Hydroxymethylene steroids

A total of 3 g (0.13 moles) of sodium hydride is added to a solution consisting of 10 g of 17 -hydroxy-5a-androstan-3-one (36 mmoles) in 200 ml of benzene and 10 ml of ethyl formate. The reaction mixture is allowed to stand under nitrogen for 3 days followed by dropwise addition of 10 ml of methanol to decompose the excess of sodium hydride. The solution is then diluted with 300 ml water and the layers are separated. The basic aqueous solution is extracted with ether to remove neutral material. The aqueous layer is acidified with 80 ml of 3 A hydrochloric acid and the hydroxymethylene steroid is extracted with benzene and ether. The combined organic extracts are washed with water and saturated sodium chloride solution and then dried over magnesium sulfate and concentrated. The residue, a reddish-yellow oil, crystallized from 10 ml of ether to yield 9.12 g (83%) of 17 -hydroxy-2-hydroxymethylene-5a-androstan-3-one mp 162-162.5°. Recrystallization from chloroform-ether gives an analytical sample mp 165-165.5° [a]o 53° (ethanol) 2 ° 252 mjj. (g 11,500), 307 m u (e 5,800). 

The corresponding 2a-allyl steroids in the androstane series have been obtained similarly by alkylation of the hydroxymethylene ketone with allyl bromide. 

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... 

Bomah and co-workers [99] developed an efficient procedure for the synthesis of ring-A fused [3,2-h]pyrimidines 53 in a steroidal moiety. The novel steroidal pyrimidines were prepared via a solid phase three-component reaction of a 2-hydro-xymethylene-3-keto steroid, an arylaldehyde and ammonium acetate under micro-wave irradiation. This protocol has been applied successfully to the cyclization of bicyclic, monocyclic and acyclic 2-hydroxymethylene ketones with diversely substituted aromatic aldehydes (Scheme 39). 

The boronic acid binding site can also be used for interactions with monoalcohols. In the presence of an ort/zo-hydroxymethylene group (see entry 1), an intramolecular cyclic monoester is formed (boronophthalide). This compound still has one hydroxyl group left for the esterification of monoalcohols, a reaction that can be used in the imprinting procedure [46,47,72]. Recently this method has been revived for the binding of steroid alcohols [73,986,c]. 

Oxidation of oxygen functions. DDQ is useful for the selective oxidation of allylic " and benzylic alcohols. The reagent has the advantage of not showing the variability encountered with active manganese dioxide. It dehydrogenates 2-hydroxymethylene-3 ketosteroids in about 50% yield. The steroid is treated in dioxane solution at room temperature with 1.1 -1.5 equivalents of DDQ for 1 -5 min.. 

Reactions of Enols and Enolate Anions.—Several methods are described for transposition of an oxo-function to the adjacent site. They involve formation of a suitable a-substituted derivative (hydroxymethylene ° or benzylidene ) and subsequent steps which transform the substituent into an isolated oxo-group. Condensations leading to both the 2-hydroxymethylene- and the 2-arylidene-3-oxo-steroids are described for 3-ketones of the 5jS-series, and also of the 5j8,9j5,10a-( retro ) series.Condensations of aromatic aldehydes at C-2 in the 5 -series are unusually slow enolisation towards C-4 is preferred, but steric compression between C-4 and C-6 in 5/3-compounds severely hinders the condensation reaction at C-4, allowing reaction at C-2 via the 2-enol. Reduction of a 21-hydroxymethylene-pregnan-20-one (337) with sodium borohydride afforded the homopregnanediol (338), although reduction of enolised P-dicarbonyl compounds frequently proceeds via elimination to give enones, and thence allylic alcohols. 

The distribution of 0 between the hydroxyl and hydroxymethylene functions of 19a and 19b, determined by the fragmentation pattern of these two species during mass spectrometry, could only result from addition of the carboxyl of the enzyme to the a face of the steroid. Had the carboxyl added to the spiro carbon from the jS face, the 0 would have been located in the hydroxymethylene function of 19a. Clearly, if the binding of the oxiranyl steroids is analogous to that of steroid substrates, Asp-38 could not be involved in the normal intramolecular proton transfer associated with the isomerization reaction. However, as recently emphasized by Pollack ei al., the oxiranyl steroids could conceivably bind to the active site in an upsidedown orientation in comparison to that of the substrate steroids (133). In this case, Asp-38 would still be the most probable base involved in the intramolecular proton transfer reaction. Perhaps upsidedown binding accounts for the report that the C-4a hydrogen of 5-androstene-3,17-dione undergoes slow labilization in the presence of the isomerase (134, 135). 

Oxymetholone. I7-HydrOxy-2-(hydroxymethyl-enei-17-methylandrosta n-3-one 2-hydroxy methylene-I Tame thy ldi hydro testosterone 4,5 a -di hydro -2 -hydroxymeth -ylene-17a-methyltestosterone 2-hydroxymethylene-17a methyl -17d-hydrOxy -5et -androstan -3 -one 2-hydroxymeth -ylene-l7 -methylandrostan-17S-ol-3-one anasterone Adroyd Anapolon Anadrol Pardroyd Plenastril Proiana-bol Nastenon Synasteron. C, Hj,03 mol wt 332.47. C 75.86%, H 9.70%, O 14.44%. Anabolic steroid. Prepn Ringold et al., J. Am. Chem Soc. 81, 427 (1959) Ringold, Rosenkranz, Ger, pat. 1,070,632 (1959 to Syntex). 

This was accomplished by conversion of 3 to vinylogous amide 15 (Steroids-4) via intermediate Cg-hydroxymethylene ketone 14. 

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