A. 3β-Acetoxy-20β-hydroxy-5-pregnene. In a 2-l. five-necked flask fitted with a mechanical stirrer, 250-ml. dropping funnel, thermometer, nitrogen-inlet tube, and reflux condenser with calcium chloride tube is placed 750 ml. of anhydrous tetrahydrofuran (Note 1). The vessel is flushed with nitrogen, and 101.6 g. (0.4 mole) of lithium aluminum tri-t-butoxyhydride² (Note 2) is added. The suspension is cooled to about 2°, and 71.7 g. (0.2 mole) of pregnenolone acetate (Note 3) is added in one portion while stirring, the particles adhering to the wall of the flask being rinsed into the solution with an additional 50 ml. of tetrahydrofuran. The reaction mixture is stirred at 0–5° for 6 hours. A solution of 100 g. of ammonium sulfate in 150 ml. of water is added, with stirring, over a 15–20 minute period through the dropping funnel, the temperature of the reaction mixture being kept below 10° by efficient cooling with ice. A considerable quantity of hydrogen is evolved. There is added 20 g. of filter aid (Celite^® or Hyflo Supercel^®), the mixture is stirred for another 30 minutes, and it is finally filtered with suction through a layer of filter aid. The reaction vessel is rinsed and the filter residue thoroughly washed with 1.5 l. of tetrahydrofuran (Note 4). The filtrate is evaporated to dryness under reduced pressure. The crystalline residue is dissolved in 750 ml. of hot acetone, filtered (if necessary), and the solution is concentrated to a volume of about 200 ml. (crystallization may begin during this evaporation). The flask is kept overnight at 0° to −10° and the product isolated by suction filtration. The crystals are washed with 75 ml. of ice-cold acetone and dried at 60°. The yield of the product is 54–57 g. (75–79%), m.p. 161–164°,³ [α]²⁵D −74° (c 1.0, CHCl₃) (Note 5).

B. 3β-Acetoxy-18-iodo- and 18-hydroxy-18,20β-oxido-5-pregnene. In a 5-l. three-necked flask fitted with a mechanical stirrer, a thermometer, and a reflux condenser are placed 3 l. of cyclohexane (Note 6), 180 g. (ca. 0.37 mole) of commercial lead tetraacetate containing approximately 10% acetic acid (Note 7), 24 g. (0.095 mole) of iodine and 30 g. (0.083 mole) of 3β-acetoxy-20β-hydroxy-5-pregnene. The reaction mixture is stirred and heated to the boiling point by irradiation with a 1000-watt lamp (Note 8) from underneath. When the iodine color has disappeared (usually after about 60–90 minutes) (Note 9), the reaction mixture is cooled to room temperature, filtered with suction, and the filter residue with 600 ml. of cyclohexane. The filtrate is washed with two 500-ml. portions of 5% sodium thiosulfate solution and then with water. The combined aqueous solutions are extracted once with 500 ml. of ether. To the combined organic layers is added 6 ml. of pyridine, the solution is dried over sodium sulfate, filtered (Note 10), and the solvent evaporated under reduced pressure at a bath temperature of 35–40° (preferably by using a rotary evaporator). About 60 g. of an oily residue (Note 11), which is immediately oxidized (Note 12), is obtained.

C. Oxidation to the 18,20-lactone of 3β-acetoxy-20β-hydroxy-5-pregnene-18-oic acid. The above residue is dissolved in 600 ml. of acetone (Note 13), the solution is transferred to a 3-l. three-necked flask with a rigid mechanical stirrer, a dropping funnel, and a thermometer; the evaporation flask is rinsed with an additional 120 ml. of acetone. The solution is cooled to 0° to +5°, and 38.4 ml. of a chromic acid solution⁴ (prepared by mixing 13.3 g. of chromium trioxide and 11.5 ml. of concentrated sulfuric acid and carefully diluting the mixture to 50.0 ml. with water while cooling) is slowly added within 10 minutes from the dropping funnel. The mixture is stirred (Note 14) for another 30 minutes at 0° to +5°, and a solution of 270 g. of crystalline sodium acetate in 780 ml. of water is added. The dark green solution is transferred to a separatory funnel, and it is extracted once with 2.4 l. and once with 600 ml. of benzene. Each extract is washed twice with 600 ml. of half-saturated sodium chloride solution, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The combined semisolid residue (48–50 g.) is triturated with 50 ml. of ether and kept overnight at 0° to −10°. The crude product is filtered, and the filter residue is washed with pentane. The yield of crystalline lactone is 14–16 g. (45–52% based on pure 3β-acetoxy-20β-hydroxy-5-pregnene). For further purification the product is dissolved in 200 ml. of hot acetone, if necessary 250 mg. of charcoal is added, the mixture is brought to the boiling point on a steam bath, filtered through a layer of filter aid, and the filter residue is washed with warm acetone. The solution is concentrated on the steam bath to a volume of about 90 ml. During this operation, crystallization begins. Then 150 ml. of hexane is added. the mixture is again concentrated to a volume of about 50–80 ml. with swirling, and finally kept at 0° overnight. A first crop of 12.0–13.5 g. (39–43%) of pure lactone, m.p. 201–206°, is obtained, [α]²⁵D −44° to −45° (c 1.0, CHCl₃). Concentration of the mother liquor yields a second crop of 0.3–2.7 g. of less pure lactone.