(3aS,4R,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: In particular, when (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is reacted with disuccinimidyl carbonate, 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]-carbonyl]oxy)-2,5-pyrrolidinedione is obtained. Said compound is a preferred (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivative:

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

Procedure: Enantiomerically pure (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (bis-THF) 27 (85 mg, 0.65 mmol) was diluted in dry CH2Cl2 (6 mL) under argon, the solution was cooled to 0° C. and anhydrous Na2HPO4 (52 mg, 0.36 mol) was added. Dess-Martin periodinane (360 mg, 0.85 mmol) was added at once at 0° C. and the resulting suspension warmed to 23° C. and stirred for 3 h. The reaction was then quenched by successive addition of sat. aq. NaHCO3 and sat. aq. Na2SO3 solutions (1.5+1.5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 then EtOAc. The combined organic phases were dried (Na2SO4), filtered on a small pad of silica gel, and evaporated to dryness. The residue was purified by column chromatography on silica gel using hexanes/EtOAc (3:1) to furnish ketone 28 (73 mg, 87%) as a white crystalline solid. TLC: Rf=0.57 (hexanes/EtOAc=1:1); Spectral data corresponded to those previously reported in the literature.35 the resulting suspension warmed to 23° C. The reaction was then quenched by successive addition of sat. aq. NaHCO3 and sat. aq. Na2SO3 solutions (1.5+1.5 mL) The phases were separated the aqueous phase was extracted with CH2Cl2 The combined organic phases were dried (Na2SO4) filtered on a small pad of silica gel evaporated to dryness The residue was purified by column chromatography on silica gel

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

Procedure: Enantiomerically pure (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol (bis-THF) 27 (85 mg, 0.65 mmol) was diluted in dry CH2Cl2 (6 mL) under argon, the solution was cooled to 0° C. and anhydrous Na2HPO4 (52 mg, 0.36 mol) was added. Dess-Martin periodinane (360 mg, 0.85 mmol) was added at once at 0° C. and the resulting suspension warmed to 23° C. and stirred for 3 h. The reaction was then quenched by successive addition of sat. aq. NaHCO3 and sat. aq. Na2SO3 solutions (1.5+1.5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 then EtOAc. The combined organic phases were dried (Na2SO4), filtered on a small pad of silica gel, and evaporated to dryness. The residue was purified by column chromatography on silica gel using hexanes/EtOAc (3:1) to furnish ketone 28 (73 mg, 87%) as a white crystalline solid. TLC: Rf=0.57 (hexanes/EtOAc=1:1); Spectral data corresponded to those previously reported in the literature.35 the resulting suspension warmed to 23° C. The reaction was then quenched by successive addition of sat. aq. NaHCO3 and sat. aq. Na2SO3 solutions (1.5+1.5 mL) The phases were separated the aqueous phase was extracted with CH2Cl2 The combined organic phases were dried (Na2SO4) filtered on a small pad of silica gel evaporated to dryness The residue was purified by column chromatography on silica gel

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

Procedure: Into a mixed solution of methanol (25 ml) and 2-propanol (25 ml) was suspended (3aR, 6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (10 g, 78.1 mmol), and sodium boron hydride (0.89 g, 23.4 mmol) was added divisionally to this at 0° C. and the mixture was stirred for 1.5 hours. After completion of the reaction, methanol (15 ml) and ammonium chloride (1.17 g, 21.9 mmol) were added and the mixture was stirred, then, the solvent was distilled off. To the concentrated residue was added 2-propanol (40 ml) and the mixture was concentrated again, and 2-propanol (40 ml) was added to this to cause dissolution. Insoluble materials were filtrated, then, concentration was performed to obtain a title compound in the form of yellow oil (9.87 g, yield 97.2%, (3R,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol/(3S,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol ratio=97.9/2.1). was added divisionally to this at 0° C. were added the mixture was stirred the solvent was distilled off To the concentrated residue was added 2-propanol (40 ml) the mixture was concentrated again 2-propanol (40 ml) was added to dissolution Insoluble materials were filtrated concentration

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

Procedure: Into a mixed solution of methanol (25 ml) and 2-propanol (25 ml) was suspended (3aR, 6aR)-tetrahydrofuro[2,3-b]furan-3(2H)-one (10 g, 78.1 mmol), and sodium boron hydride (0.89 g, 23.4 mmol) was added divisionally to this at 0° C. and the mixture was stirred for 1.5 hours. After completion of the reaction, methanol (15 ml) and ammonium chloride (1.17 g, 21.9 mmol) were added and the mixture was stirred, then, the solvent was distilled off. To the concentrated residue was added 2-propanol (40 ml) and the mixture was concentrated again, and 2-propanol (40 ml) was added to this to cause dissolution. Insoluble materials were filtrated, then, concentration was performed to obtain a title compound in the form of yellow oil (9.87 g, yield 97.2%, (3R,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol/(3S,3aS,6aR)-hexahydrofuro[2,3,b]furan-3-ol ratio=97.9/2.1). was added divisionally to this at 0° C. were added the mixture was stirred the solvent was distilled off To the concentrated residue was added 2-propanol (40 ml) the mixture was concentrated again 2-propanol (40 ml) was added to dissolution Insoluble materials were filtrated concentration

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

Procedure: 100 mmol (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in ethyl acetate were added onto 120 mmol of disuccimidylcarbonate (95%) in acetonitrile. Following, a solution of 140 mmol triethylamine in ethylacetate was added and stirred. The mixture was cooled and treated with a suspension of 92 mmol of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene sulfonamide in ethyl acetate. 20 mmol methylamine, 41% aqueous solution in ethanol were added and the mixture was warmed. The reaction was washed twice with 10% Na2CO3-solution and with water. Solvent was evaporated and ethanol was added. Another portion of solvent was distilled off. The temperature was kept around 40-45° C. and crystallization was initiated by seeding. After stirring the mixture was cooled, stirred for another 90 min stirred, cooled and again stirred for 60 min. The precipitate was filtered and washed with ethanol. The wet product was dried in vacuo at 40° C. 43.5 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate were suspended in ethanol abs. and dissolved. The clear solution was cooled and seeding was applied. Crystallization occurred while cooling the mixture. Stirring was continued for another 60 min, followed by cooling, stirring and filtering off the product, which was washed with cold ethanol abs. The wet product was dried in vacuo at 40° C. Yield: 42.1 g=71%. The mixture was cooled the mixture was warmed The reaction was washed twice with 10% Na2CO3-solution and with water Solvent was evaporated ethanol was added Another portion of solvent was distilled off was kept around 40-45° C. crystallization After stirring the mixture was cooled stirred for another 90 min stirred cooled again stirred for 60 min The precipitate was filtered washed with ethanol The wet product was dried in vacuo at 40° C and dissolved The clear solution was cooled Crystallization while cooling the mixture Stirring by cooling stirring filtering off the product, which was washed with cold ethanol abs The wet product was dried in vacuo at 40° C

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

Procedure: In particular, when the (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol is processed with disuccinimidyl carbonate, 1-([[(3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl]oxy)-2,5-pyrrolidinedione is obtained. Said compound is a preferred (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl derivate.