Reaction Steps
To a solution of 0.493 g 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-2,2-dimethylpropan-1-one from Step A Example 1 in 20 mL anhydrous THF at −78° C. under nitrogen was added 2.0 mL 2 M LDA in heptane, THF, and ethylbenzene. After 50 minutes, 0.40 g 2,2-dimethylbutanal was added. Remove the cooling bath and let the reaction mixture warm up to room temperature. After 70 minutes, the reaction was quenched by adding 2 mL saturated ammonium chloride and the reaction mixture was evaporated under reduced pressure to remove solvents. Dilute the residue with ether, wash with 1 M HCl (2×) and saturated brine, dry over anhydrous Na2SO4, and evaporate to give a crude product. It was purified on RP-HPLC using 65˜100% MeCN in water without TFA to give the title compound as colorless solid after lyophilization. 1H NMR (CDCl3, 500 MHz) 7.44 (d, 9.1 Hz, 1H), 7.20 (d, 2.0 Hz, 1H), 7.10 (dd, 2.5 & 9.1 Hz, 1H), 3.86 (s, 3H), 3.58 (dd, 1.6 & 10.6 Hz, 1H), 3.29˜3.34 (m, 1H), 2.90˜2.95 (m, 1H), 1.51˜1.59 (m, 1H), 1.39˜1.46 (m, 1H), 1.40 (s, 9H), 1.02 (s, 3H), 1.01 (s, 3H), 0.92 (t, 7.6 Hz, 3H). LC-MS: 4.47 min. (m/Z=329.3, 369.2, 347). A faster-eluting isomeric side-product was also isolated during purification and was identified as 1-[2-(1-hydroxy-2,2-dimethylpropyl)-5-methoxy-1-benzofuran-3-yl]-3,3-dimethylpentan-2-one. 1H NMR (CDCl3, 500 MHz) 7.30 (d, 9.0 Hz, 1H), 6.84 (dd, 2.5 & 8.9 Hz, 1H), 6.75 (d, 2.5 Hz, 1H), 4.44 (s, 1H), 4.07 (AB d, 18.5 Hz, 1H), 4.04 (AB d, 18.5 Hz, 1H), 3.78 (s, 3H). 1.74 (q, 7.6 Hz, 2H), 1.263 (s, 3H), 1.260 (s, 3H), 0.99 (s, 9H), 0.91 (t, 7.4 Hz, 3H). LC-MS: 3.95 min. (m/Z=369.3=M+Na, 329.3,).
