Ethyl chloroformate → N-Benzyloxycarbonyl-glycyl-L-prolyl-L-norvaline benzyl ester

HRID 250802Notes

Reaction equation

C([N:8]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=O)=[O:11])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OCC)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:56]([O:63][C:64](=[O:70])[C@H:65]([CH2:67][CH2:68][CH3:69])[NH2:66])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>ClCCl>[CH2:56]([O:63][C:64](=[O:70])[C@H:65]([CH2:67][CH2:68][CH3:69])[NH:66][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[O:11])[CH2:9][NH:8][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1

Participants

Conditions

Temperature: 0 °C

Procedure

To a stirred solution of benzyl N-benzyloxycarbonyl-glycyl-L-proline 3 (0.4 g, 1.3 mmol) under nitrogen in dry dichloromethane (20 cm3) was added diisopropylethylamine (0.31 cm3, 1.76 mmol). The suspension was stirred for 5 min (a solution was obtained), cooled to 0° C. and ethyl chloroformate (0.166 cm3, 1.73 mol) was added. After 45 min a solution of diisopropylethylamine (0.31 cm3, 1.76 mmol) and p-toluenesulphonate 2 (0.644 g, 1.70 mmol) in dry dichloromethane (20 cm3) was added dropwise over 5 min. The cooling bath was removed and the resultant solution was stirred overnight. The solvent was removed in vacuo and the residue was chromatographed (silica gel, 50-100% ethyl acetate-hexane) to give fully protected tripeptide 4 (0.502 g, 78%) as a colourless oil. Tripeptide 4 was shown to be a 84:16 trans.-cis mixture of conformers by 13C NMR analysis (the ratio was estimated from the integration of the ψEβ-C carbons at δ 34.0 and 33.6 and the Eγ-C carbons at δ 18.5 and 18.8 of the major and minor conformers respectively): [α]D −70.3 (c 0.8 in dichloromethane); δH (300 MHz; CDCl3; Me4Si) 0.87 (3H, d, J 6.0, Eγ-CH3), 1.26-1.33 (2H, m, Eγ-H2), 1.58-1.68 (1H, m, Eβ-HAHB), 1.70-2.26 (5H, m, Eβ-HAHB, Proβ-H2, and Proγ-H2), 3.38 (0.84H, d, J 7.6, Proδ-HAHB), 3.51-3.56 (0.84H, m, Proδ-HAHB), 3.60-3.65* (0.32H, m, Proδ-H2), 3.76* (0.16H, d, J 16.5, Glyα-HAHB), 3.91 (1.84H, m, Glyα-H2), 4.37* (0.16H, br s, Proα-H), 4.49-4.62 (2H, m, Proα-H, Eα-H), 5.09-5.21 (4H, m, 2×OCH2Ph), 5.85 (1H, br s, Gly-NH), 7.2 (1H, d, J 5.5, Eα-NH) and 7.34 (10H, s, 2×Ph); δC (75 MHz; CDCl3) 13.4 (CH3, Eγ-CH3), 13.5* (CH3, Eγ-CH3), 18.5 (CH2, Eγ-C), 18.8* (CH2, Eγ-C), 22.2* (CH2, Proγ-C), 24.7 (CH2, Proγ-C), 27.7, (CH2, Proβ-C) 31.9* (CH2, Proβ-C) 33.6* (CH2, Eβ-C), 34.0 (CH2, Eβ-C), 43.3 (CH2, Glyα-C), 46.2 (CH, Proδ-C), 47.0* (CH, Proδ-C), 52.1* (CH, Eα-C), 52.3 (CH, Eα-C), 59.9 (CH, Proα-C), 66.8 (CH2, OCH2Ph), 67.1* (CH2, OCH2Ph), 127.9 (CH, Ph), 127.99 (CH, Ph), 128.0 (CH, Ph), 128.1* (CH, Ph), 128.2 (CH, Ph), 128.4 (CH, Ph), 128.5 (CH, Ph), 135.4 (quat., Ph), 136.3 (quat., Ph), 156.2 (quat., NCO2), 156.4* (quat., NCO2), 167.9 (quat., Gly-CO), 168.2* (quat., Gly-CO), 170.7 (quat., Pro-CON), 171.1* (quat., Pro-CON) and 172.1 (quat., Eα-CO); m/z (FAB+) 495.2381 (MH+.C27H33N3O6 requires 495.2370). ψE refers to the proline analog portion in question* Denotes resonances assigned to minor conformer.

Workup

customwas obtained),
customThe cooling bath was removed
stirringthe resultant solution was stirred overnight
customThe solvent was removed in vacuo
customthe residue was chromatographed (silica gel, 50-100% ethyl acetate-hexane)

Sources & evidence

ORD record: ord-cc9769615475465c8dbde8c59da6e537
Source dataset: uspto-grants-2011_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07863304B2

Reaction notes

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