Azidonitration of a double bond; 2-azido saccharide (3,4-di-O-acetyl-2-azido-2,6-dideoxy-D-galactopyranosyl nitrate)

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

Chemicals Used
carbohydrate (3,4-di-O-acetyl-6-deoxy-D-2,3-galactal) (1 equiv.), ceric ammonium nitrate (Avocado, 3 equiv.), sodium azide (Aldrich, 1.5 equiv.), acetonitrile (distilled from calcium hydride, 5 mL/mmol), diethyl ether (5 mL/mmol), water (3 x 2.5 mL/mmol), saturated aqueous sodium hydrogen carbonate (2 x 2.5 mL/mmol)

Procedure
A solution of the carbohydrate (3,4-di-O-acetyl-6-deoxy-D-2,3-galactal) (5.10 g, 23.83 mmol, 1 equiv.) in acetonitrile (128 mL), cooled to -25 ºC, was added dropwise to a mixture of ceric ammonium nitrate (CAN) (39.2 g, 71.50 mmol, 3 equiv.) and sodium azide (2.32 g, 35.75 mmol, 1.5 equiv.) also kept at -25 ºC (under nitrogen). The resulting yellow suspension was allowed to stir for 8 hours at -15 °C until starting material could no longer be detected by thin layer chromatography. To the orange suspension was added diethyl ether (130 mL) at -15 °C resulting in a yellow suspension, followed by water (65 mL) to give a yellow solution. Extraction of the organic layer with cold water (2 x 65 mL) and cold saturated aqueous sodium hydrogen carbonate solution (2 x 65 mL), followed by drying over sodium sulfate and concentration in vacuo gave the crude product. This was purified by flash column chromatography (petroleum ether/ethyl acetate, 5 : 1 to 0 : 1) to give a mixture of alpha, beta and talo-isomers of the desired compound (4.25 g, 56 %, alpha : beta : talo - 59 : 33 : 8). Also isolated was N-acetyl-3,4-di-O-acetyl-2-azido-2,6-dideoxy-alpha-D-galactopyranosylamine (0.74 g, 10 %).

Author's Comments
Some nitrates (e.g. the derivative in this example) are unstable at room temperature (produce nitrogen oxides) and should be stored in the freezer (and away from light). The alpha/beta ratio is dependant on the starting material employed and only small traces of talo-isomer were observed with galactose (see reference) as well as fucose. Moreover it should be noted that the anomer ratios change upon column chromatography. The side product observed (usually <10 %) is due to recation with the solvent employed. It should also be noted that the stereochemical outcome of this transformation is very much dependant on the stereochemistry of the glycal employed and selectivity for the equatorial 2-azido group is not always as good as in this example. This reaction has been carried out on a maximum of 5 g, but has been reported to have been on up to 30 g of starting material for some glycals. In the nmr data the anomeric proton is referred to as H-1.

Data
d_H(300 MHz; CDCl₃) 6.43 (1 H, dd, J 6.5 and 2.0, H-1), 5.55-5.43 (1 H, m, H-4), 5.25 (1 H, dt, J 5.0 and 2.0, H-3), 4.60 (1 H, dt, J 6.5 and 2.0, H-2), 4.18 (1 H, q, J 6.5, H-5), 2.12 (3 H, s, CH₃CO), 1.98 (3 H, s, CH₃CO), 1.24 (3 H, d, J 6.4, CH₃)

Lead Reference
R. U. Lemieux, R. M. Ratcliffe, Can. J. Chem., 1979, 57, 1244

Other References

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