Reaction Steps
Step 1. To a solution of thiomorpholine (1.0 g, 9.7 mmol) and 1-chloro-3-iodopropane (1.98 g, 9.7 mmol) in dry THF (30 ml) was added activated zinc powder (0.64 g, 9.7 g atom). After the mixture was stirred at rt overnight, it was filtered, washed with EtOAc (20 ml), and concentrated. The residue was dissolved in EtOAc (50 ml), washed with 10% aq. NaHCO3 (10 ml), water (2×10 ml), dried over MgSO4, and concentrated. The residue was dissolved in ether (20 ml) before a 1 M ethereal HCl solution (9.7 ml, 9.7 mmol) was added dropwise at 0° C. The resulting precipitate was filtered, washed with ether (2×10 ml), and dried to afford 4-(3-chloropropyl)thiomorpholine hydrochloride (0.40 g, 19%) as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 2.20-2.25 (m, 2H), 2.78-2.81 (m, 2H), 3.09-3.27 (m, 6H), 3.68-3.71 (m, 2H), 3.74 (t, J=6.4 Hz, 2H), 11.20 (brs, 1H). Step 2. To a solution of OZ288 (0.38 g, 1.07 mmol) in dry acetonitrile (50 ml) were added powdered NaOH (0.09 g, 2.13 mmol) and tetrabutylammonium hydrogensulfate (0.07 g, 0.21 mmol). After the mixture was stirred at rt for 30 min, 4-(3-chloropropyl)thiomorpholine hydrochloride (0.23 g, 1.07 mmol) was added. The mixture was stirred at 60° C. overnight before the inorganic solid was filtered off and washed with EtOAc (2×25 ml). After removal of the solvents in vacuo, the residue was dissolved in EtOAc (50 ml). The organic layer was washed with water, brine, dried over MgSO4, and concentrated to afford OZ462 free base (0.433 g, 81%) as a colorless solid. To a solution of the above free base (0.41 g, 0.82 mmol) in EtOAc (10 ml) at 0° C. was added dropwise a solution of methanesulfonic acid (0.08 g, 0.82 mmol) in ether (10 ml). The resulting precipitate was filtered, washed with ether (25 ml), and dried under vacuum at 40° C. to afford trioxolane OZ462 (0.42 g, 86%) as a colorless solid. mp 156-158° C.; 1H NMR (500 MHz, CDCl3) δ 1.64-2.08 (m, 22H), 2.32-2.41 (m, 2H), 2.46-2.54 (m, 1H), 2.70 (d, J=14.7 Hz, 2H), 2.80 (s, 3H), 2.96-3.07 (m, 2H), 3.24-3.34 (m, 2H), 3.45-3.54 (m, 2H), 3.87 (d, J=11.8 Hz, 2H), 4.06 (t, J=5.4 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.3 Hz, 2H), 11.19 (brs, 1H); 13C NMR (125.7 MHz, CDCl3) δ 23.66, 24.86, 26.44, 26.84, 31.57, 34.66, 34.76, 36.37, 36.75, 39.42, 41.97, 54.35, 56.23, 64.61, 108.32, 111.36, 114.22, 127.74, 139.14, 156.40. Anal. Calcd for C30H45NO7S2: C, 60.48; H, 7.61; N, 2.35. Found: C, 60.60; H, 7.54; N, 2.17.
