Reaction Steps
A reaction mixture of (S)—N-(2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide (0.38 g, 0.83 mmol) and 3,4,5-triacetoxy-6-(2,2,2-trichloro-acetimidoyloxy)-tetrahydro-pyran-2-carboxylic acid benzyl ester (0.46 g, 0.83 mmol) in dichloromethane (40 mL) was chilled to −15° C. to −20° C., treated with BF3.OEt2 (0.10 mL, 0.83 mmol), and stirred for 2 hours at −15° C. to −20° C. After 2 hours, the reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (10 vol) then washed with saturated aqueous NaHCO3 (5 vol), 2% NaCl (5 vol), dried (MgSO4), and concentrated. The crude mixture was eluted through a 120 g ISCO column, 5% to 20% EtOAc/CH2Cl2. After concentration of the fractions, the product was dried under vacuum for 12 hours, which afforded (2S,3S,4S,5R,6S)-2-(benzyloxycarbonyl)-6-(4-((S)-1-(7-(cyclopropanecarboxamido)-1-oxoisoindolin-2-yl)-2-(methylsulfonyl)ethyl)-2-ethoxyphenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (250 mg, 56% yield) as a light yellow solid: 1H-NMR (DMSO-d6): 10.4 (s, 1H), 8.26-8.23 (d, J=8 Hz, 1H), 7.53-7.48 (t, J=7 Hz, 1H), 7.39-7.31 (m, 5H), 7.20-7.18 (d, J=7 Hz, 1H), 7.13-7.12 (d, J=2 Hz, 1H), 7.09-7.07 (d, J=9 Hz, 1H), 6.95-6.92 (dd, J=1.8 Hz, 1H), 5.9-5.88 (dd, J=4, 10 Hz, 1H), 5.44-5.37 (overlapping d and t, Jd=8 Hz, Jt=10 Hz, 2H), 5.17-5.03 (m, 4H), 4.70-4.63 (m, 2H), 4.38-4.30 (m, 1H), 4.21-4.15 (d, J=18 Hz, 1H), 4.08-3.95 (m, 3H), 3.04 (s, 3H), 2.00 (s, 3H), 1.97 (s, 3H), 1.81-1.76 (m, 4H), 1.32-1.27 (t, J=7 Hz, 3H), 0.89-0.86 (d, J=6 Hz, 4H). HPLC: Waters Nova-Pak C18 column, 150×3.9 mm, 4 μm; Gradient CH3CN/0.1% aq H3PO4 10/90 to 90/10 in 20 min, 1.0 mL/min, tR 14.022 min, 98.5 AP at 240 nm.
