Synthetic studies in steroids.

Abstract

The thesis entitled, "Synthetic Studies in Steroids", consists of two parts.

Part I

Chapter I of Part I is a brief review of the chemistry of -norsteroids with special emphasis on their syntheses and biological properties.

Chapter II of Part I is divided into three sections.

Section I is an introduction to the present work.

Section II embodies the unambiguous total synthesis of a -norsteroid derivative, viz., 1,5-dimethoxy-6,6-dimethyl--norestra-1,3,5(10),8,14-pentaen-17-one (1). This was achieved in two stages.

In the first stage, the synthesis of 5,7-dimethoxy-3,3-dimethylindan-1-one (2) is described. Treatment of 3,5-dimethoxybenzoyl chloride with the magnesium salt of diethyl malonate in ethanol–ether mixture followed by hydrolysis and decarboxylation gave 3,5-dimethoxyacetophenone. Knoevenagel condensation of this acetophenone with methyl cyanoacetate afforded a mixture of cis- and trans-methyl -cyano-p-methyl-3,5-dimethoxycinnamate (3). Conjugate 1,4-addition with MeMgI to the unsaturated cyanoester (3) yielded methyl 2-cyano-3-(3',5'-dimethoxyphenyl)-3-methylbutyrate (4).

Hoesch reaction (ZnCl/HCl/ether) of the saturated cyanoester (4) did not give either 2-carbomethoxy-5,7-dimethoxy-3,3-dimethylindan-1-one or the indanone (2) in good yield. However, the required indanone (2) was obtained in good yields by refluxing the cyanoester (4) with wet DMSO containing NaCl and subsequent cyclisation of the resulting product, viz., 5-(3',5'-dimethoxyphenyl)-3-methylbutyronitrile, under Hoesch reaction conditions.

In the second stage, the indanone (2) was converted to 1,3-dimethoxy-6,6-dimethyl--norestra-1,3,5(10),9(11)-tetraen-8,14-seco-14,17-dione (1) by Grignard reaction with vinyl magnesium bromide and subsequent condensation with 2-methylcyclopentane-1,3-dione (6). Cyclodehydration of the seco-dione (1) with p-toluenesulphonic acid furnished the -norsteroid derivative (1), which was identical with the compound obtained earlier by the cyclisation of 1-(2,5-diketo-1-methylcyclopentyl)-3-(2,4-dimethoxyphenyl)-5-methylhexa-2,4-diene with conc. HSO in methylene chloride, thus confirming its structure.

Section III deals with the total synthesis of -norestrone analogues. 4,6-Dimethoxy-3,5-dimethylindan-1-one (D) on Grignard reaction with vinyl magnesium bromide yielded a vinyl alcohol, which on condensation with the dione (6) afforded 2,4-dimethoxy-6,6-dimethyl--norestra-1,3,5(10),9(11)-tetraene-8,14-seco-14,17-dione (8). Cyclodehydration of the seco-dione (8) with AcOH-HCl (5:1) mixture furnished 2,4-dimethoxy-6,6-dimethyl--norestra-1,3,5(10),8,14-pentaen-17-one (9).

The keto group of this pentaenone was reduced with NaBH to yield the 17-alcohol (10). Stereoselective reduction of the 14,15-double bond in this alcohol (10) in the presence of 2% Pd-CaCO catalyst gave 2,4-dimethoxy-6,6-dimethyl--norestra-1,3,5(10),8-tetraen-17-ol (11). Metal-ammonia reduction of the 8,9-double bond in the above tetraenol (11) in the presence of aniline resulted in the formation of a mixture of two isomers, which was directly oxidised with CrO-pyridine complex. The structure of 5-deoxy-2,4-dimethoxy-6,6-dimethyl--norestrone (12) has been tentatively assigned to the major isomer obtained from the above oxidation product. 8,9-configuration has been tentatively assigned to the minor isomer. Catalytic hydrogenation of the pentaenol (12) gave a single isomer, which on oxidation with CrO-pyridine complex furnished the iso(8,9) derivative of -norestrone analogue (13).

Part II

Part II consists of two chapters.

Chapter I is an introduction to the present work.

Chapter II describes an attempted synthesis of 11-oxa-steroid analogues. Further, the base-catalysed isomerisation of a few isoxazoles has also been discussed.

2,2-Dimethyl-5-methoxychroman-4-one on formylation with ethyl formate in the presence of sodium methoxide gave 2,2-dimethyl-3-hydroxymethylene-6-methoxychroman-4-one, which on refluxing with hydroxylamine hydrochloride in glacial acetic acid furnished 2,2-dimethyl-6-methoxychromano[3,4-d]isoxazole (12) in good yield. The isoxazole (12) on treatment with potassium t-butoxide followed by methylation with MeI gave 3-cyano-6-methoxy-2,2,3-trimethylchroman-4-one (14). However, the -ketonitrile (14) failed to undergo condensation with dimethyl succinate in the presence of potassium t-butoxide, under Stobbe reaction conditions.

In an earlier work, it was reported that 7-methoxychromano[3,4-d]isoxazole undergoes the above isomerisation–methylation reaction to give ‘abnormal’ products resulting from the opening of the isoxazole ring as well as the chromanone ring. However, in the present case, the isoxazole (14) gave only the normal product (14).

Thus, in order to study the generality as well as the substituent effects on the base-catalysed cleavage of isoxazoles, two more isoxazoles were synthesised and their behaviour towards base studied.

6-Methoxychroman-4-one was converted to 6-methoxychromano[5,4-d]isoxazole (15) via the hydroxymethylene derivative. The isoxazole (15) on treatment with potassium t-butoxide followed by methylation with MeI gave a single product, which was shown to be 3-cyano-6-methoxy-3-methylchroman-4-one. On the other hand, 7-methoxy-5-methylchromano[3,4-d]isoxazole, obtained from the corresponding chromanone, gave a mixture of products in this isomerisation reaction. From rigorous column chromatography followed by preparative TLC of this mixture, three compounds were isolated and their structures were shown to be 3-i-butoxy-2-cyano-2,6'-dimethyl-2,4'-dimethoxypropiophenone, 3-t-butoxy-2-cyano-6'-methyl-1,2',4'-trimethoxy-(1-propenyl)benzene and methyl 2,4-dimethoxy-6-methylbenzoate.

It has been concluded from the study that the position of the methoxy group on the aromatic ring alone plays an important role in the ‘abnormal’ cleavage of chromanoisoxazoles.

Appendix lists the following published papers:

Acid catalysed cyclisation of 1-(2,5-diketo-1-methylcyclopentyl)-3-(2,4-dimethoxyphenyl)-5-methylhexa-2,4-diene – Synthesis of -norsteroid derivative. T.R. Kasturi, E.M. Abraham and R.S. Prasad, Tetrahedron Lett., 971 (1974).

Synthesis of 4,6-(and 5,7-)dimethoxy-3,5-dimethyl-1-indanones. T.R. Kasturi, E.M. Abraham and R.S. Prasad, Tetrahedron, 2887 (1974).

Base catalysed isomerisation of isoxazoles. T.R. Kasturi and R.S. Prasad, Indian J. Chem. (in press).