| dc.description.abstract | The thesis, entitled "Synthetic Investigations in Steroids", consists of two chapters and an appendix.
Chapter I contains a brief review of the various total syntheses of the female sex hormone, oestrone, and the objective of the present investigation, viz. the study of the ring closure of 9,10-seco-14-iso-8-hydroxy-oestrone-3-methyl ether (3) and 9,10-seco-1,3,5(10),8(9)-oestratetraene-3-methyl ether (5) and 9,10-seco-1,3,5(10),8(14)-oestratetraene-3-methyl ether (6) to give oestrone methyl ether and/or its isomer(s).
8-Methyl-hydrindan-1,4-dione (1), the starting material, was prepared by the methods of Banerjee and Shafer and Inhoffen and Prinz. The dione prepared by the two different procedures was found to be identical by comparison of the infrared spectra of their derivatives, viz. mono-2,4-DNP, disemicarbazone, monothioketal, and dithioketal. There was no depression in the melting points when their corresponding derivatives were admixed.
The ring fusion of the dione (1) was proved to be cis by Banerjee and Shafer by its Clemmensen reduction to cis-8-methylhydrindan-1-one (2) in only 13% yield. Their conclusion has now been fully confirmed by desulfurizing the monothioketal of the dione (1) to cis-8-methylhydrindan-1-one (2) in 66% yield, the overall yield from the parent dione (1) being 55%.
The homogeneity of the dione (1) has been proved by vapour phase chromatography and 100 MHz NMR spectrum. Condensation of the dione (1) with m-methoxyphenylethyl magnesium bromide afforded 9,10-seco-14-iso-8-hydroxy-oestrone-3-methyl ether (3) in 80% yield.
Cyclisation of the hydroxy ketone (3) using sublimed aluminium chloride, with or without anhydrous hydrogen chloride, led mainly to 9,10-seco-1,3,5(10),8(14)-oestratetraene-3-methyl ether (4), which showed the presence of four aromatic protons and the absence of any vinyl proton in the NMR spectrum.
Dehydration of the hydroxy ketone (3) with formic acid yielded a mixture of the unsaturated ketones, viz. 9,10-seco-1,3,5(10),8(9)-oestratetraene-3-methyl ether (5) and 9,10-seco-1,3,5(10),8(14)-oestratetraene-3-methyl ether (6), in an approximate ratio of 2:3, as determined by the NMR spectrum.
Cyclisation of the mixture of the unsaturated ketones (5 and 6) with polyphosphoric acid gave a product, which was directly converted to its semicarbazone. The semicarbazone showed three aromatic protons, indicating ring closure. The semicarbazone was converted to a 2,4-DNP, whose melting point, 202–204°C, is close to those of 2,4-DNP of three dl-oestrone methyl ether isomers, prepared earlier by W.S. Johnson and his collaborators. The identity of our product by direct comparison is awaited.
Chapter II consists of a review of the isolation, the elucidation of structure and configuration, and the partial synthesis of the urinary metabolite, 18-hydroxyoestrone, designated as K0-6A, along with the candidate's attempts at its total and partial synthesis. Our approach involved the preparation of 2-carbethoxycyclopentane-1,3-dione (7) as the starting material following the reported procedure of Buohi by the Dieckmann cyclisation of 5-carbo-t-butoxypropionylmalonate (8) using potassium t-butoxide.
However, the Dieckmann cyclisation of (8) afforded 4-carbo-t-butoxycyclopentane-1,3-dione (9) and not 2,4-dicarbo-t-butoxycyclopentane-1,3-dione as described by Buohi. The product (9), on refluxing with p-toluenesulphonic acid or hydrochloric acid, gave the known cyclopentane-1,3-dione (10). Interaction of cyclopentane-1,3-dione (10) with formaldehyde gave methylene-bis-cyclopentane-1,3-dione (11) and not the desired 2-hydroxy-cyclopentane-1,3-dione (12).
Reaction of cyclopentane-1,3-dione (10) with the isothiouronium salt of 6-methoxy-1-vinyl-1-tetralol (13) gave 3-methoxy-14,17-dioxo-8,14-seco-18-noroestra-1,3,5(10),9(11)-tetraene (14) in excellent yield. Attempts to introduce the hydroxymethylene group at the angular position of the seco-dione (14) by interaction with formaldehyde in presence of a variety of bases were unsuccessful.
Methylation of the seco-dione (14) and subsequent cyclisation afforded dl-oestrone methyl ether, as one of the products. This constitutes a modified procedure for the preparation of the important intermediate, dl-oestrapentaene-3-methyl ether, for the total synthesis of oestrone.
The Appendix to Chapter II describes the preparation of d-cis-19-nor-pregna-3,17,20-trihydroxy-1,3,5(10)-triene (15) from d-oestrone through the sequence of reactions involving protection of the phenolic hydroxyl as tetrahydropyranyl ether, Wittig reaction with triphenylphosphonium ethyl iodide, and hydroxylation with osmium tetroxide. Our attempt to oxidize the angular methyl group of the triol (15) to give the desired 18,20-oxido compound with lead tetraacetate and iodine was not successful. | |
