A. 16-Oximinoandrost-5-en-3β-ol-17-one. A 2-l., three-necked, round-bottomed flask fitted with a reflux condenser, a mechanical stirrer, and a pressure-equalizing dropping funnel is charged with 750 ml. of anhydrous tert-butyl alcohol (Note 1). As the tert-butyl alcohol is slowly stirred, a stream of dry nitrogen is passed through the flask and 12.2 g. (0.312 g.-atom) of potassium metal is added cautiously. The flask is surrounded by a water bath maintained at 70° to assist in dissolving the potassium metal. After 1.5 hours the stirred mixture is homogeneous, the water bath is removed, and the reaction mixture is allowed to cool to room temperature. To the potassium tert-butoxide solution is slowly added 45.0 g. (0.156 mole) of dehydroisoandrosterone (Note 2), and stirring is continued for one hour until the gold-colored mixture is again homogeneous. To the reaction mixture is now added, dropwise, 36.5 g. (42.0 ml., 0.312 mole) of isoamyl nitrite (Note 3), and stirring is continued overnight at room temperature.

The deep-orange reaction mixture is diluted with an equal volume of water, poured into a 2-l. separatory funnel, and acidified with 3 M hydrochloric acid. The addition of 400 ml. of diethyl ether assists in effecting the separation of the clear, yellow, aqueous, lower layer from the fluffy-white ethereal suspension that forms the upper layer. This suspension is filtered through a 250-ml. coarse sintered glass funnel, and the precipitate of oximino ketone is washed with ether several times. After drying overnight in a vacuum desiccator at −5°, 48.0–48.5 g. (79% (Note 5) and (Note 6)) of a white product, m.p. 245–247° (dec.), is obtained; its ¹H NMR spectrum (pyridine) shows it to be a 1:1 solvate of the oximino ketone with tert-butyl alcohol (Note 4). This product is used without further purification in the synthesis of the α-diazo ketone (Note 7).

B. 16-Diazoandrost-5-en-3β-ol-17-one. A 1-l., three-necked, round-bottomed flask is fitted with a mechanical stirrer, a 50-ml., pressure-equalizing dropping funnel, and a thermometer. As stirring is initiated, 375 ml. of methanol and 72 ml. of 5.0 M aqueous sodium hydroxide (0.36 mole) is added to the flask, followed by 18.0 g. (0.0460 mole) of the 1:1 solvate of 16-oximinoandrost-5-en-3β-ol-17-one with tert-butyl alcohol. The oximino ketone readily dissolves, giving a yellow solution. To the reaction mixture is added 28.3 ml. of concentrated aqueous ammonia (0.425 mole), and the flask is surrounded by an ice bath, maintaining the reaction temperature at 20°. Through the dropping funnel 133 ml. of 3.0 M aqueous sodium hypochlorite (0.40 mole) is added dropwise. The sodium hypochlorite solution should be kept near 0°; 25-ml. portions should be added to the addition funnel and the remaining solution should be kept in an ice bath (Note 8). It is important that the rate of addition of the sodium hypochlorite, and the position of the ice bath be adjusted so as to maintain the temperature of the reaction mixture at 20° ± 1° (Note 9). As soon as all of the sodium hypochlorite has been added, the ice bath is removed, and the reaction mixture is allowed to warm to room temperature and stirred for 6 hours.

The reaction mixture is diluted with an equal volume of water and extracted with 400-ml. and 200-ml. portions of dichloromethane. The combined dichloromethane extracts are washed with three 250-ml. portions of 20% aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated, leaving a yellow solid. Recrystallization from acetone gives 8.0–9.3 g. (55–64%) of crystalline α-diazo ketone, m.p. 200–202° (dec.) (Note 10).

C. D-Norandrost-5-en-3β-ol-16α- and 16β-carboxylic acids. In a solution of 500 ml. of 1,4-dioxane, 1250 ml. of ether, and 250 ml. of water contained in a 3-l. three-necked, round-bottomed flask is dissolved 7.50 g. (0.0239 mole) of 16-diazoandrost-5-en-3β-ol-17-one. The flask is fitted with a reflux condenser, a quartz immersion well, and a nitrogen inlet. After the reaction vessel has been flushed with nitrogen, the diazo ketone solution is irradiated for 48 hours with a 450-watt Hanovia lamp with a Corex filter (Note 11). The photolysis mixture is decanted in portions into a 2-l. separatory funnel, washed three times with 500-ml. portions of water, removing the dioxane, and dried over magnesium sulfate. The ether is evaporated, leaving a pale-yellow residue. The residue is digested with 125 ml. of boiling dichloromethane under reflux for 30 minutes. The dichloromethane solution is allowed to cool to room temperature and filtered, separating about 1.4 g. of the crude α-isomer as a white powder. This solid is recrystallized by dissolving it in a large volume of methanol (125 ml.) and concentrating the solution to a small volume (25 ml.), yielding 1.2 g. (17%) of D-norandrost-5-en-3β-ol-16α-carboxylic acid as a white solid, m.p. 271–274° (Note 12). The β-isomer is most readily obtained by concentrating the dichloromethane mother liquor and dissolving the residue in a mixture of 75 ml. of methanol and 25 ml. of ether. This solution is treated with an excess of diazomethane in ether at room temperature. After one hour at room temperature, the excess diazomethane is removed with a stream of nitrogen, the solvent is evaporated, and the solid residue is chromatographed on 175 g. of Woelm neutral alumina Activity Grade II. Elution with a 3:1 (v/v) benzene–ether mixture gives 3.9 g. of a white solid, which is recrystallized from ether-heptane, giving 3.0–3.1 g. (39–41%) of white, crystalline methyl D-norandrost-5-en-3β-ol-16β-carboxylate, m.p. 161–163° (Note 13) and (Note 14).