1214741-21-5

1214741-20-4

1214741-21-5

GENERAL STEPS: To a 500 mL three-necked flask (1) equipped with a stirrer, thermometer, and nitrogen inlet was added (3R,7aR)-3-(tert-butyl)-7a-vinyl dihydro-1H,3H-pyrrolo[1,2-c]oxazole-1,5(6H)-dione (30.0 g, 132 mmol) and tetrahydrofuran (THF, 300 mL). After cooling the mixture to -20 °C, lithium tris(tert-butoxy)aluminum hydride (1 M THF solution, 162 mL) was slowly added over a period of 2 h while maintaining the reaction temperature at about -20 °C. The reaction temperature was then raised to 0 °C and the reaction continued for 12 hours. Ethyl acetate (EtOAc, 12.0 mL) was added over 30 minutes to quench the reaction, followed by stirring at 0 °C for 30 minutes. Next, glacial acetic acid (AcOH, 12.0 mL) was added slowly over 30 minutes. In another 1 L three-necked flask (2) equipped with a stirrer, thermometer and nitrogen inlet, finely ground sodium sulfate decahydrate (30 g, 93 mmol) and THF (150 mL) were added at 0 °C. The reaction mixture in flask (1) was slowly transferred to flask (2) containing sodium sulfate decahydrate solution while maintaining the temperature at 0 °C. The temperature of flask (2) was raised to 20 °C within 1 h and stirred for 1 h at this temperature. The contents of flask (2) were filtered and the wet filter cake was washed three times with THF (180 mL, 120 mL, 120 mL in that order). The filtrates were combined and concentrated under vacuum to about 60 mL. Water (300 mL) was added to another 1000 mL three-neck flask (3) equipped with a stirrer, thermometer and nitrogen inlet. The concentrated mixture from flask (2) was cooled to 5 °C and then water was slowly added under strong stirring over a period of 2 h. The product subsequently precipitated. The slurry was concentrated under vacuum to 450 mL and the solids were separated by filtration. The wet filter cake was dried at 50 °C for 12 h to give 25.1 g (3R,7aR)-3-(tert-butyl)-1-hydroxy-7a-vinyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (compound of formula H) as a white to off-white solid in 83% yield. Melting point: 88°C. 1H-NMR (500 MHz, DMSO-d6) δ 6.92 (d, J = 3.9 Hz, 1H), 6.03 (dd, J = 15.8, 11.1 Hz, 1H), 5.36 (d, J = 3.9 Hz, 1H), 5.24 (d, J = 17.6 Hz, 1H), 5.11 (d, J = 11.1 Hz, 1H) 4.75 (s, 1H), 2.72 (ddd, J = 16.8, 10.2, 8.7 Hz, 1H), 2.28 (ddd, J = 16.7, 10.5, 3.7 Hz, 1H), 2.45 (ddd, J = 12.8, 10.4, 8.9 Hz, 1H), 1.82 (ddd, J = 12.9, 10.5, 3.7 Hz , 1H), 0.85 (s, 9H). 13C-NMR (125 MHz, DMSO-d6) δ 180.7, 142.1, 113.3, 96.2, 93.9, 73.6, 34.5, 33.2, 26.8, 25.9 ppm. LC/MS: Calculated value C12H20NO3 [M+H]+ (m/z) 226.14377, measured value 226.14398.