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J. Org. Chem. 1988, 53, 452-455 1 ), 1.2 (t, J = 7.0 Hz, 1.3 ), 1.28 (t, J = 7.0 Hz, 0.7 H), 1.38 (d, J = 6.0 Hz, 1.7 ), 1.55 (d, J = 6.0 Hz, 1.3 ), 4.17-5.92 (m, 6 ), 6.50 (s, 0.2 H), 6.58 (s, 0.2 H), 6.94 (s, 0.3 ), 7.0 (s, 0.3 ), 7.20-7.56 (m, 7 ), 7.71-7.83 (m, 3 H); IR (neat) 1665, 1700 cm"1; MS (FAB), m/e 352 (M 1)+.
IR spectra were recorded on a Perkin-Elmer 727B spectrophotometer. Optical rotations were measured on a JASCO DIP-140 digital polarimeter. Melting points were measured on a Reichert hot stage melting point apparatus. Fast atom bombardment (FAB) mass spectra were obtained on a Finnigan MAT 312 double-focusing mass spectrometer in glycerol-thioglycerol matrix with xenon atom bombardment. High-resolution mass spectra were obtained under similar conditions by peak matching against albuterol. Preparation of (2S,3JZ )-2-Bromo-3-acetoxybutyroyl Chloride (4). Acetyl chloride (6.8 g, 86.9 mmol) was added dropwise to the acid 3 (neat, 15.2 g, 83.1 mmol) with stirring. The reaction mixture was cooled in a bath at 5 °C as exotherm began. After completion of addition, the cooling bath was removed. After 45 min, the mixture was heated at 45-50 °C for 1.5 h. Heating was discontinued, and 10 mL of toluene was added. The mixture was cooled in an ice bath, and oxalyl chloride (11.5 g, 90.4 mmol) was added dropwise. After completion of addition, the mixture was allowed to warm to room temperature, followed by heating at reflux for 30 min. Toluene and excess of reagents were removed by fractonal distillation. The residue was subjected to bulb-to-bulb distillation at 80-90 °C under high vacuum (1 mmHg) to yield 18.4 g (91%) of acid chloride 4: NMR (200 MHz, CDC13) 1.44 (d, J = 6.0 Hz, 3 ), 2.11 (s, 3 H), 4.67 (d, J = 6.0 Hz, 1 H), 5.41 (m, 1 H); IR (neat) 1810, 1790, 1740 cm"1.
Hz,
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(35.45) -l-[Phenylethoxymethyl]-3-(l(S)-hydroxy-
ethyl)-4-benzoyl-2-azetidinone (9), To a solution of epoxy ketone 6 (1.25 g, 3.5 mmol) in 10 mL of dry benzene, cooled in a bath at 8 °C, was added a solution of lithium hexamethyldisilazide in hexanes (Aldrich) (5.3 mL, 5.3 mmol). The reaction mixture was stirred at 8-12 °C for 1.5 h, and 8 mL of 20% aqueous solution of citric acid was added, followed by 20 mL of ethyl acetate. Layers were separated, and the aqueous phase was extracted with ethyl acetate (15 mL). The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to chromatography on silica gel with 30% ethyl acetate in hexanes to give 890 mg (71%) of azetidinone 9. Polar diastereomer: NMR (200 MHz, CDC13) 1.32 (d, J = 7.0 Hz, 3 ), 1.42 (t, J = 6.0 Hz, 3 H), 3.34-3.46 (m, 1 H), 3.65-3.82 (m, 1 ), 3.94-4.10 (m, 1 ), 4.28-4.50 (m, 1 ), 5.30 (d, J = 2.5 Hz, 1 ), 6.14 (s, 1 ), 7.10-7.28 (m, 3 ), 7.30-7.68 (m, 4 H), 7.72-7.84 (m, 3 H); IR (CH2C12) 1685, 1760 cm"1; MS
(FAB), m/e 352 (M 1)+. Less polar diastereomer: NMR (200 MHz, CDC13) 1.16 (d, J = 7.0 Hz, 3 ), 1.18 (t, J = 6.0 Hz, 3 H), 3.33-3.46 (m, 1 ), 3.53-3.70 (m, 1 ), 3.88-4.03 (m, 1 ), 4.13-4.28 (m, 1 H), 4.80 (d, J = 2.0 Hz, 1 ), 6.03 (s, 1 H), 7.26-7.48 (m, 7 H), 7.48-7.86 (m, 3 H); IR (CH2C12) 3550-3650, 3200-3650,1760,1685 cm"1; MS (FAB), m/e 352 (M 1)+. (35.45) -3-(l(JR)-Hydroxyethyl)-4-benzoyl-2-azetidinone (10). To a solution of azetidinone 9 (890 mg, 2.5 mmol) in 2 mL of tetrahydrofuran was added 1 mL of 1 N H2S04. The reaction mixture was stirred at room temperature for 24 h. To this was added 10 mL of ethyl acetate and 10 mL of water. Solid sodium bicarbonate was added until the aqueous phase was neutral. Layers were separated, and the aqueous phase was extracted with ethyl acetate (10 mL). Combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to chromatography over silica gel with 60% ethyl acetate in hexanes to yield 408 mg (74%) of azetidinone 10, which was crystallized from dichloromethane-ether: mp 134-135 °C; [
