反应详情

Flask A: To a clear solution of mono-tert-butyl malonate (29.3 mL, 190 mmol) and magnesium chloride anhydrous (Aldrich; 18.12 g, 190 mmol) in 400 mL THF in a 3 neck 3000 mL RBF with temperature probe and mechanical stirrer at 2° C. was added potassium tert-butoxide (1.0 M solution in THF, Aldrich; 190 mL, 190 mmol) slowly dropwise via addition funnel such that the temperature did not exceed 10° C. The reaction became cloudy over the addition and was easy to stir. the ice bath was removed, and the reaction was stirred at RT for 3 h. Flask B: To a clear solution of Boc-D-alanine (Chem Impex Intl.; 30.0 g, 159 mmol) in 300 mL THF at RT under N2 (fitted with N2 inlet and gas outlet to bubbler) was added 1,1′-carbonyldiimidazole (Aldrich; 0.926 g, 5.71 mmol) in three portions separated by 5 min. Gas evolution observed. The reaction was stirred 3 h. Then the contents in Flask B were added via funnel to Flask A and the cloudy white reaction was stirred 39 h at RT. The resulting white suspension was cooled in an ice bath and 500 mL 1 N HCl was added at a rate such that the internal temperature did not exceed 20° C. 0.8 L Et2O was added and the mixture transferred to a separatory funnel. The layers were separated and the organic layer was washed sequentially with 1×200 mL 1 N HCl, 1×200 mL water, 2×200 mL sat'd aq. NaHCO3, 1×200 mL brine, and was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting clear/colorless oil was treated with small crystals of the desired product and was further concentrated on the rotovap to give a white solid. The material was dried in vacuo for 2 h to give (R)-tert-butyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate (34.3 g, 119 mmol, 75% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 5.15 (1H, br. s.), 4.30-4.51 (1H, m), 3.38-3.58 (2H, m), 1.48 (9H, s), 1.46 (9H, s), 1.37 (3H, d, J=7.2 Hz). m/z (ESI, +ve) 310.1 (M+Na)+.

1. additionslowly dropwise via addition funnel such that the temperature
2. customdid not exceed 10° C
3. additionover the addition
4. customthe ice bath was removed
5. stirringthe reaction was stirred at RT for 3 h
6. customseparated by 5 min
7. stirringThe reaction was stirred 3 h
8. additionThen the contents in Flask B were added via funnel to Flask A
9. customthe cloudy white reaction
10. stirringwas stirred 39 h at RT
11. temperatureThe resulting white suspension was cooled in an ice bath
12. customdid not exceed 20° C
13. customthe mixture transferred to a separatory funnel
14. customThe layers were separated
15. washthe organic layer was washed sequentially with 1×200 mL 1 N HCl, 1×200 mL water, 2×200 mL
16. dry with materialwas dried over anhydrous magnesium sulfate
17. filtrationfiltered
18. concentrationconcentrated in vacuo
19. additionThe resulting clear/colorless oil was treated with small crystals of the desired product
20. concentrationwas further concentrated on the rotovap
21. customto give a white solid
22. customThe material was dried in vacuo for 2 h