 Jan 2020 09:08
Last Modified: 14 Jan 2020 09:08

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