Dimethyl Sulfide → 9-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydro-2H-furo[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one

HRID 1478469Notes

Reaction equation

HRID 1478469 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.CSC.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:9][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:5]([CH:13]2[CH:22]3[C:23](=[O:24])[O:25][CH2:26][CH:21]3[CH:20]([OH:27])[C:19]3[C:14]2=[CH:15][C:16]2[O:30][CH2:29][O:28][C:17]=2[CH:18]=3)=[CH:4][C:3]=1[O:2][CH3:1]

Participants

5

Reactant 3

HCID 1068Dimethyl Sulfide2×HCID 6395Methanesulfonic AcidHCID 10607Podophyllotoxin

Product 1

HCID 5001819-Hydroxy-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydro-2H-furo[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-oneYield 5.7%

Reagents, catalysts & solvents 1

HCID 6422Trifluoroacetic acidSolvent

Procedure

10 g (24 mmol) of podophyllotoxin are dissolved in 60 ml of trifluoroacetic acid. 5.4 ml (72 mmol) of dimethyl sulphide and 47 ml (72 mmol) of methanesulphonic acid are successively added. Stirring is maintained for 9 hours, 5.4 ml (72 mmol) of dimethyl sulphide are again added and stirring is maintained for 9 hours. The medium is run quickly onto ice (600 ml) and extracted with ethyl acetate (3×300 ml). The organic phases are washed with water and then with a NaHCO3 solution to neutrality. After drying over sodium sulphate, filtering and evaporating, 6.3 g of crude demethylation product are obtained. Flash chromatography on silica (elution: CH2Cl2/acetone 9/1) makes it possible to isolate 550 mg of 5-(4-hydroxy-3,5-dimethoxyphenyl)-9-hydroxy-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one, that is to say 4′-demethylepipodophyllotoxin of formula (Va). 1.10 g of 5-(3,4-dihydroxy-5-methoxyphenyl)-9-hydroxy-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one (Analysed: C20H18O8.0.15H2O; calculated: C % 61.74, H % 4.74. found: C % 61.67, H % 4.68), and then 1.9 g of 9-hydroxy-5-(3,4,5-trihydroxyphenyl)-5,8,8a,9-tetrahydro-5aH-furo[3′,4′:6,7]naphtho[2,3-d][1,3]dioxol-6-one are also isolated. The latter compound has a proton NMR spectrum with the following characteristics: 1H NMR (d6-DMSO) δ 8.65 (m, 2H), 7.95 (m, 1H), 6.71 (s, 1H, H5), 6.47 (s, 1H, H8), 5.98 (d, 2H, J=2 Hz, OCH2O), 5.93 (s, 2H, H2, H6′), 4.68 (d, 1H, J=3.2 Hz, H4), 4.34 (t, 1, J=8 Hz, H11), 4.29 (d, 1H, J=5.2 Hz, H1), 4.16 (dd, 1H, J=8 Hz, J′=10 Hz, H11b), 3.17 (dd, 1H, J=5.2 Hz and J′=14 Hz, H2), 2.76 (m, 1H, H3).

Workup

  1. temperatureis maintained for 9 hours
  2. stirringstirring
  3. temperatureis maintained for 9 hours
  4. extractionextracted with ethyl acetate (3×300 ml)
  5. washThe organic phases are washed with water
  6. dry with materialAfter drying over sodium sulphate
  7. filtrationfiltering
  8. customevaporating
  9. custom6.3 g of crude demethylation product are obtained

Sources & evidence

ORD record
ord-f4632eccb1264051b62b1388ea14277b
Source dataset
uspto-grants-2016_08
Patent number
US09403840B2

Reaction notes

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