Reaction Steps
To a mixture of N-methyl morpholine-N-oxide (146.2 g, 60% in water, 0.749 mol) and osmium tetroxide (9.75 g, 2.5% in tert-butanol, 0.959 mmol) in acetone (1 L) stirring at -8° C. in an ice-acetone bath was added in one portion (-)-(1R,4S)-tert-butyl N-[4-hydroxymethyl)-2-cyclopenten-1-yl]carbamate (152.10 g, 0.7132 mol, from Example 24). The resulting mixture was allowed to warm to room temperature over 16 hours, during which time it became homogeneous. More osmium tetroxide was added (2.602 g, 0.256 mmol), and the solution was stirred at 20° C. for four hours, then 40° for two hours, at which time the reaction was judged complete by TLC (silica, 10% methanol-chloroform, visualization with iodine followed by vanillin char, starting material: Rf =0.51, products: Rf =0.22, (2S,3R)-isomer, and Rf =0.36, (2R,3S)-isomer). The ratio of (2S, 3R)/(2R,3S) isomers was about 73:27 as judged by 1H-NMR and TLC. Water (75 mL) was added, followed by chloroform (2 L). The resulting two-phase mixture was cooled in an ice bath, and with very gentle agitation (to discourage phase mixing), anhydrous copper sulfate (457.8 g, Alfa) was added in several portions. The resulting slurry was allowed to stir at room temperature about 16 hours, then was filtered with filter aids (Celite 545 and 512). The cake was washed with tetrahydrofuran (6 L) until no more product eluted. The filtrate was evaporated under vacuum to a dark oil substantially free of N-methyl morpholine. The oil was filtered through silica gel (300 g), and eluted with tetrahydrofuran (3 L) until all of the product was eluted. The eluate was concentrated to 200 mL, and hexanes (about 300 mL) was added. Crystallization began spontaneously, and was allowed to continue at -5° C. for about 16 hours. The crystals were recovered by filtration, washed sparingly with 50% ethyl acetate-hexanes, and dried by suction to a constant weight (105.78 g, 0.428 mol, 60.0% of theoretical). Recrystallization from refluxing ethyl acetate (200 mL) provided the title compound as white crystals (93.85 g, 0.3795 mol, 53.2% of theoretical); m.p. 115.8°-117°; 1H-NMR (DMSO-d6) δ: 6.71 (br d, J=7.4 Hz, 1H, NH), 4.52 (t, J=5.2 Hz, 1H, CH2OH), 4.43 (d, J=5.1 Hz, 1H, CHOH), 4.31 (d, J=4.9 Hz, 1H, CHOH), 3.54-3.41 (overlapping multiplet, 3H, CHN and CHOH), 3.34 (m, overlapping with HOD, w1/2=20 Hz, CH2OH), 1.99 (dt, J=12.5, 6.8, 6.8 Hz, 1H, HOCH2CH), 1.85 (br. m, w1/2=30 Hz, 1H, 1/2CH2), 1.39 (s, 9H, C(CH3 )3), 0.98 (dt, J=12.4, 7.8, 7.8 Hz, 1H, 1/2CH2); [α]20589 -8.08°, [α]20578 -8.57°, [α]20546 -9.95°, [α]20436 -18.22°, [α]20365 -29.36° (c=1.02, methanol); CI-MS (CH4) 248(M+1).
