| 77% |
With hydrogenchloride; In water; at 20℃;pH 3.0; |
To a solution of (R)-3-(acetoxymethyl)hexanoic acid (13, 145 mg, 0.78 mmol) in methanol (13mL) potassium carbonate (0.600 g, 4.35 mmol) was added. The reaction mixture was kept at reflux under stirring (3 h), monitoring the reaction progress by TLC (hexane/acetone 8:2) until starting material disappearance. The solvent was removed at reduced pressure (30 mmHg, 40 C) and the residue was taken up with water (6 mL). The solution of hydroxyacid 14 was cooled at 0-5 C and pH was adjusted to 3 by addition of a 1M aqueous hydrogen chloride solution. The solution was stirred at room temperature overnight. The reaction progress was monitored by TLC (hexane/acetone 8:2). The reaction mixture was extracted with dichloromethane (3 Chi 15 mL). The collected organic phases were dried over sodium sulfate; after filtration, the solvent was removed at reduced pressure, to afford crude (R)-4-propyldihydrofuran-2(3H)-one (4, 102 mg) which was purified by silica gelcolumn chromatography. Elution with hexane/acetone 9:1 afforded pure (R)-4 (75 mg, 0.60 mmol, 77%). Rf 0.55 (hexane/acetone 8:2). GC (column: Macherey-Nagel Lipodex E, 25m 250 m; FID detector at 220 C, carrier gas helium; injector 200 C; column inlet pressure 60 kPa; split ratio 1:100 gradient: 68 min run (70 C/1 min, 70 to 122 C/52 min, 122 C/15 min). Rt (R)-lactone 4 57.75 min. The (S)-lactone peak (Rt 58.57 min) is not detectable. 1H-NMR [5,6]: 4.41 (dd, J = 7.3 and 9.2 Hz, Ha-5),3.92 (dd, J = 7.1 and 9.3 Hz, Hb-5), 2.50-2.65 (m, 2H, Ha-3 and H-4), 2.17 (dd, J= 7.8 and 16.1 Hz, Hb-3),1.42-1.49 (m, 2H, CH2-CH), 1.29-1.39 (m, 2H, CH2CH3), 0.93 (t, J = 7.3 Hz, 3H, CH3). 13C-NMR [5,6]:177.2 (C-2), 73.4 (C-5), 35.5 (C-4), 35.3 (CH2-CH), 34.5 (C-3), 20.6 (CH2CH3), 13.9 (CH3). IR [6] 3530.81, 2960.55, 2930.02, 2873.93, 1774.46, 1466.22, 1420.21, 1379.61, 1170.61, 1015.84 cm-1. [alpha]20D + 8.4(c 1, ethanol). For for (S)-enantiomer lit. [5] 5.6 (c 0.9, ethanol), for (R)-enantiomer lit. [6] +6.7 (c 3.9,ethanol). MS (m/z) 150.9 [M + Na]+. |
| 12 g |
With toluene-4-sulfonic acid; In toluene; for 20h;Reflux; |
(3) The compound represented by the formula (IV) (20.3 g, 1 eq.) was suspended in a mixture of 30 mL of ethanol and 10 mL of water, NaOH (3 g) was added, and after refluxing for 20 hours, it was cooled to 0 degree Celsius.After neutralization with 1 N hydrochloric acid, spin-drying was performed to obtain a crude carboxylic acid derivative represented by the intermediate formula (V).The crude product was directly suspended in 300 mL of toluene and p-toluenesulfonic acid (41.3 g, 1.5 equivalents) was added and refluxed overnight.The reaction solution was washed successively with 100 mL of water, 100 mL of a saturated aqueous solution of sodium hydrogencarbonate and 100 mL of saturated saline, and the solvent was spun down to obtain a crude product.Distillation under reduced pressure gave the butyrolactone derivative represented by the formula (I) (12 g, yield: 59%). |
| 7.8 g |
With toluene-4-sulfonic acid; In toluene;Reflux; |
(3) The compound represented by the formula (III) (12.7 g, 1 equivalent) was suspended in a mixture of 30 mL of ethanol and 10 mL of water, NaOH (2 g) was added, refluxed for 20 hours, cooled to 0 degree Celsius, and adjusted with 1N hydrochloric acid. After neutralization, it was spin-dried to give a crude product of the intermediate carboxylic acid derivative represented by formula (IV). The crude product was directly suspended in 200 mL of toluene, p-toluenesulfonic acid (25.8 g, 1.5 equivalents) was added and the mixture was refluxed overnight. The reaction solution was washed successively with 100 mL of water, 100 mL of a saturated aqueous sodium bicarbonate solution, and 100 mL of saturated saline, and the solvent was spin-dried. The crude product was obtained and distilled under reduced pressure to obtain the butyrolactone derivative represented by formula (I) (7.8 g, yield 61%). |
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