428440-11-3

397246-14-9

1. Slowly add acetyl chloride (54.6 mL, 0.75 mol) dropwise to ethanol (316 mL) at 0-5 °C. After the dropwise addition was completed, the ice bath was removed, the solution was stirred and warmed to room temperature, and stirring was continued for 30 minutes. D-aspartic acid (25 g, 0.188 mol) was then added and the reaction mixture was refluxed for 2 hours. Upon completion of the reaction, the solution was concentrated in vacuum and dried overnight under high vacuum (0.4 mmHg) to afford compound 2 (42 g, 99% yield), which was used directly in the next step. 2. Boc2O (44.7 g, 0.21 mol) was added to a 0 °C solution of compound 2 (42 g, 0.19 mol), trimethylamine (51.9 mL, 0.37 mol), dioxane (140 mL), and water (56 mL) in batches over 10 minutes. After addition, stirring was continued for 10 minutes, the ice bath was removed, and the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate (150 mL) and washed sequentially with 0.5N HCl (200 mL x 3). The organic layer was dried with magnesium sulfate, filtered, and the filtrate was concentrated in vacuum to give compound 3 (52 g, 97% yield), which was used directly in the next step. 3. NaBH4 (54.4 g, 1.44 mol) was added to a 0 °C solution of compound 3 (52 g, 86.4 mmol) and ethanol (600 mL) in batches over 30 min. Note that the reaction is exothermic and the temperature needs to be carefully controlled. After addition, the reaction mixture was heated to reflux for 1 hour. After cooling to room temperature, the reaction mixture solidified and was broken into a slurry and poured into brine (250 mL). It was filtered, the filtrate was concentrated in vacuum, the residue was stirred vigorously with ether (200 mL x 5), the ether layer was combined by decantation, dried with magnesium sulfate, filtered, and the filtrate was concentrated in vacuum to give compound 4 (25.2 g, 68% yield). 4. tert-Butyldiphenylchlorosilane (31.9 mL, 0.123 mol) was added to a solution of compound 4 (25.2 g, 0.123 mol) and diisopropylethylamine (42.8 mL), and stirred at room temperature for 24 hours. The reaction solution was washed with 0.5 N HCl (150 mL x 3) and brine (150 mL), the organic layer was dried with magnesium sulfate, filtered and the filtrate was concentrated in vacuum. The residue was purified by fast column chromatography (silica gel, 4:1 hexane:EtOAc) to afford compound 5 (42 g, 77% yield). 5. Iodine (24 g, 94.7 mmol) was added batchwise to a 0 °C solution of compound 5 (28 g, 63.1 mmol), Ph3P (24.8 g, 94.7 mmol), imidazole (6.4 g, 94.7 mmol), ethyl ether (450 mL), and acetonitrile (150 mL) over 15 minutes. The ice bath was removed and warmed to room temperature within 30 min. Upon completion of the reaction (TLC monitoring, 4:1 hexane:EtOAc), the organic layer was quenched with water (400 mL), the organic layer was separated, and the aqueous layer was extracted with ether (100 mL). The organic layers were combined, washed sequentially with saturated aqueous Na2SO3 (100 mL x 2) and brine (100 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuum. The residue was purified by fast column chromatography (silica gel, 4:1 hexane:EtOAc) to afford compound 6 (32 g, 92% yield).