SYNTHESIS OF 1,2-O-CYCLOHEXYLIDENE-𝛼-D-GLUCOFURANOSE

• Heat a solution of 20 g (0.06 mol) of l,2:di-0-cyclohexylidene-𝛼-D-glucofuranose in 100ml of aqueous acetic acid (75% v/v) in a round-bottomed flask immersed in a hot-water bath held at 70-80 °C for 90 minutes with intermittent shaking; then remove the solvent under reduced pressure on a rotary evaporator. 

• To the residual syrup add 20 ml of hot water, then sufficient solid sodium hydrogen carbonate to neutralise the remaining acetic acid, and finally 90 ml of heptane. 

• Heat the heterogeneous liquid mixture until two clear layers are obtained and then remove the upper heptane layer by careful decantation (1). 

• Cool the aqueous layer to 0°C, filter off the crystals of 1,2-O-cyclohexylidene-𝛼-D-glucofuranose which separate and recrystallise from water to give the pure product, m.p. 149-150 °C, [𝛼]ᴅ²⁰ + 5.9° (c1 in Me₂CO). The yield is 11.5 g (75%).

Notes to keep in mind: 

1.  The solid which separates from the cooled heptane layer may be shown to be unchanged starting material by t.l.c. analysis on silica gel plates using methanol-benzene (4:96) as the developing solvent.

Cognate preparation: 3-O-Benzyl-l,2-O-cyclohexylidene-𝛼-D-glucofuranose

• Dissolve 100g (0.23 mol) of 3-O-benzyl-l,2:5,6-di-O-cyclohexylidene-𝛼-D- glucofuranose in 400 ml of aqueous acetic acid (75% v/v) maintained at 70-80 °C for 3 hours, remove the solvent under reduced pressure and dissolve the residual oil in 500 ml of dichloromethane. 

• Wash this solution with aqueous sodium hydrogen carbonate and with water, dry over calcium sulphate and remove the dichloromethane by evaporation under reduced pressure with a rotary evaporator. 

• Remove the last traces of solvent using an oil rotary immersion pump, transfer the warm fluid yellow syrup to the retort of a molecular still and distil using a vapour diffusion pump to give a pale yellow glass, b.p. 195-200 °C/2 x 10⁻³ mmHg, [𝛼]ᴅ²⁰ -36.4° (c4 in CHC1₃). 

• The yield is 76 g (94%), and the product is pure enough for most purposes. 

• However t.l.c. analysis on silica gel plates (solvent system; benzene-methanol 9:1) reveals one major and two minor components. 

• Purification may be effected by either of the two methods described below.

Method 1: Chromatographic purification of 3-O-benzyl-l ,2-O-cyclohexylidene-𝛼-D-glucofuranose. (The chromatographic column should be set up in a fume cupboard.)

• Prepare a silica gel column using benzene as a solvent; use 10 g of adsorbent for each 1 g of monosaccharide derivative to be chromatographed. 

• Dissolve the latter in the smallest volume of benzene and transfer the solution to the chromatographic column with a pipette. 

• Elute the column with benzene and collect suitable-sized fractions; evaporate the solvent from each fraction and weigh the residues which consist of 3-O-benzyl-l,2:5,6-di-O-cyclohexylidene-𝛼-D-glucofuranose. 

• When all of this has been eluted continue the development with methanol which elutes the required product. 

• Evaporate the methanol and distil the residual syrup using a molecular still; about 50 per cent recovery of the purified product may be expected.

Method 2: Purification of 3-O-benzyl-l,2-O-cyclohexylidene-𝛼-D-glucofuranose by benzoylation

• Dissolve 5 g of the crude product in 10 ml of pure dry pyridine and add 5 g of benzoyl chloride. 

• Leave the reaction mixture overnight at room temperature, pour it on to ice and stir thoroughly. 

• Extract the oil which separates into 50 ml of dichloromethane and wash the dichloromethane solution successively with 30 ml of ice-cold dilute aqueous hydrochloric acid (2 m), 30 ml of saturated aqueous sodium hydrogen carbonate, and 2 x 30 ml of water. 

• Dry over sodium sulphate and evaporate the dichloromethane. 

• The viscous oil crystallises on trituration with methanol and is recrystallised from methanol to give the pure derivative 5,6-di-O-benzoyl-3-O-benzyl- 1,2-O-cyclohexylidene-𝛼-D-glucofuranose, m.p. 104-106 °C,  [𝛼]ᴅ²⁰ — 26.4° (c1 in CHC1₃), in a yield of 3.6 g (57%). 

• Remove the benzoyl groups by dissolving 3 g of the foregoing product in 20 ml of methanol and adding 20 ml of a solution of sodium methoxide in methanol (0.5%). 

• After 2 hours neutralise the solution by adding ion exchange resin Zeolite 225 (H⊗), filter and evaporate. 

• Distil the resulting colourless oil in a molecular still to obtain chromatographically pure 3-O-benzyl-l,2-O-cyclohexylidene-𝛼-D-glucofuranose; the yield is 1.6 g (70% from the dibenzoate).