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3 beta,16 alpha,19-Trihydroxy-5-androsten-17-one and 16 alpha,17-dihydroxy-4-androstene-3,17-dione were synthesized from the 5 alpha-bromo-6 beta,19-epoxy-17-ketone derivative 1, using the bromination at C-16 alpha of the 17-ketone 1 and the controlled alkaline hydrolysis of the 16 alpha-bromo-17-ketones 2 and 11 as key reactions. Zinc dust reductive cleavage of the 6 beta,19-epoxy-16 alpha-hydroxy-17-ketones 4 and 12, produced by controlled hydrolysis, gave the corresponding 19-alcohol derivatives 6 and 14, which were rearranged to the 17 beta-hydroxy-16-ketones 7 and 15 when treated with sodium hydroxide. The 3 beta,16 alpha,17 beta,19-tetrol 8 was obtained from the 16 alpha-ketol 6 by reaction with sodium borohydride.

Reaction of the 3-oxo-4-androsten-derivative 1 or 4 with 1.2eq of o-iodosylbenzoic acid in methanolic KOH gave the methoxy products, the 4-methoxide 2 or 5 and the 6β-methoxide 3 or 6, along with the dehydrated compound, the 4, 6-dienone 7 or 8, respectively. Treatment of the 6-methoxide 3 or 6 with trimethylsilyl iodide yielded the 5α-androstane-3, 6-dioxo derivative 11 or 12 in high yield. The same hypervalent oxidation of the 17-oxo steroid 15, 18, 21 or 24 using excess iodine and a longer reaction time produced the corresponding 16α-hydroxy-17, 17-dimethylacetal 16, 19, 22 or 25, which was converted into the 16α-hydroxy-17-one 17, 20, 23 or 26 by treatment with diluted HCl in every case.

Synthesis of 1, 3, 5 (10)-estratriene-3, 16α, 17β-triol-d6 and -d7 (4), 3, 16α-dihydroxy-1, 3, 5 (10)-estratrien-17-one-d5 (5) and sodium 3, 17β-dihydroxy-1, 3, 5 (10)-estratrien-16α-yl-β-D-glucopyranosuronate-d6 (8) is described. Treatment of 2, 4, 16α-tribromo-3-hydroxy-1, 3, 5 (10)-estratrien-17-one (1) with sodium hydroxide-OD in deuterium oxide-pyridine under controlled conditions gave the [16β-2H] 16α-hydroxy-17-one (2). The ketol 2 was converted into the triol-d6 (4) via sodium borodeuteride reduction in the presence of palladium chloride. Similar treatment of the 17-ethyleneacetal of 2 followed by acid hydrolysis gave compound 5-d5. Reaction of 2 with methyl 1-bromo-1-deoxy-2, 3, 4-tri-O-acetyl-α-D-glucopyranosuronate using silver carbonate as a catalyst yielded the 16-monoglucuronide acetate methyl ester (6). The reductive removal of the bromines of 6 and subsequent alkaline hydrolysis gave the glucuronide-d6 (8). Mass spectrometric analysis showed compounds 4, 5, and 8 to have good isotopic purity.

16α-Hydroxy-4-androstene-3, 17-dione-d5 (4) and 3β, 16α-dihydroxy-5-androsten-17-one-d6 (10) were synthesized. Treatment of 16α-bromo-5-androstene-3, 17-dione (2) with deuterium oxide and methanol-OD gave the 4-en-3-oxo derivative-d 3. The bromide 3 was converted into the 16α-hydroxide-d5 4 via controlled alkaline hydrolysis using sodium hydroxide-OD in deuterium oxide-pyridine. 3β-Hydroxy-5-androsten-17-one-d5 (8), which was obtained from 17, 17-ethylenedioxy-5-androsten-3-one (5) via treatment with potassium tert-butoxide in tert-butanol-OD, followed by lithium aluminum tri-tert-butoxydeuteride reduction and then acid hydrolysis, was derivatized to the 16α-bromide 9 by treatment with cupric bromide. The bromide 9 was similarly hydrolyzed to yield the 16α-hydroxide-d6 10.

Epimerizations of 16 alpha-chloro- (1a), bromo- (1b), and iodo-3 beta-hydroxy-5-androsten-17-one (1c) by a brief treatment with 0.2 equiv NaOH in aqueous pyridine reached equilibrium between 16 alpha- and 16 beta-halo ketones. 16 alpha-/16 beta-Halo ketone ratios at equilibrium were 1.5 for Cl, 1.25 for Br, and 1.0 for I. Kinetic analysis showed that compounds 1a-c were stereoselectively converted to the corresponding 16 alpha-hydroxy derivative 3 by an SN2 mechanism, in which the order of the apparent reactivity was Br greater than I greater than Cl. The hydrolysis of a number of 16 alpha-bromo-17-ketones and 2 alpha-bromo-3-ketones was carried out. The yields of the corresponding alcohols were found to depend on remote structural features in the steroids.

Le deplacement SN 2 direct du brome par des nucleophiles soufres est possible dans les α-bromocetones sans epimerisation anterieure des bromocetones

Reaction of androst-4-ene-3,17-dione (1) with o-iodosylbenzoic acid in methanolic potassium hydroxide gave the methoxylated products, the 4- and 6β-methoxides (2) and (3), along with the dehydrogenated compound, the 4,6-dienone (4).

Reaction of the 3-oxo-4-androsten-derivative 1 or 4 with 1.2eq of o-iodosylbenzoic acid in methanolic KOH gave the methoxy products, the 4-methoxide 2 or 5 and the 6β-methoxide 3 or 6, along with the dehydrated compound, the 4, 6-dienone 7 or 8, respectively. Treatment of the 6-methoxide 3 or 6 with trimethylsilyl iodide yielded the 5α-androstane-3, 6-dioxo derivative 11 or 12 in high yield. The same hypervalent oxidation of the 17-oxo steroid 15, 18, 21 or 24 using excess iodine and a longer reaction time produced the corresponding 16α-hydroxy-17, 17-dimethylacetal 16, 19, 22 or 25, which was converted into the 16α-hydroxy-17-one 17, 20, 23 or 26 by treatment with diluted HCl in every case.

Reaction of androst-4-ene-3,17-dione (1) with o-iodosylbenzoic acid in methanolic potassium hydroxide gave the methoxylated products, the 4- and 6β-methoxides (2) and (3), along with the dehydrogenated compound, the 4,6-dienone (4).