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

HRID 659900Notes

Reaction equation

HRID 659900 reaction equation
[CH2:1]([Li])[CH2:2][CH2:3][CH3:4].O=O.Br[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:10]=1.CON(C)[C:27](=[O:79])[C@H:28]([O:71]CC1C=CC=CC=1)[C@@H:29]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[C@H:30]([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:31]([OH:54])([CH2:43][O:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1.[Al].O1C[CH2:85][CH2:84][CH2:83]1>>[CH2:1]([O:71][CH:28]1[C@@H:29]([O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[C@H:30]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:31]([CH2:43][O:44][CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[O:54][C:27]1([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:10]=1)[OH:79])[C:2]1[CH:85]=[CH:84][CH:83]=[CH:4][CH:3]=1

Participants

7

Reactant 6

HCID 977OxygenHCID 8028Tetrahydrofuran2×HCID 5359268AluminumHCID 59226798(2R,3S,4S)-2,3,4-tris-benzyloxy-5-hydroxy-6-(4-methoxy-benzyloxy)-5-(4-methoxy-benzyloxymethyl)-hexanoic acid methoxy-methyl-amideHCID 666159264-Bromo-2-(4-chlorobenzyl)-1-fluorobenzeneHCID 178418339Butyllithium

Product 1

HCID 86639770(4S,5S)-3,4,5-tris-benzyloxy-2-[3-(4-chloro-benzyl)-4-fluoro-phenyl]-6,6-bis-(4-methoxy-benzyloxymethyl)-tetrahydro-pyran-2-olYield 64%

Procedure

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).

Workup

  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)

Sources & evidence

ORD record
ord-162bf3d50e83404183fdf26dd3a50bc5
Source dataset
uspto-grants-2011_12
Patent number
US08080580B2

Reaction notes

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