Protection of an alcohol as a carboxylic ester; acetate (1,2,3,4-tetra-O-acetyl-6-deoxy-D-galactose)

Melanie Reich ([email protected]),
A contribution from the Caddick Group, Sussex

Chemicals Used
alcohol (D-fucose) (prepared, 1 equiv.), acetic anhydride (Avocado, 1.5 equiv./hydroxyl group), pyridine (Avocado, 0.2 equiv.), dichloromethane (GPR, 4 mL/mmol), saturated bicarbonate solution (2 x 1.5 mL/mmol), water (1 mL/mmol), brine (1 mL/mmol)

Procedure
To a suspension of the alcohol (D-fucose) (6.11 mmol) in acetic anhydride (35 mL, 37.41 g, 36.64 mmol, 6 equiv.) was added a catalytic amount of pyridine (1.0 mL, 0.97 g, 12.21 mmol, 0.2 equiv.). Additional sugar (54.96 mmol) was added to the resulting white suspension in portions keeping the internal temperature between 30 and 40 °C (if necessary by cooling in a cold water or ice-bath). After addition was complete the reaction mixture was allowed to stir at room temperature. After 24 hours, when the reaction mixture had turned clear and colourless, dichloromethane (250 mL) was added, followed by extraction with saturated sodium bicarbonate solution (2 x 100 mL), water (50 mL) and brine (50 mL). The organic fraction was dried over sodium sulfate and the solvent removed in vacuo to give the crude product consisting of both anomers of the protected sugar (20.2 g, > 99 %, beta : alpha (2 : 1)). Separation of the 2 anomers can be achieved by flash column chromatography (petroleum ether/ethyl acetate, 5 : 1).

Author's Comments
This transformation has been carried out numerous times on 1 to 10 g of fucose, always in quantitative yield from the corresponding isopropylidene protected sugar (over 2 seps). It should however be noted that this protection can also be carried out utilising other Lewis acids, such as perchloric acid (70 % aqueous) [more exothermic, faster reaction] and hydrobromic acid (in acetic acid) [slower reaction] to give alpha-sugars only (see other references). Those methods usually work very well (e.g. galactose, literature yields were achieved), but are incompatible with the crude sugar employed in this procedure. In the nmr data the anomeric proton is referred to as H-1.

Data
beta-isomer: d_H(300 MHz; CDCl₃) 5.65 (1 H, d, J 8.5, H-1), 5.29 (1 H, dd, J 10.5 and 8.5, H-2), 5.24 (1 H, dd, J 3.5 and 1.0, H-4), 5.04 (1 H, dd, J 10.5 and 3.5, H-3), 3.93 (1 H, qd, J 6.5 and 1.0, H-5), 2.16 (3 H, s, CH₃CO), 2.09 (3 H, s, CH₃CO), 2.01 (3 H, s, CH₃CO), 1.96 (3 H, s, CH₃CO), 1.20 (3 H, d, J 6.5, CH₃); alpha-isomer: d_H(300 MHz; CDCl₃) 6.30 (1 H, d, J 2.5, H-1), 5.32-5.28 (3 H, m, H-2, H-3 and H-4), 4.24 (1 H, q, J 6.5, H-5), 2.15 (3 H, s, CH₃CO), 2.11 (3 H, s, CH₃CO), 1.98 (3 H, s, CH₃CO), 1.97 (3 H, s, CH₃CO), 1.12 (3 H, d, J 6.5, CH₃)

Lead Reference
B. Iselin, T. Reichstein, Helv. Chim. Acta, 1944, 27, 1200

Other References
(a) A. P. Kozikowski, J. Lee, J. Org. Chem., 1990, 55, 863 (perchloric acid); (b) B. K. Shull, B. K., Z. Wu, M. Koreeda, J. Carbohydr. Chem., 1996, 15, 8, 955 (hydrobromic acid)

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