Chlorotrimethylsilane → (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester

HRID 1592057Notes

Reaction equation

HRID 1592057 reaction equation
BrCCBr.C[Si](Cl)(C)C.[CH2:10]([O:17][C:18](=[O:30])[C@@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]I)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.I[C:32]1[CH:33]=[C:34]([N:38]2[S:42](=[O:44])(=[O:43])[N:41]([CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[C:40](=[O:54])[CH2:39]2)[CH:35]=[CH:36][CH:37]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:10]([O:17][C:18](=[O:30])[C@@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH2:39][C:40](=[O:54])[N:41]([CH2:45][C:46]3[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=3)[S:42]2(=[O:43])=[O:44])[CH:33]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

8

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 80271Tri-o-tolylphosphineHCID 2756804N-Boc-3-Iodo-L-alanine benzyl esterHCID 67139575HCID 67139575, compound

Product 1

HCID 67139722(S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent3×

Conditions

Temperature
50 °C

Procedure

Onto zinc foil (99.9% Aldrich 35, 602-6,118.5 mg, 1.813 mmol) is cut in small pieces is added DMF (freshly distilled from CaH2 under argon, 0.4 mL) and 1,2-dibromoethane (0.006 mL, 0.065 mmol) under argon. The mixture is heated at 50° C. for 10 min, then allowed to cool and trimethylsilyl chloride (0.003 mL, 0.026 mmol) is added. The reaction is stirred for 25 min and a solution of (R)-2-t-butoxycarbonylamino-3-iodo-propionic acid benzyl ester (Fluka, 342 mg, 0.844 mmol) in DMF (1 mL) is added. After 1 h, the mixture is decanted to a solution of the title C compound, 5-(3-iodo-phenyl)-2-(4-methoxy-benzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (300 mg, 0.65 mmol), tri-o-tolylphosphine (29.9 mg, 0.13 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (29.9 mg, 0.033 mmol) in DMF (2 mL). After stirring for 1.5 h, the resulting reaction mixture is poured onto water (100 mL), extracted with EtOAc (2×100 mL). The combined EtOAc layers are washed with water (1×200 mL) and brine (1×200 mL), dried over anhydrous MgSO4, filtered and concentrated to give a yellow oil. This is chromatographed on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 12:88 over 40 min. Fractions containing product are combined and concentrated to yield (S)-2-t-butoxycarbonylamino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid benzyl ester as a clear oil: [M+NH4]+=627.0, [M−HCO2]−=654.1.

Workup

  1. distillationfreshly distilled from CaH2 under argon
  2. temperatureto cool
  3. waitAfter 1 h
  4. stirringAfter stirring for 1.5 h
  5. customthe resulting reaction mixture
  6. additionis poured onto water (100 mL)
  7. extractionextracted with EtOAc (2×100 mL)
  8. washThe combined EtOAc layers are washed with water (1×200 mL) and brine (1×200 mL)
  9. dry with materialdried over anhydrous MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto give a yellow oil
  13. customThis is chromatographed on a 35 g silica gel RediSep column (Isco, Inc.) with a 30 mL/min gradient elution of 0:100 (EtOAc:CH2Cl2) to 12:88 over 40 min
  14. additionFractions containing product
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-68d39012b9ed4201aea6f5e860aa9c5f
Source dataset
uspto-grants-2007_11
Patent number
US07291635B2

Reaction notes

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