Synthetic investigation in steroids

Abstract

The thesis entitled “Synthetic Investigations in Steroids” consists of four chapters. Chapter I is a brief review on the total synthesis of aromatic steroids. The problems associated with the development of the total synthesis of steroid hormones and possible solutions are discussed with suitable examples. Chapter II is divided into four sections. Section I deals with the biological activity and synthesis of arylcyclohexane derivatives. In Sections II, III, and IV, the synthesis of 2-(p-methoxyphenyl)-5-diethoxycarbonylcyclohexanone (2.5), a potential synthone in our projected synthesis of oestrone, which was achieved by three methods, is discussed. In the first synthesis, 6-(p-methoxyphenyl)-1-nitro-3-cyclohexene (2.2), obtained from the Diels-Alder reaction of p-methoxy-?-nitrostyrene (2.1) and butadiene, was converted into 6-(p-methoxyphenyl)-2-cyclohexenone (2.3) by Neff’s reaction followed by isomerisation. Addition of HCN to (2.3) gave 2-(p-methoxyphenyl)-5-cyanocyclohexanone (2.4) which was converted into the ester, 2-(p-methoxyphenyl)-5-methoxycarbonylcyclohexanone (2.5), by refluxing with methanolic sulfuric acid. Attempted Diels-Alder reactions of 5-(p-methoxyphenyl)-2,4-pentadienoic acid with various dienophiles to give the desired compound (2.5) are also discussed. In the second synthesis, based on Dieckmann cyclisation, ethyl ?-cyano-?(p-methoxyphenyl)acetate (2.7) was alkylated with ethyl 5-carbethoxy-3-cyano-5-bromopentanoate (2.9) to afford diethyl 5-carbethoxy-3,6-dicyano-6-(p-methoxyphenyl)pimelate (2.10). The bromo compound (2.9) was obtained by alkylation of cyanosuccinic ester (2.8) with 1,2-dibromoethane. Hydrolysis of the pimelate (2.10) with conc. hydrochloric acid gave the triacid (2.11) which on esterification with methanolic sulfuric acid afforded dimethyl 3-methoxycarbonyl-6-(p-methoxyphenyl)pimelate (2.12). Dieckmann cyclisation of (2.12) gave 2,5-dimethoxycarbonyl-6-(p-methoxyphenyl)cyclohexanone (2.13) which was hydrolysed to 2-(p-methoxyphenyl)-5-oxycarbonylcyclohexanone (2.14) by refluxing with dil. sulfuric acid. Esterification of the acid (2.14) with diazomethane gave the synthone (2.5). In the third synthesis, p-methoxyphenylmagnesium bromide (2.15) was added to methyl 4-oxocyclohexanecarboxylate (2.16), the product on dehydration gave methyl 4-(p-methoxyphenyl)-3-cyclohexenecarboxylate (2.17). This compound (2.17) was converted into the synthone (2.5) by:

converting it into the epoxide with perbenzoic acid followed by treatment with methanolic sulfuric acid, hydroboration to the carbinol followed by oxidation using pyridinium chlorochromate. Of the three methods described, the last one is more promising to proceed for further investigation.

Chapter III is divided into two sections. In Section I, the total synthesis of steroid hormones from “AC” synthones has been briefly reviewed, and the merits of our approach to the synthesis of oestrone and its derivatives from 2-(p-methoxyphenyl)-5-methyl-5-methoxycarbonylbicyclo[4.4.0]decal-9-one (3.4), in the light of other syntheses, has been critically evaluated. In Section II, the synthesis of the intermediate (3.4) has been described. The synthesis of 2-(p-methoxyphenyl)-5-oxycarbonylbicyclo[4.4.0]decal-1(10)-en-9-one (3.1) by alkylation of the keto diester (2.13) with 1-diethylamino-3-butanone followed by base-catalysed cyclisations under different conditions were unsuccessful. Next, treatment of 2-hydroxymethylene-3-methoxycarbonyl-6-(p-methoxyphenyl)cyclohexanone (3.2) with methyl vinyl ketone followed by base-catalysed cyclisation gave (3.1) in 18% yield. All our efforts to improve the yield in the annelation step were unsuccessful. Lithium-ammonia reduction of (3.1) gave 2-(p-methoxyphenyl)-5-oxycarbonylbicyclo[4.4.0]decal-9-one (3.3) which was esterified with diazomethane to the ester (3.4). Ketalisation of (3.4) followed by alkylation with methyl iodide in the presence of suitable conditions was attempted.