Reacción #87468

Ecuación de reacción

(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

Rendimiento 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

Rendimiento 33.0%

Disolventes

toluene

THF

toluene

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturacooled 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
   Otrowas 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
    OtroThe layers were separated
12. 12
    Extracciónthe aqueous layer was extracted two additional times with ethyl acetate (100 mL)
13. 13
    LavadoThe combined organic layers were washed with brine
14. 14
    Secadodried over sodium sulfate
15. 15
    Filtraciónfiltered
16. 16
    Concentraciónconcentrated under reduced pressure
17. 17
    OtroThe crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (two 120 g silica gel columns)
18. 18
    Lavadoeluting with a gradient of 0 to 30% methanol in dichloromethane

Procedimiento

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).

Fuente