| 100% |
With potassium carbonate In methanol at 25℃; for 12h; |
|
| 100% |
With potassium carbonate In methanol |
|
| 100% |
With sodium methoxide In methanol at 20℃; for 2h; |
|
| 100% |
With methanol; sodium methoxide at 20℃; for 4h; |
|
| 100% |
With sodium methoxide In methanol at 20℃; for 4h; |
|
| 100% |
With methanol; sodium methoxide for 0.333333h; |
Step 1: Formation of IntA1 by De-Acetylation of Tri-O-Acetyl D-Glucal The Tri-O-Acetyl-D-Glucal [SM-A] (100 g, 367 mmol) is dissolved in dry MeOH [1.5 L], and then NaOMe (110 mmol, 5.95 g) is added into reaction mixture. Within about 20 minutes, TLC (40% EtOAc/60% hexanes & 100% EtOAc) confirmed de-acetylated glucal. The reaction is quenched with 50WX4 cation exchange resin until pH is near 7.0 by pH strip paper. The mixture is filtered and evaporated to dryness under vacuum to yield syrupy glucal intermediate IntA1 (59 g). Theoretical yield=100 g*(146/272)=53.7 g TLC IntA1Rf=0.1, SiO2, 100% Ethyl Acetate |
| 100% |
With methanol; potassium carbonate at 20℃; |
|
| 100% |
With methanol; potassium permanganate; trimethyl-sulfonium iodide at 25℃; for 0.0833333h; chemoselective reaction; |
|
| 100% |
With sodium methoxide In methanol at 0 - 20℃; for 2h; |
1 Preparation of ( 2R, 3S, 4R)-2-(hydroxymethyl)-3, 4-dihydro-2H-pyran-3, 4-diol (A2)
To a stirred solution of compound Al (2.72 g, 10.0 mmol, 1.0 equiv) in MeOH (20 mL) was added NaOMe (216 mg, 4.0 mmol, 0.4 equiv) at 0°C, and the mixture was stirred at rt. for 2 h. The reaction was quenched with NH4Q (aq.), then concentrated, the residue was taken up with EA, washed with water and brine, dried over Na2SO4. Concentration and purification by silica gel (PE-PE:EA=5: l-DCM:MeOH=20: l) provided compound A2 as a colorless oil (1.5 g, yield: 100 %). |
| 99% |
With sodium methoxide In methanol at 25℃; for 3h; |
|
| 99% |
With potassium carbonate In methanol |
|
| 99% |
With methanol; sodium methoxide at 22℃; for 1.5h; |
1; 1.i
The starting material, 1, (8 g, 29.38 mmol) was vacuum dried overnight prior to initiating the reaction the following day. At ambient temperatures (22°C) and with N2, MeOH (40 mL) was added to dissolve the starting material and the reaction was initiated with the addition of a freshly prepared solution of 2 M NaOMe in MeOH (0.5 mL, 0.13 M). The reaction was completed after 1.5 h, as was indicated by TLC, with Rf: (9: 1 CH2Cl2 : MeOH) 0.25. The crude reaction mixture was concentrated in-vacuo to a crude oil and purified by silica gel column chromatography. The crude was eluted with 9:1 v/v CH2Cl2 :MeOH and the purified product 2, was collected in yields of 4.30 g (99%) as a white crystalline solid after drying with high vacuum.D-glucal, 2_, (4.30 g, 29.42 mmol) was flushed with a constant flow of N2 and at -400C was added anhydrous DMF (145 mL, 2.87 mol) and stirred to complete solution. The reaction was initiated with the slow (dropwise for 5 min) addition of t- Bu2Si(OTf)2, (15 mL, 40 mmol) and the reaction was completed after 45 min by confirmation with TLC, Rf : (5 : 1 Hex : EtOAc) 0.33. The crude reaction mixture was quenched with anhydrous pyr (3.6 mL, 44 mmol) and stirred for an additional 15 min. The crude product was extracted in Et2O (600 mL) , and quenched, washed with saturated NaHCO3 (150 mL) and H2O (150 mL) . The organic solution was dried with MgSO4 and the solvent evaporated prior to silica gel column chromatography. The purified product was collected as a white crystalline solid in yields of 7.4 g (88%) .1H NMR (3, 400 MHz, CDCl3) δ: 6.25 (IH, d, J = 6 Hz, Hl), 4.75(IH, d, J = 6.4 Hz, H2), 4.29 (IH, , J = 6.8 Hz, H3 ) , 4.17(IH, dd, J = 4.8, 10.4 Hz, H6), 3.95 (IH, t, J = 10.4 Hz IH, H6'), 3.90 (IH, d, J= 10.4 Hz, H4) , 3.84 (IH, dd, J= 4.8, 10.4Hz, H5), 2.36 (IH, s, OH), 1.07 (9H, s, t-Bu Me), 0.99 (9H, s, t-Bu Me) .13C NMR (3_, 100 MHz, 1H decoupled 400 MHz, CDCl3) δ : 144 (Cl), 103 (C2), 77.4 (C4), 72.6 (C5), 70.1(C3), 66.1 (C6), 27.9 (t-Bu Me), 27.4 (t-Bu Me), 23.25 (t-Bu), 20.27 (t-Bu); ESI-MS Calcd. for C14H26O4Si: 286.4, found: 286.1. |
| 99% |
With lipase A from Aspergillus niger In aq. phosphate buffer; acetonitrile at 25℃; for 1h; Enzymatic reaction; |
|
| 99% |
With methanol; sodium methoxide at 20℃; for 0.5h; |
3.1. General Procedure for the Synthesis of Glycals
General procedure: A catalytic amount of MeONa (0.03 g, 0.57 mmol) was added to a solution of tri-O-acetyl-D-glycal (2.5 g, 9.18 mmol) in methanol (25 mL) and the resulting reaction mixture was stirred at rt. The progress of reactions was monitored by silica gel thin-layer chromatography plates. After 30 min, the solution was filtered on a Schott funnel over a resin layer (Amberlite IR120) and celite. Evaporation of the organic solvent afforded a pure product. 3.1.1. D-Glucal (1)Colorless solid, 1.67 g, 99% yield; Rf = 0.06 (hexane/ethyl acetate, 7:3); [α]D20 = -7.6 (c0.9, CHCl3), {Lit. [90]: [α]D20 = -8.0 (c 1.19, H2O)}; m.p. = 54-56 °C, {Lit. 90]: m.p. = 58-60°C}; δH (600 MHz, D2O): 3.61 (dd, 1H, J = 9.0, 7.1, H-4), 3.72-3.86 (m, 3H, H-5, 2H-6), 4.17(dt, 1H, J = 7.1, 2.0, H-3), 4.73 (dd, 1H, J = 6.0, 2.0, H-2), 6.35 (dd, 1H, J = 6.0, 1.4, H-1).1H NMR spectral data matched that reported by Crotti [91]. |
| 98% |
With lithium hydroxide monohydrate; triethylamine In methanol |
|
| 98% |
With tris(2,4,6-trimethoxyphenyl)phosphine In methanol at 22℃; for 5h; |
|
| 98% |
With methanol; natrium at 20℃; for 0.166667h; Inert atmosphere; |
D-Glucal
A) Sodium (626 mg, 27.2 mmol) was allowed to react with methanol (600 mL) and then treated with a solution of S4 (26.11 g, 95.9 mmol) in methanol (225 mL). The reaction was stirred at room temperature for 10 minutes and then the solution was concentrated to provide crude D-glucal. The crude product was treated successively with portions of methanol (3 x 5 mL), acetone (100 mL) and diethyl ether (200 mL), which led to the precipitation of impurities. The solution was filtered and the filtrate concentrated to afford D-glucal as a white glassy substance (13.68 g, 98%). Spectral data matched those which have been reported previously.1 |
| 98% |
With methanol; sodium methoxide at 20℃; for 5h; |
D-Glucal (3).
To a solution of tri-O-acetyl-D-glucal (1.1 g, 4.00 mmol) in MeOH (20 mL) was added NaOMe (10.8 mg, 0.2 mmol), and the mixture was stirred at room temperature for 5 h. The solution was then neutralized with 1.25M HCl in MeOH and the solvent was concentrated under reduced pressure. The residue was purified using silica gel column chromatography with EtOAc to obtain D-glucal (3) (0.573 g, 3.92 mmol, 98%) as a white solid. 1H NMR (400 MHz, DMSO-d6) = 3.57 (1H, dd, J = 9.6, 7.2 Hz), 3.70-3.74 (1H, m), 3.79 (1H, dd, J = 12.0, 5.6 Hz), 3.88 (1H, dd, J = 12.0, 1.2 Hz), 4.12 (1H, ddd, J = 6.8, 2.0, 2.0 Hz), 4.68 (1H, dd, J = 6.4, 2.0 Hz), 6.35 (1H, dd, J = 6.0, 1.6 Hz) ppm. 13C NMR (100 MHz, CD3OD) = 62.2, 70.5, 70.8, 80.3, 104.5, 144.9 ppm. |
| 97% |
With sodium methoxide In methanol for 4h; Ambient temperature; |
|
| 97% |
With methanol; sodium methoxide at 20℃; for 5h; |
|
| 97% |
With sodium methoxide In methanol |
|
| 97% |
With methanol; potassium carbonate at 20℃; for 12h; |
|
| 97% |
With methanol; potassium carbonate at 20℃; for 4h; |
1
Put compound 7 (13.8g, 50.7mmol) and potassium carbonate (0.74g, 5.35mmol) in a 250mL round bottom flask, add 100mL of anhydrous methanol, and react at room temperature for 4 hours. TLC detects that the substrate reaction is complete, and the reaction system is rotated. After evaporation and concentration, it was purified by silica gel column chromatography (DCM/MeOH=5:1→3:1) to obtain compound 8 (7.2g, 49.3mmol, 97%) as a white solid. For the specific process, please refer to VDBussolo, M. Caselli, M. Pineschi, P. Crotti, Org. Lett. 2003, 5, 2173-2176 |
| 96% |
With sodium methoxide |
|
| 96% |
With sodium methoxide In methanol at 20℃; for 1h; |
|
| 96.8% |
With methanol; potassium carbonate |
|
| 95% |
With methanol; sodium methoxide at 20℃; for 0.5h; Inert atmosphere; |
|
| 94% |
With lithium hydroxide In methanol for 0.166667h; Ambient temperature; |
|
| 93.3% |
With natrium In methanol for 18h; Ambient temperature; |
|
| 93% |
With sodium methoxide In methanol at 20℃; for 5h; |
|
| 93% |
With potassium carbonate In methanol at 23℃; for 5h; Inert atmosphere; |
|
| 93% |
With methanol; potassium carbonate at 23℃; for 5h; Inert atmosphere; |
|
| 93% |
With sodium methoxide In methanol at 20℃; for 1.5h; |
1 Preparation of D-glucose (11)
To compound 10 (2 g, 7.35 mmol) at room temperatureMethanol solution (15mL)Meona (158.75 mg, 2.94 mmol, 0.4 equiv.) was added.Reaction for 1.5 hours,After the reaction was completed, the pH was adjusted to 7.0 with H+ ion exchange resin, and filtered.Condensed by steaming,The oily compound 11 (1 g, yield 93%,Percentage of mass),Rf0.25 (DCM/MeOH 10/1),Used directly in the next step. |
| 93% |
With methanol; sodium methoxide at 20℃; for 2h; |
4.2.1. 3,4,6-Tri-O-allyloxycarbonyl-D-glucal (7)
General procedure: β-D-Glucose pentaacetate 5 (10 g, 25.6 mmol) was dissolved in dryCH2Cl2 (60 mL) and hydrogen bromide, 33% w/w (45% w/v) solutionin acetic acid (4.9 mL) was added dropwise at 0 °C. The mixture wasthen allowed to warm to room temperature and stirred for 6 h. Thereaction mixture was diluted with CH2Cl2 (150 mL) and washed successivelywith saturated aqueous solution of NaHCO3 (80 mL). Theorganic layer was drying over Na2SO4 and concentrated to give 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (10.1 g, 96%) as a colorlesssyrup. Rf = 0.60 (PE: EtOAc, 2:1). To a solution of 2,3,4,6-tetra-Oacetyl-α-D-glucopyranosyl bromide (5.0 g, 12.16 mmol) dissolved inacetone was added zinc power (7.63 g, 117 mmol) and saturatedNaH2PO4 solution (30 mL). The mixture was stirred overnight at roomtemperature and the mixture was filtered and concentrated. The resultingmixture was diluted with CH2Cl2 and washed successively withsaturated aqueous solution of NaHCO3 and then dried over Na2SO4 andconcentrated to afford 3,4,6-tri-O-acetyl-D-glucal (3.1g, 94%).Rf = 0.30 (petroleum ether: EtOAc, 5:1). To a solution of 3,4,6-tri-Oacetyl-D-glucal (2 g, 7.35 mmol) in dry MeOH (15 mL) was addedNaOMe (159 mg, 2.94 mmol) and stirred for 2 h. The reaction mixturewas neutralized with amberlite IR120 resin, filtered and concentratedin vacuo to obtain D-glucal 6 (1 g, 93%). Rf = 0.25 (CH2Cl2: MeOH,10:1). To a solution of D-glucal 6 (2 g, 13.69 mmol) in anhydrouspyridine (20 mL), allyl chloroformate (17.5 mL, 12 equiv.) was addeddropwise at 0 °C. The mixture was stirred for 12 h at room temperature.The residue was diluted with CH2Cl2 and washed first with 1.0 M HCland then saturated aqueous NaHCO3. The organic layer was dried overNa2SO4 and concentrated. The residue was purified by flash chromatography(petroleum ether: EtOAc, 20:1) to give compound 7 (2.2 g,40%) as yellow syrup. Rf = 0.8 (petroleum ether: EtOAc, 2:1); [α][20]D-23.3 (c 0.24, CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.46 (d, 1H,J = 5.6 Hz), 5.96-5.82 (m, 3H), 5.38-5.28 (d, 3H, J = 17.2 Hz),5.28-5.15 (m, 4H), 5.07 (s, 1H), 4.92 (s, 1H), 4.65-4.55 (m, 6H),4.49-4.41 (m, 1H), 4.38-4.32 (s, 1H), 4.32-4.24 (m, 1H). 13C NMR(101 MHz, CDCl3) δ 154.48, 154.01, 153.60, 145.86, 131.27, 131.23,130.97, 119.29, 118.97, 118.90, 97.79, 73.27, 70.62, 69.94, 69.07,68.68, 68.64, 64.56. HRMS m/z calcd for C18H22O10Na [M+Na]+:421.1111, found: 421.1086. |
| 92% |
With sodium methoxide In methanol Large scale reaction; |
|
| 90% |
With methanol; natrium at 20℃; for 0.166667h; Inert atmosphere; |
|
| 90% |
With sodium methoxide In methanol at 20℃; for 1h; |
185.iv
0.206 mL of perchloric acid was slowly added to 40 mL of acetic anhydride,Stirring at 40 30min,After the temperature was lowered to 30 ° C,10 g of D-glucose was slowly added and stirred for 30 min.The reaction solution was cooled to 10 ° C,3.1 g of red phosphorus,5.8 mL of liquid bromine and 3.6 mL of water were added slowly in that order,After warming to 30 ° C to continue stirring 2h.The reaction solution was quenched with 50 mL of ice water,Ethyl acetate extraction,The ester layer was dried over anhydrous sodium sulfate and concentrated.The concentrate was dissolved in 50 mL of ethyl acetate,Cooled to 0 ° C,16.1 g of zinc dust,212 mg of CuSO4.5H2O and 1.06 g of sodium acetate130mL 60% acetic acid aqueous solution,Was added to the reaction solution. 0 Reaction 1h rose to room temperature reaction 1h,The reaction solution was filtered,After extraction with ethyl acetate,The ester layer was dried over anhydrous sodium sulfate and concentrated,Pressure column chromatography,Petroleum ether: ethyl acetate = 3: 1 (v / v)10.4 g of 3,4,6-tris (O-acetyl) -D-glucal(68% yield over two steps) |
| 90% |
With methanol; sodium methoxide; potassium carbonate at 20℃; |
3 Synthesis of D-glucal.
Potassium carbonate (50g) was added to the solution of per-O-acetylated glucal (0.177mol) in methanol (500 mL). The reaction mixture was stirred at room temperature overnight. Inorganic salts were filteredoff, and filtrate was evaporated to dryness. Product was purified by column chromatography (SilicaGel 60) using chloroform:methanol as eluents, to give 0.159 mol of crystalline D-glucal (Yield 90%) (NMR spectra match that of literature). |
| 90% |
With sodium methoxide In methanol at 20℃; for 1h; |
185.iv
0.206 mL of perchloric acid was slowly added to 40 mL of acetic anhydride, stirred at 40 ° C for 30 min,After the temperature dropped to 30 ,10 g of D-glucose was added slowly and stirred for 30 min.The reaction solution was cooled to 10 ° C,3.1 g of red phosphorus, 5.8 mL of liquid bromine and 3.6 mL of water were added slowly,After warming to 30 ° C, continue stirring for 2 h.The reaction solution was quenched with 50 mL of ice water and extracted with ethyl acetate. The ester layer was dried over anhydrous sodium sulfate and concentrated.The concentrate was dissolved in 50 mL of ethyl acetate, cooled to 0 ° C,16.1 g of zinc powder, 212 mg of CuSO4 · 5H2OAnd 1.06 g of sodium acetate were mixed with 130 mL of a 60% aqueous acetic acid solution,Was added to the reaction solution.0 reaction 1h after the reaction to room temperature for 1h,The reaction solution was filtered and extracted with ethyl acetate. The ester layer was dried over anhydrous sodium sulfate and concentrated.Column chromatography,Petroleum ether: ethyl acetate = 3: 1 (v / v)To give 10.4 g of 3,4,6-tris (O-acetyl) -D-glucoside(Two-step yield 68%), 5.2 g of 3,4,6-tris (O-acetyl) -D-glucoside (19.1 mmol) was dissolved in 100 mL of methanol,Add 300mg sodium methoxide, room temperature reaction 1h,The reaction solution was adjusted to pH 7 with a cationic resin, concentrated by filtration,Pressure column chromatography (elution with ethyl acetate) gave 2.5 g of D-glucal,Yield 90%; 5.6 g of D-glucosinol (38.4 mmol) was dissolved in 100 mL of pyridine,Cooling to 0 ,11.34 mL of triisopropylchlorosilane (54.22 mmol) and 15.6 g of imidazole (230.4 mmol) were added,Room temperature reaction 2h, with 50mL ice water quenching,Ethyl acetate, the ester layer was dried over anhydrous sodium sulfate and concentrated,The column was separated by column chromatography, petroleum ether: ethyl acetate = 5: 1 (v / v) to give 5.2 g of compound 185d,Yield 46%. |
| 89% |
With triethylamine In methanol; lithium hydroxide monohydrate at 20℃; for 24h; |
|
| 89% |
With lithium hydroxide monohydrate; triethylamine In methanol at 20℃; for 24h; |
|
| 82% |
With IRA-400(OH) resin In methanol for 2h; |
|
| 75% |
With methanol; potassium carbonate for 2h; Inert atmosphere; |
|
| 50% |
With sodium methoxide In methanol at 25℃; |
|
|
With ammonia |
|
|
With sodium methoxide In methanol for 16h; Ambient temperature; |
|
|
With sodium methoxide In methanol for 1h; Ambient temperature; |
|
|
With anhydrous sodium carbonate In methanol |
|
|
With sodium methoxide In methanol |
|
|
With sodium methoxide In methanol at 23℃; for 1.5h; |
|
|
hydrolysis; |
|
|
With anion-exchange resin ( Amberlite IRN-78, OH- form) In methanol for 15h; Ambient temperature; |
|
|
With sodium methoxide In methanol |
|
|
With sodium methoxide In methanol at 0 - 25℃; |
|
| 16.08 g |
With anhydrous sodium carbonate In methanol; lithium hydroxide monohydrate for 2h; Ambient temperature; |
|
|
With lithium hydroxide monohydrate; triethylamine In methanol for 5h; Ambient temperature; |
|
|
With sodium methoxide In methanol for 5h; |
|
|
With potassium carbonate In ethanol; lithium hydroxide monohydrate for 19h; Ambient temperature; |
|
|
With sodium methoxide In methanol |
|
|
With sodium methoxide for 16h; Ambient temperature; |
|
|
With sodium methoxide In methanol for 5h; Ambient temperature; |
|
|
With sodium methoxide In methanol at 25℃; for 2h; |
|
|
In methanol |
|
|
With sodium methoxide In methanol Yield given; |
|
|
With methanol; sodium methoxide |
|
|
With methanol; potassium carbonate |
|
|
With triethylamine In methanol; lithium hydroxide monohydrate at 20℃; for 8h; |
|
|
With methanol; potassium carbonate |
|
|
With NaCO3 In methanol |
|
|
With triethylamine In methanol; lithium hydroxide monohydrate at 20℃; for 5h; |
|
|
With sodium methoxide In methanol at 20℃; |
|
|
With sodium methoxide In methanol |
|
|
With potassium carbonate In methanol for 0.666667h; |
|
|
With potassium carbonate In methanol at 20℃; for 3h; |
|
|
With potassium carbonate In methanol at 25℃; for 24h; |
|
|
With methanol at 20℃; for 1h; |
|
|
With sodium methoxide In methanol at 23℃; for 0.416667h; |
|
|
With sodium methoxide In methanol at 20℃; for 1h; |
|
|
With methanol; sodium methoxide at 25℃; |
|
|
With sodium methoxide In methanol |
|
|
With lithium hydroxide monohydrate; triethylamine In methanol at 20℃; for 1h; |
2
A solution of commercially available tri-O-acetyl-D-glucal (2.72 g, 10 mmol) was dissolved in MeOH-H2O-Et3N (10:10:1, 125 mL) and stirred for 1 hour at ambient temperature, followed by removal of all volatiles under reduced pressure. The residue was dried by co-evaporation with dioxane (3x 50 mL). The resulting clear oil was used without any further purification. |
|
With potassium carbonate In methanol at 20℃; for 4h; |
|
|
With methanol; sodium methoxide at 20℃; for 2h; |
|
|
With methanol; potassium carbonate |
|
|
With sodium methoxide In methanol |
|
|
With sodium methoxide In methanol at 20℃; |
|
|
With potassium carbonate In methanol at 20℃; for 12h; |
|
|
Stage #1: D-glucal triacetate With sodium methoxide In methanol at 0 - 20℃; for 1h; Inert atmosphere;
Stage #2: In methanol |
|
|
With methanol; sodium methoxide at 20℃; for 0.5h; |
|
|
With potassium carbonate In methanol Inert atmosphere; |
|
|
With sodium methoxide In dichloromethane at 20℃; for 4h; |
|
|
With Resin (OH) |
|
|
With methanol; potassium carbonate at 20℃; for 12h; |
|
|
With methanol; sodium methoxide at 20℃; Inert atmosphere; |
|
|
With methanol; sodium methoxide at 20℃; for 3h; |
|
|
With sodium methoxide In methanol at 20℃; |
|
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