Lithium Chloride → (3aR,4R,5R,6aS)-4-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate

HRID 561751Notes

Reaction equation

HRID 561751 reaction equation
[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2[CH:19]=O)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Li+].[S:29]1[CH:33]([C:34](=[O:44])[CH2:35]P(=O)(OCC)OCC)[CH:32]=[C:31]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:30]12>C(Cl)Cl.C1COCC1>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:2]=[CH:3][C:4]([C:7]([O:9][C@@H:10]2[CH2:18][C@@H:13]3[O:14][C:15](=[O:17])[CH2:16][C@@H:12]3[C@H:11]2/[CH:19]=[CH:35]/[C:34]([C:33]2[S:29][C:30]3[CH:48]=[CH:47][CH:46]=[CH:45][C:31]=3[CH:32]=2)=[O:44])=[O:8])=[CH:5][CH:6]=1

Participants

6

Reactant 3

HCID 433294Lithium ChlorideHCID 10473055(3aR,4R,5R,6aS)-4-Formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylateHCID 86633825Diethyl 2-(2,7a-dihydrobenzo[b]thiophen-2-yl)-2-oxoethylphosphonate

Product 1

HCID 57856996(3aR,4R,5R,6aS)-4-((E)-3-(benzo[b]thiophen-2-yl)-3-oxoprop-1-enyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

A reactor equipped with a mechanical stirrer, under nitrogen, was charged with a mixture consisting of (3aR,4R,5R,6aS)-4-formyl-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl biphenyl-4-carboxylate in DCM and a mixture consisting of lithium chloride (1 molar equivalent) in THF. Diethyl 2-(2,7a-dihydrobenzo[b]thiophen-2-yl)-2-oxoethylphosphonate (1 molar equivalent) was added neat and rinsed with DCM. Some lithium chloride precipitated from solution when the THF and DCM mixtures were combined. The mixture was stirred under nitrogen and cooled to −20° C. After adding the phosphonate and further stirring and cooling, the lithium chloride dissolved. After stirring for 2.5 hours, triethylamine (1 molar equivalent) was added neat via addition funnel and the temperature was maintained at −5° C. for 19 hours. The temperature was adjusted to 0° C. and the reaction mixture was treated with 5% aqueous citric acid. The layers were separated and the organic layer was dried over magnesium sulfate and filtered. The crude product was purified on silica gel, eluted with ethyl acetate-hexanes (1:1) to afford the title intermediate 27; 1H NMR (CDCl3) δ 8.10-8.15 (m, 2H), 8.05 (s, 1H), 7.89-7.95 (m, 2H), 7.60-7.75 (m, 4H), 7.38-7.60 (m, 5H), 6.98-7.17 (m, 2H), 5.45-5.55 (m, 1H), 5.18-5.25 (m, 1H), 2.93-3.15 (m, 3H), 2.55-2.77 (m, 2H), 2.38-2.47 (m, 1H).

Workup

  1. customA reactor equipped with a mechanical stirrer, under nitrogen
  2. additionwas charged with a mixture
  3. washrinsed with DCM
  4. customSome lithium chloride precipitated from solution when the THF and DCM mixtures
  5. additionAfter adding the phosphonate
  6. stirringfurther stirring
  7. temperaturecooling
  8. dissolutionthe lithium chloride dissolved
  9. stirringAfter stirring for 2.5 hours
  10. additiontriethylamine (1 molar equivalent) was added neat via addition funnel
  11. temperaturethe temperature was maintained at −5° C. for 19 hours
  12. customwas adjusted to 0° C.
  13. additionthe reaction mixture was treated with 5% aqueous citric acid
  14. customThe layers were separated
  15. dry with materialthe organic layer was dried over magnesium sulfate
  16. filtrationfiltered
  17. customThe crude product was purified on silica gel
  18. washeluted with ethyl acetate-hexanes (1:1)

Sources & evidence

ORD record
ord-4da6e4db51cb490e9b536f5b53a9e5a1
Source dataset
uspto-grants-2011_11
Patent number
US08063240B2

Reaction notes

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