反应详情

To a solution of 4-bromo-1-chloro-2-(4-(2-(cyclopentyloxy)ethoxy)benzyl)benzene (Intermediate AC) (0.41 g) in anhydrous toluene/THF (v/v=2:1, 10 mL), n-BuLi (1.3 eq) was added dropwise at −78° C. and stirred for 1 h. Then the mixture was transferred to a solution of 2,3,4,6-tetra-O-trimethylsilyl-β-D-glucolactone (also called (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-((trimethylsilyloxy)methyl)tetrahydro-2H-pyran-2-one) (1.5 eq) in anhydrous toluene (10 mL) at −78° C. The mixture was stirred at −78° C. for 2 h until starting material was consumed. The reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH), and the mixture was allowed to warm to room temperature and stirred overnight. Then 20 mL of water was added. The organic phase was separated, and the water phase was extracted with EtOAc. The organic phases were combined, washed with saturated NaHCO3, water and brine, and then dried with anhydrous Na2SO4, filtered and concentrated. The residue was purified on a flash column (0.8 g, Rf=0.1-0.2, EA:PE=2:1) to collect the crude product. The crude product was dissolved in anhydrous CH3CN (10 mL), Et3SiH (1 mL) was added, the mixture was cooled to −5° C., and BF3.Et2O (0.6 mL) was added dropwise. Then the reaction was allowed to warm to 20° C. and stirred overnight. After the reaction reached completion, it was quenched with saturated aqueous NaHCO3. The solvent was removed under reduced pressure and the residue was extracted with EtOAc and washed with water and brine. The product was dried with anhydrous Na2SO4, filtered, concentrated to a solid, and purified by preparative HPLC to obtain compound AD as a white powder upon freeze-drying. 1H NMR (CD3OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 4.07 (m, 5H), 3.87 (s, 1H), 3.71 (m, 3H), 3.15 (m, 1H), 3.10 (m, 2H), 3.07 (m, 6H), 1.72 (m, 6H), 1.55 (m, 2H); MS ESI (m/z): 494 (M+H)+, calc. 493.

1. customat −78° C
2. stirringThe mixture was stirred at −78° C. for 2 h
3. customwas consumed
4. customThe reaction was quenched with methanesulfonic acid (0.3 g in 10 mL MeOH)
5. stirringstirred overnight
6. additionThen 20 mL of water was added
7. customThe organic phase was separated
8. extractionthe water phase was extracted with EtOAc
9. washwashed with saturated NaHCO3, water and brine
10. dry with materialdried with anhydrous Na2SO4
11. filtrationfiltered
12. concentrationconcentrated
13. customThe residue was purified on a flash column (0.8 g, Rf=0.1-0.2, EA:PE=2:1)
14. customto collect the crude product
15. dissolutionThe crude product was dissolved in anhydrous CH3CN (10 mL)
16. additionEt3SiH (1 mL) was added
17. temperaturethe mixture was cooled to −5° C.
18. additionBF3.Et2O (0.6 mL) was added dropwise
19. temperatureto warm to 20° C.
20. stirringstirred overnight
21. customwas quenched with saturated aqueous NaHCO3
22. customThe solvent was removed under reduced pressure
23. extractionthe residue was extracted with EtOAc
24. washwashed with water and brine
25. dry with materialThe product was dried with anhydrous Na2SO4
26. filtrationfiltered
27. concentrationconcentrated to a solid
28. custompurified by preparative HPLC
29. customto obtain compound AD as a white powder
30. customupon freeze-drying