Lithium Hydroxide → (6S,9R,13S)-9-Benzyl-13-((E)-4-tritylsulfanyl-but-1-enyl)-6-tritylsulfanylmethyl-14-oxa-4,7,10,17-tetraaza-spiro[2.15]octadecane-5,8,11,15,18-pentaone

HRID 1915976Notes

Reaction equation

HRID 1915976 reaction equation
C[O:2][C:3](=O)[CH2:4][NH:5][C:6]([C:8]1([NH:11][C:12](=[O:76])[C@H:13]([NH:35][C:36](=[O:75])[C@H:37]([NH:45][C:46](=[O:74])[CH2:47][C@H:48](O)/[CH:49]=[CH:50]/[CH2:51][CH2:52][S:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:14][S:15][C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[Li+].[OH-:79].CC1C=CC=C([N+]([O-])=O)C=1C(OC(C1C([N+]([O-])=O)=CC=CC=1C)=O)=O>C1COCC1.O.CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:38]([C@H:37]1[NH:45][C:46](=[O:74])[CH2:47][C@@H:48](/[CH:49]=[CH:50]/[CH2:51][CH2:52][S:53][C:54]([C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[O:79][C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:7])[C:8]2([CH2:10][CH2:9]2)[NH:11][C:12](=[O:76])[C@@H:13]([CH2:14][S:15][C:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:35][C:36]1=[O:75])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1

Participants

8

Reactant 3

HCID 3939Lithium HydroxideHCID 104726482-Methyl-6-nitrobenzoic anhydrideHCID 58257064[(1-{(S)-2-[(R)-2-((E)-(S)-3-Hydroxy-7-tritylsulfanyl-hept-4-enoylamino)-3-phenyl-propionylamino]-3-tritylsulfanyl-propionylamino}-cyclopropanecarbonyl)-amino]-acetic acid methyl ester

Product 1

HCID 58257004(6S,9R,13S)-9-Benzyl-13-((E)-4-tritylsulfanyl-but-1-enyl)-6-tritylsulfanylmethyl-14-oxa-4,7,10,17-tetraaza-spiro[2.15]octadecane-5,8,11,15,18-pentaoneYield 58%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 4 (305 mg, 0.29 mmol, 1 eq) in THF (10 mL) at 0° C. was added a solution of LiOH (10.3 mg, 0.43 mmol, 1.5 eq) in H2O (2 mL) dropwise. The mixture was stirred for 2 h, then quenched with 1N HCl (3 mL) and brine (10 mL). The organic layer was separated and the resulting aqueous layer was further extracted with EtOAc (2×15 mL) and (15 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The resulting carboxylic acid was then dried on the high-vacuum pump for 2 h. To a solution of MNBA (118 mg, 0.34 mmol, 1.2 eq) and DMAP (84 mg, 0.69 mmol, 2.4 eq) in CH2CL2 (200 mL) was added a solution of the crude carboxylic acid in CH2Cl2 (130 mL) and THF (20 mL) dropwise over 3 h. The reaction mixture was then left to stir up at rt overnight. The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography with hexane/EtOAc (1:9→0:1) to yield 5 as a white solid (171 mg, 58%).

Workup

  1. customquenched with 1N HCl (3 mL) and brine (10 mL)
  2. customThe organic layer was separated
  3. extractionthe resulting aqueous layer was further extracted with EtOAc (2×15 mL) and (15 mL)
  4. dry with materialThe combined organic extracts were dried over MgSO4
  5. customthe solvent was removed in vacuo
  6. dry with materialThe resulting carboxylic acid was then dried on the high-vacuum pump for 2 h
  7. waitThe reaction mixture was then left
  8. stirringto stir up at rt overnight
  9. customThe solvent was then removed in vacuo
  10. customthe residue was further purified by silica gel column chromatography with hexane/EtOAc (1:9→0:1)

Sources & evidence

ORD record
ord-30138c1eebfb4c539c974bb3026b3342
Source dataset
uspto-grants-2013_12
Patent number
US08614193B2

Reaction notes

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