A.
Protection of the 17-hydroxyl group. A solution of
androstanolone ((Note 1), 4.10 g, 14 mmol) in
60 mL of dichloromethane in a
250-mL, one-necked, round-bottomed flask equipped with a
magnetic stirring bar and a
rubber septum bearing two syringe needles (argon inlet and exit) is cooled to −20°C (
refrigerated bath).
Argon is allowed to pass over the surface of the mixture for 15 min and then
boron trifluoride etherate ((Note 2), 0.125 mL, 0.90 mmol) is added rapidly, via syringe, followed by anhydrous
phosphoric acid ((Note 3), 0.053 mL, 1.0 mmol).
Isobutene (Note
4) is added as a gas through a
large-bore syringe needle until approximately 100 mL has condensed. The steroid precipitates during addition of the
isobutene and redissolves as the reaction proceeds. The drying tube is replaced with a
stopper, the tightly sealed flask is allowed to warm to 25°C, and the mixture is stirred at this temperature for 4 hr (Note
5). The flask is cooled to 0°C, opened, and warmed to 25°C to allow excess
isobutene to evaporate. The residue is poured into
2 N aqueous ammonium hydroxide (100 mL) and
ethyl acetate (75 mL) is added. After the layers are vigorously shaken, the aqueous solution is washed with a second portion of
ethyl acetate. The combined organic extracts are washed with saturated
sodium chloride solution, dried over anhydrous
magnesium sulfate, filtered, and concentrated by rotary evaporation. The residue is recrystallized from
hexane to give colorless crystals, mp
146–148°C,
4.10 g (
86%, (Note
6)).
B.
Preparation and reductive cleavage of the vinyl phosphorodiamidate. A
dry, 250-mL flask equipped with
magnetic stirrer,
syringe port (Note
7), and
argon outlet is flushed three times with
argon. To the flask are added
40 mL of dry tetrahydrofuran (THF) and
1.17 mL (8.4 mmol) of dry diisopropylamine (Note
8). The flask is cooled in an
acetone–dry-ice bath while
7.4 mmol of butyllithium in hexane (Note
9) is added dropwise with stirring. After the addition is complete, the solution is allowed to warm for 15 min. The flask is then cooled in an
ice–water bath. To this solution is added
1.61 g (4.6 mmol) of 17β-tert-butoxy-5α-androstan-3-one in 30 mL of 2:1 THF/DMPU (Note
8) solution. The reaction mixture is stirred with ice cooling for 15 min.
N,N,N',N'-Tetramethyldiamidophosphorochloridate, 5.83 mL (0.038 mol) (Note
10), is added dropwise with stirring. After 15 min, the bath is removed; the flask is allowed to warm to 25°C and is stirred for an additional 2 hr. The excess reagent is hydrolyzed by slow addition of
30 mL of saturated aqueous sodium bicarbonate solution and stirring for 30 min. After three extractions with
100-mL portions of diethyl ether, the combined organic layers are washed twice with 100 mL of water and
100 mL of saturated sodium chloride solution. The solution is dried over anhydrous
magnesium sulfate and the
ether is removed under reduced pressure on a
rotary evaporator to afford
2.9–3.0 g of a crude yellow solid (Note
11). The crude
phosphorodiamidate is dissolved in
40 mL of dry THF and added to a
dry, three-necked, 250-mL flask equipped with overhead stirrer,
cold finger condenser (acetone–dry ice), argon bubbler, and acetone–dry-ice bath. Dry
ammonia is distilled into the flask until the
phosphorodiamidate begins to precipitate. The bath is removed and the solution is allowed to warm to reflux. Dry
tert-butyl alcohol (1.75 mL, (Note 12)) is added in one portion. To the clear solution is added 1.5 cm of 1/8-in., cleaned
lithium wire in 0.3-cm portions. The blue color is maintained (by the addition of
lithium wire if necessary) with stirring for 4 hr and then allowing the stirred solution to warm to room temperature overnight.
Sodium benzoate is added in 25-mg portions until the blue color is discharged.
Ammonium chloride (0.50 g) is added in one portion, the condenser removed, and the
ammonia allowed to evaporate. The residue is taken up in
100 mL of diethyl ether and 100 mL of water. The layers are separated and the aqueous phase is extracted with
100 mL of diethyl ether. The combined organic layers are washed with
100 mL of saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and filtered. The
ether is removed under reduced pressure on a rotary evaporator. The crude olefin is filtered through
15 g of silica gel (Note
13) using
benzene–ethyl acetate (2:1) as eluant, to give an off-white solid that is recrystallized from a minimum amount of
absolute ethanol to give, after drying,
1.0 g (
67%) (Note
14) of
17β-tert-butoxy-5α-androst-2-ene, mp
114–117°C (Note
15).