N-tert-Butoxycarbonyl-l-serine β-lactone and (S)-3-Amino-2-oxetanone p-toluenesulfonic acid salt could be produced through the following synthesis routes.

A. N-(tert-Butoxycarbonyl)-L-serine β-lactone (CAS NO.: ). A 2-L, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, an argon inlet adaptor, a low temperature thermometer, and a rubber septum. The flask is charged with tetrahydrofuran (1.1 L) and triphenylphosphine (42.1 g, 160 mmol). The triphenylphosphine is dissolved with stirring, and the flask is cooled to -78°C with a dry ice-acetone bath maintained at that temperature. Distilled diethyl azodicarboxylate (DEAD) (27.86 g, 160 mmol) is then added dropwise with a syringe over 10 min. The resulting pale yellow solution is stirred at -75°C to -78°C for 10 min, at which point a milky slurry is obtained. The rubber septum on the flask is quickly replaced with a 1-L, pressure-equalizing dropping funnel containing a solution of N-(tert-butoxycarbonyl)-L-serine (32.8 g, 160 mmol) in tetrahydrofuran (240 mL) which is then added dropwise to the mixture over 30 min. After completion of the addition, the mixture is stirred at -75°C to -78°C for 20 min, the cooling bath is removed, and the mixture is slowly warmed with stirring to room temperature over 2.5 hr. The solvent is removed on a rotary evaporator at 35°C. The residual pale yellow syrup is suspended in hexane/ethyl acetate (85/15, 20 mL), slurried, and the solid is removed by filtration. The filtrate is diluted with ethyl acetate (30 mL) to give a solution which is applied to a 10 × 23-cm column of flash silica gel4 (800 g) packed in hexane/ethyl acetate (85/15). The flask and the sides of the column are rinsed with additional ethyl acetate (20 mL), which is added to the column that is then eluted with hexane/ethyl acetate (85/15, 2.7 L). The solvent is changed to hexane/ethyl acetate (7/3) and 500-mL fractions are collected. Concentration of fractions 6–12 on a rotary evaporator gives 12.07 (40%) of pure N-(tert-butoxycarbonyl)-L-serine β-lactone.

B. (S)-3-Amino-2-oxetanone p-toluenesulfonic acid salt (CAS NO.: ). A 500-mL, single-necked, round-bottomed flask is equipped with a magnetic stirring bar and an argon inlet adaptor. The flask is charged with a mixture of N-(tert-butoxycarbonyl)-L-serine β-lactone (14.0 g, 74.8 mmol) and anhydrous p-toluenesulfonic acid (13.5 g, 78.5 mmol). The argon inlet adaptor is replaced with a rubber septum and an argon inlet and the flask is cooled in an ice bath for ca. 15 min. Anhydrous trifluoroacetic acid (200 mL) is added by cannula along the sides of the flask over 20 min (stirring is initiated when possible). The pale yellow solution is stirred at 0°C for 10 min, the trifluoroacetic acid is removed on a rotary evaporator at below 30°C, and the resulting syrup is placed under high vacuum (0.2 mm) for ca. 1 hr. Anhydrous ether (200 mL) is added to the resulting solid, the mixture is triturated to break up lumps, and the suspension is filtered. The solid thus obtained is washed with ether (100 mL), air dried (5 min), and then dried under reduced pressure (0.2 mm) overnight to give 18.4 g (95% yield) of (S)-3-amino-2-oxetanone p-toluenesulfonic acid salt.