Steroidal l,4-dien-3-ones

An unusual reaction was been observed in the reaction of old yellow enzyme with a,(3-unsat-urated ketones. A dismutation took place under aerobic or anaerobic conditions, with the formation from cyclohex-l-keto-2-ene of the corresponding phenol and cyclohexanone, and an analogous reaction from representative cyclodec-3-keto-4-enes—putatively by hydride-ion transfer (Vaz et al. 1995). Reduction of the double bond in a,p-unsaturated ketones has been observed, and the enone reductases from Saccharomyces cerevisiae have been purified and characterized. They are able to carry out reduction of the C=C bonds in aliphatic aldehydes and ketones, and ring double bonds in cyclohexenones (Wanner and Tressel 1998). Reductions of steroid l,4-diene-3-ones can be mediated by the related old yellow enzyme and pentaerythritol tetranitrate reductase, for example, androsta-A -3,17-dione to androsta-A -3,17-dione (Vaz etal. 1995) and prednisone to pregna-A -17a, 20-diol-3,ll,20-trione (Barna et al. 2001) respectively. 

Iodylbenzoic acid (720 mg, 2.57 mmol) and diphenyl diselenide (50 mg, 0.16 mmol) were refluxed with stirring in benzene or toluene or chlorobenzene (20 ml) until the yellow colour of the diselenide disappeared (about 15 min). The steroid (300 mg) was added and heating with stirring continued until completion of the reaction. The reaction mixture was washed with water and dried. Concentration and recrystallization gave steroidal l,4-dien-3-ones in 70-89% yield. From the combined aqueous extracts 3-iodylbenzoic acid and diphenyl diselenide could be recovered. Not only steroidal ketones [1,2] but also substrates with similar features were dehydrogenated in this way, sometimes to provide only enones (Table 11.1). 

The conversions of various steroidal l,4-dien-3-ones (109) into 5-ene-la,3/3-diols (111) via deconjugation to the l,5-dien-3-one, reduction to the l,5-dien-3/8-ol (110), and hydroboration have been described in a series of papers.125 The corresponding 5,7-diene-la,3j8-diols (118), required for photo-isomerization as a key step in the preparation of la-hydroxylated derivatives of vitamin D, have been obtained either by allylic bromination-dehydrobromination of the 5-ene-la,3/3-diols or by the alternative route outlined in Scheme 2. The key step in this reaction sequence is the protection of the 5,7-diene system as the adduct (116) with 4-phenyl-... 

Steroid l,4-dien-3-ones have been considered resistant to enol esterification, but powerful bases [PhsC , HC=C , or (Me3Si)2N ] convert the diene-dione (328) into its enolate anion, which affords the 3-benzoate (329) with benzoyl chloride. The 1,3,5-trienolate ion is, however, the product of kinetically... 

The base converts steroidal l,4-dien-3-ones into 1,3,5-trieno-lates which yield 1,5-dien-3-ones upon addition of water (eq 13). This reaction does not occur with t-BuOK/f-BuOH. The t-BuOK/ DMSO reagent isomerizes cyclic 1,4- (eq 14) and 1,5-dienes (eq 15) into the corresponding conjugated dienes. 

The 17-ethylene ketal of androsta-l,4-diene-3,17-dione is reduced to the 17-ethylene ketal of androst-4-en-3,17-dione in about 75% yield (66% if the product is recrystallized) under the conditions of Procedure 8a (section V). However, metal-ammonia reduction probably is no longer the method of choice for converting l,4-dien-3-ones to 4-en-3-ones or for preparing 5-en-3-ones (from 4,6-dien-3-ones). The reduction of l,4-dien-3-ones to 4-en-3-ones appears to be effected most conveniently by hydrogenation in the presence of triphenylphosphine rhodium halide catalysts.15,25 Steroidal 5-en-3-ones are best prepared by base catalyzed deconjugation of 4-en-3-ones.65,72a... 

Dehydrogenation of 3-kelo steroids. The dehydrogenation of 3-keto steroids to l,4-diene-3-ones with benzeneseleninic anhydride (8, 31) can be carried out in comparable yield by use of a process in which the benzeneseleninic anhydride is used in catalytic amounts and is continuously regenerated from diphenyl diselenide by oxidation with iodylbenzene. In practice, m-iodylbenzoic acid is a more convenient reagent, since m-iodobenzoic acid is easily recovered. 12-Keto and 12-hydroxy steroids arc oxidized by the catalytic system to A9(1 - -keto steroids in high yield. In fact, methyl desoxycholate (1) can be oxidized in this way directly to the trienedione 2 in 64% yield.1... 

Steroidal 1,4-dien-3-ones react with phosphorus pentasulphide in an inert solvent to give the purple-blue l,4-diene-3-thiones (235) (Amax330 and 565—580nm).204 The thiones are remarkably stable, but can be oxidized to give syn- and anti-S-oxides, which are separable but are interconverted on standing. Diphenyl-diazomethane reacts with the dienethione at room temperature to give the 3-(diphenylmethylene)-1,4-diene (236) directly.204... 

The fused pyrrole ring system (204) has been obtained by the reaction of 17/3-hydroxy-17-methylandrosta-l,4-dien-3-one with tosylmethyl isocyanide in the presence of sodium hydride in DMSO,92 and 17/3-hydroxy-17-methyl-7-oxa-5o -androstano-[3,2-c]- (205) or -[2,3-d]-isoxazoles (206 X = O) have been prepared by treating 7-oxa-2-(hydroxymethylene)-17/3 -hydroxy-17-methyl-5 a -androstan-3-one with hydroxylamine hydrochloride.93 In the presence of pyridine, the isox-azole (206 X = O) is formed, but when the reaction is catalysed by sodium acetate in acetic acid the isomeric steroid (205) results. Cycloaddition of hydrazine hydrate to the same 2-hydroxymethylene-7-oxa-steroid results in the [3,2-c]pyrazole (206 X = NH). A similar addition is encountered in the reactions between 3/3-hydroxy-16-(hydroxymethylene)-5a-androstan-17-one and the substituted hydrazines RNHNH2 (R = H, o-COC6H4NH2, or p-COQHUNH ,) when the corresponding [17,16-c]pyrazoles (207) are formed after cyclization of the intermediate hydrazones.94... 

Androsta-l,4-diene-3,17-dione reacted selectively at C-17 with potassium acetylide to give the 17a-ethynyl-17/8-alcohol the dihydroxyacetone side-chain was then elaborated by use of known transformations, without interference from the l,4-dien-3-one system/ Ethynylation of a [16- H]- or [16- H2]-17-oxo-steroid proceeds without loss of label/ ... 

Reaction of l,4-diene-3-one steroids with isonicotinic acid hydrazide (isoniazid) pro-... 

It also has been used as spray reagent and for quantitation in paper and thin layer chromatographic systems (Section 6.5). It should be noted that l,4-diene-3-one steroids react much less readily with isonicotinic acid hydrazides than do 4-ene-3-one steroids2 . 

In a personal communication to the present writer, Harkness (H5) pointed out that a number of steroid drugs with hydrocarbon skeletons which are not found in the naturally occurring steroids have been reduced and the products separated by GLC (A3). One application of such a technique in clinical chemistry is the detection of steroid drugs which in vivo are completely altered metabolically without changing their carbon skeletons. For example, after the administration to normal men of therapeutic doses of the anabolic steroid 17a-methyl-17 8-hydroxyan-drosta-l,4-dien-3-one (Dianabol Ciba) none of the imaltered drug could be detected in urine. A further difiBculty in detecting their administration... 

Several routes applicable to the large scale conversion of testosterone into 4,5a-dihydrotestosterone have been investigated. The method of choice appears to be via catalytic reduction of a 17-acyloxy-3,3-ethylenedioxyandrost-5-ene. Platinum-catalysed hydrogenation of 19-acetoxy, hydroxy-, or methoxy-cholestan-3-ones affords higher proportions of 3a-alcohols than does the 19-unsubstituted steroid. Tritiation of 17)S-hydroxyandrosta-l,4-dien-3-one affords testosterone having a tritium ratio of 1 3.4 (a P) at C-1 and 1 1.4 at C-2 implying that reduction must proceed, in part, by 1,4-addition. ... 

Androsta-l,4,6-trien-3-ones react with N-bromoamides to give solely the 6)3,7a-dibromo-derivatives with no detectable products of allylic bromination. The 6/5,7a-dibromides eliminated HBr with rearrangement to 4-bromo-l,4-dien-3-ones on treatment with organic bases. 5a,6)5-Dichloro-steroids may be prepared in fair yield from 3)8-acetoxy-5-enes by treatment with a mixture of lead tetra-acetate and acetyl chloride (1 4). ... 

The inverse procedure, double bond tritiation followed by re-oxidation, allows for the tritium labeling of a,/8-unsaturated carbonyl compounds (Figure 10.7). Applied to the complex steroid 22 it provided [ H]25, in which 95% of the tritium was located at C2. If most tritium in the intermediate 34 had been on the a-face and equally distributed between Cl and C2, in analogy with the preparation of [ C]24 under very similar conditions, then the benzeneselenic anhydride-mediated dehydrogenation must have constituted a net la,2)3 elimination. This selectivity is consistent with the DDQ dehydrogenation of [la,2a- H]androst-4-ene-3,17-dione (36) to give [2- H]androsta-l,4-dien-3,17-dione (2Z) with little tritium at Cl, and DDQ dehydrogenation of [l)3,2)3- H]testosterone 1381 to provide mainly 17)3-hydroxy[l- H]androsta-l,4-dien-3-one (39) . 

The Sterol fraction of Gymnocrinus richeri contains 14 derivatives nine usual sulfated sterols (A5 and AO) and some unusual steroids, including 5a-ergosta-7,22-diene-3p,5,6P-triol, cholesta-l,4-diene-3-one and three A6-5a, 8a epidioxysterols (De Riccardis et al., 1991b). 

Weiss and co-workersprepared a series of oxazohnylidene steroids 343 as luminescence dyes for application as potential intracellular diagnostic agents (Scheme 6.72). The key intermediate 2-aryl-5,5-dimethyl-4(57/)-thiooxazolones 341 were readily available from the corresponding 4(57/)-oxazolones 339. Reaction of 341 with 342, generated in situ from the hydrazone 340, gave 343 as expected. It was not possible to prepare 343 from 3-thio-androsta-l,4-dien-17-one since the requisite corresponding heterocyclic diazo compounds could not be prepared. 

Boldenone (17 -boldenone) is an androgenic steroid with known anabolic properties. As the oxidation of 17-ol to 17-one steroids is a recurring pathway both in vivo and in vitro, boldenone studies in cattle liver microsomes performed in vitro showed that the most prominent metabolite formed was androst-l,4-diene-3,17-dione 111). Not long ago, it was assumed drat the presence of boldenone or its main metabolite in the urine implied illegal administration of this steroid to the animal. Evidence has been recently presented that the presence of only the boldenone metabolite in urine cannot be taken as a proof of the illegal use of tills compound because boldenone is a naturally occurring steroid in urine of cattle (12). Nevertheless, the presence of 17 -boldenone in urine at levels above... 

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