Citric Acid → 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl]-3(R)-(p-benzyloxyphenylmethyl)-dihydrofuran-2-(3H)-one

HRID 2394082Notes

Reaction equation

HRID 2394082 reaction equation
[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:41]([O:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53]I)=[CH:51][CH:50]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O.CN1CCCN(C)C1=O>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:53][C:52]2[CH:55]=[CH:56][C:49]([O:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:50][CH:51]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]

Participants

9

Reactant 5

HCID 311Citric AcidHCID 1032Propionic AcidHCID 2733832Lithium HexamethyldisilazideHCID 11723738p-Benzyloxybenzyl iodideHCID 54401688[(S)-2-(4-Benzyloxy-phenyl)-1-((S)-5-oxo-tetrahydro-furan-2-yl)-ethyl]-carbamic acid tert-butyl ester

Product 1

HCID 156595605(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl]-3(R)-(p-benzyloxyphenylmethyl)-dihydrofuran-2-(3H)-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×HCID 816462(1H)-Pyrimidinone, tetrahydro-1,3-dimethyl-Solvent

Conditions

Temperature
0 °C

Procedure

2.47 g (6.0 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)ethyl]dihydrofuran-2-(3H)-one dissolved in 12 ml of THF and 1.2 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone are treated, at -70° C. and under a protective gas, with 11.73 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, and this mixture is stirred for 15 min; it is then alkylated with 1.946 g (6.0 mmol) of p-benzyloxybenzyl iodide (Example 1d)) in 3 ml of THF (60 min). For hydrolysing, 2.23 ml of propionic acid and 2.23 ml of water are added and the mixture is warmed to 0° C. The reaction mixture is poured onto 30 ml of 10% citric acid solution, and this mixture is extracted twice with ethyl acetate; the organic phases are washed twice with saturated NaHCO3 solution and, finally, with saline. Drying the organic phases with Na2SO4 and evaporating them, and column chromatography (SiO2, hexane/ethyl acetate 4:1) of the residue, and subsequent crystallization from ethyl acetate/hexane, affords the pure title compound: TLC Rf (D)=0.45; tRet (I)=19.9 min; FAB-MS (M+H)+ =608.

Workup

  1. extractionthis mixture is extracted twice with ethyl acetate
  2. washthe organic phases are washed twice with saturated NaHCO3 solution
  3. dry with materialDrying the organic phases with Na2SO4
  4. customevaporating
  5. customthem, and column chromatography (SiO2, hexane/ethyl acetate 4:1) of the residue, and subsequent crystallization from ethyl acetate/hexane

Sources & evidence

ORD record
ord-56a2c0236a194d27a3ebe4a1f3a4b5b1
Source dataset
uspto-grants-1998_09
Patent number
US05807891

Reaction notes

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