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

HRID 346948Notes

Reaction equation

HRID 346948 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 rt under N2 for 16 h, 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 EtOAc (3×). The combined EtOAc extracts were dried (MgSO4) 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 rt under N2 for 16 h, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and pH 4 buffer (biphthalate). The organic phase was washed with sat. aq. NaHCO3, dried (MgSO4), 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 EtOAc (3×)
  4. dry with materialThe combined EtOAc extracts were dried (MgSO4)
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-f452d8b042244eba8d9b233067968d60
Source dataset
uspto-grants-2007_02
Patent number
US07173004B2

Reaction notes

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