Acetic Acid → Boc-His(Ts) 1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-cyclohexyl-butylamide

HRID 327344

Reaction equation

HRID 327344 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[CH3:18][C:19]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20].C1OCCOCCOCCOCCOCCOC1.[NH:45]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:46]([C:63]([OH:65])=[O:64])[CH2:47][C:48]1[N:52]=[CH:51][N:50]([S:53]([C:56]2[CH:62]=[CH:61][C:59]([CH3:60])=[CH:58][CH:57]=2)(=[O:55])=[O:54])[CH:49]=1.[CH:73]1([CH2:79][C@@H:80]([CH:82]=[O:83])[NH2:81])[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1.C(O)(=O)C.[Cl-].[NH4+]>C1COCC1>[NH:45]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:46]([C:63]([OH:65])=[O:64])[CH2:47][C:48]1[N:52]=[CH:51][N:50]([S:53]([C:56]2[CH:57]=[CH:58][C:59]([CH3:60])=[CH:61][CH:62]=2)(=[O:55])=[O:54])[CH:49]=1.[CH:73]1([CH2:79][C@H:80]([NH-:81])[C@@H:82]([OH:83])[CH2:18][C:19](=[O:20])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1

Participants

9

Reactant 7

HCID 176Acetic AcidHCID 1140TolueneHCID 13207Cyclohexyl methyl ketoneHCID 25517Ammonium ChlorideHCID 2855718-Crown-6HCID 3251421Potassium bis(trimethylsilyl)amideHCID 131717823Boc-His(Ts) 3-cyclohexylalaninal

Product 1

HCID 131717824Boc-His(Ts) 1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-cyclohexyl-butylamideYield 15%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Procedure

To a 0.5N potassium bis-trimethylsilylamide solution in toluene (9.2 ml, 4.60 mmol, 2.5 eq) is added dropwise at -78° C. cyclohexyl methyl ketone (0.58 g, 4.60 mmol, 2.5 eq) in THF (9 ml) with stirring under a nitrogen atmosphere over 10 minutes. After 20 minutes stirring at the same temperature, 18-crown-6 (1.216 g, 4.60 mmol, 2.5 eq) in THF (10 ml) is dropwise added to the mixture over two minutes. Further, the dipeptidealdehyde [14a] (1.0 g, 1.83 mmol) in THF (10 ml) is dropwise added over 15 minutes at -78° C., and the mixture is stirred for one hour at the same temperature. The reaction is quenched by adding a solution of acetic acid (0.60 g, 10 mmol, 5.5 eq) in THF (10 ml) and after the addition of saturated aqueous ammonium chloride (30 ml) the mixture is extracted with ethyl acetate (50 ml×3). The organic layer is washed with saturated aqueous sodium chloride, dried over MgSO4, concentrated to dryness in vacuo, and purified with silica gel chromatography (Lobar column, CH2Cl2 :MeOH=95:5) to obtain Boc-His(Ts)-1(S)-cyclohexylmethyl-2(S)-hydroxy-4-oxo-4-cyclohexyl-butylamide [10b] (0.18 g, 15%) in amorphous powder.

Workup

  1. additionis dropwise added to the mixture over two minutes
  2. stirringthe mixture is stirred for one hour at the same temperature
  3. customThe reaction is quenched
  4. extractionis extracted with ethyl acetate (50 ml×3)
  5. washThe organic layer is washed with saturated aqueous sodium chloride
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated to dryness in vacuo
  8. custompurified with silica gel chromatography (Lobar column, CH2Cl2 :MeOH=95:5)

Sources & evidence

ORD record
ord-23183dfc9f25499d96b37d8d228aa3f8
Source dataset
uspto-grants-1993_12
Patent number
US05272268

Linked notes

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