Cesium carbonate → (2S,5S)-1-tert-butyl 2-(3-(2-((2S,5S)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 5-methylpyrrolidine-1,2-dicarboxylate

HRID 590677Notes

Reaction equation

HRID 590677 reaction equation
[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:41]([CH3:44])[CH2:42][CH3:43])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17][CH2:18][C:19]([C:21]1[CH:22]=[CH:23][C:24]2[C:33]3[CH:32]=[C:31]4[CH2:34][CH2:35][CH:36](Br)[C:37](=[O:38])[C:30]4=[CH:29][C:28]=3[O:27][CH2:26][C:25]=2[CH:40]=1)=[O:20])=[O:16])=[O:8])=[O:4].[C:45]([O:49][C:50]([N:52]1[C@@H:56]([CH3:57])[CH2:55][CH2:54][C@H:53]1[C:58]([OH:60])=[O:59])=[O:51])([CH3:48])([CH3:47])[CH3:46].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[CH3:57][C@@H:56]1[N:52]([C:50]([O:49][C:45]([CH3:46])([CH3:48])[CH3:47])=[O:51])[C@H:53]([C:58]([O:60][CH:36]2[CH2:35][CH2:34][C:31]3=[CH:32][C:33]4[C:24]5[CH:23]=[CH:22][C:21]([C:19](=[O:20])[CH2:18][O:17][C:15]([C@@H:10]6[CH2:11][CH2:12][C@H:13]([CH3:14])[N:9]6[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C@@H:41]([CH3:44])[CH2:42][CH3:43])=[O:16])=[CH:40][C:25]=5[CH2:26][O:27][C:28]=4[CH:29]=[C:30]3[C:37]2=[O:38])=[O:59])[CH2:54][CH2:55]1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 15516206(5S)-1-(tert-Butoxycarbonyl)-5-methyl-L-prolineHCID 86723609(2S,5S)-2-(9-Bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carboxylate

Product 1

HCID 86723611(2S,5S)-1-tert-butyl 2-(3-(2-((2S,5S)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 5-methylpyrrolidine-1,2-dicarboxylateYield 43%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of (2S,5S)-2-(9-bromo-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)-2-oxoethyl 1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carboxylate (5.95 g, 8.88 mmol) in THF (60 mL) was added (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-2-carboxylic acid (3.05 g, 13.3 mmol) and Cs2CO3 (2.31 g, 7.09 mmol). The resulting solution was heated to 50° C. for 18 h. The solution was cooled to room temperature and diluted with EtOAc and washed with aqueous HCl (0.5 M). The aqueous layer was backextracted with EtOAc (2×), and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 25-100% EtOAc (5% MeOH)/Hexanes) to provide (2S,5S)-1-tert-butyl 2-(3-(2-((2S,5S)-1-((2S,3S)-2-(methoxycarbonylamino)-3-methylpentanoyl)-5-methylpyrrolidine-2-carbonyloxy)acetyl)-8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-9-yl) 5-methylpyrrolidine-1,2-dicarboxylate (3.116, 43% over 2 steps) as a orange foam. LCMS-ESI+: calc'd for C44H55N3O12: 817.38 (M+). Found: 817.65 (M+).

Workup

  1. temperatureThe solution was cooled to room temperature
  2. washwashed with aqueous HCl (0.5 M)
  3. dry with materialthe combined organic layers were dried over Na2SO4
  4. concentrationconcentrated
  5. customThe crude oil was purified by column chromatography (SiO2, 25-100% EtOAc (5% MeOH)/Hexanes)

Sources & evidence

ORD record
ord-1058065be41d45cb90ab4502a9832ca7
Source dataset
uspto-grants-2016_01
Patent number
US09233974B2

Reaction notes

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