Glycine → (3Ar,7as)-hexahydro-2-benzofuran-1(3h)-one

HRID 1533501Notes

Reaction equation

HRID 1533501 reaction equation
NCC(O)=O.[OH-].[Na+].[C@@H:8]1([CH2:16][OH:17])[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][OH:15].COC1C=CC(C=O)=CC=1>O.C(O)C.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.C(OCC)(=O)C.C(Cl)Cl>[C@H:9]12[CH2:14][O:15][C:16](=[O:17])[C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10]2

Participants

9

Reactant 4

HCID 750Glycine2×HCID 14798Sodium Hydroxide4×HCID 312444-MethoxybenzaldehydeHCID 2724019cis-1,2-Cyclohexanedimethanol

Product 1

HCID 245563(3Ar,7as)-hexahydro-2-benzofuran-1(3h)-oneYield 92.6%

Reagents, catalysts & solvents 4

HCID 5892NadideCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 21226138Dichloromethane ethylacetateSolvent

Procedure

Glycine (18.8 grams) is dissolved in 2 liters of deionized water, and the pH is adjusted by the addition of 10% sodium hydroxide to 9.0. Cis-1,2-cyclohexane dimethanol (10.0 grams) is added to the glycine solution with stirring until dissolution occurs, followed by the addition of β-NAD+ (Sigma, 2 grams) and flavin mononucleotide (Sigma, 30 grams). To the resulting clear orange solution is added horse liver alcohol dehydrogenase (Sigma, 250 mg, approximately 400 units). After the enzyme has dissolved the pH is readjusted to 9.0 with 10% sodium hydroxide, and the reaction mixture is stirred at 30° C. During the reaction, the pH is maintained at 9.0 with a pH-stat by the addition of 10% sodium hydroxide. Progress of the reaction is monitored by thin layer chromatography (Silica gel plates, eluent 1:1 ethyl acetate-methylene chloride; visualization by dipping in a solution of 5% anisaldehyde in ethanol and heating). When the reaction is complete as judged by thin layer chromatography, the reaction mixture is adjusted to a pH of 13 with 10 M sodium hydroxide and then extracted 3 times with 250 ml of methylene chloride. The pH of the aqueous mixture is then adjusted to 3 with concentrated HCl, followed by continuous extraction with 1 liter of ethyl acetate for 24 hours. The ethyl acetate extract is dried over anhydrous magnesium sulfate and evaporated under reduced pressure to yield (1R,6S)-(+)-8-oxabicydo[4.3.0]nonan-7-one (9 grams) as an orange oil. The product may be further purified by distillation at reduced pressure to yield a colorless oil, [∂]D=+46° c=1.1, chloroform. The enantiomeric excess is 98% as determined by chiral gas chromatography (Lipodex D column, column temperature 165=° C., injection temperature 180=° C., detector temperature=260° C.).

Workup

  1. dissolutionAfter the enzyme has dissolved the pH
  2. stirringthe reaction mixture is stirred at 30° C
  3. customDuring the reaction
  4. temperatureheating)
  5. extractionextracted 3 times with 250 ml of methylene chloride
  6. extractionfollowed by continuous extraction with 1 liter of ethyl acetate for 24 hours
  7. extractionThe ethyl acetate extract
  8. dry with materialis dried over anhydrous magnesium sulfate
  9. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-f4c56979471d45489ecfcdd01af52ce6
Source dataset
uspto-grants-2001_03
Patent number
US06207862B1

Reaction notes

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