反应详情

n-Butyl lithium (1.0 mL, 2.5 M/hexanes, 3.1 equivalents) was added dropwise (1 drop every 5 seconds) to an oxygen degassed solution (placed in a pre dried Biotage™ microwave vial 10-20 mL sealed with its cap and placed under a positive stream of nitrogen gas) of 4-Bromo-2-(4-chloro-benzyl)-1-fluoro-benzene (702 mg, 2.9 equivalents) in anhydrous tetrahydrofuran (3.0 mL) at −78° C. and the resulting solution was stirred at this temperature for 25 minutes. A solution of (2R,3S,4S)-2,3,4-tris-benzyloxy-5-hydroxy-6-(4-methoxy-benzyloxy)-5-(4-methoxy-benzyloxymethyl)-hexanoic acid methoxy-methyl-amide (I-1g) (621 mg) in anhydrous tetrahydrofuran (1.5 mL) was then added dropwise using a syringe pump (0.9 mL/hour) and the resulting mixture was stirred at low temperature for an additional 17 hours (placed in a deep Dewar covered with aluminum foil to maintain cold temperature; size of Dewar: external diameter 10 cm, internal diameter 8 cm, height 9 cm). The reaction was quenched by dropwise addition of aqueous 1M hydrochloric acid solution (1.5 mL). The resulting biphasic mixture was stirred at room temperature for 30 minutes. The mixture was diluted with saturated aqueous ammonium chloride (15 mL) and was extracted with ethyl acetate (15 mL×3). The combined organic solution was washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated. Chromatography over silica gel using a gradient of 10 to 40% ethyl acetate in heptane gave the product as a mixture of isomers (477 mg, 64% yield).

1. customdried Biotage™ microwave vial 10-20 mL
2. customsealed with its
3. customcap
4. customat −78° C.
5. stirringthe resulting mixture was stirred at low temperature for an additional 17 hours (
6. temperatureto maintain cold temperature
7. customThe reaction was quenched by dropwise addition of aqueous 1M hydrochloric acid solution (1.5 mL)
8. stirringThe resulting biphasic mixture was stirred at room temperature for 30 minutes
9. additionThe mixture was diluted with saturated aqueous ammonium chloride (15 mL)
10. extractionwas extracted with ethyl acetate (15 mL×3)
11. washThe combined organic solution was washed with brine (30 mL)
12. dry with materialdried over magnesium sulfate
13. filtrationfiltered
14. concentrationconcentrated
15. customChromatography over silica gel using a gradient of 10 to 40% ethyl acetate in heptane gave the product
16. additionas a mixture of isomers (477 mg, 64% yield)