(R,S)-Mevalonolactone-2-¹³C could be produced through the following synthetic routes.

A. 4-Benzyloxy-2-butanone (CAS NO.: ). A 100-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, a condenser mounted with a nitrogen inlet, and a pressure-equalizing dropping funnel. The flask is charged with 4.40 g (0.050 mol) of 4-hydroxy-2-butanone, 50 mL of dry toluene, and 13.9 g (0.060 mol) of freshly prepared silver oxide. The suspension is stirred and cooled in an ice bath while 12.0 g (0.070 mol) of benzyl bromide is added over ca. 5 min. The ice bath is removed, and the mixture is allowed to stir for 18 hr at room temperature. The suspension is filtered through Celite, the filter cake is washed with two 50-mL portions of toluene, and the combined filtrates are evaporated under reduced pressure. The remaining liquid, which weighs 9.6–10.4 g, is dissolved in 15 mL of 5% tetrahydrofuran in hexane. The cloudy solution is applied to a 5-cm × 47.5-cm column prepared with 380–385 g of silica gel packed in 5% tetrahydrofuran in hexane. The column is eluted with 5% tetrahydrofuran in hexane, and 250-mL fractions are collected and analyzed by TLC. A total of 12 or 13 fractions (3–3.25 L) is collected first to separate benzyl bromide, dibenzyl ether, and other minor by-products. The product is then eluted with 0.5–1.0 L of tetrahydrofuran, the solvent is evaporated, and the remaining 6.0–6.5 g of liquid is distilled under reduced pressure. After separation of a 0.7–1.0 g forerun, bp 30–68°C (0.2 mm), consisting mainly of benzyl alcohol, 3.87–4.33 g (43–49%) of 4-benzyloxy-2-butanone, bp 77–79°C (0.2 mm), nD25 1.5018 is collected.

B. 5-Benzyloxy-3-hydroxy-3-methylpentanoic-2-13C acid (CAS NO.: 57830-65-6). A 50-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, a rubber septum, a condenser connected to a nitrogen inlet, and a pressure-equalizing dropping funnel. The apparatus is purged with nitrogen and dried, and the flask is charged with 1.79 g (2.4 mL, 0.0177 mol) of freshly distilled diisopropylamine and 6.5 mL of dry tetrahydrofuran. The solution is stirred and cooled in an ice bath while 7.22 mL (0.0169 mol) of 2.34 M butyllithium in hexane is added from the dropping funnel over 30 min. After 30 min a solution of 0.439 g (0.00720 mol) of acetic acid-2-13C in 3 mL of tetrahydrofuran is added by syringe over ca. 10 min. The solution is stirred and cooled in an ice bath for 3.5 hr, after which 1.30 g (0.0073 mol) of 4-benzyloxy-2-butanone in 4 mL of tetrahydrofuran is added by syringe over 15 min. Stirring is continued for 2 hr at 0°C and 18 hr at room temperature. The reaction mixture is cooled in an ice bath, hydrolyzed by adding 4.5 mL of water, and concentrated under reduced pressure to remove most of the tetrahydrofuran. The remaining aqueous suspension is basified by addition of 6 mL of aqueous 4% sodium hydroxide and extracted with 30 mL of diethyl ether. The ethereal layer is extracted with 40 mL of 4% sodium hydroxide, the combined alkaline extracts are cooled and acidified to pH 3 with ca. 10 mL of 18% hydrochloric acid, and the aqueous mixture is extracted with three 25-mL portions of ether. The combined ethereal extracts are dried over anhydrous sodium sulfate and evaporated. The remaining viscous, yellow liquid weighs 0.95–1.01 g (55–59%) and is used in part C without further purification.

C. Mevalonolactone-2-¹³C. In a 250-mL Parr hydrogenation bottle are placed 50 mL of 95% ethanol, 0.107 g (0.001 mol) of palladium black, and 0.519 g (0.00217 mol) of 5-benzyloxy-3-hydroxy-3-methylpentanoic acid-2-13C. The bottle is attached to a Parr hydrogenation apparatus, charged to 50 psig with hydrogen and shaken at room temperature for 2 hr. The hydrogen is flushed from the bottle with nitrogen, and the suspension is filtered by gravity through a layer of Celite with a medium-porosity sintered-glass Büchner funnel to separate the catalyst. The palladium is pyrophoric and must always be kept wet with ethanol during filtration to prevent contact with air. The bed of Celite and adhering catalyst is rinsed with three 5-mL portions of ethanol. The combined filtrates are returned to the Parr bottle, 0.107 g (0.001 mol) of fresh palladium black is added, and the hydrogenation is continued for another 8 hr. The catalyst is separated by filtration as previously described, and the combined filtrates are evaporated under reduced pressure. Distillation of the residual liquid with a Kugelrohr apparatus at 90–100°C and 0.01 mm affords 0.235–0.249 g (83–88%) of mevalonolactone-2-¹³C as a slightly yellow oil.

Notice: Benzyl bromide is a lachrymator. This procedure should be conducted in a ventilated hood.