反应详情

To a 100 mL three-necked flask equipped with a magnetic stir bar, an argon inlet, a thermometer probe and rubber septum, was charged 1-(4-chloro-phenyl)-cyclobutanecarbonitrile (CCBC) (8.0 g, 41.9 mmol (96%)) and CuBr (0.12 g, 2%). After purging the flask with argon for 10 min, MTBE (15 mL) and iBuMgCl (68 mL, 0.61 mol in MTBE) were added and the reaction mixture was refluxed for 4–6 h. The reaction was monitored on HPLC for the disappearance of CCBC. The reaction mixture was cooled to ambient temperature and added drop-wise to the solution of (2S,4R,5S)-4-methyl-5-phenyl-3-(4-methyl phenyl-sulfonyl)-[1,2,3]-oxathiazolidine-2-oxide (15.0 g, 42 mmol) in THF (100 mL) in a 500 mL round-bottomed flask at −78° C. The reaction mixture was stirred for 4 h and warmed up to 10° C. under stirring. The reaction was monitored on TLC for the disappearance of 1-[1-(4-chloro-phenyl)-cyclobutyl]-3-methyl-butylideneamine. Then the reaction mixture was cooled to 0° C. and aqueous ammonium acetate (30%, 50 mL) was added, follows by MTBE (200 mL) and warmed up to ambient temperature. The organic phase was washed with 30% KHCO3 (50 mL) and 20% NaCl (50 mL) and polish filtered through two layers of filter paper. After the resulting organic phase was distilled under reduced pressure to about 50 mL (KF=0.58%), anhydrous THF (80 mL) and Ti(OPri)4 were added and the mixture was stirred at ambient temperature for 1 h and cooled to −45° C. NaBH4 (6.4 g, 168 mmol) was added in one portion and the mixture was stirred for 6 h and warmed up to −20° C. and the reaction was monitored on TLC for the disappearance of starting material. To the reaction mixture was slowly added aqueous HCl dissolved in MeOH (60 mL, 4M) and the mixture was warmed to ambient temperature and stirred for 3 h. After the mixture was cooled to 0° C., NaOH (5 M) was added slowly to pH ˜12 for the solution, the mixture was diluted with toluene (200 mL), and was distilled under reduced pressure to remove the low boiling point solvents. The organic phases were allowed to separate for 20 min and the organic phase was washed twice with aqueous NaCl (50 mL, 20%). The mixture was heated to 60–70° C. and D-tartaric acid (6.3 g) in water (13 ml) and acetone (6 mL) was added slowly. The mixture was distilled under azeotropic condition until the internal temperature reached >95° C. The mixture was then cooled to ambient temperature and stirred for 1 h. The slurry formed was filtered and the wet cake was washed with toluene (30 mL×2) and MTBE (30 mL) and dried at 45° C. for 24 h under reduced pressure to afford the (R)-DDMS.D-TA with 85% yield and 70% ee.

1. customTo a 100 mL three-necked flask equipped with a magnetic stir bar, an argon inlet
2. customAfter purging the flask with argon for 10 min
3. temperaturethe reaction mixture was refluxed for 4–6 h
4. temperaturewarmed up to 10° C.
5. stirringunder stirring
6. temperatureThen the reaction mixture was cooled to 0° C.
7. temperaturewarmed up to ambient temperature
8. washThe organic phase was washed with 30% KHCO3 (50 mL) and 20% NaCl (50 mL)
9. filtrationpolish filtered through two layers of filter paper
10. distillationAfter the resulting organic phase was distilled under reduced pressure to about 50 mL (KF=0.58%), anhydrous THF (80 mL) and Ti(OPri)4
11. additionwere added
12. stirringthe mixture was stirred at ambient temperature for 1 h
13. temperaturecooled to −45° C
14. stirringthe mixture was stirred for 6 h
15. temperaturewarmed up to −20° C.
16. temperaturethe mixture was warmed to ambient temperature
17. stirringstirred for 3 h
18. temperatureAfter the mixture was cooled to 0° C.
19. distillationwas distilled under reduced pressure
20. customto remove the low boiling point solvents
21. customto separate for 20 min
22. washthe organic phase was washed twice with aqueous NaCl (50 mL, 20%)
23. temperatureThe mixture was heated to 60–70° C.
24. additionD-tartaric acid (6.3 g) in water (13 ml) and acetone (6 mL) was added slowly
25. distillationThe mixture was distilled under azeotropic condition until the internal temperature
26. customreached >95° C
27. temperatureThe mixture was then cooled to ambient temperature
28. stirringstirred for 1 h
29. customThe slurry formed
30. filtrationwas filtered
31. washthe wet cake was washed with toluene (30 mL×2) and MTBE (30 mL)
32. customdried at 45° C. for 24 h under reduced pressure