tert-butyl (1S,4S)-3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of tert-butyl 3-oxo-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate 8 (1 g, 4.69 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (743 mg, 6.27 mmol) and sodium 2-ethylhexanoate (1.22 g, 7.12 mmol) in water (7 mL) was stirred for 2 days at 50° C. The reaction was acidified with 1N aqueous hydrogen chloride solution, saturated with sodium chloride and stirred with ethyl acetate for 1 hour. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica using a gradient of methylene chloride to a mixtures of methylene chloride and methanol (v:v 19:1) to yield the amide 9 as an off-white solid (763 mg, 55.1%). MS ISN (m/e): 294.3 (100) [(M−H)]+. The organic layer was separated the aqueous layer was extracted with ethyl acetate The combined organic layers were washed with saturated aqueous sodium chloride solution dried over Na2SO4 filtered concentrated under reduced pressure The residue was chromatographed on silica using a gradient of methylene chloride to a mixtures of methylene chloride and methanol (v:v 19:1)

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,4S)-3-Oxo-2-oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester (100.0 g, 469 mmol) was dissolved in ethyl acetate (970 mL) and methanesulfonic acid (43.5 mL, 659 mmol) was added at 45° C. The mixture was stirred for 16 h at 45° C. The suspension was cooled to room temperature, filtered, and the precipitate was washed with ethyl acetate (240 mL) and dried in vacuo to yield the title compound as a white crystalline solid (94.2 g, 96%). MS (EI, neg): m/z=113 [cation-H]+, 69 [cation-H—CO2]+, 68 [cation-H—HCO2]+. 1H NMR (DMSO-d6, 600 MHz): δ 2.12 (dd, J=1.2 Hz, 12.0 Hz, 1H), 2.33 (s, 3H), 2.59 (d, J=12.0 Hz, 1H), 3.33 and 3.50 (ABX, JAB=12.0 Hz, JAX=1.9 Hz, JBX=0 Hz, each 1H), 4.58 (s, 1H), 5.41 (s, 1H), 9.74 (br s, 2H). The suspension was cooled to room temperature filtered the precipitate was washed with ethyl acetate (240 mL) dried in vacuo

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1S,4S)-3-Oxo-2-oxa-5-aza-bicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester (100.0 g, 469 mmol) was dissolved in ethyl acetate (970 mL) and methanesulfonic acid (43.5 mL, 659 mmol) was added at 45° C. The mixture was stirred for 16 h at 45° C. The suspension was cooled to room temperature, filtered, and the precipitate was washed with ethyl acetate (240 mL) and dried in vacuo to yield the title compound as a white crystalline solid (94.2 g, 96%). MS (EI, neg): m/z=113 [cation-H]+, 69 [cation-H—CO2]+, 68 [cation-H—HCO2]+. 1H NMR (DMSO-d6, 600 MHz): δ 2.12 (dd, J=1.2 Hz, 12.0 Hz, 1H), 2.33 (s, 3H), 2.59 (d, J=12.0 Hz, 1H), 3.33 and 3.50 (ABX, JAB=12.0 Hz, JAX=1.9 Hz, JBX=0 Hz, each 1H), 4.58 (s, 1H), 5.41 (s, 1H), 9.74 (br s, 2H). The suspension was cooled to room temperature filtered the precipitate was washed with ethyl acetate (240 mL) dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (100 g, 0.443 mol) and PPh3 (227 g, 0.866 mol) in dry THF (1 L) was added dropwise DEAD (151 g, 0.866 mol) at 0° C. under nitrogen. After the addition, the reaction was allowed to warm up to room temperature and stirred overnight. The reaction was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1˜5:1) which gave the title compound Va as a yellow solid (106.5 g). After the addition The reaction was concentrated in vacuo the residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1˜5:1) which