(2R,4R)-4-Hydroxypyrrolidine-2-carboxylic acid hydrochloride (0.50 g, 3.0 mmol) was dissolved in 6 mL of THF/H2O (2:1) mixed solvent, followed by the addition of 10% NaOH aqueous solution (1.25 mL) for neutralization. Next, di-tert-butyl dicarbonate (0.95 g, 4.42 mmol) was added to the reaction system. The reaction mixture was stirred at room temperature overnight and then the THF was removed by rotary evaporator.The residue was adjusted to pH 2 with 10% aqueous KHSO4 solution and then extracted with ethyl acetate several times. The organic phases were combined, washed sequentially with water and saturated saline and dried over anhydrous Na2SO4. The solvent was concentrated under reduced pressure to give (2R,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (542 mg, 78%) as a slurry, which was used directly in the next step of the reaction. [α]D25 = +15.3 (c 1.02, MeOH). IR (thin film method): νmax 3462, 2976, 2934, 1740, 1639 cm1. 1H NMR (400 MHz, CDCl3) δ 7.22 (br s, 1H), 5.11-5.09 (m, 2H), 4.94-4.93 (m, 1H) , 4.40 (s, 1H), 3.64-3.62 (m, 1H), 3.49-3.44 (m, 2H), 2.27-1.90 (s, 9H).13C NMR (100 MHz, CDCl3) δ 172.47, 151.74, 75.81, 67.15, 55.24, 52.27, 35.97, 25.63 ppm. HRMS (ESI): m/z [M + H]+ calcd for C10H18NO5 232.1185; found 232.1171.
