반응 #87488

반응 방정식

(3R,4S,5R,6R)-3,4,5-tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one

n-butyl lithium

hexane

[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane

→

product

수율 33.0%

(2S,3R,4S,5S,6R)-2-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol

수율 33.0%

용매

toluene

THF

toluene

반응 조건

후처리

1. 1
   온도cooled at −78 degrees Celsius under nitrogen
2. 2
   workup.ADDITIONthe addition
3. 3
   workup.WAITAfter 1.5 hours following
4. 4
   workup.ADDITIONthe addition the reaction
5. 5
   기타was quenched at −78 degrees Celsius by the dropwise addition of 5 mL of methanol
6. 6
   workup.ADDITIONcontaining methanesulfonic acid (0.5 mL)
7. 7
   workup.ADDITIONAn additional 4.5 mL of methylsulfonic acid in 50 mL of methanol was added dropwise at room temperature
8. 8
   workup.STIRRINGthe reaction mixture was stirred at room temperature for an additional 24 hours
9. 9
   workup.ADDITIONA solution of saturated aqueous sodium bicarbonate (300 mL) and ethyl acetate (100 mL) were added
10. 10
    workup.STIRRINGthe resulting mixture was stirred for 1 hour
11. 11
    기타The layers were separated
12. 12
    추출the aqueous layer was extracted two additional times with ethyl acetate (100 mL)
13. 13
    세척The combined organic layers were washed with brine
14. 14
    건조dried over sodium sulfate
15. 15
    여과filtered
16. 16
    농축concentrated under reduced pressure
17. 17
    기타The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (two 120 g silica gel columns)
18. 18
    세척eluting with a gradient of 0 to 30% methanol in dichloromethane

실험 절차

A 2.5 M solution of n-butyl lithium in hexane (15 mL, 37.5 mmol) was slowly added to a stirred solution of [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane (12.6 g, 30.6 mmol) in 75 mL of a dry THF (25 mL) and toluene (50 mL) solution cooled at −78 degrees Celsius under nitrogen. After stirring for 30 minutes following the addition, the solution was transferred by cannula to a stirring solution of (3R,4S,5R,6R)-3,4,5-tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one (18.6 g, 40 mmol) in 50 mL of toluene at −78 degrees Celsius. After 1.5 hours following the addition the reaction was quenched at −78 degrees Celsius by the dropwise addition of 5 mL of methanol containing methanesulfonic acid (0.5 mL) and the resulting mixture was allowed to warm to room temperature overnight (˜16 hours). An additional 4.5 mL of methylsulfonic acid in 50 mL of methanol was added dropwise at room temperature and the reaction mixture was stirred at room temperature for an additional 24 hours. A solution of saturated aqueous sodium bicarbonate (300 mL) and ethyl acetate (100 mL) were added and the resulting mixture was stirred for 1 hour. The layers were separated and the aqueous layer was extracted two additional times with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (two 120 g silica gel columns) and eluting with a gradient of 0 to 30% methanol in dichloromethane. 4.2 g (33% yield) of product obtained as an off white solid. LCMS 433 (M+Na+, positive mode). 1H NMR (500 MHz, METHANOL-d4) delta ppm 3.08 (s, 3 H), 3.10 (d, J=9.5 Hz, 1 H), 3.43 (t, J=9.3 Hz, 1 H), 3.60 (ddd, J=9.9, 5.7, 2.0 Hz, 1 H), 3.76 (t, J=9.1 Hz, 1 H), 3.82 (dd, J=12.0, 5.6 Hz, 1 H), 3.94 (dd, J=12.1, 1.8 Hz, 1 H), 3.96-4.10 (m, 2 H), 6.69 (d, J=8.3 Hz, 2 H), 7.02 (d, J=8.3 Hz, 2 H), 7.37 (d, J=8.3 Hz, 1 H), 7.46 (dd, J=8.3, 2.0 Hz, 1 H), 7.54 (d, J=1.7 Hz, 1 H).

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