Santonox → (1R,2S,5S)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester

HRID 1527404Notes

Reaction equation

HRID 1527404 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[C@H:10]([O:31]2)[C@H:9]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 7308Santonox2×HCID 70297m-Chloroperbenzoic acid2×HCID 58815105(S)-2,5-Dihydro-pyrrole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester

Product 1

HCID 86673847(1R,2S,5S)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of (S)-2,5-dihydro-pyrrole-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester (6.14 g, 20.2 mmol) were added 3-chloroperbenzoic acid (6.99 g, 40.5 mmol) and 4,4′ thiobis(6-tert-butyl-m cresol) (0.726 g, 2.02 mmol). The mixture was refluxed under nitrogen atmosphere overnight then an additional batch of 3-chloroperbenzoic acid (6.99 g, 40.5 mmol) and 4,4′ thiobis(6-tert-butyl-m cresol) (0.726 g, 2.02 mmol) was added. Refluxing was continued for 24 h. The reaction mixture was diluted with CH2Cl2, washed with sodium metabisulphite aqueous (5%), saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated. The diastereomeric epoxides in a ratio of 65/35 (determined by NMR on the crude mixture) were separated by flash column chromatography (c-hexane to c-hexane/EtOAc 4:1) to give (1R,2S,5S)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester: TLC, Rf (c-hexane/EtOAc 4:1)=0.20; MS (LC/MS): 220 [MH−Boc]+, 342 [M+Na]+; tR (HPLC conditions f): 2.14 min and (1S,2S,5R)-6-oxa-3-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-benzyl ester 3-tert-butyl ester: TLC, Rf (c-hexane/EtOAc 4:1)=0.15; MS (LC/MS): 220 [MH−Boc]+, 342 [M+Na]+; tR (HPLC conditions f): 2.03 min.

Workup

  1. temperatureThe mixture was refluxed under nitrogen atmosphere overnight
  2. temperatureRefluxing
  3. washwashed with sodium metabisulphite aqueous (5%), saturated aqueous NaHCO3, brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customwere separated by flash column chromatography (c-hexane to c-hexane/EtOAc 4:1)

Sources & evidence

ORD record
ord-0e44a8d548344c659fe936338e9557c6
Source dataset
uspto-grants-2015_07
Patent number
US09085555B2

Reaction notes

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