| dc.description.abstract | The thesis entitled “SYNTHETIC STUDIES IN STEROIDS — TOTAL SYNTHESIS OF SUBSTITUTED HYDROBENZ[E]INDANE, HYDROPHENANTHRENE AND 11??HOMO?EQUILINEN METHYL ETHER” consists of five chapters.
In Chapter I, various methods available for the synthesis of the hydrobenz[e]indanes and hydrophenanthrenes and their conversion to steroids and D?homosteroids respectively are reviewed. The chapter concludes with a discussion of the objective of the present investigation.
With a view to modifying an earlier procedure of steroid synthesis for better stereoselectivity, a number of reducing conditions (catalytic hydrogenation with Pd–C and PtO?, metal in ammonia reductions and Ni–Al reduction) were studied with model compounds, viz., 2?methyl?2?carboxycyclohex?1?ylideneacetic acid (1) and its dimethyl ester (2). These compounds (1 and 2) were prepared following the reported procedure. The products of reduction were isolated, characterized and compared. An alternative synthesis of an ?,??unsaturated diacid (1) using Knoevenagel condensation of 2?carbethoxy?2?methylcyclohexanone with ethyl cyanoacetate was also studied and the results are discussed in detail in Chapter II.
In Chapter III, the synthesis of cis?1,2,3a,4,5,9b?hexahydro?3a?methyl?5?carbomethoxy?7?methoxy?3H?benz[o]inden?3?one (4) and a mixture of cis? and trans?2,3,3a,4,5,9b?hexahydro?3?acetoxy?3a?methyl?5?cyano?7?methoxy?1H?benz[e]indene (5 and 6) is described. The strategy involved the Michael condensation of 2?methyl?1,3?cyclopentanedione with m?methoxyatropionitrile to give the cyano diketone (8), which on cyclization and hydrogenation gave the cis?cyano benzohydrindanone (3). At this stage, the stereochemistry at the C/D?ring junction was established by its conversion to the known cis?benzohydrindanone (3a) by reductive decyanation (Na, NH?, EtOH) followed by Jones oxidation. Methanolic hydrogen chloride treatment of the cis?cyano benzohydrindanone (3) gave the cis?benzohydrindanone ester (4). This could also be obtained from the cyano diketone (8) by cyclization with methanolic hydrogen chloride followed by hydrogenation. A mixture of cis? and trans?cyano benzohydrindane acetate (5 and 6) was obtained in the ratio of 70:30 from the cyano diketone (8) in four steps involving lithium tri?tert?butoxyaluminium hydride reduction, acetylation of the resulting hydroxy group, cyclization, and hydrogenation. The configuration at the C/D?ring junction was established by conversion into the known cis? and trans?benzohydrindanones (9a and 9b) and the isomer ratio was determined using the angular methyl proton signal in the NMR spectra.
An alternative to the Michael addition, the alkylation of 2?methyl?1,3?cyclopentanedione with 3?halo?2?(m?methoxyphenyl)propionitriles (10 and 11) — these compounds having been prepared from 3?cyano?3?(m?methoxyphenyl)pyruvate, obtained from m?methoxyphenylacetonitrile and diethyl oxalate in the presence of sodium ethoxide, by treatment with 35% formalin and aqueous potassium carbonate followed by phosphorus tribromide or thionyl chloride and pyridine — yielded the cyano diketone (8) in comparable yield. In addition, the Michael addition of acyclic 3?ketoadipate (12–14) to ethyl m?methoxyatropate and ethyl atropate was also investigated. The keto triester (19) was transformed to the cis?benzohydrindanone ester (4) in six steps involving cyclization, reductive methylation, Dieckmann cyclization, hydrolysis, decarboxylation and esterification. A few unusual products isolated in the acid?catalyzed cyclodehydration of the desmethoxy cyano diketone (7) or the keto triesters (16 and 19) were characterized.
An analogous approach to the synthesis of cis? and trans?1,2,3,4,4a,9,10,10a?octahydro?1?hydroxy?9?carbomethoxy?10a?methylphenanthrene (22 and 23) by Michael addition or alkylation of 2?methyl?1,3?cyclohexanedione with m?methoxyatropionitrile and the corresponding cyano halides (10 and 11) respectively, constitutes the subject matter of Chapter IV. The isomer ratio (cis:trans) of the cyano octahydrophenanthrenol (20 and 21) and the corresponding ester (22 and 23) obtained via modified routes was compared, and the results are discussed with reference to the stereochemistry of the compounds (20 and 21). The configuration at C10a in these compounds (20 and 21) was assigned by conversion to and comparison with the known cis? and trans?3,4,4a,9,10,10a?hexahydro?7?methoxy?10a?methyl?2H?phenanthren?1?one (24 and 25).
The extension of the above strategy toward the total synthesis of equilenin and D?homoequilenin derivatives is described in Chapter V. The required 2?(6?methoxy?1?naphthyl)acrylonitrile was prepared from 6?methoxynaphthalene acetonitrile by parallel procedure (vide supra). The synthesis of 11??cyano?D?homoequilenin methyl ether (26) was accomplished from the cyano diketone (34) and the structure was confirmed by spectral data. The yield of the corresponding five?membered cyano diketone (28) was, however, low, and subsequent cyclization yielded the conjugated five?membered ketone (30) as indicated by NMR spectral data. Attempted cyclization with desmethoxy cyano diketone (27), obtained from 2?(1?naphthyl)acrylonitrile and 2?methyl?1,3?cyclopentanedione, resulted in the formation of the ring?cleavage product (31) and the diketo ester (29). Treatment of the cyano diketone (33) either with methanolic hydrogen chloride or with PPA at 100?°C followed by esterification gave exclusively the keto diester (32), whereas the cyclization of the cyano diketone (34) with PTS in benzene at reflux followed by esterification with diazomethane furnished the cyano keto ester (35) and the cyano ester (36). | |
