反应详情

To a solution consisting of (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (intermediate 4, 18.5 g, 119 mmol) in dry THF (400 mL) at −75° C. was added lithium diisopropylamide (74.5 mL, 149 mmol, 2 M in heptanes/THF/ethylbenzene from Sigma Aldrich) dropwise over 20 minutes, then stirred for one hour. The reaction mixture was then treated with a solution consisting of N-fluorobenzenesulfonimide (56.6 g, 167 mmol, NFSi, from Oakwood Chemical) in THF (300 mL) with steady addition over 30 minutes, and the resulting mixture was stirred for 16 hours, warming to room temperature. To the reaction mixture was added a saturated aqueous solution of ammonium chloride. The organic material was extracted twice with ethyl acetate. The organic layer was washed with a 50% aqueous solution of sodium chloride, followed by a saturated solution of sodium chloride, and dried over sodium sulfate, filtered, and concentrated. The residue was redissolved in ethyl acetate (200 mL) and treated with heptane (200 mL), causing the formation of a white precipitate. The precipitate was filtered and washed with 50% ethyl acetate in heptane. The combined filtrate was concentrated. The residue was dissolved in ethyl acetate (200 mL) and treated with heptane (200 mL), forming a second precipitate. The second precipitate was filtered and washed with 50% ethyl acetate in heptane. The filtrate was concentrated and the residue (31 g) was purified by silica gel chromatography. Elution with ethyl acetate-hexanes (1:3 v/v) afforded pure samples of each of the two diastereomers of the title compound as tan solids (4.1 g of each) and a portion of mixed diastereomers (3.8 g of an approximately 1:1 ratio). The total mass of the two diastereomer products isolated was 12.0 g (65% total yield).

1. additionThe reaction mixture was then treated with a solution
2. stirringthe resulting mixture was stirred for 16 hours
3. extractionThe organic material was extracted twice with ethyl acetate
4. washThe organic layer was washed with a 50% aqueous solution of sodium chloride
5. dry with materialdried over sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. dissolutionThe residue was redissolved in ethyl acetate (200 mL)
9. additiontreated with heptane (200 mL)
10. filtrationThe precipitate was filtered
11. washwashed with 50% ethyl acetate in heptane
12. concentrationThe combined filtrate was concentrated
13. dissolutionThe residue was dissolved in ethyl acetate (200 mL)
14. additiontreated with heptane (200 mL)
15. customforming a second precipitate
16. filtrationThe second precipitate was filtered
17. washwashed with 50% ethyl acetate in heptane
18. concentrationThe filtrate was concentrated
19. customthe residue (31 g) was purified by silica gel chromatography
20. washElution with ethyl acetate-hexanes (1:3 v/v)