Methanol → L-Proline, 1-[(2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxo-8-nonen-1-yl]-4-hydroxy-, (4R)-

HRID 1674557Notes

Reaction equation

HRID 1674557 reaction equation
C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11](=[O:28])[C@@H:12]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])=[O:4].CO.O.[OH-].[Li+]>C1COCC1>[C:24]([O:23][C:21]([NH:20][C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19])[C:11]([N:6]1[CH2:7][C@H:8]([OH:10])[CH2:9][C@H:5]1[C:3]([OH:4])=[O:2])=[O:28])=[O:22])([CH3:27])([CH3:26])[CH3:25]

Participants

6

Reactant 4

HCID 887MethanolHCID 962WaterHCID 3939Lithium HydroxideHCID 587986201-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester

Product 1

HCID 20765202L-Proline, 1-[(2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxo-8-nonen-1-yl]-4-hydroxy-, (4R)-Yield 96.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

1-(2(S)-tert-Butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid methyl ester (4.7 g, 11.8 mmol) was dissolved in THF (80 mL), methanol (20 mL), and water (40 mL). Powdered lithium hydroxide (5.6 g, 233 mmol) was added. The light yellow slurry was stirred at room temperature under N2 for 16 hours, and then concentrated in vacuo. The residue was partioned between ether and water. The ether phase was discarded, and the aqueous phase was treated with 1N HCl until the pH was 4. This acidic solution was extracted with ethyl acetate (3×). The combined ethyl acetate extracts were dried (MgSO4), filtered, and concentrated in vacuo to give 4.36 g (96%) of 1-(2(S)-tert-butoxycarbonylamino-8-nonenoyl)-4(R)-hydroxy-pyrrolidine-2(S)-carboxylic acid as a white solid. This acid was then dissolved in 150 mL of DMF and (1R,2S)-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride (2.61 g, 13.6 mmol), N-methyl morpholine (2.5 mL, 22.6 mmol), and HATU (5.2 g, 13.7 mmol) was added. The reaction mixture was stirred at room temperature under N2 for 16 hours, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with saturated aqueous NaHCO3, dried (MgSO4), filtered, and concentrated in vacuo to give the crude product. Flash chromatography (60%-80% ethyl acetate/hexane) gave 6.0 g (98%) of 1-{[1-(2(S)-tert-butoxycarbonylamino-non-8-enoyl)-4(R)-hydroxy-pyrrolidine-2(S)carbonyl]-(1R)-amino}-2(S)-vinyl-cyclopropanecarboxylic acid ethyl ester as a white solid. 1H NMR (500 MHz, CD3OD) δ 1.25 (t, J=7.2 Hz, 3H), 1.33-1.80 (m, 10H), 1.46 (s, 9H), 2.09 (m, 3H), 2.25 (m, 2H), 3.76 (m, 2H), 4.14 (m, 2H), 4.27 (dd, J=8.5, 5.2 Hz, 1H), 4.50 (m, 2H), 4.94 (d, J=10.1 Hz, 1H), 5.01 (dd, J=17.1, 1.8 Hz, 1H), 5.11 (dd, J=10.4, 1.8 Hz, 1H), 5.30 (d, J=15.6 Hz, 1H), 5.80 (m, 2H), 8.57 (s, 1H); LC-MS (Method A, retention time: 3.21 min), MS m/z 522 (M++1).

Workup

  1. concentrationconcentrated in vacuo
  2. additionthe aqueous phase was treated with 1N HCl until the pH was 4
  3. extractionThis acidic solution was extracted with ethyl acetate (3×)
  4. dry with materialThe combined ethyl acetate extracts were dried (MgSO4)
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c1e6e12410ae472eaaed1f51a83b2815
Source dataset
uspto-grants-2011_08
Patent number
US08003604B2

Reaction notes

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