* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2699 - 2702
2
[ 2847-00-9 ]
[ 2595-05-3 ]
Yield
Reaction Conditions
Operation in experiment
80%
With sodium tetrahydroborate; water In ethanol at 0℃; for 1 h;
To a stirred solution of 2 (4.5 g, 19 mmol) in aq. ethanol(EtOH–H2O 19 : 1; 100 mL), NaBH4 (0.37 g, 9.7mmol) was added at 0 °C and then reaction mixture wasstirred for 1 h. Solvent was evaporated in vaccuo, residuetreated with saturated NH4Cl solution (10 mL) and stirredat room temperature for additional 10 min. The reactionmixture was extracted with EtOAc (2 × 50 mL) and organiclayer separated was washed with water (50 mL), brine(50 mL), dried (Na2SO4) and evaporated. Residue obtainedwas purified by column chromatography (60–120mesh silica gel , 60percent ethyl acetate in pethrol ether) to afford3 (3.8g , 80percent) as a white solid; mp 82 oC; [α]20D =+82.49 (c 1.62, CHCl3); IR (KBr): ν 3413, 2994, 2927,1632, 1375, 1220, 1162, 1072, 1010 cm–1; 1H NMR (300MHz, CDCl3, 298 K): δ 5.75 (d, 1H, J = 3.7 Hz, C1H),4.56 (d, 1H, J = 4.2 Hz, C2H), 4.23 (m, 1H, C5H),4.07–3.91 (m, 3H, C4H, 2 × C6H), 3.74 (dd, 1H, J = 8.0,4.3 Hz, C3H), 2.44 (d, 1H, J = 8.4 Hz, OH), 1.56 (s, 3H,CH3), 1.44 (s, 3H, CH3), 1.36 (s, 6H, 2 × CH3); 13C NMR(75 MHz, CDCl3): δ 112.8, 109.8, 103.9, 79.7, 79.0, 75.5,72.5, 65.8, 26.6, 26.5, 26.3, 25.3; MS: m/z (M++Na)283.1171.
10.4 g
With sodium tetrahydroborate In ethanol; water at 0 - 20℃;
Compound 1 (13.0 g, 0.05 mol) in 80 mL CH2Cl2 was stirred at 0 °C, Dess-Martin oxidant (35.0 g, 0.08 mol) was added in batches. After stirring for 2 h at 0 °C, the reaction solution was warmed up to room temperature and kept stirring for 20 h. Then 80 mL saturated NaHCO3 and 9.6 g Na2S2O3 were added and stirred intensely. Organic phase was concentrated and dissolved in 100 mL ethanol. NaBH4 (1.9 g, 0.05 mol) was dissolved in the mixture solution of ethanol/H2O (20 mL/20 mL) and dropped slowly to the reaction solution at 0 °C. After that, kept stirring for 4 h at room temperature, saturated NH4Cl was added to quench the reaction and ethyl acetate was used to extract. The organic phase was washed with brine, dried over anhydrous Na2SO4. The concentrate was purified by column chromatography (PE: EtOAc=5:1) to give compound 3 (10.4 g), the yield of two steps is 80percent. 1H NMR (CDCl3, 400 MHz): δ 5.78 (d, J1,2=3.6 Hz, 1H, H-1), 4.58 (dd, J2,1=4.0 Hz, J2,3=5.2 Hz, 1H, H-2), 4.29 (ddd, J5,6a=4.8 Hz, J5,6b=6.4 Hz, J5,4=6.4 Hz, 1H, H-5), 3.97–4.08 (m, 3H, H-3, H-4, H-6a), 3.80 (dd, J6b,5=4.5 Hz, J6b,6a=8.4 Hz, 1H, H-6b), 2.58 (br, 1H, 3-OH), 1.55, 1.44, 1.36, 1.34 (4×s, 4×3H). 13C NMR (CDCl3, 100 MHz): δ 112.7, 109.7, 103.8, 79.6, 78.8, 75.5, 72.4, 65.7, 26.5, 26.4, 26.2, 25.2. ESI-MS: calcd for C12H20NaO6 [M+Na]+ 283.1260, found: 283.1169.
71.7 g
With sodium tetrahydroborate In ethanol; water at 0 - 18℃; for 4 h;
General procedure: To a 2 Liter, 3 necked flask fitted with a mechanical stirring and a condenser connected at the top to a mineral oil bubbler, a solution of 1,2,5,6-di-O-isopropylidine-α-d-glucofuranose (5) (114.5g, 0.44mol) in EtOH free CHCl3 (520mL), K2CO3 (18.5g), KIO4 (170g, 0.74mmol), benzyltriethylammonium chloride (1.03g, 4.39mmol) and activated RuO2xH2O (2g). The mixture was stirred for 1h at 0°C then at room temperature over night. The mixture was filtered over a Celite pad and the organic phase was separated, washed with H2O. The aqueous phase was washed with CHCl3 and the combined organic phases was dried (MgSO4), evaporated and dried under reduced pressure and the residue was used in the next step without any further purification. The residue was dissolved in EtOH: H2O (7:3, 700mL) and treated with NaBH4 (10g) portion wise at 0°C. The mixture turned colorless and was stirred for 3h at 0°C and 1h at room temperature. The solvent was concentrated to 500mL and another 500mL H2O was added to the mixture and the whole was concentrated to 500mL. The mixture was washed with CH2Cl2 (400mL×4 times). The organic phase was dried (MgSO4) and evaporated to give 1,2,5,6-di-O-isopropylidine-α-d-allofuranose (71.7g, 63percent yield) as a white solid: MS [FAB] m/z 261.3 [M+H]+; 1H NMR (DMSO-d6) δH 5.66 (1H, d, H-1, J=3.6Hz), 5.05 (1H, d, 3-OH, J=7.1Hz), 4.45 (1H, t, H-2, J=4.2Hz), 4.23 (1H, dt, H-5, J=7.2, J=2.8Hz), 3.93 (1H, dd, H-4, J=9.1, J=7.2Hz), 3.83 (2H, m, H-6a,b), 3.74 (1H, dd, H-3, J=4.6, J=9.1Hz), 1.45 (3H, s, CH3), 1.32 (3H, s, CH3), 1.28 (3H, s, CH3), 1.27 (3H, s, CH3).
68 mg
With sodium tetrahydroborate In ethanol; water at 20℃; for 3 h;
A solution of diacetoneD-glucose6(100 mg, 0.4 mmol) in dichloromethane (0.6 mL) was added to a mixture of pyridinium dichromate (108 mg, 0.3 mmol) and Ac2O (0.1 mL, 1.2 mmol) in dichloromethane (1.2 mL) at room temperature under nitrogen. The whole mixture was refluxed for 2h, then cooled to room temperature, and the solvent was evaporated under reduced pressure. EtOAc (1 mL) was added to dissolve the solid residue, and the resulting solution was filtered through short-column of silica gel. The filtrate was concentrated in vacuo and the resulted ketone was dissolved in 56percent EtOH aq. (0.4 mL). A solution of sodium borohydride (15 mg, 0.4 mmol) in water (0.4 mL) was added at room temperature to this solution. After stirring for 3h, the mixture was extracted with dichloromethane (CH2Cl2, 3×5 mL), and the combined organic layers were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from diethyl ether-hexane to afford the product7(68 mg, 67percent) as colorless solid.Rfvalue 0.33 (hexane : EtOAc = 1 : 1). m.p. 72–73°C. HRMS (ESI):m/zfor C12H20NaO6([M+Na]+) cacld 283.11576, found 283.11508 (error -0.68 mmu, -2.40 ppm).
Reference：
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[30] Organometallics, 2014, vol. 33, # 8, p. 2059 - 2070
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3
[ 582-52-5 ]
[ 2595-05-3 ]
Reference：
[1] Tetrahedron Letters, 2006, vol. 47, # 34, p. 6041 - 6044
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 23, p. 5803 - 5807
[3] Helvetica Chimica Acta, 2003, vol. 86, # 1, p. 204 - 209
[4] Carbohydrate Research, 2008, vol. 343, # 6, p. 1012 - 1022
[5] Journal of the American Chemical Society, 2007, vol. 129, # 26, p. 8150 - 8155
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[7] Nucleosides, Nucleotides and Nucleic Acids, 2003, vol. 22, # 5-8, p. 915 - 917
[8] Organic Letters, 2003, vol. 5, # 2, p. 221 - 223
[9] Journal of the American Chemical Society, 2002, vol. 124, # 36, p. 10642 - 10643
[10] Journal of Organic Chemistry, 2008, vol. 73, # 6, p. 2462 - 2465
[11] Chemistry - A European Journal, 2011, vol. 17, # 23, p. 6369 - 6381
[12] Organic Letters, 2011, vol. 13, # 21, p. 5834 - 5837
[13] Letters in Organic Chemistry, 2011, vol. 8, # 8, p. 592 - 595
[14] Organic Letters, 2012, vol. 14, # 8, p. 2142 - 2145
[15] Tetrahedron Letters, 2012, vol. 53, # 26, p. 3361 - 3363
[16] Advanced Synthesis and Catalysis, 2012, vol. 354, # 10, p. 1933 - 1940
[17] Journal of Organic Chemistry, 2012, vol. 77, # 16, p. 6834 - 6848
[18] European Journal of Organic Chemistry, 2013, # 35, p. 7941 - 7951
[19] Organometallics, 2014, vol. 33, # 8, p. 2059 - 2070
[20] Journal of Agricultural and Food Chemistry, 2014, vol. 62, # 26, p. 6065 - 6071
[21] Journal of Agricultural and Food Chemistry, 2014, vol. 62, # 26, p. 6065 - 6071
[22] Patent: US2015/133395, 2015, A1,
[23] Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10444 - 10447
[24] Tetrahedron, 2016, vol. 72, # 2, p. 285 - 297
[25] Bioorganic Chemistry, 2016, vol. 65, p. 9 - 16
[26] Amino Acids, 2017, vol. 49, # 2, p. 223 - 240
[27] Arkivoc, 2017, vol. 2017, # 4, p. 249 - 264
[28] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 6, p. 3250 - 3257
[29] Acta Chimica Slovenica, 2017, vol. 64, # 4, p. 1030 - 1041
[30] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1848 - 1858
[31] Journal of Heterocyclic Chemistry, 2018, vol. 55, # 7, p. 1564 - 1573
With sodium tetrahydroborate; water; In ethanol; at 0℃; for 1h;
To a stirred solution of 2 (4.5 g, 19 mmol) in aq. ethanol(EtOH-H2O 19 : 1; 100 mL), NaBH4 (0.37 g, 9.7mmol) was added at 0 C and then reaction mixture wasstirred for 1 h. Solvent was evaporated in vaccuo, residuetreated with saturated NH4Cl solution (10 mL) and stirredat room temperature for additional 10 min. The reactionmixture was extracted with EtOAc (2 × 50 mL) and organiclayer separated was washed with water (50 mL), brine(50 mL), dried (Na2SO4) and evaporated. Residue obtainedwas purified by column chromatography (60-120mesh silica gel , 60% ethyl acetate in pethrol ether) to afford3 (3.8g , 80%) as a white solid; mp 82 oC; [alpha]20D =+82.49 (c 1.62, CHCl3); IR (KBr): nu 3413, 2994, 2927,1632, 1375, 1220, 1162, 1072, 1010 cm-1; 1H NMR (300MHz, CDCl3, 298 K): delta 5.75 (d, 1H, J = 3.7 Hz, C1H),4.56 (d, 1H, J = 4.2 Hz, C2H), 4.23 (m, 1H, C5H),4.07-3.91 (m, 3H, C4H, 2 × C6H), 3.74 (dd, 1H, J = 8.0,4.3 Hz, C3H), 2.44 (d, 1H, J = 8.4 Hz, OH), 1.56 (s, 3H,CH3), 1.44 (s, 3H, CH3), 1.36 (s, 6H, 2 × CH3); 13C NMR(75 MHz, CDCl3): delta 112.8, 109.8, 103.9, 79.7, 79.0, 75.5,72.5, 65.8, 26.6, 26.5, 26.3, 25.3; MS: m/z (M++Na)283.1171.
With methanol; sodium tetrahydroborate; at 20℃; for 2h;
Intermediate 4c-(3aR,5S,6R,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-ol Into a 2-L 4-necked round-bottom flask, was placed a solution of intermediate 4b (370 g, 1.29 mol) in methanol (1300 mL). To the above was added sodium borohydride (26.4 g, 706.38 mmol), in portions at room temperature. The resulting solution was allowed to react, with stirring, for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The reaction was then quenched by the addition of 1000 mL of 5% aqueous ammonium chloride solution. The resulting solution was extracted with 3*500 mL of dichloromethane and the organic layers combined. The resulting solution was washed with 2*300 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by re-crystallization from petroleum ether. This resulted in intermediate 4c.
10.4 g
With sodium tetrahydroborate; In ethanol; water; at 0 - 20℃;
Compound 1 (13.0 g, 0.05 mol) in 80 mL CH2Cl2 was stirred at 0 C, Dess-Martin oxidant (35.0 g, 0.08 mol) was added in batches. After stirring for 2 h at 0 C, the reaction solution was warmed up to room temperature and kept stirring for 20 h. Then 80 mL saturated NaHCO3 and 9.6 g Na2S2O3 were added and stirred intensely. Organic phase was concentrated and dissolved in 100 mL ethanol. NaBH4 (1.9 g, 0.05 mol) was dissolved in the mixture solution of ethanol/H2O (20 mL/20 mL) and dropped slowly to the reaction solution at 0 C. After that, kept stirring for 4 h at room temperature, saturated NH4Cl was added to quench the reaction and ethyl acetate was used to extract. The organic phase was washed with brine, dried over anhydrous Na2SO4. The concentrate was purified by column chromatography (PE: EtOAc=5:1) to give compound 3 (10.4 g), the yield of two steps is 80%. 1H NMR (CDCl3, 400 MHz): delta 5.78 (d, J1,2=3.6 Hz, 1H, H-1), 4.58 (dd, J2,1=4.0 Hz, J2,3=5.2 Hz, 1H, H-2), 4.29 (ddd, J5,6a=4.8 Hz, J5,6b=6.4 Hz, J5,4=6.4 Hz, 1H, H-5), 3.97-4.08 (m, 3H, H-3, H-4, H-6a), 3.80 (dd, J6b,5=4.5 Hz, J6b,6a=8.4 Hz, 1H, H-6b), 2.58 (br, 1H, 3-OH), 1.55, 1.44, 1.36, 1.34 (4×s, 4×3H). 13C NMR (CDCl3, 100 MHz): delta 112.7, 109.7, 103.8, 79.6, 78.8, 75.5, 72.4, 65.7, 26.5, 26.4, 26.2, 25.2. ESI-MS: calcd for C12H20NaO6 [M+Na]+ 283.1260, found: 283.1169.
71.7 g
With sodium tetrahydroborate; In ethanol; water; at 0 - 18℃; for 4h;
General procedure: To a 2 Liter, 3 necked flask fitted with a mechanical stirring and a condenser connected at the top to a mineral oil bubbler, a solution of 1,2,5,6-di-O-isopropylidine-alpha-d-glucofuranose (5) (114.5g, 0.44mol) in EtOH free CHCl3 (520mL), K2CO3 (18.5g), KIO4 (170g, 0.74mmol), benzyltriethylammonium chloride (1.03g, 4.39mmol) and activated RuO2xH2O (2g). The mixture was stirred for 1h at 0C then at room temperature over night. The mixture was filtered over a Celite pad and the organic phase was separated, washed with H2O. The aqueous phase was washed with CHCl3 and the combined organic phases was dried (MgSO4), evaporated and dried under reduced pressure and the residue was used in the next step without any further purification. The residue was dissolved in EtOH: H2O (7:3, 700mL) and treated with NaBH4 (10g) portion wise at 0C. The mixture turned colorless and was stirred for 3h at 0C and 1h at room temperature. The solvent was concentrated to 500mL and another 500mL H2O was added to the mixture and the whole was concentrated to 500mL. The mixture was washed with CH2Cl2 (400mL×4 times). The organic phase was dried (MgSO4) and evaporated to give 1,2,5,6-di-O-isopropylidine-alpha-d-allofuranose (71.7g, 63% yield) as a white solid: MS [FAB] m/z 261.3 [M+H]+; 1H NMR (DMSO-d6) deltaH 5.66 (1H, d, H-1, J=3.6Hz), 5.05 (1H, d, 3-OH, J=7.1Hz), 4.45 (1H, t, H-2, J=4.2Hz), 4.23 (1H, dt, H-5, J=7.2, J=2.8Hz), 3.93 (1H, dd, H-4, J=9.1, J=7.2Hz), 3.83 (2H, m, H-6a,b), 3.74 (1H, dd, H-3, J=4.6, J=9.1Hz), 1.45 (3H, s, CH3), 1.32 (3H, s, CH3), 1.28 (3H, s, CH3), 1.27 (3H, s, CH3).
With sodium tetrahydroborate; In ethanol; water;
(I) From 3 (5.0 g; 0.02 mol) with Austin?s method (Austinet al. 1987), the product 13 formed white crystals (3.3 g;67%). M.p.: 75-77 C; lit. m.p. (Austin et al. 1987):77-78 C; Rf = 0.57 (hexane-EtOAc 1:1).(II) 1,2:5,6-Di-O-isopropylidene-alpha-D-glucofuranose (3)(5.0 g; 0.02 mol) was dissolved in DCM (20 ml) then TEMPO(0.75 g; 4.7 mmol; 0.25 eqv.) and BAIB (2.5 eqv.) wereadded in several portions. The reaction mixture was stirredfor 2 days at room temperature. The solution was diluted withDCM (100 ml) and washed with saturated Na2S2O3 solution(2 × 50 ml). The aqueous phase was extracted with DCM(5 × 50 ml). The organic phase was washed with saturatedNaHCO3 solution (2 × 50 ml) and brine (2 × 50 ml). Thecombined organic extracts were dried (Na2SO4), filtered andconcentrated in vacuo. The crude ketone was transformedwithout any isolation and purification. The reduction was carriedout as in the case of method (A). The crude material waspurified with column chromatography (hexane-EtOAc 1:1)to give the pure product 13 (2.6 g; 52%).
With sodium tetrahydroborate; ethanol;Cooling with ice;
A round-bottom flask equipped with a reflux condenser and magnetic stirring bar was charged with CH2Cl2 700 (mL) and CrO3 (60 g, 600 mmol). The flask was immersed in ice-water, and pyridine (97 mL, 1200 mmol) was added portion wise during 10 min. The cooling bath was removed. After stirring for 1 h at rt, the dark brown mixture was cooled again with ice-water bath and 7 (39.3 g, 151 mmol) was added portionwise. After each addition of 7 a small volume of Ac2O was added. The total volume of Ac2O was 75 mL, 61.3 g, 600 mmol. After these intermittent additions which required 15 min the cooling bath was removed and oxidation continued for 25 min counting from the end of additions. TLC showed complete conversion of 7 Rf 0.49 into more polar ulose 8 Rf 0.33 (hexane - EtOAc 1:1). Most of CH2Cl2 was evaporated below 40 C and 1:1 mixture of toluene - EtOAc, (500 mL) was added. This resulted in precipitation of insoluble black tar. The supernatant was decanted and the solid residue was washed twice with the same solvent. The combined solutions were passed through a short silica gel column prepared in toluene - EtOAc 1:2 using over pressure. The column was eluted with the same solvent system and product-containing fractions were evaporated. Xylenes (100 mL) were added and evaporation was continued to expel all residual pyridine. The oil obtained was dissolved in 96% EtOH (300 mL), cooled in ice-water bath and NaBH4 (5 g, 132 mmol) was added portionwise while maintaining magnetic stirring. The cooling bath was removed and stirring was continued overnight. TLC showed allose 9 Rf 0.36 slightly less polar than the ulose 8 (hexane - EtOAc 1:1). Acetone (10 mL) was added to destroy the excess of NaBH4 and most of the volatiles were evaporated. The residue was taken up in CH2Cl2 and washed with water. The organic phase was dried (MgSO4) and evaporated to yield solid crude 9 (31.1 g, 79% for two steps). Mp 72-75 C (hexane - EtOH), [alpha]D26 +36.7 (c 2 CHCl3); lit.32 mp 74-75 C (toluene), [alpha]D +38.8 (c 1.03 CHCl3). NMR: see L-enantiomer 29.
68 mg
With sodium tetrahydroborate; In ethanol; water; at 20℃; for 3h;
A solution of diacetoneD-glucose6(100 mg, 0.4 mmol) in dichloromethane (0.6 mL) was added to a mixture of pyridinium dichromate (108 mg, 0.3 mmol) and Ac2O (0.1 mL, 1.2 mmol) in dichloromethane (1.2 mL) at room temperature under nitrogen. The whole mixture was refluxed for 2h, then cooled to room temperature, and the solvent was evaporated under reduced pressure. EtOAc (1 mL) was added to dissolve the solid residue, and the resulting solution was filtered through short-column of silica gel. The filtrate was concentrated in vacuo and the resulted ketone was dissolved in 56% EtOH aq. (0.4 mL). A solution of sodium borohydride (15 mg, 0.4 mmol) in water (0.4 mL) was added at room temperature to this solution. After stirring for 3h, the mixture was extracted with dichloromethane (CH2Cl2, 3×5 mL), and the combined organic layers were dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuo. The residue was recrystallized from diethyl ether-hexane to afford the product7(68 mg, 67%) as colorless solid.Rfvalue 0.33 (hexane : EtOAc = 1 : 1). m.p. 72-73C. HRMS (ESI):m/zfor C12H20NaO6([M+Na]+) cacld 283.11576, found 283.11508 (error -0.68 mmu, -2.40 ppm).
With sodium tetrahydroborate; In water; at 10 - 15℃;
Ethyl acetate (20 vol. equiv.) was added to a 20L reactor at 20 - 35C. l,2:5,6-Di-0- isopropylidene-a-D-glucofuranose S-l (1 wt. equiv.) was added and stirred into ethyl acetate. A 10% Potassium bromide solution (0.3 wt. equiv.) was added into the reaction mass at 20 - 35C and the reaction was stirred for 5 - 10 minutes at 20 - 35C. TEMPO (0.05 wt. equiv.) was added into reaction mass at 20-35C. The reaction was stirred for 15 - 20 minutes at 20-35C and then cooled to 0 - l0C. A solution of aqueous basic Sodium hypochlorite (10-14%, 9 vol. equiv.) was then added to the reaction mixture slowly at 0 - 10 C. A solution of sodium bicarbonate was prepared using sodium bicarbonate (1 wt. equiv.) and water (5 vol. equiv.) at 20 - 35 C and then cooled to below 20 C and then NLT 10% of sodium hypochlorite below 20 C. The mixture was stirred well and the solution kept at 5 - 10 C. The content of the well stirred solution was added to the reaction. The reaction was stirred for 3-4 hours at 20 - 25C until full conversion of the 1, 2:5, 6-di- O-isopropyliden-a-D-glucofuranose (S-l) to intermediat P-D-S-2 as detected by TLC. Extraction followed with ethyl acetate (5 vol. equiv. and 5 vol. equiv.). The organic phases were concentrated and charged into a clean reactor. A cold stirred solution of NaBEE (0.09 wt. equiv) in water (2 vol. equiv.) was added and the reaction stirred for 2-3 hours at 10- l5C. The reaction was settled for 10 - 15 minutes and the upper layer (Ethyl acetate) was submitted to quality control for P-D-S-3 content by TLC. The reaction mass was homogeneous biphasic (top layer was organic layer, bottom layer was aqueous layer). Purification: Layers were separated (below was the aqueous layer and above was the organic layer). The organic layer was kept and the aqueous layer was charged back in the in the reactor at 20 - 30C. Dichloromethane (5 vol. equiv.) was added to the aqueous layer at 20 - 30C and then stirred for 10 -15 minutes at 20 - 30C. The reaction was settled for 10 - 15 minutes at 20 - 30 C. This extraction was repeated once more and then the organic layers were combined. The combined organic layers were charged with water in a clean reactor and the organic layers were distilled below 55C till 1 - 2 volumes was left inside the reactor with respect to the input. Cyclohexane (2 vol. equiv.) was charged into the reaction mass below 55C. Cyclohexane was then distilled out under vacuum below 55 C until 1 - 2 volume was left inside the reactor with respect to the input. This cycle of distillation was repeated until quality control to check for the ethyl acetate and dichloromethane content by gas chromatography. Cyclohexane (2 vol. equiv.) was added at 20 - 30C. The reaction was cooled to 8 - l2C and stirred for 2 - 3 hours at 8 - l2C. The solid mass was filtered and washed with pre chilled (8 - l2C) cyclohexane (1 vol. equiv.). The solid was dried under vacuum (above 550 mm/Hg) at 45 - 50C for 6 - 8 hours. HNMR (CDCb, Bruker 400 MHz): d (ppm) 5.8 (d, 1H); 4.62 (dd, 1H); 4.3 (dd, 1H), 3.95- 4.15 (m, 3H), 3.8 (dd, 1H), 2.5 (d, 1H), 1.33 (s, 3H), 1.36 (s, 3H), 1.45 (s, 3H), 1.55 (s, 3H) Melting point: 73-76 C LCMS: 261.3 (M+H)+ observed 283.3 with M+ sodium adduct Specific optical rotation at 20 C (0) (C=l% in chloroform) w/v: +35.4
With silica supported polyphosphoric acid; In acetonitrile; at 55℃; for 0.5h;
General procedure: 3-O-Benzyl-1,2:5,6-di-O-isopropylidene-a-D-allofuranose (1) (100 mg) wasdissolved in CH3CN (2 ml) and PPA-SiO2 (100mg, 0.16 mmol, based uponPPA weight) was added.[3] The reaction mixture was stirred at 55 C for30 min. After completion of the reaction (monitored by TLC), the mixturewas allowed to cool to room temperature. Further, the reaction mixturewas filtered through filter paper, washed with CH3CN (1 x 5 ml).Evaporation of the solvent under reduced pressure yielded 3-O-Benzyl-1,2-O-isopropylidene-a-D-allofuranose (2)[17] as a crude oily compound. Thecrude compound 2 was purified by column chromatography to obtain colorless oily compound (75 mg, 85%); Rf0.31 (petroleum ether: EtOAc 1:1).
77%
With acetic acid; In water; at 20℃; for 18h;
A mixture of 1,2:5,6-di-O-isopropylidene-alpha-d-allofuranose (6.51 g, 25 mmol) and 60% aqueous AcOH (75 mL) was stirred at rt for 18 h. The solution was then concentrated under reduced pressure and coevaporated with toluene (2 * 10 mL). The crude product was purified with flash chromatography using EtOAc/ethanol (10:1, Rf = 0.28) to yield triol 7 (4.21 g, 77%) as colorless crystals. The analytical sample was crystallized from EtOAc, mp 128-129 C (lit. 40 129-130 C). 1H NMR (400.27 MHz, CDCl3): delta 5.80 (d, J = 3.8 Hz, 1H), 4.62 (dd, J = 5.0, 3.8 Hz, 1H), 4.11 (td, J = 8.4, 5.0 Hz, 1H), 4.02 (?quint, J = 3.5 Hz, 1H), 3.84 (dd, J = 8.4, 3.3 Hz, 1H), 3.89-3.74 (m, 2H), 3.16 (d, J = 8.4 Hz, 1H), 2.51 (br t, J = 6.0 Hz, 1H), 2.47 (d, J = 3.5 Hz, 1H), 1.57 (s, 3H), 1.36 (s, 3H). 13C NMR (100.65 MHz, CDCl3): delta 113.1, 103.9, 81.1, 79.0, 70.3, 70.2, 62.9, 26.6, 26.4.
With sulfuric acid; In methanol;
General procedure: To a cold (ice bath) solution of 9 (35 g, 134.6 mmol) in MeOH (300 mL) was added cold 0.8% H2SO4 (250 mL), and the mixture was left overnight at rt. TLC showed that 9 (Rf 0.36 in hexane - EtOAc 1:1) reacted to form 10 Rf ~0 in the same solvent system, or Rf 0.21 in CH2Cl2 - MeOH 9:1. Amberlite IRA 410 (OH-) was added to neutralize the acid and was removed by filtration and washed with MeOH. The volatiles were removed by evaporation to yield crude 10 as a syrup. A small amount of this material was purified by chromatography using CH2Cl2 - MeOH 9:1 to get the crystalline material, mp 130-134 C (EtOAc - EtOH); lit.32 mp. 131-133 C (Et2O - MeOH) The bulk of the crude product was dissolved in 96% EtOH (250 mL) and treated with a suspension of NaIO4 (30 g, 140 mmol), in H2O (100 mL) with magnetic stirring. A white precipitate started to deposit immediately. After 4 h TLC showed a conversion of 10 into the aldehyde 11 Rf 0.29 in hexane - EtOAc 1:2. The whole mixture was filtered on a sintered glass and the solid material was washed with EtOH. NaBH4 (6 g, 158.7 mmol) was added to the cold (ice bath) filtrate and the mixture was stirred magnetically during 5 h at rt. The work-up and purification as described above furnished 12 (16.9 g, 76% for three steps). 12: mp 85 C (hexane - EtOAc), [alpha]D26 + 69 (c 2.2, EtOH); lit.73 85.5-86 C, [alpha]D + 65 (c 1.0 EtOH). NMR: see L enantiomer 32.
With pyridine; In dichloromethane; at -30℃; for 0.75h;
Starting material (C3-epimerized 1) (664mg, 2.55mmol) was dissolved in dry DCM (7.6ml, 0.04M). Pyridine (0.41ml, 5.15mmol) was added and the solution cooled to -30 C. Triflic anhydride (864mg, 3.06mmol) was added dropwise over 15min and stirring was continued at -30 C for 30min. The reaction was then quenched with MeOH (1ml), warmed to rt, diluted with DCM (5ml) washed with H2O (5ml x 2), dried over Na2SO4 and concentrated to a clear, slight yellow oil (1.05g, quantitative) A small amount of material was purified by chromatography using 25% EA:HEX for characterization.
95%
With pyridine; at 0 - 20℃;Inert atmosphere;
A solution of compound 3 (20.0 g, 0.08 mol) in 24 mL pyridine under argon was cooled to 0 C. Tf2O (20.3 mL, 0.12 mol) was added in. After stirring 3.5 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3 and brine, dried over Na2SO4. The concentrate was purified by column chromatography (PE: CH2Cl2=1:1) to give compound 4 (28.6 g) with a yield of 95%. 1H NMR (CDCl3, 300 MHz): delta 5.83 (d, J1,2=3.6 Hz, 1H, H-1), 4.90 (dd, J3,4=6.3 Hz, J3,2=5.7 Hz, 1H, H-3), 4.76 (dd, J2,3=4.8 Hz, J2,1=4.2 Hz, 1H, H-2), 4.08-4.20 (m, 3H, H-6b, H-4, H-6a), 3.90 (dd, J5,6a=4.5 Hz, J5,6b=8.7 Hz, 1H, H-5), 1.58, 1.44, 1.38, 1.34 (4*s, 4*3H).
92%
With pyridine; at 0 - 20℃; for 3.5h;
To a cooled (0C) solution of1,2:5,6-di-O-isopropyidene-D-allofuranose7(0.3 g, 1.3 mmol) in pyridine (0.4 mL), triflic anhydride (0.4 mL, 2 mmol) was slowly added. After stirring 3.5h at room temperature, the reaction mixture was diluted with CH2Cl2, washed with saturated NaHCO3and brine, dried.The resulting residue after evaporation under reduced pressure waspurified by column chromatography (hexane :EtOAc= 5 : 1) to afford the title compound8(0.5 g, 92%) as a colorless oil.Rfvalue 0.75 (hexane : EtOAc = 1 : 1). HRMS (FAB):m/zfor C13H20F3O8S ([M+H]+) cacld 393.0831, found 393.0829 (error -0.20 mmu, -0.50 ppm).
89%
With pyridine; at 0℃; for 1h;
Triflic anhydride (7.8 mL, 46.39 mmol) was added over 30 minutes to a cold (0C) solution of the diacetone allofuranose (10.50 g, 40.34 mmol) in pyridine (100 mL). After stirring in the ice-bath for 1 hour, the reaction was diluted with ethyl acetate (250 mL) and the organic layer was washed with a mixture of saturated sodium bicarbonate and brine (50 mL + 50 mL), dried (Na2S04) and concentrated under reduced pressure to provide the crude triflate. The crude residue was purified using a normal phase flash column (0-10% EA/Hex) to give the title compound (14.15 g, 89%) as a colorless oil. 1 HNMR (300 MHz, Chloroform-d): 5.85 (d, 1 H); 4.93 (dd, 1 H); 4.79 (dd, 1 H); 4.21 (dd, 1 H); 4.1 1 -4.17 (dt, 1 H); 3.90-3.95 (dt, 1 H); 1 .61 (s, 3H); 1 .47 (s, 3H); 1 .41 (s, 3H); 0.3 (s, 3H).
With pyridine; In dichloromethane; at -30℃; for 2h;
Triflic anhydride (10.2mL, 59.0mmol) was added dropwise to a stirred solution of diacetone allose 25 (11.8g, 45.4mmol) and pyridine (0.3mL) in dichloromethane (40mL) at -30C. The mixture was stirred at -30C for 2h until TLC analysis (cyclohexane/ethyl acetate, 2:1) indicated the complete conversion of starting material (Rf 0.40) to product (Rf 0.70). The reaction mixture was diluted with dichloromethane (10mL), washed successively with HCl (2M, aq, 10mL) and sodium bicarbonate (satd, aq, 50mL), dried and concentrated in vacuo to afford the crude triflate. Sodium azide (3.9g, 60.5mmol) was added to a solution of the crude triflate in DMF (30mL) at room temperature and stirred overnight. TLC analysis (cyclohexane/ethyl acetate, 2:1) showed one major product formed (Rf 0.75). The reaction mixture was diluted with ethyl acetate (30mL), washed with brine/water (1:1, 2×30mL). The aqueous layers were combined and extracted with ethyl acetate (2×20mL). The organic extracts were combined, dried, and concentrated in vacuo. Flash column chromatography (cyclohexane/ethyl acetate 10:1) gave the azide 26 as a colorless oil. Proton NMR signals showed the existence of small amount of impurities. Column chromatography in less polar solvents (toluene/acetone, 100:1) afforded the pure product (10.1g, 78%) as a colorless syrup.
With pyridine; In dichloromethane; at -10℃; for 2h;Inert atmosphere;
General procedure: 1,2:5,6-Di-O-isopropylidene-alpha-d-glucofuranose (3) (3.0 g;0.01 mol) was dissolved in dichloromethane (30 ml) containingpyridine (2.8 ml). The reaction mixture was cooledat -10 C and under N2-atmosphere trifluoromethanesulfonicanhydride (2.9 ml) was dropped to the solution. Thereaction mixture was stirred for 2 h. After the solution waspoured into ice-water, the aqueous phase was extractedwith dichloromethane. The organic phase was dried(Na2SO4), filtered and concentrated in vacuo. The whitecrystalline product 8 crystallized from n-hexane (4.1 g;90%). M.p.: 76-77 C; lit. m.p. (Hall and Miller 1976):70 C; Rf = 0.61 (hexane-EtOAc 1:2).
With pyridine; In dichloromethane; at 0℃; for 0.25h;
Triflic anhydride (1.4 mL) in DCM (1.0 mL) was added dropwise in a solution of 1:2,5:6-di-O-isopropylidene-alpha-D-allofuranose (0.503 g, 2.12 mmol) in 19:1 DCM-Pyridine (20 mL) at 0C. After stirring for 15 minutes, the mixture was then extracted with ice-cold 5% HCl and water, dried with MgSO4 and concentrated to an orange liquid. This product was dissolved in dry DMF (25 mL) and cooled to 0C. To this solution was added NaN3 (0.64 g; 9.8 mmol) and the mixture was stirred for 2 hours at r.t. and was then diluted with DCM, washed water and brine and dried with MgSO4. The residue was purified in a silica gel chromatography column (6:1 hexane-ethyl acetate) to give the 3-azido-3-deoxy-1:2,5:6-di-O-isopropylidene-alpha-D-glucofuranose intermediate (0.290 g, 1.11 mmol, 53%) as a colorless oil. TFA 90% (3.25 mL) was added dropwise to a solution of 3-azido-3-deoxy-1:2,5:6-di-O-isopropylidene-alpha-D-glucofuranose (0.293 g, 0.001 mmol) at 0C. After stirring for 15 minutes, the mixture was concentrated under reduced pressure and then was dissolved in pyridine (9.70 mL), cooled to 0C and treated with acetic anhydride. The mixture was stirred overnight at r.t. and then concentrated under reduced pressure. The crude product was purified in a silica gel chromatography column, using hexane and ethyl acetate (6:4) to yield 10 (0.190 g, 0.5 mmol, 45%) as a mixture of anomers alpha and beta (1:0.26). 1H NMR (400 MHz, CDCl3) delta: 6.31 (1H, d, J 3.6 Hz, H-1alpha), 5.67 (0.26H, d, J 8.3 Hz, H-1beta), 5.03-4.94 (1.52H, m, H-2beta, H-4alpha, H-4beta), 4.95 (1H, dd, J 3.6; 10.7 Hz, H-2alpha), 4.23 (0.26H, m, H-6bbeta), 4.22 (1H, dd, J 4.6; 12.7 Hz, H-6balpha); 4.12-4.02 (2.26H, m, H-5alpha, H-6aalpha, H-6abeta); 3.97 (1H, t, J 10.4 Hz, H-3alpha), 3.79 (0.26H, ddd, J 2.3 Hz, 4.6 Hz, 9.9 Hz, H-5beta), 3.69 (0.26H, t, J 10.1 Hz, H-3beta), 2.19, 2.14, 2.10, 2.10 (12H, 4s, 4 x COCH3, major isomer). 13C NMR (100 MHz, CDCl3) delta: 170.6, 169.3, 169.0, 169.0, 168.5 (5 x C=O), 91.9 (C-1), 87.3 (C-1), 73.5, 70.1, 70.0, 69.9, 67.8, 67.8, 64.2, 61.5 (C-6), 60.8, 20.8, 20.6, 20.6, 20.4 (4 x COCH3).
With pyridine; In dichloromethane; toluene; at -78 - 40℃; for 168h;
[00910] Allofuranose diacetonide (10 g, 38.4 mmol) was dissolved in 35 mL of dry DCM and pyridine at -78 C. To the cold solution, 2.7 M Deoxyfluor in toluene (20 mL, 54 mmol) was added dropwise. The reaction was stirred for 7 days at 40 C. The reaction was quenched with sat NaHCCb, and the aqueous phase was extracted with DCM (3 x 50 mL). Combined organic phases were washed with NaHCC (100 mL) and dried with Na2S04. The crude material was purified by MPLC to afford the title compound (9.54 g, 36.4 mmol, 95%). Acetonides fragment on mass spec: MS (ESI) [M - both acetonides + Na]+ = 205.1.
95%
With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; toluene; at -78 - 40℃; for 168h;
Example 21 Step 1 (3aR,5R,6S,6aS)-5-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-6-fluoro-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[3,3-d][1,3]dioxole . [0578] Allofuranose diacetonide (10 g, 38.4 mmol) was dissolved in 35 mL of dry DCM and pyridine at -78 C. To the cold solution, 2.7 M Deoxyfluor in toluene (20 mL, 54 mmol) was added dropwise. The reaction was stirred for 7 days at 40 C. The reaction was quenched with sat NaHCO3, and the aqueous phase was extracted with DCM (3 x 50 mL). Combined organic phases were washed with NaHCO3 (100 mL) and dried with Na2S04. The crude material was purified by MPLC to afford the title compound (9.54 g, 36.4 mmol, 95%). Acetonides fragment on mass spec: MS (ESI) [M - both acetonides + Na]+ = 205.1.
With sodium hydroxide; tetra-(n-butyl)ammonium iodide; In dichloromethane; water; at 23℃; for 5h;
Step 2: The preparation of In a reactor equipped with a mechanical stirrer, a solution of 1,2, 5, 6-di-o-isopropylidene- alpha-D-allofuranose (commercially available from Aldrich, 100 g, 364 MMOL) in of DCM (1. 6 I) is treated sequentially with allyl bromide (55 ML, 653 MMOL) and aqueous sodium hydroxide (50%, 1.6 I) and tetrabutylamonium iodide (14.2 g, 38.4 MMOL). After stirring vigorously at +23C for 5 hours, the phases are separated. The aqueous layer is extracted with TBME (2 x 500 ML). The organic extracts are combined, washed with aqueous saturated ammonium chloride (1 1 + addition of solid ammonium chloride for the neutrali- zation of sodium hydroxide), dried over magnesium sulphate and concentrated in vacuo to give the crude allyl ether (122 g) as a mixture of oil and crystalline material. Purification by RECRYSTALLIZATION in hexane affords the allyl ether as colorless crystals (106.3 g, 92%). 1 H-NMR (300 MHz, CDCI3) 5 ppm: 1.38 (s, 3H); 1.59 (s, 3H), 1.48 (s, 3H); 1.37 (s, 3H); 3.93 - 3. 85 (m, 1H) ; 4.13-3. 96 (m, 4H); 4.28-4. 15 (m, 1 H) ; 4.45-4. 35 (m, 1H) ; 4.68-4. 59 (m, 1 H); 5.27-5. 19 (dd, 1 H); 5.48-5. 28 (dd, 1 H); 5.77 (d, 1 H); 6.05-5. 89 (m, 1 H).
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃;
Stage #2: With sodium tetrahydridoborate In methanol at 0℃;
83%
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With piridinium dichromate; acetic anhydride In dichloromethane
Stage #2: With sodium tetrahydridoborate In ethanol
82%
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With dimethyl sulfoxide; triethylamine; trifluoroacetic anhydride In dichloromethane at -65 - 20℃;
Stage #2: With sodium tetrahydridoborate In methanol at 0℃; for 1h;
68%
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With 4 Angstroem MS; pyridinium chlorochromate
Stage #2: With sodium tetrahydridoborate In ethanol; water monomer Further stages.;
65%
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With piridinium dichromate; acetic anhydride In dichloromethane
Stage #2: With sodium tetrahydridoborate In ethanol; water monomer Further stages.;
57%
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1h; Inert atmosphere;
Stage #2: With triethylamine In dichloromethane at -78℃; for 0.166667h; Inert atmosphere;
Stage #3: With sodium tetrahydridoborate; ethanol at 0℃; for 0.5h; Inert atmosphere;
54%
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With PDC; acetic anhydride
Stage #2: With methanol; sodium tetrahydridoborate
Multi-step reaction with 2 steps
1: PDC
2: NaBH4
Multi-step reaction with 2 steps
1: NaBH4
Multi-step reaction with 2 steps
1: 91 percent / pyridinium dichromate; acetic anhydride / CH2Cl2 / 4 h / 75 °C
2: 90 percent / NaBH4 / ethanol; H2O / 1 h / 0 °C
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With piridinium dichromate; acetic anhydride
Stage #2: With sodium tetrahydridoborate Further stages.;
Multi-step reaction with 2 steps
1: pyridinium dichromate; acetic anhydride / dichloromethane / 18.5 h / 20 °C / Inert atmosphere; Reflux
2: sodium tetrahydridoborate / ethanol / 0 - 20 °C / Inert atmosphere
Multi-step reaction with 2 steps
1: Dess-Martin periodane / dichloromethane / 18.25 h / 0 - 20 °C
2: sodium tetrahydridoborate / ethanol; water monomer / 0 - 20 °C
Multi-step reaction with 2 steps
1: pyridine; chromium(VI) oxide; acetic anhydride / dichloromethane / 20 °C
2: sodium tetrahydridoborate / ethanol; water monomer / 0 - 20 °C
Multi-step reaction with 2 steps
1: Dess-Martin periodane / dichloromethane / 18.25 h / 0 - 20 °C
2: sodium tetrahydridoborate / ethanol; water monomer / 2 h / 0 - 20 °C
Multi-step reaction with 2 steps
1: piridinium dichromate; acetic anhydride / dichloromethane / 2 h
2: sodium tetrahydridoborate / ethanol / 2 h
Multi-step reaction with 2 steps
1: oxalyl dichloride; dimethyl sulfoxide; triethylamine / dichloromethane / 3 h / -78 °C
2: sodium tetrahydridoborate / ethanol; water monomer / 1 h / 0 °C
Multi-step reaction with 2 steps
1: piridinium dichromate; acetic anhydride / dichloromethane
2: sodium tetrahydridoborate / ethanol; water monomer / 3 h / 20 °C
Multi-step reaction with 2 steps
1: chromium(VI) oxide; acetic anhydride; pyridine / Inert atmosphere; Schlenk technique
2: sodium tetrahydridoborate / ethanol; water monomer / 3 h / 0 °C / Inert atmosphere; Schlenk technique
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With acetic anhydride; pyridinium chlorochromate In dichloromethane
Stage #2: With sodium tetrahydridoborate In ethanol
Multi-step reaction with 2 steps
1: Dess-Martin periodane / dichloromethane / 0 - 20 °C
2: sodium tetrahydridoborate / water monomer; ethanol / 0 - 20 °C
Multi-step reaction with 2 steps
1: potassium carbonate; benzyl-triethyl-ammonium chloride; potassium metaperiodate; ruthenium(IV) oxide hydrate / chloroform / 0 - 18 °C
2: sodium tetrahydridoborate / water monomer; ethanol / 4 h / 0 - 18 °C
Multi-step reaction with 2 steps
1: 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / dichloromethane / 48 h / 20 °C
2: sodium tetrahydridoborate / ethanol; water monomer
Multi-step reaction with 2 steps
1: chromium(VI) oxide; pyridine; acetic anhydride / dichloromethane / 0.42 h / Cooling with ice
2: sodium tetrahydridoborate; ethanol / Cooling with ice
Multi-step reaction with 2 steps
1: phosgene; triethylamine / dichloromethane / 1.5 h / -78 - 20 °C
2: sodium tetrahydridoborate / ethanol; water monomer / 1 h / 0 - 20 °C
Multi-step reaction with 2 steps
1: phosgene; triethylamine / dichloromethane / 1.5 h / -78 - 20 °C
2: sodium tetrahydridoborate; ethanol / water monomer / 1 h / 0 - 20 °C
Multi-step reaction with 2 steps
1: acetic anhydride; piridinium dichromate / dichloromethane / 2 h / Inert atmosphere; Reflux
2: sodium tetrahydridoborate / water monomer; ethanol / 3 h / 20 °C
Multi-step reaction with 2 steps
1.1: oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.75 h / -78 °C
1.2: -78 - 25 °C
2.1: sodium tetrahydridoborate / ethanol; water monomer / 1 h / 0 °C
Multi-step reaction with 2 steps
1: piridinium dichromate / acetic anhydride
2: sodium tetrahydridoborate / ethanol; water monomer
Multi-step reaction with 2 steps
1: potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium chlorine monoxide; Sodium hydrogenocarbonate / water monomer; ethyl acetate / 0 - 35 °C
2: sodium tetrahydridoborate / water monomer / 10 - 15 °C
Multi-step reaction with 2 steps
1: acetic anhydride; piridinium dichromate / dichloromethane / 2 h / 40 °C
2: sodium tetrahydridoborate / ethanol; water monomer / 3 h / 20 °C
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranoside With Dess-Martin periodane In dichloromethane
Stage #2: With sodium tetrahydridoborate In methanol
Multi-step reaction with 2 steps
1: piridinium dichromate; acetic anhydride / dichloromethane / 16 h / 20 °C
2: ethanol; water monomer; sodium tetrahydridoborate / 16 h / 20 °C
Sodium hydride (86.4 g of a 60% dispersion in mineral oil, 2.16 mol) was suspended in acetonitrile (3.2 L) and cooled to 0 C under nitrogen. A solution of 1,2:5,6-di-O-isopropylidene-alpha-D-allofuranose 11 (500 g, 1.73 mol) in acetonitrile (1.3 L) was added dropwise over 1 h followed by a solution of benzyl bromide (370 g, 2.16 mol) in acetonitrile (900 mL) over 0.5 h. The reaction mixture was stirred for 4 h before careful addition of methanol (900 mL). The mixture was stirred for 30 min then treated with water (10 L). The mixture was extracted with ethyl acetate (2 x 2.5 L) and the combined organics were washed with water (4 L) and brine (1 L), dried over magnesium sulfate and concentrated under reduced pressure to give an oil. The oil was treated with hexane (1.3 L) and cooled to 0C. The solid was filtered and washed with ice-cold hexane (450 mL), dried and combined with a second batch carried out on the same scale to give 3-O-benzyl-1,2:5,6-di-O-isopropylidene-alpha-D-allofuranose (1 kg, 83%) as a white solid. The combined liquors were concentrated to a solid and recrystallized from hexane to give further 3-O-benzyl-1,2:5,6-di-O-isopropylidene-alpha-D-allofuranose (95 g, 90% total).
General procedure: To a 2 Liter, 3 necked flask fitted with a mechanical stirring and a condenser connected at the top to a mineral oil bubbler, a solution of 1,2,5,6-di-O-isopropylidine-alpha-d-glucofuranose (5) (114.5g, 0.44mol) in EtOH free CHCl3 (520mL), K2CO3 (18.5g), KIO4 (170g, 0.74mmol), benzyltriethylammonium chloride (1.03g, 4.39mmol) and activated RuO2xH2O (2g). The mixture was stirred for 1h at 0C then at room temperature over night. The mixture was filtered over a Celite pad and the organic phase was separated, washed with H2O. The aqueous phase was washed with CHCl3 and the combined organic phases was dried (MgSO4), evaporated and dried under reduced pressure and the residue was used in the next step without any further purification. The residue was dissolved in EtOH: H2O (7:3, 700mL) and treated with NaBH4 (10g) portion wise at 0C. The mixture turned colorless and was stirred for 3h at 0C and 1h at room temperature. The solvent was concentrated to 500mL and another 500mL H2O was added to the mixture and the whole was concentrated to 500mL. The mixture was washed with CH2Cl2 (400mL×4 times). The organic phase was dried (MgSO4) and evaporated to give 1,2,5,6-di-O-isopropylidine-alpha-d-allofuranose (71.7g, 63% yield) as a white solid: MS [FAB] m/z 261.3 [M+H]+; 1H NMR (DMSO-d6) deltaH 5.66 (1H, d, H-1, J=3.6Hz), 5.05 (1H, d, 3-OH, J=7.1Hz), 4.45 (1H, t, H-2, J=4.2Hz), 4.23 (1H, dt, H-5, J=7.2, J=2.8Hz), 3.93 (1H, dd, H-4, J=9.1, J=7.2Hz), 3.83 (2H, m, H-6a,b), 3.74 (1H, dd, H-3, J=4.6, J=9.1Hz), 1.45 (3H, s, CH3), 1.32 (3H, s, CH3), 1.28 (3H, s, CH3), 1.27 (3H, s, CH3). To a stirred suspension of NaH (95%, 5.4g) in DMF (90mL) was added 1,2:5,6-di-O-isopropylidine-alpha-d-alloofuranose (55.5g, 0.217mol) in DMF (60mL) dropwise at 0C and the mixture was stirred for 1h at room temperature. Benzyl bromide (27mL) was added dropwise via a Cannula to the mixture at 0C. The mixture was stirred overnight at room temperature. H2O (100mL) was added to the mixture and the product was allowed to crystalize overnight in refrigerator. The crystals were filtered off washed with H2O, dried under reduced pressure, and dissolved in 70% AcOH (360mL). The mixture was stirred for 7h at 36C. The volatiles were removed to give 6 [34-36] (57.9g, 86%) as clear viscus oil.
1,2e5,6-Di-O-isopropylidene-a-D-allofuranose (5.21 g, 20.0 mmol, 1 eq.) wasdissolved in a mixture (7/3 ratio) of glacial acetic acid (36.8 mL,1.80 mL/mmol) and water (15.8 mL, 0.8 mL/mmol). The resultingsolutionwas stirred at ambient temperature overnight, after which TLC analysis (50% EA/PE) showed full conversion of the startingmaterial. Then, the solutionwas concentrated in vacuo. The residuewas co-evaporated twice with water (~40 mL), followed by coevaporationwith toluene (~40 mL, 2 times). The resulting oil wasimmediately used in the next step. Water (44.0 mL, 2.2 mL/mmol)was added, and the solutionwas placed in an ice bath. After stirringat this temperature for 5e10 min, NaIO4 (5.17 g, 24.0 mmol, 1.2 eq.)was added. Then, after another 5 min, the ice bath was removedand the mixture stirred for 30 min at ambient temperature, afterwhich TLC analysis (100% EA) showed full conversion of the intermediatediol. Then, the mixture was placed in an ice bath and EtOH(88.0 mL, 4.40 mL/mmol) was added. The resulting suspension wasfiltered, and the residue rinsed once with EtOH (44.0 mL, 2.2 mL/mmol). The filtrate was placed in an ice bath, and NaBH4 (0.770 g,20.0 mmol, 1 eq.) was added portionwise. After stirring for 30 min,TLC analysis (100% EA) showed full conversion of the intermediatealdehyde. Then, solid NH4Cl (5.14 g, 100 mmol, 5 eq.) was carefullyadded and the mixture stirred for ~10 min. The mixture was subsequentlyevaporated till dryness, co-evaporated with EtOH andpre-adsorbed onto Celite. Purification by column chromatography(2.5 / 5% MeOH/DCM) gave 63 as a clear oil (3.72 g, 19.6 mmol),which solidified upon standing, in 98% yield. 1H NMR (300 MHz,CDCl3): 1.37 (s, 3H, CH3), 1.56 (s, 3H, CH3), 2.57 (br. s, 2H, OH), 3.73(ddd, J 12.0, 3.9, 0.9 Hz, 1H, H3), 3.81e3.86 (m, 1H, H4), 3.92e4.02(m, 2H, H5), 4.58 (t, J 4.5 Hz, 1H, H2), 5.81 (d, J 3.6 Hz, 1H, H1).Spectral data are in accordance with literature values
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; for 24.75h;
6.a; 11
Sodium hydride (1.15 g of a 60 % dispersion in mineral oil, 28.75 mmol) was suspended in dry DMF (10 mL) under N2 and cooled in an ice bath. A mixture of 1,2:5,6-di-O-isopropylidene-α-D-allofuranose 101 (5.0 g19.21 mmol) and 4-(chloromethyl)-biphenyl (4.67 g, 23.04 mmol, Fluka, > 97 %) in dry THF (50 mL) was added dropwise over 45 min. The cooling bath was removed and the mixture was stirred at room temperature for 24 h. The brownish mixture was cooled in an ice bath and water (20 mL) was carefully added. Layers were separated and the aqueous layer was extracted with ether (50 mL). The combined organic layers were washed with water (2 x 50 mL) and brine (50 mL), dried (Na2SO4) and evaporated under reduced pressure. To the resulting brown oil, which crystallised on standing, was added 80% acetic acid (40 mL) and the reaction mixture was stirred at room temperature for 24 hours. The mixture was extracted with light petroleum ether (2 x 25 mL) and the acetic acid was evaporated under reduced pressure followed by coevaporation with ethanol. The residue was partitioned between CH2Cl2 (100 mL) and saturated aqueous NaHCO3 (50 mL). Layers were separated and the aqueous layer was extracted with CH2Cl2 (100 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4) and evaporated under reduced, affording a sticky pale yellow foam (6.9 g). This crude 5,6-diol product 103 (6.9 g) was dissolved in THF/H2O (50 % v/v, 100 mL) and NalO4 (4.6 g, 21.51 mmol) was added. The reaction mixture was stirred at room temperature for 60 min. and the resulting thick white slurry was filtrated. The formed precipitate was washed with ether (100 mL) and the combined filtrates were extracted with ether (2 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (100 mL). The solvents were removed under reduced pressure and p-dioxane (40 mL) was added to this crude aldehyde product. To the stirred solution was added 37% aqueous formaldehyde (4.0 mL) followed by addition of 2 M aqueous NaOH (18 mL) and the reaction mixture was stirred at room temperature for 21 hours. Saturated aqueous NaHCO3 (100 mL) was added and the mixture was extracted with CH2Cl2 (3 x 200 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL), dried (Na2SO4) and evaporated under reduced pressure. The residual pale yellow solid material was recrystallised from ether and gave diol 104 as a white solid material (3.7 g). The remaining material in the mother liqueur was not further purified for the time being. 1H NMR (400 MHz, CDCl3) δ: 1.34 (3H, s, CH3), 1.65 (3H, s, CH3) 3.61 (1H, "d", J 12.08, H-1 "a) 3.81 (1H, d, J 12.10, H-1 "b), 3.91 (1H, d, J 10.78, H-5'a) 3.96 (1H, d, J 10.78, H-5'b), 4.26 (1H, d, J 5.31, H-3'), 4.61 (1H, d, J 11.72, phenylbenzyl-CHa), 4.68 (1H, dd, J 4.03 and 5.13, H-2'), 4.84 (1H, d, J 11.72, phenylbenzyl-CHb), 5.78 (1H, d, J 3.84, H-1'), 7.36-7.58 (5H, m, Ar), 7.59-60 (4H, m, Ar). 13C NMR (400 MHz, CDCl3) δ: 25.78, 26.45 (C(CH3)2, isopropylidene), 63.13, 64.14, 72.30, 77.22, 78.31 (C-1'', C-5', CH2-phenylbenzyl, C-3', C-2'), 86.16 (C-4'), 104.32 (C-1'), 113.40 (C(CH3)2), 126.96, 127.17, 127.29, 128.14, 128.66, 136.08, 140.53, 141.00 (Ar).
With sodium hydride; In N,N-dimethyl-formamide; for 1.16667h;Cooling with ice;
Commercially available l,2;5,6-di-0-isopropylidene-a-D-allofuranose, Compound 1, (135 g, 519.0 mmol) and 2-(bromomethyl)-naphthalene (126 g, 570.0 mmol) were dissolved in DMF (500 mL) in a three- necked flask (500 mL) and the reaction was cooled in an ice bath. Sodium hydride (60% w/w, 29 g, 727.0 mmol) was carefully added (6 g portions every 10 minutes) to the reaction and the stirring was continued for another 60 minutes after the addition was complete. At this time TLC analysis showed complete consumption of Compound 1. The reaction was carefully poured onto crushed ice (ca. 500 g) and the resulting slurry was stirred vigorously until all the ice melted. The resulting off-white solid was collected by filtration and suspended in water. The suspension was stirred vigorously using a mechanical stirrer for 30 minutes after which the solid was collected by filtration and suspended in hexanes. The suspension was stirred vigorously for 30 minutes after which the solid was collected by filtration and air dried for 4-6 hours and then dried under high vacuum over P205 for 16 hours to provide Compound 2 (206.0 g, 99%) as an off- white solid. Compound 2: 'H NMR (300 MHz, CDC13): delta 7.85 (m, 4H), 7.48 (m, 3H), 5.74 (s, 1H), 4.92 (d, 1H, J= 1 1.7), 4.75 (d, 1H, J= 1 1.6), 4.58 (m, 1H), 4.36 (m, 1H), 4.15 (m, 1H), 4.03-3.86 (m, 3H), 1.61 (s, 3H), 1.36 (s, 9H).
99%
With sodium hydride; In N,N-dimethyl-formamide; for 1h;Cooling with ice;
Commercially available l,2;5,6-di-0-isopropylidene-a-D-allofuranose, Compound 43, (135 g, 519.0 mmol) and 2-(bromomethyl)-naphthalene (126 g, 570.0 mmol) were dissolved in DMF (500 mL) in a three-necked flask (500 mL) and the reaction was cooled in an ice bath. Sodium hydride (60% w/w, 29 g, 727.0 mmol) was carefully added (6 g portions every 10 minutes) to the reaction and the stirring was continued for another 60 minutes after the addition was complete. At this time TLC analysis showed no more starting Compound 43. The reaction was carefully poured onto crushed ice (ca. 500 g) and the resulting slurry was stirred vigorously until all the ice melted. The resulting off-white solid was collected by filtration and suspended in water. The suspension was stirred vigorously using a mechanical stirrer for 30 minutes after which the solid was collected by filtration and suspended in hexanes. The suspension was stirred vigorously for 30 minutes after which the solid was collected by filtration and air dried for 4-6 hours and then dried under high vacuum over P2O3 for 16 hours to provide Compound 44 (206.0 g, 99%) as an off-white solid. Compound 44: 1H MR (300 MHz, CDC13): delta: 7.85 (m, 4H), 7.48 (m, 3H), 5.74 (s, 1H), 4.92 (d, 1H, 7= 11.7), 4.75 (d, 1H, 7= 11.6), 4.58 (m, 1H), 4.36 (m, 1H), 4.15 (m, 1H), 4.03-3.86 (m, 3H), 1.61 (s, 3H), 1.36 (s, 9H).
99%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; for 1h;Cooling;
1,2: 5,6-Di-O-isopropylidene-a-D-allofuranose (135 g,519.0 mmol, commercially available from Pfanstiehl Eabo45 ratories, Inc.; orderD-126), Compound 1, and 2-(bromom-ethyl)-naphthalene (126 g, 570.0 mmol) were dissolved in DMF (500 mE) in a three-necked flask (500 mE) and the reaction was cooled in an ice bath. Sodium hydride (60%w/w, 29 g, 727.0 mmol) was careffilly added (6 g portionsevery 10 minutes) to the reaction and the stirring was continued for another 60 minutes afier the addition was complete.At this time TEC analysis showed that the starting sugar, Compound 1, had been consumed. The reaction was carefullypoured onto crushed ice (ca. 500 g) and the resulting slurrywas stirred vigorously until all the ice melted. The resultingoff-white solid was collected by filtration and suspended in water. The suspension was stirred vigorously using a mechanical stirrer for 30 minutes afier which the solid wascollected by filtration and suspended in hexanes. The suspen60 sion was stirred vigorously for 30 minutes afier which thesolid was collected by filtration and air dried for 4-6 hours and then dried under high vacuum over P205 for 16 hours to provide Compound la (206.0 g, 99%) as an off-white solid.?H NMR (300 MHz, CDC13) d 7.85 (m, 4H), 7.48 (m, 3H),5.74 (s, 1H), 4.92 (d, 1H, J=11.7), 4.75 (d, 1H, J=11.6), 4.58(m,1H),4.36(m, 1), 4.15 (m, 1H),4.03-3.86(m,3H), 1.61 (s, 3H), 1.36 (s, 9H).
98%
A) Alcohol (22); Sodium hydride (2.39 g, 59.8 mmol) was added carefully to a cold (0 C.) solution of commercially available 1,2:5,6-Di-O-isopropylidene-alpha-D-allofuranose 1 (12.0 g, 46 mmol) in DMF (75 mL). After stirring for 20 minutes, napthyl bromide (11.12 g, 50.8 mmol) was added to the reaction and the stirring was continued for another 2 h. The reaction was carefully quenched with H2O and then poured into EtOAc and the organic layer washed with water, brine, dried and concentrated. Purification by column chromatography (SiO2, 10% to 33% EtOAc/hexanes) provided alcohol 22 as a white solid (18.1 g, 98%).
98%
A) Compound 1Sodium hydride (2.39 g, 59.8 mmol) was added carefully to a cold (0 C.) solution of commercially available 1,2:5,6-Di-O-isopropylidene-alpha-D-allofuranose, Compound 1 (12.0 g, 46 mmol) in DMF (75 mL). After stirring for 20 minutes, napthyl bromide (11.12 g, 50.8 mmol) was added to the reaction and the stirring was continued for another 2 hours. The reaction was carefully quenched with water and then poured into EtOAc and the organic layer was washed with water, brine, dried and concentrated. Purification by column chromatography (SiO2, 10% to 33% EtOAc/hexanes) provided the alcohol, Compound 2 as a white solid (18.1 g, 98%).
With sodium hydride; In N,N-dimethyl-formamide; for 1.16667h;Cooling with ice;
EXAMPLE 7A) Compound 47Commercially available sugar 1,2:5,6-Di-O-isopropylidene-alpha-D-allofuranose (135 g, 519.0 mmol, commercially available from Pfanstiehl Laboratories, Inc.; order No. D-126) Commercially available sugar 2 (135 g, 519.0 mmol) and 2-(bromomethyl)-naphthalene (126 g, 570.0 mmol) were dissolved in DMF (500 mL) in a three-necked flask (500 mL) and the reaction was cooled in an ice bath. Sodium hydride (60% w/w, 29 g, 727.0 mmol) was carefully added (6 g portions every 10 minutes) to the reaction and the stirring was continued for another 60 minutes after the addition was complete. At this time TLC analysis showed no more starting sugar 2. The reaction was carefully poured onto crushed ice (ca. 500 g) and the resulting slurry was stirred vigorously until all the ice melted. The resulting off-white solid was collected by filtration and suspended in water. The suspension was stirred vigorously using a mechanical stirrer for 30 minutes after which the solid was collected by filtration and suspended in hexanes. The suspension was stirred vigorously for 30 minutes after which the solid was collected by filtration and air dried for 4-6 hours and then dried under high vacuum over P2O5 for 16 hours to provide Compound 47 (206.0 g, 99%) as an off-white solid. 1H NMR (300 MHz, CDCl3) delta: 7.85 (m, 4H), 7.48 (m, 3H), 5.74 (s, 1H), 4.92 (d, 1H, J=11.7), 4.75 (d, 1H, J=11.6), 4.58 (m, 1H), 4.36 (m, 1H), 4.15 (m, 1H), 4.03-3.86 (m, 3H), 1.61 (s, 3H), 1.36 (s, 9H).
With tetrabutylammomium bromide; sodium hydroxide; In dichloromethane; water; at 20℃; for 4h;
Into a 5000-mL 4-necked round-bottom flask, was placed a solution of intermediate 4c (350 g, 1.34 mol) in dichloromethane (700 mL). To this was added tetrabutylammonium bromide (476.8 g, 1.48 mol). To the mixture was added 50% sodium hydroxide/water (700 g). To the above was added 2-(bromomethyl) naphthalene (340 g, 1.54 mol) in several batches. The resulting solution was allowed to react, with stirring, for 4 h at room temperature. The reaction was then quenched by the addition of 1800 mL of dichloromethane/water (1:1). The resulting solution was extracted with 2×1 L of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×1000 mL of water. The residue was dissolved in 1000/1000 mL of petroleum ether/water. The crude product was purified by re-crystallization from petroleum ether. This resulted in intermediate 4d.
General procedure: (I) 1,2:5,6-Di-O-isopropylidene-alpha-D-glucofuranose (3)(1.0 g; 4.0 mmol) was dissolved in DMF (20 ml), cooledat 0 C and under N2-atmosphere NaH (0.14 g; 6.0 mmol)was added to the solution. The suspension was stirred for30 min and cooled to -35 to -40 C. After N?,N-sulfonyldiimidazole(1.2 g; 6.0 mmol) in DMF (12 ml) was droppedto the reaction mixture and stirred for 30 min again at-40 C. MeOH was added (0.8 ml) to the solution andstirred for 30 min at -40 C. The solution was poured intoice-water (200 ml). The precipitate was filtered, washedwith cold water to get the white crystalline product 11(1.2 g; 80%). M.p.: 97-98 C; lit. m.p. (Vatle and Hanessian1996): 98-99 C; Rf = 0.70 (EtOAc-hexane 1:1).(II) From 3 (25.0 g; 96.0 mmol) the yield was 84% (31.5 g).
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