Reacción #87467

Ecuación de reacción

aluminum

tetrahydrofuran

(2R,3S,4S)-2,3,4-tris-benzyloxy-5-hydroxy-6-(4-methoxy-benzyloxy)-5-(4-methoxy-benzyloxymethyl)-hexanoic acid methoxy-methyl-amide

tetrahydrofuran

n-Butyl lithium

oxygen

4-bromo-1-chloro-2-(4-ethoxy-benzyl)-benzene

→

(4S,5S)-3,4,5-tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6,6-bis-(4-methoxy-benzyloxymethyl)-tetrahydro-pyran-2-ol

Rendimiento 38.0%

Disolventes

Diethyl ether

Condiciones de reacción

Tratamiento posterior

1. 1
   Otrodried Biotage™ microwave vial 10-20 mL
2. 2
   Otrosealed with its
3. 3
   Otrocap
4. 4
   Otroat −78° C.
5. 5
   workup.STIRRINGthe resulting mixture was stirred at −78° C. for 1 hour
6. 6
   Temperaturato maintain cold temperature
7. 7
   Otrothe reaction was quenched by dropwise addition of aqueous 1M hydrochloric acid solution
8. 8
   workup.STIRRINGThe resulting biphasic mixture was stirred at room temperature for 15 minutes
9. 9
   OtroThe organic phase was separated
10. 10
    Lavadowashed with brine
11. 11
    Secadodried over magnesium sulfate
12. 12
    Filtraciónfiltered
13. 13
    Concentraciónconcentrated
14. 14
    OtroChromatography over silica gel using a gradient of 10 to 40% ethyl acetate in heptane gave the product
15. 15
    workup.ADDITIONas a mixture of isomers (280 mg, 38% yield)

Procedimiento

n-Butyl lithium (1.0 mL, 2.5 M/hexanes, 3.25 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-1-chloro-2-(4-ethoxy-benzyl)-benzene (815 mg, 3.25 equivalents) in anhydrous tetrahydrofuran (2.9 mL) at −78° C. and the resulting solution was stirred at this temperature for an additional hour. 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) (600 mg) in anhydrous tetrahydrofuran (1.45 mL) was then added dropwise over 1.3 hours using a syringe pump and the resulting mixture was stirred at −78° C. for 1 hour before being allowed to warm to −25° C. over 14 hours (put 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). Diethyl ether was added and the reaction was quenched by dropwise addition of aqueous 1M hydrochloric acid solution. The resulting biphasic mixture was stirred at room temperature for 15 minutes. The organic phase was separated, washed with brine, 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 (280 mg, 38% yield).

Fuente