Synthetic investigations in steroids: a new approach to the total synthesis of estrone and its analogues.

Abstract

The object of the present investigation is to develop a new strategy for the synthesis of aromatic steroids and their analogues. The thesis entitled “SYNTHETIC INVESTIGATIONS IN STEROIDS: A NEW APPROACH TO THE TOTAL SYNTHESIS OF ESTRONE AND ITS ANALOGUES” is divided mainly into four Chapters. The literature pertaining to the synthetic approaches towards aromatic steroids has been reviewed in Chapter I, the emphasis being a critical analysis of the newly developed methodologies for estrone. Total synthesis of 3?methoxy?D?homo?14?isoestra?1,3,5,8?tetraene?16?one (23), a potential aromatic steroid intermediate and its desoxy (24) and 18?homo (25) analogues is described in Chapter II, which is subdivided into four sections. Section I deals with the preparation of dihydrobenzenes by reduction of aromatic compounds with alkali metals, alcohol in liquid ammonia and their regiospecific addition to dienophiles to form Diels–Alder adducts of significant importance in organic synthesis. In Section II, preparation of the keto adducts (15), (16), (17) and (18) is described. 4?Methylanisole (1) on reduction with sodium–ethanol in liquid ammonia resulted in the dihydro compound (3), which on conjugation with potassium amide in liquid ammonia afforded the conjugated diene (5). The enones (21) and (22) were prepared by the reaction of acrolein with m?methoxyphenylpropylmagnesium bromide or phenylpropylmagnesium bromide respectively, followed by oxidation of the vinylic carbinols (19) and (20). Diels–Alder reaction of the diene (5) with the enones (21) and (22) resulted in the keto adducts (15) and (16). Similarly the compounds (17) and (18) were prepared by reaction of the enones (21) and (22) with diene (6), obtained by sodium–ethanol in liquid ammonia reduction of 2?ethylanisole (2), followed by the base?catalysed conjugation of the resulting diene (4) with potassium amide in liquid ammonia. The keto compounds (15), (16) and (17) were prepared also from the adducts (7) and (8), obtained from the dienes (5) and (6) by Diels–Alder reaction with acrolein. Grignard reaction of the adducts (7) and (8) with m?methoxyphenylpropylmagnesium bromide resulted in the alcohols (12) and (14) respectively, PCC oxidation of which resulted in the formation of the keto compounds (15) and (17). Similarly the compound (16) was prepared by reacting the adduct (7) with phenylpropylmagnesium bromide followed by oxidation. Attempts to prepare the ketone (15) either by reaction of the lithio salt of the acid (11) with m?methoxyphenylpropyllithium or the cyano compound (9) with m?methoxyphenylpropylmagnesium bromide resulted in a poor yield of the product (15). The compounds (11) and (9) were readily made from the diene (5) and methyl acrylate or acrylonitrile. The conversion of the ketones (15), (16) and (17) to the tetracyclic compounds (23), (24) and (25) is described in Section III. Acid?catalysed cleavage of the adducts (15) and (17) resulted in the formation of the tetracyclic ketones (23) and (25) directly. However, the reaction was not facile in the case of the cleavage of (16) and resulted in a mixture of the enedione (27) and the tetracyclic tetraenone (24). In all these cases pure enediones (26), (27) and (28) were obtained by milder acid treatment. Intramolecular Michael reaction of the enediones resulted in the diones (29 to 31). Michael reaction of (26) with different bases was investigated which resulted in the same product (29). AB ring closure of the seco compounds (29 to 31) afforded the tetracyclic compounds (23 to 25). An attempt to synthesise the tetracyclic compounds (23) and (24) by an alternative route is described in Section IV. Alkylation of the dihydro compound (3) with m?methoxyphenylpropyl bromide or phenylpropyl bromide in the presence of potassium amide in liquid ammonia afforded the products (33) and (34) respectively. Diels–Alder reaction of these dienes with methyl vinyl ketone was expected to give the adducts (35) and (36), which could be converted to the unsaturated ketones (37) and (38), which in turn could be cyclised to yield the tetracyclic compounds (23) and (24) respectively. However, the cycloaddition of (33) and (34) with methyl vinyl ketone yielded the adducts (39) and (40) which on hydrolysis afforded the enones (41) and (42) respectively. Chapter III deals with the conversion of the tetraenone (23) to d?estrone methyl ether. The pentenone (43) was conveniently prepared by: (i) oxidation of (23) with palladium chloride or rhodium chloride in THF; (ii) bromination of (32) followed by dehydrobromination. Reduction of the pentenone (43) with lithium–aniline–liquid ammonia resulted in the compound (45) having trans?anti?trans stereochemistry which was confirmed by converting it to the compound (46), via its tosylhydrazone and comparing it with an authentic sample. The unsaturated aldehyde (47) was obtained by hydroxymethylation of the compound (40) followed by oxidation with selenium dioxide. Oxidative cleavage of the unsaturated aldehyde with potassium permanganate resulted in the diacid (48), which on esterification with ethereal diazomethane gave the diester (49). This diester was found to be identical with the sample prepared by the D?ring cleavage of estrone methyl ether with sodium hypoiodite followed by esterification. Since the diester (49) has been converted to estrone methyl ether, this constitutes a formal total synthesis of dl?estrone methyl ether. Catalytic hydrogenation of (43) resulted in the 8?iso compound (50). The structure and stereochemistry of (50) was established by its conversion to (51) through the tosylhydrazone and its comparison with an authentic sample. Chapter IV comprises the experimental part with analytical and spectral data.