Methyl iodide → tert-Butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamate

HRID 1743741Notes

Reaction equation

HRID 1743741 reaction equation
[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH:11]([CH3:21])[CH2:10][C@H:9]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

5

Reactant 3

HCID 6328Methyl iodideHCID 2733832Lithium HexamethyldisilazideHCID 11129853Di-tert-butyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate

Product 1

HCID 21015973tert-Butyl N-tert-butoxycarbonyl-4-methyl-L-pyroglutamateYield 88%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of tert-butyl N-tert-butoxycarbonyl-pyroglutamate (11.5 g, 40 mmol) in THF (200 mL) stirring at −78° C., was added a 1M solution of lithium hexamethyldisilazide in THF (42 mL, 42 mmol) dropwise over 5 minutes. After 30 minutes, methyliodide (3.11 mL, 50 mmol) was added. After an additional 2 hours at −78° C., the cooling bath was removed and 50% saturated aqueous ammonium chloride (200 mL) was added. The solution was stirred for 20 minutes, then extracted with ether (3×200 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue was chromatographed with 1:1 ethylacetate/hexanes to give Boc-PyroGlu(4-methyl)-OtBu (10.6 grams, 35.4 mmol, 88%) as a mixture of isomers (2:1 cis to trans). Step 2. Synthesis of Tert-butyl N-tert-butoxycarbonyl-4,4-dimethyl-L-pyroglutamate (Boc-PyroGlu(4,4-dimethyl)-OtBu):

Workup

  1. waitAfter an additional 2 hours at −78° C.
  2. customthe cooling bath was removed
  3. addition50% saturated aqueous ammonium chloride (200 mL) was added
  4. extractionextracted with ether (3×200 mL)
  5. washThe combined organic layers were washed with brine (200 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was chromatographed with 1:1 ethylacetate/hexanes

Sources & evidence

ORD record
ord-6db4f5cfe08246e7b7fda024b4d0e59f
Source dataset
uspto-grants-2006_03
Patent number
US07012066B2

Reaction notes

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