Reaction #87499

Reaction equation

water

dichloromethane

acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester

N-bromosuccinimide

→

acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-{4-chloro-3-[(4-ethoxy-phenyl)-hydroxy-methyl]-phenyl}6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester

Yield 89.4%

Solvents

carbon tetrachloride

Conditions

Workup

1. 1
   Temperaturethe reaction mixture was heated
2. 2
   Temperatureat reflux under nitrogen
3. 3
   OtherThe layers were separated
4. 4
   Extractionthe aqueous layer was extracted two additional times with dichloromethane (25 mL)
5. 5
   WashThe combined organic layers were washed with brine (20 mL)
6. 6
   Dryingdried over magnesium sulfate
7. 7
   Filtrationfiltered through a pad of celite
8. 8
   Concentrationconcentrated under reduced pressure
9. 9
   OtherThe crude material was chromatographed with the Biotage SP4 automated chromatography unit (SNAP 25 g silica gel column)
10. 10
    Washeluting with a gradient of 0-80% ethyl acetate in heptane

Procedure

To a solution of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester (Example 2; 344 mg, 0.569 mmol) in carbon tetrachloride (8 mL) was added N-bromosuccinimide (159 mg, 0.893 mmol) followed by the addition of 2,2′-azobisisobutyronitrile (AIBN, 8 mg, 0.05 mmol) and the reaction mixture was heated at reflux under nitrogen. After 16 hours, the reaction mixture was cooled to room temperature, water (50 mL) and dichloromethane (25 mL) were added and the resulting mixture was stirred for 24 hours at room temperature. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane (25 mL). The combined organic layers were washed with brine (20 mL), dried over magnesium sulfate, filtered through a pad of celite, and concentrated under reduced pressure. The crude material was chromatographed with the Biotage SP4 automated chromatography unit (SNAP 25 g silica gel column) eluting with a gradient of 0-80% ethyl acetate in heptane to produce 316 mg (89% yield) of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-{4-chloro-3-[(4-ethoxy-phenyl)-hydroxy-methyl]-phenyl}6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester as a mixture of diastereoisomers at the bis-benzylic position.

Source