Reaction Steps
N-Isopropyl-N,N-diethylamine (8.17 g, 63.4 mmol) was added to a mixture of compound 3 (9.60 g, 31.7 mmol) and t-butyl 3-iodobutyrate [a) V. Chaleix, V. Sol, Y.-M. Huang, M. Guilloton, R. Granet, J. C. Blais, P. Krausz, Eur. J. Org. Chem. 2003, 1486-1493; b) M. P. Glenn, P. Kahnberg, G. M. Boyle, K. A. Hansford, D. Hans, A. C. Martyn, P. G. Parsons, D. P. Fairlie J. Med. Chem. 2004, 47, 2984-2994] (10.7 g, 34.9 mmol) in a screw-cup bottle, and the reaction mixture was stirred at +110° C. (bath temp.) for 4 days. After cooling, the reaction mixture was diluted with diethyl ether, passed through a plug of silica gel (eluting with ether), and the solvents were evaporated in vacuo. The residue was dissolved in a hexane/ether (3/1) mixture, washed with sat. aq. NaHCO3, and the solution was passed again through a plug of silica gel (eluting with hexane/ether (3/1) mixture). According to TLC (hexane/ether=10/1), two spots were detected in the eluate: that of compound 3 (Rf=0.48) and compound 4 (Rf=0.43). After evaporation of solvents in vacuo, the oily residue was distilled in the Kugelrohr distillation apparatus. Compound 4 (4.16 g, 27% yield) was collected at 180° C. (0.6 Torr). The first fraction (4.0 g, b.p. 150° C. at 0.6 Torr) was shown to be compound 3 (ca. 95% pure), and the second one (2.0 g, b.p. 150-180° C. at 0.6 Torr) a mixture of compounds 3 and 4 in ca. 1/3 ratio. 1H NMR (300 MHz, CDCl3): δ=0.21 (s, 6 H, SiMe2But), 0.98 (s, 9 H, SiMe2But), 1.28 (s, 6 H, 2×Me), 1.46 (s, 9 H, CO2But), 1.86 (m, 2 H, NCH2CH2CH2CO2But), 1.95 (d, J=0.5 Hz, 3 H, Me), 2.30 (m, 2 H, NCH2CH2CH2CO2But), 3.20 (m, 2 H, NCH2CH2CH2CO2But), 5.10 (d, J=0.5 Hz, 1 H, HC═), 6.02 (dd, J=1.8 and 0.4 Hz, 1 H), 6.10 (dd, J=8.5 and 1.8 Hz, 1 H), 6.88 (dd, J=8.5 and 0.4 Hz, 1 H) ppm.
