Reaction Steps
To a solution of tert-butyl ((3aR,5S,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.320 g, 0.754 mmol) and TMSCF3 (0.208 g, 1.46 mmol) in anhydrous THF (8 mL) was added TBAF (1.0 M in THF, 0.030 mL, 0.030 mmol). After addition the reaction mixture was stirred at room temperature for 2 h. Another batch of TBAF (1.0 M in THF, 1.0 mL, 1.0 mmol) was added, and the mixture was stirred at room temperature for another 2 h. The reaction solution was then diluted with EtOAc (20 mL) and brine (30 mL). The organic layer was collected, and the aqueous was extracted with EtOAc (20 mL). The combined extract was dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:2), affording tert-butyl ((3aR,5R,6S,7R,7aR)-6-(benzyloxy)-7-fluoro-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate as a pale yellow foam, with a 6.8:1 mixture of diastereomers based on 1H NMR. To a solution of the yellow foam and PMB (0.20 g, 1.3 mmol) in anhydrous DCM (6 mL) at −78° C. under N2, was added BCl3 (1.0 M in DCM, 2.0 mL, 2.0 mmol). The mixture was stirred for ˜3 h while the temperature of the cooling bath slowly warmed to room temperature. The reaction mixture was cooled at −78° C., quenched with mixed MeOH/DCM, and then concentrated to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/DCM, 1:10), affording (3aR,5S,6S,7R,7aR)-7-fluoro-2-(methylamino)-5-(R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol as a white solid (0.118 g, 77%) with a diastereomeric ratio of 6.8:1 based on 1H NMR. This mixture was separated by Prep-HPLC with the following conditions: Column, XBridge Prep. C18, 19×150 mm; mobile phase, water with 0.05% NH4OH and CH3CN (from 5% to 25% in 10 min); Dectector, UV 220 nm, to give (3aR,5S,6S,7R,7aR)-7-fluoro-2-(methylamino)-5-((S)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (the faster eluting isomer) as white solid (65 mg, 28% overall yield), 1H NMR (300 MHz, CD3OD) δ 6.46 (d, J=6.3 Hz, 1H), 4.66 (td, J=3.0, 48.3 Hz, 1H), 4.44-4.42 (m, 3H), 4.12 (d, J=6.0 Hz, 1H), 2.85 (s, 3H), MS, (ES, m/z) [M+H]+ 305.0; and (3aR,5S,6S,7R,7aR)-7-fluoro-2-(methylamino)-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-6-ol (the slower eluting isomer) (6.5 mg, 2.8% overall yield), 1H NMR (300 MHz, CD3OD) δ 6.41 (d, J=6.3 Hz, 1H), 4.63 (td, J=3.3, 48.0 Hz, 1H), 4.36-4.19 (m, 3H), 4.08-4.05 (m, 1H), 2.85 (s, 3H). (ES, m/z) [M+H]+ 305.0.
