Hydrochloric Acid → (2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4,9b-hexahydro-cyclopenta [c]chromen-8-ol

HRID 732304Notes

Reaction equation

HRID 732304 reaction equation
COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]COC)=[CH:7][C:6]=1[C@@H:15]1[CH2:19][C@H:18]([CH3:20])[CH2:17][C@@H:16]1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29]COC)=[CH:25][CH:24]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([BH3-])#N.[Na+].Cl>CO.BrCOC1C(O)=CC=C(C)C=1.CCOC(C)=O>[OH:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:21]2[C@H:16]3[CH2:17][C@@H:18]([CH3:19])[CH2:20][C@H:15]3[C:6]3[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=3[O:4]2)=[CH:28][CH:27]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 6101p-Toluenesulfonic acidHCID 5003444Sodium cyanoborohydrideHCID 59816181(1S,2R,4S)-[2-(2,5-Bis-methoxymethoxy-phenyl)-4-methyl-cyclopentyl]-(4-methoxymethoxy-phenyl)-methanone

Product 1

HCID 9948127(2S,3aS,4R,9bR)-4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4,9b-hexahydro-cyclopenta [c]chromen-8-olYield 70%

Reagents, catalysts & solvents 3

HCID 86612474BromocreosolCatalystHCID 887MethanolSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of [2-(2,5-bis-methoxymethoxy-phenyl)-4-methyl-cyclopentyl]-(4-methoxymethoxy-phenyl)-methanone 10a (2.6 g, 5.8 mmol) in anhydrous methanol (232 mL) add p-toluenesulfonic acid (1.1 g, 5.8 mmol) and heat the resulting solution to 50° C. for 18 hours under nitrogen. Cool the reaction to ambient temperature and add bromocreosol green (10 mg) and sodium cyanoborohydride (1.82 g, 29.0 mmol). Add methanol saturated with HCl (gas) drop wise until yellow color is maintained. Stir the reaction one hour past the time when no more color change is observed. Quench the reaction with saturated sodium bicarbonate, add EtOAc, and wash the organic solution with sodium bicarbonate and brine. Dry the organic solution over sodium sulfate, concentrate in vacuo, and purify by flash chromatography (silica gel, 0-40% EtOAc/hexanes and 40% ethyl acetate/hexanes) to give 4-(4-Hydroxy-phenyl)-2-methyl-1,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol 11a (1.2 g, 4.0 mmol, 70%). 1H NMR (δ, 400 MHz, MeOD) 7.23 (d, 2H, J=8.4 Hz), 6.77 (d, 2H, J=8.4 Hz), 6.68 (d, 1H, J=8.8 Hz), 6.54 (d, 1H, J=2.6 Hz), 6.50 (dd, 1H, J=8.6, 2.9 Hz), 3.45-3.38 (m, 1H), 2.63-2.55 (m, 1H), 2.52-2.43 (m, 1H), 1.96-1.84 (m, 1H), 1.41-1.32 (m, 1H), 1.23-1.07 (m, 2H), 0.87 (d, 3H, J=6.6 Hz). MS calcd. 295.1; found (electrospray, M−1) 295.1. HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 10.35 min). HPLC (Chiralpak AD, 20-80% IPA/Heptane for 20 min; 1 mL/min; tR=4.37 min).

Workup

  1. temperatureCool
  2. customthe reaction to ambient temperature
  3. customthe reaction one hour past the time when no more color change
  4. customQuench
  5. customthe reaction with saturated sodium bicarbonate
  6. washwash the organic solution with sodium bicarbonate and brine
  7. dry with materialDry the organic solution over sodium sulfate
  8. concentrationconcentrate in vacuo
  9. custompurify by flash chromatography (silica gel, 0-40% EtOAc/hexanes and 40% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-ed38dc924f8e47f99dc270936f456bba
Source dataset
uspto-grants-2009_09
Patent number
US07585985B2

Reaction notes

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