(1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate → (2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate

HRID 1666532Notes

Reaction equation

HRID 1666532 reaction equation
[C:1]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:11][N:10]([C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14](C)(C)[CH2:15][CH2:16][CH2:17][CH2:18]C=C)[C@H:9]([C:32]([NH:34][C@:35]3([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:37][C@H:36]3[CH:38]=[CH2:39])=[O:33])[CH2:8]2)=[CH:3][CH:2]=1.SC1N=CC=CC=1C(O)=O>ClCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]1([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:11][N:10]3[C:12](=[O:31])[C@@H:13]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:39]=[CH:38][C@@H:36]4[CH2:37][C@@:35]4([C:40]([O:42][CH2:43][CH3:44])=[O:41])[NH:34][C:32](=[O:33])[C@@H:9]3[CH2:8]2)=[CH:5][CH:6]=1

Participants

5

Reactant 2

HCID 86636556(1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylateHCID 178524460HCID 178524460, compound

Product 1

HCID 57988332(2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylateYield 76.3%

Reagents, catalysts & solvents 2

HCID 11763533(1,3-Bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene)(dichloro)((2-((propan-2-yl)oxy)phenyl)methylidene)rutheniumCatalystHCID 6344DichloromethaneSolvent

Procedure

A solution of (1R,2S)-ethyl 1-((2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylnon-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (75 mg, 0.097 mmol) in dichloromethane (30 mL) was purged with nitrogen for 3 min. And then Hoveyda-Grubbs Catalyst 2nd Generation (73.1 mg, 0.116 mmol) was added. The resulting green solution was heated to reflux for 5 hours. The reaction was quenched with 2-mercaptonicotinic acid (30.1 mg, 0.194 mmol) and washed with saturated Na2CO3, and brine. Dried over MgSO4, filtered, and concentrated in vacuo. The brown residue was purified by BIOTAGE® column, eluted with gradient 5%˜50% ethyl acetate-hexane to afford the desired product (2R,6S,13aS,14aR,16aS,Z)-ethyl 2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (59 mg, 0.074 mmol, 76% yield) as an off-white solid. 1H NMR (500 MHz, MeOD) δ ppm 0.83 (t, 3 H) 1.14-1.37 (m, 8 H) 1.38-1.54(m, 17 H) 1.52-1.68 (m, 4 H) 1.79-1.95 (m, 1 H) 1.97-2.10 (m, 1 H) 2.25-2.37 (m, 2 H) 2.37-2.49 (m, 2 H) 2.53 (dd, J=12.51, 10.07 Hz, 1 H) 2.88 (dd, J=12.51, 7.02 Hz, 1 H) 3.97-4.08 (m, 2 H) 4.07-4.22 (m, 3 H) 4.50 (dd, J=10.22, 2.90 Hz, 1 H) 5.17 (d, J=10.68 Hz, 1 H) 5.34 (t, J=9.77 Hz, 1 H) 5.56-5.68 (m, 1 H) 7.30-7.41 (m, 1 H) 7.41-7.50 (m, 2 H) 7.60 (d, J=8.24 Hz, 4 H) 7.77 (d, J=8.24 Hz, 2 H). LC-MS (retention time: 3.55 min, method C), MS m/z 718 (M+H).

Workup

  1. temperatureThe resulting green solution was heated
  2. temperatureto reflux for 5 hours
  3. washwashed with saturated Na2CO3, and brine
  4. dry with materialDried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customThe brown residue was purified by BIOTAGE® column
  8. washeluted with gradient 5%˜50% ethyl acetate-hexane

Sources & evidence

ORD record
ord-9d91bf10964d44408fb1bea0b7e1b660
Source dataset
uspto-grants-2011_10
Patent number
US08044023B2

Reaction notes

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