Issue in Honor of Prof. Rosa Lederkremer ARKIVOC 2005 (xii) 282-294
further purification. A portion of the acid (421.2 mg, ~1.8 mmol) was dissolved in DMF
(3.2 mL), and triethylamine (560 µl, 460 mg, 4.0 mmol, 2.2 equiv.) and benzyl chloride (450 µl, 495 mg, 3.92 mmol, 2.2 equiv.) were successively added dropwise at 0°C. The temperature was increased to 45ºC, and the reaction mixture was stirred for 4 h. The reaction was treated with water and extracted with AcOEt (5 x 25 mL). The combined organic layers were washed with 1N HCl (2 x 10 mL), 0.5N NaOH (2 x 10 mL), brine and dried over Na2SO4. The solvent was removed under reduced pressure to give a brown oil (1.06 g) as crude reaction product. The residue was purified by flash column chromatography eluting with hexane and AcOEt. Three fractions were collected: 37.6 mg (5% from 7-ADCA) of the .2-isomerized product 9c, 39.8 mg (5% from 7-ADCA) of the ß-epimer 9b, and 150.0 mg (21% from 7-ADCA) of the expected product 9a. a-Epimer 9a. [a]D25= +86.1 (c 1.6, CHCl3); IR (film) 1773 cm-1 (C=O ester), 1724 cm-1 (C=O lactam) , 1223 cm-1 (ester II band); 1H NMR d 2.05 (s, 3H, CH33'), 3.13 (d, J= 17.8 Hz, 1H, H2), 3.45 (d, J= 17.8 Hz, 1H, H2'), 3.51 (s, 3H, CH3O), 4.49 (d, J= 1.5 Hz, 1H, H7), 4.66 (d, J= 1.5 Hz, 1H, H6), 5.23 (d, J= 12.2 Hz, 1H, CHPh), 5.33 (d, J= 12.2 Hz, 1H, CH'Ph), 7.26-7.45 (m, 5H, Ar); 13C NMR d 19.3 (C3'), 31.2 (C2), 55.8 (C6), 57.8 (CH3O), 67.4 (CH2Ph), 90.2 (C7), 123.6 (C4), 128.2 (Ar), 128.4 (Ar), 128.5 (Ar), 128.8 (Ar), 135.1 (C3), 161.1 and 161.9 (ester and lactam carbonyls). ß-Epimer 9b. [a]D25= +28.3 (c 2.31, CHCl3); IR (film) 1772 cm-1 (C=O ester), 1722 cm-1 (C=O lactam), 1223 cm-1 (ester II band); 1H NMR d 2.13 (s, 3H, CH33'), 3.20 (d, J= 18,5 Hz, 1H, H2), 3.44 (d, J= 18.5 Hz, 1H, H2'), 3.57 (s, 3H, CH3O), 4.90 (s, 2H, H6 and H7), 5.22 (d, J= 12.2 Hz, 1H, CHPh), 5.30 (d, J= 12.2 Hz, 1H, CH'Ph), 7.32-7.40 (m, 5H, Ar); 13C NMR d 20.0 (C3'), 30.3 (C2), 57.6 (CH3O), 59.5 (C6), 67.3 (CH2Ph), 84.8 (C7), 122.4 (C3), 128.2 (Ar), 128.4 (Ar), 128.5 (Ar), 133.1 (C4), 135.2 (Ar), 162.0 and 164.1 (ester and lactam carbonyls). (6S,7R) 7-Methoxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester (10a). To a solution of the crude 7-a-methoxy-3’-deacetoxy-cephalosporanic acid (511.9 mg) in anhydrous chloroform (12 mL) at 0ºC was added triethylamine (350 µl,
2.5 mmol, 1 equiv.). After this, a solution of tetrabutyl ammonium iodide (330 mg, 0.9 mmol, 0.4 equiv.) and benzhydryl bromide (680 mg, 2.8 mmol, 1.1 equiv.) in chloroform (2.4 mL) were added. The mixture was stirred at reflux for 1.5 h. The reaction mixture was then diluted with ethyl acetate (200 mL) and washed with 1N HCl (2 x 5 mL), NaHCO3 5% w/w (2 x 5 mL) and brine. The organic layer was dried over Na2SO4, and solvent was evaporated under reduced pressure to give 1.025 g of brown oil as crude reaction product. A column chromatography was carefully performed eluting with hexane:ethyl acetate. Two fractions were obtained: 76.8 mg (8 % from 7-ADCA) of the .2 isomerized product 10c and 122.6 mg (12% from 7-ADCA) of the desired product 10a. Compound 10a. [a]D25= +57.9 (c 1.25, CHCl3); IR (film) 1769 cm-1 (C=O, ester), 1714 cm-1 (C=O, lactam) , 1223 cm-1 (ester II band); 1H NMR d 2.05 (s, 3H, CH3 3'), 3.15 (d, J= 17,1 Hz, 1H, H2), 3.39 (d, J= 17.1 Hz, 1H, H2'), 3.55 (s, 3H, CH3O), 4.54 (d, J= 1.6 Hz, 1H, H7), 4.69 (d, J= 1.6 Hz, 1H, H6), 6.95 (s, 1H, CH Bzh), 7.25-7,46 (m, 10H, Ar Bzh); 13C NMR d 19.5 (C3'), ISSN 1424-6376 Page 290 ©ARKAT USA, Inc
