| dc.description.abstract | The objective of the present investigation was to develop a total synthesis of racemic and optically active steroids utilizing the CD-intermediate, 2,6,7,7a-tetrahydro-1?-hydroxy-4-formyl-7a?-methylindene (I). The literature pertaining to the synthetic approaches towards steroids from CD-hydrindane precursors has been reviewed in Chapter I.
The preparation of the racemic diene aldehyde (I) following the procedure earlier reported from our laboratory has been discussed in Chapter II. It was possible, during the present study, to modify the earlier method of preparation and obtain a better overall yield of the compound (I). To overcome the difficulties encountered during an oxidation step involving selenium dioxide, an alternative route was explored to achieve a more efficient synthesis of the aldehyde (I). 2-Methoxyethyl bromide was condensed with sodium acetylide to prepare 4-methoxy-but-1-yne, which was subsequently converted to an acetylenic Mannich base with diethylamine and formaldehyde. Hydration yielded the amino ketone, N,N-diethylamino-3-oxo-5-methoxypentane. The annelation reaction between this compound and 2-methylcyclopentane-1,3-dione afforded an undesirable product. The scheme was abandoned at this stage.
Our effort directed towards the preparation of an enantiomer of the aldehyde (I) possessing the chirality of natural steroids was eminently successful. For this purpose, the amino acid-catalyzed asymmetrical aldol cyclization was adopted as the key step. Chapter III comprises a survey of the pertinent literature as well as an account of the asymmetric synthesis of the aldehyde (I). It was observed that different amino acids gave optimum results with different substrates. The available data were rationalized in terms of a hypothesis, supported by a few spectroscopic experiments. This enabled us to choose the right amino acid for our substrate, 2-methyl-2-(3-oxopentyl)-cyclopentane-1,3-dione, to achieve optimum chiral transformation. It was further substantiated by carrying out the same reaction with different amino acids and chiral amines. The chirality of the product and the optical yield was determined by chemical resolution as well as by the use of chiral shift reagent.
Chapter IV describes the construction of the BCD tricyclic system and attempted conversion of the tricyclic compounds into the tetracyclic steroids. After a large number of unsuccessful attempts, the synthesis of the compound, 3?-hydroxy-3a?-methyl-1,2,3,3a,4,5,5a,6-octahydro-6-carbethoxy-7H-benzo(e)indene-7-one (II), was successfully accomplished. The compound was, however, obtained as an isomeric mixture. That this isomerism involved the C-9 carbon (steroid nomenclature) was proved. The tricyclic compound (II) was also prepared in the optically active form from the optically active aldehyde (I). The attempts to prepare the steroid molecule utilizing the compound (II) were fraught with the most unexpected difficulties. The compound (II) was hydrogenated to afford the dihydro derivative (III). All attempts to effect an annelation reaction either by methyl vinyl ketone or 1,3-dichloro-2-butene failed, and surprisingly, the parent dehydro compound (II) was isolated from the reaction mixture as the major component. Tentative explanations have been offered to account for such an unusual transformation. The reactions of substituted ethyl acetoacetate with the aldehyde (I), a bis-annelation strategy to overcome the above bottleneck, was also not fruitful. | |
