A. Diethyl 5-methylcoprost-3-en-3-yl phosphate. A dry, 100-ml., three-necked flask equipped with a magnetic stirring bar, a pressure-equalizing dropping funnel, a nitrogen inlet tube, and a rubber septum is charged with 384 mg. (0.00201 mole) of copper(I) iodide (Note 1) and 20 ml. of anhydrous diethyl ether (Note 2). After the reaction vessel has been flushed with nitrogen, a static oxygen-free nitrogen atmosphere is maintained in the reaction vessel throughout the remainder of the reaction. The reaction mixture is cooled in an ice bath and an ether solution, containing 0.0040 mole of methyllithium (Note 3), is added with a hypodermic syringe, dropwise and with stirring. As the methyllithium is added, the initial yellow precipitate of polymeric methylcopper(I) redissolves, forming a colorless to pale-yellow solution of lithium dimethylcuprate (Note 4). To the resulting cold solution is added, dropwise and with stirring over 20 minutes, a solution of 576 mg. (0.00150 mole) of cholest-4-en-3-one (Note 5) in 20 ml. of ether (Note 2). During the addition of the enone, a yellow precipitate of polymeric methylcopper(I) separates from the reaction solution. After the addition is complete, the cooling bath is removed, and the reaction mixture is stirred for 2 hours at room temperature. The dropping funnel is replaced with a second dry dropping funnel which contains a loose plug of glass wool above the stopcock. The reaction mixture is again cooled in an ice bath and a mixture of 4.0 ml. of triethylamine (Note 6) and 2.00 g. (0.0115 mole) of diethyl phosphorochloridate (Note 7) is added from the dropping funnel to the reaction mixture, rapidly and with stirring. After this addition, the cooling bath is removed, and stirring is continued for one hour. Saturated aqueous sodium hydrogen carbonate is added to hydrolyze any remaining organometallic reagents before the reaction mixture is transferred to a separatory funnel and washed successively with two 50-ml. portions of cold (0°) 1 M ammonium hydroxide and a 50-ml. portion of water. The aqueous washes are extracted in turn with a 30-ml. portion of ether. The combined ether solutions are dried over anhydrous sodium sulfate and concentrated with a rotary evaporator. A solution of the residual liquid in 3 ml. of ether is applied to a 2.5 cm. by 15 cm. chromatographic column packed with a slurry of 50 g. of silica gel (Note 8) in ether. The column is eluted with ether. After the first 70 ml. of eluent has been collected and discarded, the next 120 ml. of ether eluent is collected and concentrated with a rotary evaporator, yielding 420–480 mg. of crude phosphate ester (Note 9), a colorless liquid, sufficiently pure for use in the following procedure.

B. 5-Methylcoprost-3-ene. A dry, 100-ml., three-necked flask equipped with a polyethylene-coated magnetic stirring bar, two gas-inlet tubes, and a pressure-equalizing dropping funnel is immersed in a 2-propanol–dry ice cooling bath maintained at −15° to −20°. The reaction vessel is flushed with either helium or argon, and a static atmosphere of one of these gases is maintained in the reaction vessel throughout the reaction. Ethylamine (Note 10) is distilled through a tower of sodium hydroxide pellets into the cold reaction flask until 50 ml. of the liquid amine has been collected. A 70-mg. (0.010 g.-atom) piece of lithium wire is cleaned by dipping it successively into methanol and pentane and added to the reaction flask. The resulting cold (−15°) mixture is stirred for 10 minutes to dissolve the lithium before a solution of the diethyl 5-methylcoprost-3-en-3-yl phosphate and 0.50 ml. (0.39 g., 0.0053 mole) of tert-butyl alcohol (Note 11) in 15 ml. of tetrahydrofuran (Note 2) is added, dropwise and with stirring over 15 minutes, to the cold, blue lithium–amine solution. The blue solution is stirred for an additional 15 minutes before 1 ml. of saturated ammonium chloride is added to consume excess lithium. The resulting colorless mixture is warmed, evaporating ethylamine, and the residue is diluted with 90 ml. of 10% aqueous sodium hydroxide and extracted with two 30-ml. portions of pentane. The combined organic solutions are washed with 50 ml. of aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated with a rotary evaporator. The residual, viscous liquid is subjected to evaporative distillation, from a 25-ml. flask into a male 14–20 standard-taper glass joint as shown in Figure 1. The air bath is heated to 150–180° while the pressure in the system is maintained at 0.05 mm. to 0.4 mm. Distillation of 5-methylcoprost-3-ene yields 260–295 mg. (45–51%) of colorless liquid, n²⁵D 1.5115–1.5123 (Note 12).