Synthetic studies in steroids

Abstract

The thesis entitled “Synthetic Studies in Steroids” consists of three chapters. The first chapter contains a brief review of the total synthesis of aromatic steroids, highlighting some of the theoretical and experimental advances that made it possible to evolve ingenious strategies for this important group of compounds. The total synthesis of some potential intermediates of the aromatic steroids-namely, the tetracyclic ketone (9) and D?homo?3?methoxy?oestra?1,3,5(10),6,8?pentaen?16?one (12)-is discussed in Chapter II, which is divided into three sections. Section I A brief introduction to the strategy involved in the synthesis of the above?mentioned compounds. Birch reduction of 4?methyl resorcinol dimethyl ether gave the dihydro compound (1a). In situ conjugation followed by Diels–Alder reaction with acrylonitrile in sealed?tube conditions gave adduct (2a). Attempts to elaborate this adduct through Grignard reaction were unsuccessful, as hydrolysis to the ketone (3) competed strongly, reducing yields. At this stage, m?cresol methyl ether was adopted as the starting material. Various Diels–Alder adducts (2b–d) were prepared by reacting the diene (1b) with acrylonitrile, methyl acrylate, and acrolein, respectively. Lithiation and Grignard reactions were attempted on these adducts using m?methoxyphenylpropyl bromide. The Grignard reaction on aldehyde adduct (2d) was most successful, yielding the hydroxy compound (6a) in 60% yield. This was oxidised to the ketone (6b) using pyridinium chlorochromate. Section II Attempts to synthesise intermediates (9) and (12) using other methods. Conjugation of the dihydro compound (1a) using potassamide in liquid ammonia, followed by alkylation with m?methoxyphenethyl bromide, gave the alkylated diene (4). This was subjected to Diels–Alder reaction with methyl vinyl ketone. Although the diketone (5) was obtained and characterised, poor yields led to discontinuation of this route. Section III Elaboration of ketone (6b) to intermediate (9). Acid?catalysed (perchloric acid–acetic acid) ring?opening of bicyclic system (6b) generated the diketone (7). Michael reaction using potassium t?butoxide in t?butanol afforded compound (8), which cyclised with p?toluenesulphonic acid (PTS) to the tetracyclic ketone (9). The stereochemistry at the CD?ring junction was established by converting (9) to (10a) via Huang–Minlon reduction and comparing it with authentic CD?trans compound (10b). The C?13 methyl protons appeared downfield by ? 0.30, showing that (9) possesses CD?cis stereochemistry. Oxidation of the tetracyclic ketone (9) with DDQ gave the hexaene (11), which on Pd–C catalytic hydrogenation yielded D?homo?3?methoxy?oestra?1,3,5(10),6,8?pentaen?16?one (12). Birch reduction of (9) afforded 3?methoxy?D?homo?8a,9?,14??oestra?1,3,5(10)?trien?16?one (13) as the major product; stereochemistry followed from literature data.

Chapter III This chapter examines cyclic styrenoid reductions using metals in liquid ammonia under varied conditions, to gain insight into the mechanism. Birch reduction of dehydroestradiol?3?methyl ethers (14a) and (15a) using lithium, followed by Jones oxidation, yielded mixtures of trans and cis products (16a, 16b) in ratios 60:40 and 70:30 respectively. Changing the metal did not improve the ratio. Metal–ammonia reduction of tricyclic systems (18a–c), containing a styrene double bond, under various conditions yielded equal mixtures of trans and cis products (19a, 19b). Reduction of dehydroestradiols (14a), (15a) and their 17??acetates (14b), (15b) in the presence of aniline, followed by Jones oxidation, gave exclusively the trans estrone?3?methyl ether. This observation enabled a one?pot conversion of acetate (14b) to 19?nortestosterone (17). These results clearly indicate that reduction mechanisms of styrenoid systems in metal–ammonia solutions do not involve dianions. Instead, a mechanism involving the initial formation and protonation of an anion radical is proposed. Electron?density calculations place the first protonation unambiguously at the homobenzylic position. If a dianion were protonated, only the trans product would form (due to anti orientation). But equal amounts of both isomers-as in (19a,b)-strongly support the radical?anion mechanism.