(3aR,4S,6aS)-2,3,3a,4,5,6a-hexahydrofuro[2,3-b]furan-4-ol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of lithium aluminum hydride (15 mg) dispersed in THF (0.2 mL) was added dropwise a solution of (3aR,6aS)-hekahydrofuro[2,3-b]furan-3-on (64 mg) obtained in Example 28 in THF (0.5 mL) at 0° C. and the mixture was stirred for 1 hr. Water (0.1 mL), 15% aqueous sodium hydroxide solution (0.1 mL) and water (0.3 mL) were successively added to the reaction mixture every 30 min and the mixture was filtered and washed well with THF. The filtrate was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated to give the title compound (57 mg, 88% ee) as an oil, which was an almost pure anti-form. The spectrum data were the same as those in Example 27. the mixture was filtered washed well with THF The filtrate was dried over anhydrous magnesium sulfate filtered the solvent was evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of lithium aluminum hydride (15 mg) dispersed in THF (0.2 mL) was added dropwise a solution of (3aR,6aS)-hekahydrofuro[2,3-b]furan-3-on (64 mg) obtained in Example 28 in THF (0.5 mL) at 0° C. and the mixture was stirred for 1 hr. Water (0.1 mL), 15% aqueous sodium hydroxide solution (0.1 mL) and water (0.3 mL) were successively added to the reaction mixture every 30 min and the mixture was filtered and washed well with THF. The filtrate was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated to give the title compound (57 mg, 88% ee) as an oil, which was an almost pure anti-form. The spectrum data were the same as those in Example 27. the mixture was filtered washed well with THF The filtrate was dried over anhydrous magnesium sulfate filtered the solvent was evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture (287 g, content 69.7%, 1.54 mol) containing (3R,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol, (3S,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol, (3S,3aR,6aS)-hexahydrofuro[2,3,b]furan-3-ol and (3R,3aR,6aS)-hexahydrofuro[2,3,b]furan-3-ol obtained by the same method as in Example 4 was dissolved in methyl ethyl ketone (2000 ml), and to this was added a solution prepared by dissolving dipotassium hydrogen phosphate (937 g, 5.38 mmol) in water (600 ml). To this was added 2,2,6,6-tetramethylpiperidinyl-1-oxy (1.2 g, 7.7 mmol), and the mixture was cooled to about 0° C. A sodium hypochlorite aqueous solution (1490 g, effective chlorine concentration 13.5%, 2.83 mol) was dropped at 15° C. or less, and the mixture was stirred for 1 hour. After completion of the reaction, a 10% sodium thiosulfate aqueous solution (220 ml) was added and the mixture was stirred for 30 minutes and neutralized with 85% phosphoric acid, and liquid-partitioned. Further, the aqueous layer was extracted twice with methyl ethyl ketone (1000 ml) and the organic layers were combined. To the organic layer was added 1.0 g of hydroquinone, and 3000 ml of the solvent was distilled off. To the concentrated residue was added anhydrous magnesium sulfate (30 g), sodium bicarbonate (20 g) and activated carbon (10 g) and the mixture was stirred for 1 hour. Magnesium sulfate, sodium bicarbonate and activated carbon were filtrated, then, 2-propanol (3000 ml) was added, and the solvent (3300 ml) was distilled off, then, recrystallization was carried out to obtain a white crystal (3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (156.5 g, purity 99.5%, yield 79.1%). At this stage, the enantiomer excess was 100% ee. obtained by the same method as in Example 4 to this was added a solution prepared To this was added 2,2,6,6-tetramethylpiperidinyl-1-oxy (1.2 g, 7.7 mmol) After completion of the reaction the mixture was stirred for 30 minutes liquid-partitioned Further, the aqueous layer was extracted twice with methyl ethyl ketone (1000 ml) To the organic layer was added 1.0 g of hydroquinone, and 3000 ml of the solvent was distilled off To the concentrated residue was added anhydrous magnesium sulfate (30 g), sodium bicarbonate (20 g) and activated carbon (10 g) the mixture was stirred for 1 hour Magnesium sulfate, sodium bicarbonate and activated carbon were filtrated 2-propanol (3000 ml) was added the solvent (3300 ml) was distilled off recrystallization

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture (287 g, content 69.7%, 1.54 mol) containing (3R,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol, (3S,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol, (3S,3aR,6aS)-hexahydrofuro[2,3,b]furan-3-ol and (3R,3aR,6aS)-hexahydrofuro[2,3,b]furan-3-ol obtained by the same method as in Example 4 was dissolved in methyl ethyl ketone (2000 ml), and to this was added a solution prepared by dissolving dipotassium hydrogen phosphate (937 g, 5.38 mmol) in water (600 ml). To this was added 2,2,6,6-tetramethylpiperidinyl-1-oxy (1.2 g, 7.7 mmol), and the mixture was cooled to about 0° C. A sodium hypochlorite aqueous solution (1490 g, effective chlorine concentration 13.5%, 2.83 mol) was dropped at 15° C. or less, and the mixture was stirred for 1 hour. After completion of the reaction, a 10% sodium thiosulfate aqueous solution (220 ml) was added and the mixture was stirred for 30 minutes and neutralized with 85% phosphoric acid, and liquid-partitioned. Further, the aqueous layer was extracted twice with methyl ethyl ketone (1000 ml) and the organic layers were combined. To the organic layer was added 1.0 g of hydroquinone, and 3000 ml of the solvent was distilled off. To the concentrated residue was added anhydrous magnesium sulfate (30 g), sodium bicarbonate (20 g) and activated carbon (10 g) and the mixture was stirred for 1 hour. Magnesium sulfate, sodium bicarbonate and activated carbon were filtrated, then, 2-propanol (3000 ml) was added, and the solvent (3300 ml) was distilled off, then, recrystallization was carried out to obtain a white crystal (3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (156.5 g, purity 99.5%, yield 79.1%). At this stage, the enantiomer excess was 100% ee. obtained by the same method as in Example 4 to this was added a solution prepared To this was added 2,2,6,6-tetramethylpiperidinyl-1-oxy (1.2 g, 7.7 mmol) After completion of the reaction the mixture was stirred for 30 minutes liquid-partitioned Further, the aqueous layer was extracted twice with methyl ethyl ketone (1000 ml) To the organic layer was added 1.0 g of hydroquinone, and 3000 ml of the solvent was distilled off To the concentrated residue was added anhydrous magnesium sulfate (30 g), sodium bicarbonate (20 g) and activated carbon (10 g) the mixture was stirred for 1 hour Magnesium sulfate, sodium bicarbonate and activated carbon were filtrated 2-propanol (3000 ml) was added the solvent (3300 ml) was distilled off recrystallization

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: are known. Ghosh et al. in J. Med. Chem. 1996, 39(17), 3278–3290, describe an enantioselective synthesis to obtain both (3R,3aS,6aR) and (3S,3aR,6aS) hexahydro-furo[2,3-b]furan-3-ol in optically pure form starting from 3(R)-diethyl malate and 3(S)-diethyl malate respectively. This process comprises several steps such as an allylation step using lithium diisopropyl amide, followed by a reduction step, and further a Swern oxidation step followed by an ozonolytic cleavage and a hydroboration step using 9-borabicyclo[3.3.1]nonane (9-BBN). Ghosh et al. also disclose a racemic synthesis of both the (3R,3aS,6aR) and (3S,3aR,6aS) enantiomers of hexahydrofuro[2,3-]furan-3-ol followed by an enzymatic resolution of the final product. This latter synthesis starts from 2,3-dihydrofuran and comprises the step of treating said intermediate with N-iodosuccinimide and allyl alcohol followed by a radical cyclisation in the presence of a catalyst i.e. cobaloxime. An ozonolytic cleavage followed by a reduction step furnished the racemic hexahydro-furo[2,3-b]furan-3-ol. Optically active compound (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol is obtained after enzymatic resolution followed by silica gel chromatography. Pezeck et al. Tetrahedron Lett. 1986, 27, 3715–3718 also describes a route for the synthesis of hexahydro-furo[2,3-b]-furan-3-ol using ozonolysis. Hexahydro-furo[2,3-b]furan-3-ol is also described as an intermediate in the synthesis of optically active perhydrofuro[2,3-b]furan derivatives (Uchiyama et al., Tetrahedron Lett. 2001, 42, 4653–4656.). The key step in this procedure is the oxyselenenylation of 2,3-dihydrofuran. This procedure is suitable for use at the laboratory level, yet not amenable for scaling up. Although the two synthetic routes described by Ghosh et al. provide (3R,3aS,6aR) and (3S,3aR,6aS) hexahydro-furo[2,3-b]furan-3-ol in reasonable yields and high enantiomeric excess, they both are only feasible on a laboratory scale, but, for a number of reasons, are not amenable to industrial scaling up. For example, these known routes suffer from the disadvantage of utilizing expensive materials, heavy metals and rare compounds, such as the N-iodosuccinimide, the catalyst cobaloxime, lithium diisopropyl amide and 9-BBN. The necessary ozonolysis step has the disadvantage of producing highly reactive and shock-sensitive ozonides and peroxides making this step too dangerous to be applied on industrial scale. Furthermore ozonolysis as well as Swern oxidation are highly exothermic and, as a consequence, have to be performed at very low temperatures. The racemic route needs an enzymatic resolution in the final step of the synthesis followed by silica gel purification. Furthermore, the racemic route suffers from the disadvantage of a low overall mass balance, originating from the fact that the resolution step, leading to the final enantiomerically pure compound, occurs in the last step of the synthesis whereby only a maximum of 50% yield of desired enantiomer can be obtained. Both art-known routes also produce a lot of waste such as solvents and salts in washings operations. Thus, these known methods are not suitable for the production of optically pure stereoisomers of hexahydro-furo[2,3-b]furan-3-ol on an industrial scale.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of lithium aluminum hydride (15 mg) dispersed in THF (0.2 mL) was added dropwise a solution of (3aR,6aS)-hekahydrofuro[2,3-b]furan-3-on (64 mg) obtained in Example 28 in THF (0.5 mL) at 0° C. and the mixture was stirred for 1 hr. Water (0.1 mL), 15% aqueous sodium hydroxide solution (0.1 mL) and water (0.3 mL) were successively added to the reaction mixture every 30 min and the mixture was filtered and washed well with THF. The filtrate was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated to give the title compound (57 mg, 88% ee) as an oil, which was an almost pure anti-form. The spectrum data were the same as those in Example 27. the mixture was filtered washed well with THF The filtrate was dried over anhydrous magnesium sulfate filtered the solvent was evaporated