(3aS,4S,6aR)-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 stirred solution of alcohol (5) (400 mg, 3.07 mmol), triphenylphosphine (1.6 g, 61.4 mmol), and p-nitrobenzoic acid (770 mg, 4.61 mmol) in dry benzene (30 mL) at 23° C. was added diisoproylazodicarboxylate (DIAD, 1.2 mL, 6.14 mmol) dropwise. After 1.5 hours, the mixture was concentrated in vacuo, and the crude ester was dissolved in a (4:3:1) mixture of MeOH:Et3N:H2O (24 mL), then treated with LiOH (450 mg, 10.7 mmol). The solution was stirred at room temperature for 2 h. The mixture then was concentrated under reduced pressure and the residue was chromatographed over silica gel to provide the bis-THF (I) (326 mg, 82%); [α]25D −12.4 (c 1.16, MeOH). the mixture was concentrated in vacuo the crude ester was dissolved in a (4:3:1) mixture of MeOH The mixture then was concentrated under reduced pressure the residue was chromatographed over silica gel

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

Procedure: To a stirred solution of alcohol (5) (400 mg, 3.07 mmol), triphenylphosphine (1.6 g, 61.4 mmol), and p-nitrobenzoic acid (770 mg, 4.61 mmol) in dry benzene (30 mL) at 23° C. was added diisoproylazodicarboxylate (DIAD, 1.2 mL, 6.14 mmol) dropwise. After 1.5 hours, the mixture was concentrated in vacuo, and the crude ester was dissolved in a (4:3:1) mixture of MeOH:Et3N:H2O (24 mL), then treated with LiOH (450 mg, 10.7 mmol). The solution was stirred at room temperature for 2 h. The mixture then was concentrated under reduced pressure and the residue was chromatographed over silica gel to provide the bis-THF (I) (326 mg, 82%); [α]25D −12.4 (c 1.16, MeOH). the mixture was concentrated in vacuo the crude ester was dissolved in a (4:3:1) mixture of MeOH The mixture then was concentrated under reduced pressure the residue was chromatographed over silica gel

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

Procedure: According to the above general procedure, a solution containing 1.44 mg (6.26 mmol) (4S,5S)-5-(acetyloxymethyl)-4-[1,3]dioxolan-2-yldihydrofuran-2-one (3c) in Et2O:THF 1:1 (20 mL) was reduced with 522 mg (13.75 mmol) LiAlH4 in Et2O (100 mL) to give the crude protected triol (4) (1.12 mg, 93%). The crude triol (4) was cyclized in 60 mL THF water (5:1) and 5 mL 1N hydrochloric acid. Column chromatography (silica gel 20 g, ethyl methanol in CHCl3 10%) gave compound (5) (515 mg, 64%) as a colorless solid, Rf=0.35, [α]25D −25.1°, c 1.0, MeOH. to give the crude

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

Procedure: According to the above general procedure, a solution containing 216 mg (0.714 mmol) (4S,5S)-5-(tert-butyldimethylsilanyloxymethyl)-4-[1,3]-dioxolan-2-yldihydrofuran-2-one (3a) in THF (25 mL) was reduced with 98 mg (2.58 mmol) LiAlH4 in THF (7 mL) to give the crude protected triol (4) (132 mg, 96%). The crude triol (4) (76 mg (0.40 mmol)) was cyclized in 6 mL acidified THF:water (5:1). Column chromatography (silica gel 20 g, ethyl methanol in CH2Cl2 10%) gave compound (5) (37.6 mg, 84%) as a colorless solid, Rf=0.35, [α]25D −25°, c 1.0, MeOH. 1H-NMR (400 MHz, CDCl3) δ: 1.67 (mc, 1H), 2.14 (mc, 1H), 2.63 (bs, 1H), 2.79 (mc, 1H), 3.75-3.88 (m, 3H), 3.94 (dd, 1H, J=3.0 Hz, J=10.2 Hz), 4.20 (d, 1H, J=2.7 Hz), 5.86 (d, 1H, J=4.9 Hz). 13C-NMR (125.8 MHz, CDCl3, Dept) δ: 29.19 (−), 52.38 (+), 69.52 (−), 75.60 (−), 78.14 (=), 109.23 (+). C6H10O3; Exact Mass: 130.06; Mol. Wt.: 130.14; C, 55.37; H, 7.74; O, 36.88. to give the crude

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: The mixture (18.9 g) containing (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (7.93 g, 60.9 mmol), (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (2.07 g, 15.9 mmol), (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (0.05 g, 0.4 mmol) and (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (0.05 g, 0.4 mmol) obtained in Example 4 was dissolved in ethyl acetate (112 ml), and dipotassium hydrogen phosphate (27.1 g, 155.3 mmol), potassium bromide (0.5 g, 3.9 mmol) and 2,2,6,6-tetramethylpiperidinyl-1-oxy (61 mg, 0.4 mmol) were added, and the mixture was cooled to 0. Into this was dropped a sodium hypochlorite aqueous solution (123.9 g, effective chlorine concentration 14%, 0.23 mol) at 15° C. or less, and after completion of dropping, the mixture was stirred for 1 hour. After completion of the reaction, 2-propanol (10 ml) was added, and the mixture was stirred for 30 minutes and liquid-partitioned. Further, the aqueous layer was extracted with ethyl acetate (50 ml) and the organic layers were combined, and dried over anhydrous sodium sulfate (1.0 g) added. Sodium sulfate was filtrated, then, the solvent was distilled off, and 2-propanol (30 ml) was added to the concentrated residue and recrystallization was performed, to obtain a pale brown white crystal (3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (7.4 g, purity 98%, yield 73%). At this stage, the enantiomer excess was 100% ee. the mixture was cooled to 0 was added the mixture was stirred for 30 minutes liquid-partitioned Further, the aqueous layer was extracted with ethyl acetate (50 ml) dried over anhydrous sodium sulfate (1.0 g) added Sodium sulfate was filtrated the solvent was distilled off 2-propanol (30 ml) was added to the concentrated residue and recrystallization

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

Procedure: The mixture (18.9 g) containing (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (7.93 g, 60.9 mmol), (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (2.07 g, 15.9 mmol), (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (0.05 g, 0.4 mmol) and (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (0.05 g, 0.4 mmol) obtained in Example 4 was dissolved in ethyl acetate (112 ml), and dipotassium hydrogen phosphate (27.1 g, 155.3 mmol), potassium bromide (0.5 g, 3.9 mmol) and 2,2,6,6-tetramethylpiperidinyl-1-oxy (61 mg, 0.4 mmol) were added, and the mixture was cooled to 0. Into this was dropped a sodium hypochlorite aqueous solution (123.9 g, effective chlorine concentration 14%, 0.23 mol) at 15° C. or less, and after completion of dropping, the mixture was stirred for 1 hour. After completion of the reaction, 2-propanol (10 ml) was added, and the mixture was stirred for 30 minutes and liquid-partitioned. Further, the aqueous layer was extracted with ethyl acetate (50 ml) and the organic layers were combined, and dried over anhydrous sodium sulfate (1.0 g) added. Sodium sulfate was filtrated, then, the solvent was distilled off, and 2-propanol (30 ml) was added to the concentrated residue and recrystallization was performed, to obtain a pale brown white crystal (3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (7.4 g, purity 98%, yield 73%). At this stage, the enantiomer excess was 100% ee. the mixture was cooled to 0 was added the mixture was stirred for 30 minutes liquid-partitioned Further, the aqueous layer was extracted with ethyl acetate (50 ml) dried over anhydrous sodium sulfate (1.0 g) added Sodium sulfate was filtrated the solvent was distilled off 2-propanol (30 ml) was added to the concentrated residue and 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: The mixture (18.9 g) containing (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (7.93 g, 60.9 mmol), (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (2.07 g, 15.9 mmol), (3S,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (0.05 g, 0.4 mmol) and (3R,3aR,6aS)-hexahydrofuro[2,3-b]furan-3-ol (0.05 g, 0.4 mmol) obtained in Example 4 was dissolved in ethyl acetate (112 ml), and dipotassium hydrogen phosphate (27.1 g, 155.3 mmol), potassium bromide (0.5 g, 3.9 mmol) and 2,2,6,6-tetramethylpiperidinyl-1-oxy (61 mg, 0.4 mmol) were added, and the mixture was cooled to 0. Into this was dropped a sodium hypochlorite aqueous solution (123.9 g, effective chlorine concentration 14%, 0.23 mol) at 15° C. or less, and after completion of dropping, the mixture was stirred for 1 hour. After completion of the reaction, 2-propanol (10 ml) was added, and the mixture was stirred for 30 minutes and liquid-partitioned. Further, the aqueous layer was extracted with ethyl acetate (50 ml) and the organic layers were combined, and dried over anhydrous sodium sulfate (1.0 g) added. Sodium sulfate was filtrated, then, the solvent was distilled off, and 2-propanol (30 ml) was added to the concentrated residue and recrystallization was performed, to obtain a pale brown white crystal (3aR,6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (7.4 g, purity 98%, yield 73%). At this stage, the enantiomer excess was 100% ee. the mixture was cooled to 0 was added the mixture was stirred for 30 minutes liquid-partitioned Further, the aqueous layer was extracted with ethyl acetate (50 ml) dried over anhydrous sodium sulfate (1.0 g) added Sodium sulfate was filtrated the solvent was distilled off 2-propanol (30 ml) was added to the concentrated residue and recrystallization

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

Procedure: To a stirred solution of alcohol (5) (400 mg, 3.07 mmol), triphenylphosphine (1.6 g, 61.4 mmol), and p-nitrobenzoic acid (770 mg, 4.61 mmol) in dry benzene (30 mL) at 23° C. was added diisoproylazodicarboxylate (DIAD, 1.2 mL, 6.14 mmol) dropwise. After 1.5 hours, the mixture was concentrated in vacuo, and the crude ester was dissolved in a (4:3:1) mixture of MeOH:Et3N:H2O (24 mL), then treated with LiOH (450 mg, 10.7 mmol). The solution was stirred at room temperature for 2 h. The mixture then was concentrated under reduced pressure and the residue was chromatographed over silica gel to provide the bis-THF (I) (326 mg, 82%); [α]25D −12.4 (c 1.16, MeOH). the mixture was concentrated in vacuo the crude ester was dissolved in a (4:3:1) mixture of MeOH The mixture then was concentrated under reduced pressure the residue was chromatographed over silica gel

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

Procedure: According to the above general procedure, a solution containing 1.44 mg (6.26 mmol) (4S,5S)-5-(acetyloxymethyl)-4-[1,3]dioxolan-2-yldihydrofuran-2-one (3c) in Et2O:THF 1:1 (20 mL) was reduced with 522 mg (13.75 mmol) LiAlH4 in Et2O (100 mL) to give the crude protected triol (4) (1.12 mg, 93%). The crude triol (4) was cyclized in 60 mL THF water (5:1) and 5 mL 1N hydrochloric acid. Column chromatography (silica gel 20 g, ethyl methanol in CHCl3 10%) gave compound (5) (515 mg, 64%) as a colorless solid, Rf=0.35, [α]25D −25.1°, c 1.0, MeOH. to give the crude

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

Procedure: According to the above general procedure, a solution containing 216 mg (0.714 mmol) (4S,5S)-5-(tert-butyldimethylsilanyloxymethyl)-4-[1,3]-dioxolan-2-yldihydrofuran-2-one (3a) in THF (25 mL) was reduced with 98 mg (2.58 mmol) LiAlH4 in THF (7 mL) to give the crude protected triol (4) (132 mg, 96%). The crude triol (4) (76 mg (0.40 mmol)) was cyclized in 6 mL acidified THF:water (5:1). Column chromatography (silica gel 20 g, ethyl methanol in CH2Cl2 10%) gave compound (5) (37.6 mg, 84%) as a colorless solid, Rf=0.35, [α]25D −25°, c 1.0, MeOH. 1H-NMR (400 MHz, CDCl3) δ: 1.67 (mc, 1H), 2.14 (mc, 1H), 2.63 (bs, 1H), 2.79 (mc, 1H), 3.75-3.88 (m, 3H), 3.94 (dd, 1H, J=3.0 Hz, J=10.2 Hz), 4.20 (d, 1H, J=2.7 Hz), 5.86 (d, 1H, J=4.9 Hz). 13C-NMR (125.8 MHz, CDCl3, Dept) δ: 29.19 (−), 52.38 (+), 69.52 (−), 75.60 (−), 78.14 (=), 109.23 (+). C6H10O3; Exact Mass: 130.06; Mol. Wt.: 130.14; C, 55.37; H, 7.74; O, 36.88. to give the crude