Reaction Steps
The title compound was prepared from diethyl malonate and ethyl acrylate using a procedure similar to that described in J. Org. Chem., 2007, 72, 7455. A solution of diethyl malonate (64 g, 400 mmol), and ethyl acrylate (88 g, 879 mmol) in THF (300 mL) in a 2 L 3-neck round bottom flask, equipped with a thermometer, a mechanical stirrer, a N2 inlet, and a condenser was cooled in a cold water bath (˜10° C.). 500 mL of a 1M THF solution of potassium tert-butoxide measured out for addition to the reaction. The reaction was initiated by very slowly introducing 2-5 mL of this solution to the reaction mixture (exothermic reaction) in order to maintain an internal temperature below 35° C. After the initial vigorous reaction subsided, the remainder of the solution was added drop-wise without a cooling bath over 1.5 h. During this period, the internal temp. remained between 20-28° C. The resulting cloudy amber solution was stirred at room temp. under N2 for 2.5 h, by which time a mass of precipitate had formed. The mixture was diluted with EtOAc (300 mL) and sat'd NH4Cl (200 mL), and then neutralized by the addition of 3N HCl (170 mL). The organic phase was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated to give the title compound (135.2 g, 400 mmol, 100% yield) as an amber oil. HPLC: retention time=3.00 min (AP 81% at λ, =220 nm). LCMS: m/z 315 (M+H). 1H NMR (500 MHz, CDCl3) δ ppm 1.22 (6H, t, J=7.2 Hz, 12,15-CH3), 1.28 (3H, t, J=7.2 Hz, 9-CH3), 2.17 (2H, t, J=6.6 Hz, 5-CH2), 2.34 (2H, t, J=6.4 Hz, 6-CH2), 2.76 (2H, s, 3-CH2), 4.12-4.23 (6H, m, 8,11,14-OCH2), 12.2 (1H, s, 1-OH). 13C NMR (126 MHz, CDCl3) δ ppm 14.1 (12,15-CH3), 14.3 (9-CH3), 26.1 (6-CH2), 26.7 (5-CH2), 27.9 (3-CH2), 53.0 (4-C), 60.6 (8-OCH2), 61.6 (11,14-OCH2), 95.3 (2-C═), 170.2 (1-OC═), 170.8 (10,13-OC═O), 172.0 (7-OC═O).
