Unsaturated 3-Keto-Steroids

The phase-I-metabolism of testosterone leads primarily to 5a-androstan-17P-ol-3-one (dihydrotestosterone), 5a-androstan-3a-ol-17-one (androsterone), and 5P-androstan-3a-ol-17-one (etiocholanolone) (Fig. 3.6,2-4, respectively), which represent important parameters of the so-called urinary steroid profile in sports drug testing (see Chapter 6). 

Steroid Nucleus Representative Compound Mol wt (Da) Fragment Ions m/z)  

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Diene carboxylates can be prepared by the reaction of alkenyl halides with acrylates[34]. For example, pellitorine (30) is prepared by the reaction of I-heptenyl iodide (29) with an acrylate[35]. Enol triflates are reactive pseudo-halides derived from carbonyl compounds, and are utilized extensively for novel transformations. The 3,5-dien-3-ol triflate 31 derived from a 4,5-unsaturated 3-keto steroid is converted into the triene 32 by the reaction of methyl acrylate[36]. 

Reactions with Carbonyl Groups. Unsaturated 3-keto steroids give the corresponding 3-chloro derivatives with oxalyl chloride (eq 18). Prolonged heating can give rise to... 

Shapiro, R.H., and Djerassi, C. (1964) Mass spectrometry in structural and stereochemical problems. L. Fragmentation and hydrogen migration reactions of a,P-unsaturated 3-keto steroids. Journal of the American Chemical Society, 86,2825-2832. 

Steroidal agents such as 5a-androstan-17P-ol-3-one (Fig. 4.5,1) and selected analogues (Fig. 4.5, 2-4) dissociate efficiently upon ESI and CID as shown exemplarily for 5a-androstan-17P-ol-3-one (Fig. 4.6a). Commonly, the saturated scaffold of cyclopenta[a]phenanthrene-derived compounds results in product ion mass spectra predominantly containing ions of low specificity, which are separated by methylene units (14 Da). Although a,P-unsaturated 3-keto-steroids also yield such product ions, the presence of double bonds commonly directs the dissociation pathway to specific and more characteristic fragments vide infra). 

Double bonds in a,/3-unsaturated keto steroids can be selectively oxidized with alkaline hydrogen peroxide to yield epoxy ketones. In contrast to the electrophilic addition mechanism of peracids, the mechanism of alkaline epoxidation involves nucleophilic attack of hydroperoxide ion on the con-... 

Many a,/ -unsaturated keto steroids undergo conjugate addition and thereby provide a unique route to aziridines. Treatment of 3j5-hydroxypregna-5, 16-diene-20-one acetate (48) with methoxyl-or ethoxylamine in ethanol under... 

Angular methylation at positions 8a, 9a and 14a has been carried out with the unsaturated keto steroids (16),158,159 (18), (20)160 and (21).161,162 The observed result is due to the presence of the double bond which controls the direction of enolization. Proton abstraction results in the formation of a conjugated dienolate anion which is alkylated from the less hindered side at the most electronegative carbon atom. 

As discussed earlier (see also Chapter 6), oxime derivatives are often prepared for polyfunctional compounds containing ketone groups in order to prevent the formation of mixed enol-silyl ethers. An alternative approach is to use a catalyst to enhance the yield of enol-silyl ethers (see also above. Section 4.2.3, for TMS ethers). The use of potassium acetate in toluene as catalyst is reported to produce a quantitative yield of TBDMS ethers and >96% yield of TBDMS-enol ethers of a, -unsaturated keto steroids [326]. An alternative to this approach, set out below, uses sodium formate to catalyse enol-silyl ether formation with fewer by-products being produced [12, 13]. 

The most frequently encountered members of this group are A -3-keto steroids. This is clearly a result of the biological importance of a number of compounds in this series. Among the remaining a, -unsaturated ketones the -20-ke-... 

The reaction can be performed under a variety of conditions. Origin-aiiyi2o,i26,234 acetylene and potassium in liquid ammonia were used. Subsequently, this was simplified by the use of potassium r-amylate in r-amyl alcohol and later this system was found to react selectively at C-17 in the presence of an A-ring a,j5-unsaturated ketone. A closer investigation of these reaction conditions revealed the formation of a small amount (2-3 %) of the disubstituted acetylene this can be avoided by reacting the 17-keto steroid with acetylenedimagnesium bromide in ether-tetrahydrofuran (see chapter 10.)... 

Photochemical processes provide an alternative approach to 10(54)n6eo-3,5-diketones. Thus, irradiation of saturated or l,2-unsaturated-4,5-epoxy-3-keto steroids such as (129) and (130) produces 3,5-dioxo-10(54)<3Z)eo-... 

Cardeiwlides. A short and efficient synthesis of digitoxigenin (4) utilizes as the key step the reaction of an ,j8-unsaturated 17-keto steroid with 1. 

Much work has been published on the microbiological reduction of a,p-unsaturated ketones. Under anaerobic conditions the reduction of A -3-keto steroids by Clostridium paraputrificum led to the 3-keto 5p-derivatives (Scheme 69) Similar transformations were observed previously with Bacillus putrifi-cus, Penicillium decumbens Rhizopus nigricans or Aspergillus niger. In most cases further reduction led to the corresponding 3a-hydroxy 5P-derivatives. 

An impressive application, where the stereochemical consequences of unsaturated sulfoxide-sulfenate rearrangements are convincingly utilized, provides an efficient and stereoselective method for the corticosteroid side chain formation, starting from 17-keto steroids (Scheme 21). ... 

Dipyrazolyl steroids (242 X = NH)and(244 X = NH) have been obtained by the reaction of the 2,6- and 4,6-diformyl compounds (241) and (243) with hydrazine whilst similar condensation with the unsaturated keto-aldehyde derived from (221) gives the pyridazine (245). 

Hydrolysis of the enol ether (60) with mineral acid was followed by oxidation and separation to provide the conjugated 19-nor-steroid analogue (61) and its y-unsaturated keto-isomer (62). The stereochemistry was established as... 

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