General procedure for the synthesis of (2R)-2,4-morpholine dicarboxylic acid 4-tert-butyl ester from (R)-N-Boc-2-hydroxymethylmorpholine: Saturated aqueous NaHCO3 (15 mL) was added to a solution of tert-butyl (R)-2-(hydroxymethyl)-morpholine-4-carboxylate (1.09 g, 5.0 mmol) in acetone (50 mL) at 0 °C with continuous stirring. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were subsequently added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was slowly added dropwise over a period of 20 min at 0 °C. After the dropwise addition, the reaction mixture was slowly warmed to room temperature and stirred overnight. After the reaction was completed, 2-propanol (3 mL) was added and stirring was continued for 30 minutes at room temperature. The reaction solution was filtered through a diatomaceous earth pad and the filtrate was concentrated under reduced pressure. The concentrate was treated with saturated aqueous Na2CO3 (15 mL), and the aqueous phase was washed with EtOAc (5 mL), acidified with 6N HCl, and extracted with EtOAc (5 x 10 mL). The organic layers were combined, dried with Na2SO4 and the solvent was removed under reduced pressure to afford (R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.07 g, 92% yield) as a white solid. The product was confirmed by 1H NMR (400 MHz, CDCl3): δ 4.20 (br, 1H), 4.12 (d, 1H), 4.02 (d, 1H), 3.84 (m, 1H), 3.62 (m, 1H), 3.04 (m, 2H), 1.44 (s, 9H); Mass Spectrometry (MS) m/z 232 (M+H+).
