Ethanol → (2S,3R,4S,5S)-2-[4-Chloro-3-(4-hydroxy-benzyl)-phenyl]-6,6-bis-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol

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A solution of methyl 1-C-[4-chloro-3-(4-{[(2,6-dichlorophenyl)sulfonyl]oxy}benzyl)phenyl]-6-O-[(2,6-dichlorophenyl)sulfonyl]-alpha-D-glucopyranoside (7 g, 8.44 mmol) dissolved in dimethylsulfoxide (35.3 mL) was placed in a pre-dried 250 mL three neck round bottom flask equipped with a thermometer to monitor internal temperature. To this solution was added 2,4,6-collidine (5.6 mL, 42.2 mmol) and the reaction mixture was heated at 127 degrees Celsius. The internal temperature reached 123 degrees Celsius after 20 minutes, at which point the heating block was turned off and after an additional 20 minutes the flask was removed from the heating block and the reaction mixture was cooled to room temperature and used in the next step without further work-up or purification. To the above crude solution was added ethanol (70 mL) and the resulting mixture was heated at 55 degrees Celsius. Paraformaldehdye (5090 mg, 169 mmol) was added followed by the addition of 21% sodium ethoxide solution in denatured ethanol (15.8 mL, 42.4 mmol) and the resulting mixture was allowed to stir at 55 degrees Celsius for 16 hours before being cooled to room temperature. The reaction was quenched by the addition of water (125 mL) containing 18 equivalents of NaHSO3 and the resulting mixture was stirred for 90 minutes. The volatiles were removed under reduced pressure. Water (625 mL) was added and the resulting mixture was extracted with ethyl acetate (250 mL). The aqueous layer was extracted 4 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The reaction was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (two 120 g silica gel columns) and eluting with a gradient of 5 to 25% methanol in dichloromethane. The crude material was purified by preparative HPLC on a Phenomenex HILIC(Diol) 250×21.2 mm 5 micrometer column eluting with a flow rate of 28 mL/minute; mobile phases A: Heptane and B: Ethanol. The product was eluted using a gradient of 5% ethanol for 1.5 minutes and increased in a linear gradient to 100% ethanol over 8.5 minutes to give the product (586 mg, 16% yield, retention time=9.8 minutes). UV detection: 220 nm. LCMS 439 (M−H+; negative mode) 1H NMR (400 MHz, METHANOL-d4) delta ppm 3.03 (d, J=9.6 Hz, 1H), 3.09 (s, 3H), 3.74 (d, J=10.0 Hz, 1H), 3.80 (d, J=11.9 Hz, 1H), 3.87-3.97 (m, 4H), 4.00-4.07 (m, 1H), 4.14 (d, J=11.5 Hz, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.45 (dd, J=8.4, 2.0 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H).

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