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CAS No. : | 97-30-3 | MDL No. : | MFCD00064086 |
Formula : | C7H14O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HOVAGTYPODGVJG-ZFYZTMLRSA-N |
M.W : | 194.18 | Pubchem ID : | 64947 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 4.0 |
Molar Refractivity : | 40.47 |
TPSA : | 99.38 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -9.37 cm/s |
Log Po/w (iLOGP) : | 0.8 |
Log Po/w (XLOGP3) : | -2.65 |
Log Po/w (WLOGP) : | -2.57 |
Log Po/w (MLOGP) : | -2.4 |
Log Po/w (SILICOS-IT) : | -1.85 |
Consensus Log Po/w : | -1.73 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.76 |
Solubility : | 1110.0 mg/ml ; 5.72 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 1.11 |
Solubility : | 2510.0 mg/ml ; 12.9 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | 1.91 |
Solubility : | 15700.0 mg/ml ; 80.7 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.3 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine at 25℃; | |
100% | With pyridine | |
100% | With indium(III) triflate at 30℃; |
99% | for 4h; Ambient temperature; | |
99% | With H-Beta zeolite for 3h; Ambient temperature; | |
99% | With iron(III) sulfate at 20℃; for 3h; | |
99% | With 4-(N,N-dimethylamino)pyridine based 1,3,5,7-tetraphenyladamantane polymer In neat (no solvent) at 25℃; for 20h; Schlenk technique; | 2.7. Acylation of alcohols General procedure: The alcohol (1.5 mmol) and anhydride (3 mmol) were mixed in a 50 mL Schlenk tube, and then TPB-DMAP or TPA-DMAP (0.045 mmol) was added. The mixture was stirred at room temperature unless otherwise indicated. After completion of the reaction, the reaction mixture was subjected to centrifugation and the solid catalyst was separated. The liquid phase was harvested by decanting and evaporated, and the residue was purified by column chromatography on silica gel to afford the pure ester product. For recycling the catalyst, the isolated catalyst was washedwith diethyl ether and dried in vacuum, the recovered yellow solid was reused directly for the next run. |
99% | With lithium perchlorate for 18h; Heating; | |
98% | With iron(III) chloride for 0.166667h; Ambient temperature; other carbohydrates, other temperatures, other reaction times; | |
98% | With iron(III) chloride for 0.166667h; Ambient temperature; | |
98% | With iodine at 20℃; for 0.0833333h; | |
98% | With 1,4-diaza-bicyclo[2.2.2]octane at 20℃; Neat (no solvent); | Typical procedure: Acetylation of methyl α-d-glucopyranoside. DABCO (1.0 mol equiv) was added to a suspension of the sugar (10.0 g, 51.5 mmol) in Ac2O (1.2 mol equiv per OH group) and the mixture was stirred at rt. After completion of the reaction (TLC, eluent, EtOAc:n-Hex, 2:3) the mixture was poured onto crushed ice and was stirred for a few min when precipitation of the desired methyl 2,3,4,6-tetra-O-acetyl-α-d-glucopyranoside took place along with dissolution of DABCO in water (the latter indicated by TLC and viewing the spot in an iodine chamber). The product was isolated by filtration at the pump followed by washing with ice-cold water and drying. It was pure enough for direct further use. Yield, 18.3 g, 98%. An analytically pure sample was obtained by recrystallization from 95% ethanol.It may be noted that addition of DABCO and stirring lead to warming up of the reaction mixture. In reactions carried out on 10-20 g scale this is advantageous in that considerable rate enhancement can be obtained in such cases. However in reactions on a much larger scale (50-100 g and above) the addition of DABCO should preferably be carried out portion-wise to keep the reaction mixture from getting over heated. |
98% | With copper(II) perchlorate hexahydrate In neat (no solvent) at 20℃; for 0.5h; Inert atmosphere; | |
98% | With 1H-imidazole In acetonitrile at 20℃; for 6h; | |
97% | With copper(II) bis(trifluoromethanesulfonate) In dichloromethane at 20℃; for 4h; | |
96% | With methanesulfonic acid In neat (no solvent) at 30 - 35℃; for 0.0833333h; Green chemistry; | |
96% | With dysprosium(III) trifluoromethanesulfonate In neat (no solvent) at 20℃; for 0.25h; Inert atmosphere; | |
95% | at 28 - 32℃; for 0.166667h; | |
95% | at 20℃; for 0.5h; | |
93% | at 50℃; for 6h; | |
89% | With pyridine for 16h; Ambient temperature; | |
88% | ||
88% | With phosphotungstic acid at 28℃; for 24h; Inert atmosphere; | |
70% | In neat (no solvent) Molecular sieve; Microwave irradiation; Green chemistry; | Optimized MW-assisted peracetylation General procedure: The substrate belonging to one of the subset reported in Table 1(NTC, TC, CP, DGNP) (0.1 mmol) was left to react under MWheating (Synthos 3000, Anton Paar) with dry acetic anhydride(1 mL, 10 mmol) in a 3 mL vial (Rotor 64MG5 ), equipped witha magnetic stirrer in the presence of molecular sieves(10 % w/w). The microwave, equipped with IR sensor forexternal temperature control (IR limit calculated as follows:Tinternal= 1.214 × TIR), has been set with the power programsprovided for its subset as described in Table 1. At the end of thereaction, the mixture was filtered, diluted with ethanol (2 mL)and left under vigorous stirring for 30 minutes at 50 °C. Themixture was then evaporated under reduced pressure and asmall amount of a saturated solution of sodium bicarbonate(3.8 mL, 10 mmol NaHCO3) was added. After the evolution ofCO2, the precipitation of the peracetylated product was observed. The products were separated by simple decantation. Forcompounds which do not precipitate upon addition of NaHCO3,an extraction with AcOEt was needed. The organic phase, afterdrying with Na2SO4, filtration and evaporation, gave the reaction crude. |
With pyridine | ||
With perchloric acid; acetic acid | ||
With pyridine Ambient temperature; | ||
With perchloric acid on silica gel at 20℃; | ||
With pyridine at 20℃; for 15h; | ||
With iodine at 23℃; | ||
With pyridine; dmap at 20℃; for 12h; | ||
With 6C2F3O2(1-)*(x)C2HF3O2*Zn4O(6+) In toluene at 70℃; for 12h; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine at 70℃; for 2h; | |
100% | With pyridine at 90℃; for 72h; Inert atmosphere; Schlenk technique; | |
98% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 30℃; for 3.5h; regioselective reaction; |
97% | With pyridine at 70℃; for 2h; | |
97% | With pyridine at 70℃; for 3.5h; | |
93% | With anhydrous sodium carbonate for 2h; | |
93% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane | |
92% | With pyridine at 90℃; for 3h; regioselective reaction; | |
92% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere; | 4.1.2.1. Methyl 6-O-(triphenylmethyl)-α-d-glucopyranoside 6 A solution of methyl-α-d-glucopyranoside 5 (1.0 g, 5.2 mmol), trityl chloride (1.5 g, 5.7 mmol) and triethylamine (1.3 ml, 9.3 mmol) in dry DMF (15 ml) was stirred overnight at room temperature under nitrogen. After 24 h, the solvent was evaporated under reduced pressure and the residue was dissolved in EtOAc (20 ml) and water (20 ml). After the separation of the layers, aqueous layer was extracted with EtOAc (3 × 10 ml). The combined organic layers were dried with MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by chromatography on a silica gel column (cyclohexane/EtOAc, 4:6 then 2:8) to give compound 6 as a white solid (2.1 g, 92%). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.47-7.30 (m, 15H, Harom), 4.71 (d, 3J(H, H) = 3.6 Hz, 1H, H1β), 3.68 (m, 1H, H5), 3.65 (dd, 3J(H, H) = 3.6, 9.1 Hz, 1H, H2), 3.45 (t, 3J(H, H) = 9.1 Hz, 1H, H3), 3.39 (m, 3H, OCH3), 3.37 (m, 1H, H4), 3.31 (m, 2H, H6); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 143.9, 128.7, 127.8, 127.0, 99.2, 86.7, 74.4, 72.0, 71.3, 70.4, 63.9, 55.0; m.p. 153-155 °C (lit. refPreviewPlaceHolder[39]: m.p. 154.5-155.5 °C); IR (neat): ν = 3429 (O-H); C26H29O6: calcd C 71.54, H 6.47; found: C 71.35, H 6.42; MS (ESI, ion polarity positive): m/z: 459 [M + Na]+. |
91.2% | With pyridine Ambient temperature; | |
91% | With pyridine at 50℃; for 6h; | |
90% | With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide at 20℃; | |
87% | With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide for 19h; Ambient temperature; | |
87% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃; | |
86% | With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h; | |
86% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane Inert atmosphere; | |
86% | With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane | (2S,3R,4S,5R,6R)-2,3,4,5-tetramethoxy-6-((trityloxy)methyl)tetrahydro-2H-pyran (S3). Trityl ether S2 (10.1 g, 23.2 mmol), prepared from a-methyl-D-glucopyranoside (S I) according to the DABCO method of Gadakh, SI was suspended in DMF (1 10 mL), placed under a strict Ar atmosphere and cooled to 0 °C. NaH (4.82 g, 120.4 mmol) was added in four portions over the period of 15 min. After stirring at 0 °C for 1.5 h, Mel (11.53 mL, 185.2 mmol) was added in a drop wise fashion. The reaction was then slowly warmed to rt and stirred at rt for 12 h. In order to optimize yield, the mixture was retreated prior to work up by cooling the flask to 0 °C and adding an additional aliquot of NaH (2.41, 60.2 mmol). After 30 min, a second aliquot of Mel (5.7 mL, 92.6 mmol) was added and the mixture was warmed to rt. After 7 h at rt, satd. NH4C1 (200 mL) was added in a drop wise fashion. The mixture was extracted with EtOAc (3 χ 200 mL), washed with H20 (200 mL) and satd. NH4C1 (200 mL), dried over Na2S04 and concentrated on a rotary evaporator. Pure S3 (9.13 g, 82%) was obtained by flash chromatography eluting with a gradient of hexanes to EtOAc. [0302] Intermediate S3: TLC (1 : 1 hexanes/EtOAc): Rf = 0.67; 1H NMR (CDC13, 500 MHz) δ 7.49 (m, 6H), 7.29 (m, 6H), 7.24 (m, 3H), 4.92 (d, J= 3.6 Hz, 1H), 3.62 (s, 3H), 3.60 (m, 1H), 3.56 (s, 3H), 3.48 (t, J= 9.2 Hz, 1H), 3.44 (s, 3H). 3.39 (dd, J= 2.0, 10.0 Hz, 1H), 3.30 (m, 2H), 3.27 (s, 3H), 3.11 (dd, 7= 4.3, 10.0 Hz, 1H); 13C MR (CDC13, 125 MHz) δ 144.1, 128.9, 127.9, 127.1, 97.4, 86.3, 83.8, 82.0, 80.0, 70.2, 62.5, 61.1, 60.6, 59.2, 55.1; HR-ESI-MS m/z calcd. for C29H3406 [M+Na]+: 501.2248, found 501.2249. |
84% | With triethylamine In N,N-dimethyl-formamide | |
84% | With pyridine | |
83% | With pyridine; 4-dimethylaminopyridine for 16h; Ambient temperature; | |
81% | With pyridine for 48h; | |
77% | With pyridine; 4-dimethylaminopyridine at 80℃; for 4h; Inert atmosphere; | |
73% | With pyridine; 4-dimethylaminopyridine at 23℃; for 20h; Inert atmosphere; | |
70% | With pyridine; 4-dimethylaminopyridine; triethylamine at 70℃; for 12h; | |
68% | With 4-dimethylaminopyridine; TEA In N,N-dimethyl-formamide | |
68% | With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide at 20℃; | |
66% | With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | |
66% | With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | |
62% | With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide at 20℃; | |
54% | With pyridine; 4-dimethylaminopyridine at 60℃; for 72h; | |
50% | With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | |
48% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃; for 48h; | |
With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide | ||
With pyridine; 4-dimethylaminopyridine for 24h; Ambient temperature; | ||
With pyridine Ambient temperature; | ||
With pyridine | ||
With triethylamine In N,N-dimethyl-formamide Ambient temperature; | ||
With pyridine; 4-dimethylaminopyridine | ||
In pyridine at 20℃; | ||
In pyridine | ||
With pyridine; 4-dimethylaminopyridine at 80℃; | ||
With pyridine at 100℃; for 3h; | ||
In pyridine at 80℃; for 16h; | ||
With 4-dimethylaminopyridine In pyridine at 20℃; for 48h; Inert atmosphere; | ||
With pyridine; 4-dimethylaminopyridine for 50h; | ||
With pyridine; 4-dimethylaminopyridine at 60℃; for 10h; | ||
With pyridine Reflux; | ||
With pyridine at 70℃; | ||
With pyridine at 80℃; for 1.5h; regioselective reaction; | ||
With 1,4-diaza-bicyclo[2.2.2]octane In dichloromethane at 20℃; for 0.0583333h; regioselective reaction; | Typical procedure: One-pot sequential tritylation-acetylation of methylα-d-glucopyranoside. Methyl-α-d-glucopyranoside (10.0 g, 51.5 mmol) was suspended in anhydrous methylene chloride (100 ml) and DABCO (2 mol equiv) followed by TrCl (2 mol equiv) were added. The mixture was then stirred at rt until the reaction was complete (TLC, eluent, CH2Cl2:MeOH, 9:1). Complete dissolution of the sugar occurred upon completion of the reaction. Ac2O (1.2 mol equiv per OH group) and DABCO (1.2 mol equiv) were then added to the reaction mixture and the stirring was continued at rt. When the acetylation was complete (TLC, eluent, EtOAc:n-Hex, 1:3) the mixture was diluted with CH2Cl2 and was washed with cold water in a separating funnel. The organic layer was dried (Na2SO4), concentrated to dryness under reduced pressure and was purified by chromatography on silica gel (eluent, EtOAc:n-Hex, 1:9) to yield pure methyl 2,3,4-tri-O-acetyl-6-O-trityl-α-d-glucopyranaoside. Yield, 25.5 g, 88%. | |
With pyridine; 4-dimethylaminopyridine at 60℃; for 5h; | ||
With pyridine at 50℃; | ||
With pyridine; 4-dimethylaminopyridine at 80℃; for 4h; | ||
With pyridine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; | ||
With pyridine; 4-dimethylaminopyridine at 20℃; | Dicobalt hexacarbonyl complex of methyl 2,3,4-tri-O-benzyl-6-O-propargyl-α-D-glucopyranoside (5) A solution of methyl α-D-glucopyranoside S5 (5.82 g, 30.0 mmol), TrCl (10.88 g, 39.0 mmol) and DMAP (147 mg, 1.2 mmol) in pyridine (100 mL) was stirred overnight at room temperature. The mixture was quenched by the addition of MeOH, and concentrated in vacuo. The residue was then diluted with EtOAc and washed brine three times. The organic layer was dried over Na2SO4 and concentrated to get the product S6. To a solution of S6 in dry DMF (100 mL) at 0 °C was added NaH (60% in mineral oil, 5.40 g, 135 mmol). The mixture was then stirred for 30 min at room temperature. Benzyl bromide (14.3 mL, 120 mmol) was added drop wise at 0 °C then the mixture was gently warmed to room temperature, and the reaction was monitored by TLC. After the complete consumption of the starting material, the reaction was cooled to 0 °C, quenched with MeOH, and concentrated in vacuo. The residue was then diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product S7 was dissolved in a mixture of DCM (100 mL) and MeOH (50 mL). To this solution a catalytic amount of camphor sulfonic acid (697 mg, 3.0 mmol) was added and the mixture was then stirred over night at room temperature. After the starting material disappeared, the mixture was quenched with Et3N and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE-EtOAc gradient elution) to afford compound 23 (9.74g, 70% over 3 steps). | |
With pyridine for 1.5h; Inert atmosphere; | ||
With 4-dimethylaminopyridine; triethylamine In N,N-dimethyl-formamide at 20℃; for 12h; | Methyl 6-O-trityl-a-D-glucopyranoside (8) A solution of methyl a-D-glucopyranoside 5 (15 g, 77.24 mmol), tritylchloride (26 g, 1.2 eq), DMAP (1.9 g, 0.2 eq), and triethylamine (20 mL) inDMF (120 mL) was stirred at rt for 12 h. Then, the reaction mixture waspoured into ice-water and extracted with ethyl acetate. The organic phasewas washed with water, dried (NaSO4), filtered, and concentrated. Thecrude product can be directly used for next reaction without further purification.And 100 mg crude product was purified by silica gel column chromatographyto obtain compound 8[24] as a white solid. Rf0.25(CHCl3:acetone 2:1). M.p. 150-151 C (lit.[32] 143-145 C). 1H NMR (500 MHz,CD3OD_SPE) d 7.44-7.37 (m, 6 H, ArH), 7.23-7.20 (m, 6 H, ArH),7.17-7.14 (m, 3 H, ArH), 4.69 (d, J3.7 Hz, 1 H, H1), 3.72-3.66 (m, 1H,H6a), 3.54 (t, J9.2 Hz, 1 H, H3), 3.45 (s, 3H, OCH3), 3.36 (m, 2 H, H2,H4), 3.22-3.14 (m, 2 H, H5, H6b). 13C NMR (126 MHz, CDCl3) d 143.0,127.8, 126.9, 126.1, 98.3, 85.8, 76.4, 76.1, 75.9, 73.4, 71.0, 70.3, 69.5, 62.9,54.1 ppm. HRMS(ESI) m/z calcd for C26H28O6Na (MNa) 459.1778,found 459.1781. | |
With pyridine at 20℃; for 48h; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-ethyl-N,N-diisopropylamine; tin(ll) chloride In acetonitrile at 20℃; for 1h; Green chemistry; regioselective reaction; | |
77% | With pyridine In dichloromethane at 20℃; for 3h; | |
With pyridine; metaboric acid; acetone |
With pyridine | ||
With bis(tri-n-butyltin)oxide 1.) toluene, 2.) toluene, -10 deg C, 4 h then -5 deg C, 17 h; Yield given. Multistep reaction; | ||
With bis(tri-n-butyltin)oxide 1.) toluene, reflux, 2.) room temperature, overnight; Yield given. Multistep reaction; | ||
With dimethyltin dichloride; N-ethyl-N,N-diisopropylamine at 0 - 20℃; for 2h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide | |
95% | Stage #1: methyl-alpha-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Stage #2: allyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | A. Synthesis of Methyl 2,3,4,6-Tetra-O-allyl-α-D-glucopyranoside (17-1) To a stirred solution of 3-1 (1.94 g, 10 mmol) in 40 mL of dried DMF cooled with an ice-water bath was added portionwise NaH (2.40 g, 60 mmol, 60% in mineral oil). After addition, the reaction mixture was stirred at this temperature until the evolution of gas subsided (typically within 30 min). Allyl bromide (7.26 g, 60 mmol) was added portionwise to the reaction mixture over 5 min. After addition, the reaction mixture was stirred at this temperature for 30 min and then at room temperature overnight, when TLC analysis indicated that the reaction completed. The reaction mixture was carefullypoured into 300 mL of ice-water while stirring, and the resulting mixture was extracted with three 100-mL portions of dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator to afford an oily residue, which was purified by column chromatography to yield the pure 17-1. White waxy solid, 3.37 g, 95%. |
88% | With sodium hydride In N,N-dimethyl-formamide for 2h; Ambient temperature; |
80% | With potassium hydroxide In tetrahydrofuran for 2.25h; Ambient temperature; | |
75% | With sodium hydroxide In water; dimethyl sulfoxide for 1h; Ambient temperature; | |
67% | Stage #1: methyl-alpha-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: allyl bromide In N,N-dimethyl-formamide at 50℃; for 1h; | |
With sodium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With pyridine at 0℃; for 16h; | |
70% | With pyridine | |
70% | With pyridine at -20℃; Inert atmosphere; |
61% | With iron(III) chloride; 1-Phenyl-4,4,4-trifluorobutane-1,3-dione; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 8h; regioselective reaction; | |
58% | With pyridine at 20℃; | |
55% | With pyridine at 0 - 20℃; | |
55% | In pyridine at -20℃; Inert atmosphere; | Synthesis of methyl-6-O-tosyl-α-D-glucopyranoside 22 To a two necks 100 mLround bottom flask equipped with a magnetic stir bar, flame dried, wereintroduced under inert atmosphere, methyl-α-D-glucopyranoside (1 equiv,8.0 mmol, 1.56 g) dissolved in 40 ml of dry pyridine, and p-toluenesulfonylchloride (1.2 equiv, 10.0 mmol, 1.9 g). The reaction mixture was cooled to -20 °C and stirredovernight under inert atmosphere. At the end of the reaction, pyridine was removed as anazeotrope of toluene via rotary evaporation, the pure product was obtained after flash columnchromatography over silica gel (gradient: 0% to 10% MeOH in EtOAc) as white precipitate(1.533 g, 55% yield). 1H NMR (d6-DMSO, 500 MHz): 7.77 (d, J=8.3 Hz, 2H, Ar), 7.48 (d, J=8.0Hz, 2H, Ar), 5.16 (d, J=5.9 Hz, 1H, OH), 4.89 (d, J=5.1, 1H, OH). 4.80 (d, J=6.4 Hz, 1H, OH), 4.48(d, J=3.6 Hz, 1H, H-1), 4.21 (dd, J=10.6, 1.8 Hz, 1H, H-6), 4.05 (dd, J=10.6, 6.4 Hz, 1H, H-6), 3.49(m, 1H), 3.20 (s, 3H, OCH3), 3.14 (m, 1H), 2.99 (m, 1H), 2.42 (s, 3H, Ts-CH3); 13C{1H} NMR (d6-DMSO, 125 MHz): 144.9, 132.4, 130.1, 127.6, 99.7, 73.0, 71.6, 70.3, 69.8, 69.4, 54.5, 21.1.23 |
52% | In pyridine at 0℃; Inert atmosphere; | 7.5 Step 5; Preparation of (3,4,5-trihvdroxy-6-methoxytetrahvdro-2H-pyran-2-yl)methyl 4- methylbenzenesulfonate (5) Methyl a-D-glucopyranoside (0.3g, 1.56 mmol) was dissolved in pyridine (3 mL) and cooled to 0 °C under argon. -Toluenesulfonyl chloride (0.3g, 1.56 mmol) was added and the solution was stirred overnight. The mixture was then concentrated under reduced pressure and purified via column chromatography (EtOAc) to afford (3,4,5-trihydroxy-6-methoxytetrahydro- 2H-pyran-2-yl)methyl 4-methylbenzenesulfonate E5 (0.28 g, 52%). |
51% | With pyridine at 0℃; for 8h; Inert atmosphere; | 4.2.14. Methyl-[O6-(toluene-4-sulfonyl)]-α-d-glucopyranoside (19) Methyl α-d-glucopyranoside (3.02 g, 15.61 mmol) was dissolved in pyridine (30 mL) and cooled to 0 °C under argon. Toluene sulfonyl chloride (2.98 g, 15.6 mmol) was added and the solution was stirred for 8 h at 0 °C. The mixture was then concentrated in vacuo and the crude mixture was purified by flash column chromatography (EtOAc) to isolate (19) as a white solid in 51% yield; mp 105-106 °C (lit.36 104-106 °C); +91 (c 1.01, CHCl3)) (lit.24 +104 (c 1.0, CHCl3)); νmax (NaCl disc/cm-1) 3371 (br, s, OH), 1449 (m, CC (arom)), 1361 (s, SO2 (antisymmetric)), 1176 (s, C-O), 1146 (m, SO2 (symmetric)), 1060 (m, C-O), 666 (m, CH (arom)); δH (250 MHz, CDCl3) 2.43 (3H, s, PhCH3), 3.33 (3H, s, OCH3), 3.39-3.51 (2H, m, H-2,4), 3.68-3.75 (2H, m, H-3,5), 4.22-4.33 (2H, m, H-6), 4.66 (1H, d, J = 3.5 Hz, H-1), 7.27-7.35 (2H, m, Ph), 7.77-7.85 (2H, m, Ph); δC (63 MHz; CDCl3) 22.1 (PhCH3), 55.7 (OCH3), 69.7 (C-6) 69.8 (C-5), 70.0 (C-4), 72.1 (C-2), 74.4 (C-3), 99.8 (C-1), 128.4-145.3 (ArC). |
45% | In pyridine at 20℃; for 24h; | |
30.5% | With pyridine at 0 - 20℃; for 120h; | |
With pyridine | ||
With bis(tri-n-butyltin)oxide Multistep reaction; | ||
With pyridine | ||
With sodium hydrogencarbonate In water at 20℃; for 1h; | ||
With pyridine at 0℃; | ||
With sodium hydrogencarbonate In water at 20℃; for 1h; | ||
With pyridine | ||
With pyridine | ||
With pyridine at 0℃; for 24h; regioselective reaction; | ||
Stage #1: p-toluenesulfonyl chloride; methyl-alpha-D-glucopyranoside In pyridine; dichloromethane at 9℃; for 0.5h; Inert atmosphere; Schlenk technique; Stage #2: In pyridine; dichloromethane at 20℃; for 1h; Inert atmosphere; Schlenk technique; | ||
With pyridine at 20℃; | General procedure for preparation of 6-azido-6-deoxymonosaccharides (21, 22) General procedure: Methyl glycoside 12 or 13 (5 mmol, 0.97 g) was dissolved in pyridine (20 mL) and p-toluene-sulfonyl chloride (0.95 g, 5 mmol, 1 equiv) was added. The reaction mixture was stirred overnight, at room temperature, then evaporated in vacuo, redissolved in CH2Cl2 (100 mL) and extracted with water (2 × 100 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo. The resulting crude product was purified by column chromatography, with CH2Cl2 /methanol (9:1) as eluent to give compounds 15 or 16. Methyl 6-O-(p-toluenesulfonyl) glycoside 15 or 16 (1.00 g, 2.9 mmol) was dissolved in pyridine (20 mL) and benzoyl chloride (1.16 mL, 10 mmol) was added. The reaction was complete in 1 h at room temperature. The reaction mixture was evaporated in vacuo, redissolved in CH2Cl2 (100 mL) and extracted with 5% aqueous KHSO4 solution (2 × 100 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo. The resulting crude product was purified by column chromatography with hexane/EtOAc (5:5) as eluent to give compound 18 or 19. Methyl 6-O-(p-toluenesulfonyl)-2,3,4-tri-O-benzoyl glycoside 18 or 19 (1.00 g, 1.5 mmol) was dissolved in dry DMF (5 mL) then sodium azide (0.49 g, 7.5 mmol) and lithium bromide (0.65 g, 7.5 mmol) were added. The reaction mixture was stirred at 120° C for 6 h. The reaction mixture was evaporated in vacuo, redissolved in CH2Cl2 and extracted with 1% aqueous KHSO4 solution (2 × 100 mL). The combined organic layers were dried over Na2SO4 and evaporated in vacuo. The resulting crude product was purified by column chromatography, with hexane/EtOAc (8:2) as eluent to give compound 21 or 22. | |
With pyridine at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium periodate In water at 0 - 25℃; for 3h; | |
70% | With sodium periodate for 3h; Ambient temperature; | |
With water; periodic acid at 20℃; |
With lead(IV) acetate; acetic acid at 25℃; | ||
With lead(IV) acetate; chloroform at 25℃; | ||
With sodium periodate | ||
With sodium periodate In water at 0 - 20℃; for 3h; | ||
With sodium periodate; sodium hydrogencarbonate In water at 5 - 20℃; | ||
With sodium periodate In water for 1.5h; | ||
With sodium periodate In water at 0 - 40℃; Darkness; | ||
With sodium periodate In methanol; water at 0 - 20℃; for 15h; | 4.1.1. Step 1: Synthesis of dialdehyde A solution of sodium periodate (5 equiv) in distilled water was added dropwise to a stirred solution of methyl α-d-glucopyranose (1 equiv) in methanol at 0 °C, and the reaction mixture stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo and the resulting colourless solid suspended in ethyl acetate, filtered through Celite and concentrated in vacuo to yield the crude dialdehyde. | |
With sodium periodate In methanol; water at 0℃; for 16h; | α-D-Methyl glucopyranoside (6.000g, 30.90 mmol) was dissolved with stirring in 200 mL of 1:1 methanol/water in a 500 mL round-bottom flask. Themixture was next chilled to 0 °C and covered with foil to exclude light before slow, portion-wise addition ofsodium periodate (14.540 g, 67.98 mmol). After addition was complete, the reaction was allowed to warm to roomtemperature and continue stirring overnight (16 hours). Reaction completion was verified with TLC using 9:1DCM/MeOH that no starting material remained. Next solvent was removed in vacuo resulting in a crude whitesolid from which the resulting dialdehyde intermediate was extracted with 50 mL methanol. The crude methanolicextract was vacuum filtered to remove inorganic solids. In a separate flame-dried 1 L round-bottom flask, activatedpowdered 4 Å molecular sieves (10 g) were suspended in 450 mL anhydrous methanol in under argon atmospherefollowed by slow addition of the crude extract with stirring. Methyl ester of glycine hydrochloride salt (3.879 g,30.90 mmol) was added slowly, portion-wise and the reaction mixture was allowed to stir for 4 hours at roomtemperature after which the mixture obtained an orange color. Next, 4.66 g (74.16 mmol) of sodiumcyanoborohydride was dissolved in 30 mL anhydrous methanol and then added slowly, dropwise to the reactionmixture resulting in a colorless solution. The reaction was allowed to continue stirring at room temperatureovernight (16 hours). Completion of the reaction was indicated by TLC (9:1 DCM/MeOH, product 10 Rf = 0.55).Molecular sieves were removed by filtration through celite and the reaction filtrate was concentrated in vacuo untilprecipitate began to form. The crude product concentrate was extracted into 150 mL DCM and washed with 20 mLdeionized water. The aqueous wash was extracted twice with 150 mL DCM or until no product was observed inaqueous phase by TLC. Combined extracts were dried over MgSO4 and then concentrated in vacuo. Crude productresidue was purified by normal phase column chromatography (Biotage) using MeOH (2% to 10%) in DCM toyield 10 a clear, pale yellow oil (5.103 g, 23.38 mmol, 75.3 % yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; water; sodium sulfate Electrolysis.anschl. Erwaermen mit wss. H2SO4; | ||
With platinum on activated charcoal; water; sodium hydrogencarbonate unter Einleiten von Luft und anschl. Behandeln mit wss. H2SO4; | ||
With water; nitric acid; sodium nitrite anschl. Erwaermen mir wss. H2SO4; |
With chloroform; dinitrogen tetraoxide anschl. mit wss. H2SO4; | ||
With tetrachloromethane; dinitrogen tetraoxide anschl. mit wss. Methanol und dann mit wss. H2SO4; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 65℃; | |
86% | With iodine; triphenylphosphine In N,N-dimethyl-formamide for 1h; Ambient temperature; | |
77% | With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran Heating; |
60% | Stage #1: methyl-alpha-D-glucopyranoside With 1H-imidazole; triphenylphosphine In toluene at 110℃; for 1h; Stage #2: With iodine In toluene at 110℃; for 3h; | |
With pyridine; p-toluenesulfonyl chloride Erwaermen des Reaktionsprodukts mit Natriumjodid in Aceton; | ||
With 1H-imidazole; iodine; 4-(N,N-Dimethylamino)triphenylphosphine In toluene at 70℃; for 3h; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene | ||
With 1H-imidazole; iodine; triphenylphosphine | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene Heating; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene at 80℃; for 3h; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene for 2.5h; Heating; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene at 70℃; for 2h; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene at 70℃; for 2h; | ||
Multi-step reaction with 2 steps 1: pyridine / 2.5 h / -15 - 20 °C 2: NaI / dimethylformamide; pyridine / 1.5 h / 40 °C | ||
Multi-step reaction with 2 steps 1: pyridine / 2.5 h / -15 - 20 °C 2: NaI / dimethylformamide; pyridine / 1.5 h / 40 °C | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene at 80 - 100℃; | D-xylo-Hexos-5-ulose; In the first step of the presented synthesis of D-xylo-Hexos-5-ulose (see Figure 6), methyl α-D-glucopyranoside 1 is converted to the corresponding 6-deoxy-6-iodo compound, according to the procedure reported by P.J. Garegg et al., J. Chem. Soc., Perkin Trans I, 1980, 2866 (hereinafter referred to as Garegg method or Garegg's procedure). Using a heterogeneous reagent system consisting of PPh3, I2 and imidazole in dry toluene at 80-100 °C, a selective substitution of the primary hydroxyl function at position C-6 with iodine can be carried out in high yields without side reactions. Without further purification the water soluble reaction product can be subjected directly to a standard acetylation procedure, employing acetic anhydride in pyridine, to furnish the fully protected intermediate 2. Elimination of HI with AgF in pyridine leads to enol ether 3 in high yields. The exocyclic double bond can be epoxidized using 3-chloroperbenzoic acid in CH2Cl2 in the presence of aqueous sodium bicarbonate. As reported in P.M. Enright et al., J. Org. Chem, 2002, 67, 3733, only the (5R)-stereoisomer of 4 is formed in this reaction process. The epoxide can be separated by flash column chromatography on a short plug of silica gel, although minor losses due to acid catalyzed hydrolysis cannot be avoided. These oxiranes are generally quite stable under slightly basic conditions. Therefore, Zemplén saponification using catalytic amounts of sodium methoxide can be carried out at -30°C without opening the oxirane. Finally, the addition of water and acidic ion exchange resin (Amberlite IR-120) results in spontaneous hydrolysis of the epoxide and the methyl acetal to furnish crude D-xylo-hexos-5-ulose 5. TLC-analysis indicates the formation of a multicomponent mixture. Previous investigations have shown that ketoaldose 5 exists in at least seven different tautomeric forms in aqueous solution, due to its two anomeric centers at C-1 and C-5. Consequently, purification by silica gel chromatography is not possible and the crude reaction product has to be employed in the following reductive amination procedures. | |
11 g | With 1H-imidazole; iodine; triphenylphosphine In toluene at 70℃; for 2h; Inert atmosphere; regioselective reaction; | Methyl α-D-2,3,4-triacetoxy-6-deoxy-6-iodoglucopyranoside (3) To a solution of methyl α-D-glucopyranoside (5.00 g, 25.8 mmol) in toluene (500 mL) at room temperature was added triphenylphosphine (10.1 g, 38.6 mmol) followed by imidazole (5.30 g, 3.00 mmol) and iodine(9.15 g, 1.40 mmol) and the reaction was heated to 70 ºC for 2 hrs. The reaction was cooled to room temperature and water (50 mL) was added and the mixture was stirred vigorously for 10min. The organic layer was extracted with water (1 X 50 mL) and the combined aqueous layers were concentrated in vacuo. The residue was placed on a high vacuum manifold to afford 11.0 g of methyl α-D-6-deoxy-6-iodoglucopyranoside as an off-white solid.To a solution of methyl α-D-6-deoxy-6-iodoglucopyranoside (11.0 g, 25.8 mmol) obtained above in pyridine (52.0 mL) at room temperature was added acetic anhydride (14.6 mL, 155 mmol)followed by 4-dimethylaminopyridine (0.32 g, 2.58 mmol) and the reaction continued stirring at room temperature for 6 hrs at which time additional acetic anhydride (7.30 mL, 77.3 mmol) was added and the reaction continued stirring at room temperature for 21 hrs. The solvent was removed in vacuo and the residue was dissolved in toluene (100 mL) and washed with water (100 mL). The combined organic layers were concentrated in vacuo to afford 9.97 g (90% from methyl α-D-glucopyranoside) of methyl α-D-2,3,4-triacetoxy-6-deoxy-6-iodoglucopyranoside(3) as an off-white solid. |
With 1H-imidazole; iodine; triphenylphosphine In toluene at 80℃; for 24h; | ||
With 1H-imidazole; triphenylphosphine In tetrahydrofuran at 70℃; for 3h; | ||
28 g | With 1H-imidazole; iodine; triphenylphosphine In toluene at 70℃; for 2h; Inert atmosphere; | Methyl α-D-2,3,4-triacetoxy-6-deoxy-6-iodoglucopyranoside (4) To a solution of methyl α-D-glucopyranoside 3 (15.00 g, 77.24 mmol) in toluene(1500 mL) was added triphenylphosphine (30.39 g, 115.9 mmol), imidazole(15.77 g, 231.7 mmol) and iodine (27.44 g, 108.1 mmol) at room temperature.After 5 min the reaction mixture was heated to 70 °C for 2 hrs. The reaction mixture was then cooled toroom temperature and water (200 mL) was added and vigorously stirred for 15 min. The aqueous layerwas separated and the organic layer was extracted with water (2 × 100 mL). The combined aqueous layerswere concentrated under reduced pressure and allowed it to dry under high vacuum afford methyl α-D-6-deoxy-6-iodoglucopyranoside (28.00 g) as an off-white solid. |
With 1H-imidazole; iodine; triphenylphosphine In N,N-dimethyl-formamide at 70℃; for 2h; | 1 Reaction Example 1 6-iodo-deoxy-1-methylglucosePreparation of glycosides Take 100ml single-necked flask, add 04.05g (15.5mmo 1) triphenylphosphine, 2 • 10g (3 lmmo 1)Imidazole, add 20ml DMF dissolved by stirring; weighed 3.63g iodine (14.4mmol) in batches into the solution(After each addition of iodine until the color fades and then add the next batch); by adding 2.0g (10.3mmol)α-methylglucoside, the water bath heated to 70 ° C,Stirring reaction 2h, stop heating, cooling to room temperature reaction 20hThe reaction was completely monitored by TLC plate (developing solvent: methanol: ethyl acetate = 1: 4.5).Stop the reaction, add 20ml of distilled water to stir, white precipitate, filter, filter cake washed, the filtrate evaporated under pressure (removeWater and DMF), the product was isolated and the product was directly added to the next step. | |
Multi-step reaction with 2 steps 1: 1H-imidazole; iodine / acetonitrile / 10 h / 70 °C 2: triethylamine / acetonitrile / 20 °C | ||
Multi-step reaction with 2 steps 1: triphenylphosphine; iodine; 1H-imidazole 2: sodium methylate; methanol | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene for 1h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride for 16h; Heating; | ||
1: 67 %Spectr. 2: 31 %Spectr. | With QuadraPure sulfonic acid 450-800 micron beads In water at 120℃; for 0.0666667h; Flow reactor; | General procedure for the Fischer glycosylation under continuous flow conditions General procedure: A methanolic sugar stock solution (2% w/v) was prepared-in case of residual insoluble material, the minimum amountof H2Owas added and is indicated as v/v % in Table 2 (e.g.,5% H2Oaddition refers to addition of 200 mm3 H2Oto 4 cm3MeOH solution). For the optimization experiments, aliquotsof this solution were filled into loops of 1 cm3 and wereinjected at flow rates corresponding to residence times of2-10 min at 120 °C using methanol as the bulk solvent.The reactor was equilibrated to the conditions by flushing atleast three reactor volumes with bulk solvent at the specificconditions, prior to injection. The outlet flow was collected(monitored by TLC) for subsequent NMR analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine at 50 - 60℃; for 1h; | |
100% | With triethylamine In N,N-dimethyl-formamide for 3h; Ambient temperature; | |
100% | With pyridine at 20℃; |
100% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0℃; for 25h; Inert atmosphere; Further stages; | Methyl 2,3,4,6-tetra-O-trimethylsilyl-α-D-glucopyranoside (14) (Wang et al., 2008) Commercially available 1-O-methyl-α-D-glucopyranoside (13, 1.16 g, 5.98 mmol) and DIPEA (5.2mL, 30 mmol) was dissolved in dry DCM (30 mL) and stirred at 0 °C under nitrogen. Then, TMSCl(4.5 mL, 36 mmol) was added dropwise and reaction mixture was stirred for 25 h after whichtemperature had reached rt. The mixture was then evaporated after which the crude product shakenvigorously with hexane (250 mL in portions) and filtered through celite. The combined filtrate wasevaporated under reduced pressure giving pure compound 14 (2.88 g, quant.). TLC (Hex/EtOAc9:1): Rf 0.53; 1H-NMR (500 MHz, CDCl3): 4.61 (d, J = 3.6 Hz, 1 H, H-1), 3.73-3.77 (m, 2 H, H-3,H-6), 3.67 (dd, J = 5.4 Hz and 11.3 Hz, 1 H, H-6’), 3.50 (dd, J = 2.0 Hz and 5.4 Hz, 1 H, H-5), 3.47(dd, J = 3.7 Hz and 9.0 Hz, 1 H, H-2), 3.43 (dd, J = 8.4 Hz and 9.5 Hz, 1 H, H-4), 3.34 (s, 1 H,OMe), 0.16 (s, 9 H, Si(CH3)3), 0.16 (s, 9 H, Si(CH3)3), 0.15 (s, 9 H, Si(CH3)3), 0.12 (s, 9 H,Si(CH3)3). 13C-NMR (125 MHz, CDCl3): 98.8, 74.5, 73.1, 71.4, 71.2, 61.4, 53.7, 0.5, 0.1, -0.3, -1.1. |
99% | In pyridine at 20℃; for 24h; | |
97% | With pyridine; tetrabutylammonium bromide at 20℃; for 0.0833333h; | |
96% | With pyridine at 0℃; Inert atmosphere; | |
95% | With triethylamine In dichloromethane | FIG. 5(a) and FIG. 5(b) illustrate the preparation of the 2,3,4,6-tetra-O-trimethylsilyl ethers according to one embodiment of the present invention. To test our strategy, D-glucose, the most abundant sugar in nature, was selected as a substrate for our studies. Methyl-D-glucopyranoside 15a and p-methylphenyl-D-thioglucopyranoside 15b were trimethylsilylated using trimethyl chlorosilane (TMSCl) and triethylamine(Et3N) to afford the corresponding ethers 16a and 16b in near-quantitative yields, respectively. The per-O-silylation of sugars not only provided the requisite O-trimethylsilylated functionalities for regioselective protection, but also dramatically improved the solubility of unprotected monosaccharides in common organic solvents. In particular, D-glucose is used in the following example to describe the method for preparing the hexose derivatives, and one skilled in the art should be appreciated that the D-glucose is one of the hexose and the present invention can also be used to prepare the derivatives of hexose such as D-talose, D-galactose, D-idose, D-gulose, D-mannose, D-altrose and D-allose, as shown in FIG. 5(b). |
85% | With pyridine at 20℃; for 4h; Inert atmosphere; | |
With pyridine; 1,1,1,3,3,3-hexamethyl-disilazane | ||
With pyridine; 1,1,1,3,3,3-hexamethyl-disilazane Ambient temperature; | ||
With triethylamine In N,N-dimethyl-formamide at 0 - 20℃; for 4h; | ||
In pyridine at 20℃; for 1h; | ||
Stage #1: methyl-α-D-glucopyranoside With pyridine for 0.5h; Inert atmosphere; Stage #2: chloro-trimethyl-silane at 23 - 45℃; for 4.5h; Inert atmosphere; | ||
With pyridine at 20℃; | ||
With pyridine at 0 - 20℃; for 2h; | ||
5.33 g | With pyridine at 0 - 20℃; | 1-O-Methyl-2,3,4-tri-O-trimethylsilyl-α-D-glucopyranoside (30) 1-O-Methyl-α-D-glucopyranoside (1.94 g, 10 mmol) was dissolved in pyridine (25 mL) and to this was added dropwise trimetylchlorosilane (TMSCl; 7.60 g, 70 mmol) at 0°C, and was stirred overnight at room temperature. The reaction mixture was diluted with 200 mL of toluene and evaporated. Oily residue thus obtained was triturated with hexane and decanted affording crude 1-O-methyl-2,3,4,6-tetra-O-trimethylsilyl-α-D-glucopyranoside 29 as a colorless oil (5.33 g). It was dissolved in MeOH (120 mL) and treated with 18 mM K2CO3 solution (4 mL) at 0°C, and stirred overnight at the same temperature. The reaction was stopped by adding 1 M AcOH (0.15 mL) and azeotroped with toluene. Purification by column chromatography (silica, hexane/ethyl acetate = 4/1) provided compound 30 as colorless crystals (2.95 g, 70.4%, 2 steps) |
With pyridine at 20℃; for 22h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridinium 4-toluenesulfonate In N,N-dimethyl-formamide | |
99% | With sodium hydrogen sulphate; mesoporous silica In acetonitrile at 20℃; for 1.5h; | |
99% | With 1,3,5-trichloro-2,4,6-triazine In acetonitrile at 60℃; for 0.166667h; Sonication; Inert atmosphere; regioselective reaction; |
99% | With DL-10-camphorsulphonic acid In acetonitrile at 20℃; for 4h; | |
95% | With copper(II) bis(trifluoromethanesulfonate) In acetonitrile for 1.5h; Inert atmosphere; Sonication; | |
95% | With DL-10-camphorsulphonic acid In acetonitrile for 5h; Reflux; | In the first approach, the present invention employs highly purified methyl-a-D- glucopyranoside (Aldrich, min. 99% purity) as a starting material for the synthesis of Monomer A. This process eliminates the possibility of the presence of any β-anomer in the final product. Thus, methyl-a-D-glucopyranoside is converted to the desired building block according to the scheme depicted below. During the further synthetic manipulations toward preparing Fondaparinux from Building Block A there are no synthetic operations that can epimerize the anomeric center in this monomer. This strategy affords a-methyl-2-azido-3-benzyl-6-benzoyl-D- glucoside free from its β-anomer. |
94% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 60℃; | |
93% | With DL-10-camphorsulphonic acid In N,N-dimethyl-formamide at 70℃; for 5h; Inert atmosphere; | 1 Synthesis of 4,6-O-benzylidene-α-D-methylglucopyranoside (2 α-D-methyl glucopyranoside 1 (19.41 g, 100 mmol), PhCH (OMe) 2 (30.44 g, 200 mmol) and CSA (2.00 g) were dissolved in dry DMF (150 mL) and heated at 70 ° C. for 5 h under N2 atmosphere, At this point TLC test found that the reaction was completed. The reaction mixture was cooled and poured into ice-water (500 mL) Stirred and extracted rapidly with CH 2 Cl 2 (200 mL × 3). The combined extracts, Washed sequentially with 2% NaHCO3 solution (100 mL) and 10% brine (200 mL) Dried over anhydrous Na2SO4, the solvent was evaporated on a rotary evaporator, The resulting residue was purified by column chromatography to give 26.25 g of 2 as a white solid in 93% yield, m.p. 163.5-165.5 deg C. |
92% | With DL-10-camphorsulphonic acid In chloroform at 65℃; | |
92% | With stannous chloride In acetonitrile at 80℃; for 1h; | |
91% | With 3,4-bis((3,5-bis(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione In acetonitrile at 20℃; for 1h; Inert atmosphere; | |
91% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 60℃; for 4h; | |
90% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 70℃; for 4h; | |
90% | With toluene-4-sulfonic acid In acetonitrile at 20℃; for 12h; | |
90% | With iodine In acetonitrile at 20℃; for 1h; | |
90% | With silica-supported perchloric acid In PEG 600 at 20℃; for 6h; | |
90% | With copper(II) bis(trifluoromethanesulfonate) In acetonitrile at 20℃; for 3h; Sonication; Schlenk technique; Inert atmosphere; | |
87% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 45℃; | |
86% | With ferric(III) chloride In acetonitrile at 20℃; for 3.5h; regioselective reaction; | |
86% | With DL-10-camphorsulphonic acid In acetonitrile at 20℃; for 48h; | |
85% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 6h; | |
85% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 60℃; for 3h; | |
84% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide; acetonitrile | |
83% | With DL-10-camphorsulphonic acid In chloroform for 6h; Heating; | |
83% | With DL-10-camphorsulphonic acid In N,N-dimethyl-formamide at 60℃; | |
83% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 0.116667h; sonication; | |
83% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 40℃; | |
82% | With pyridinium 4-toluenesulfonate In N,N-dimethyl-formamide at 85℃; for 2h; | |
81.5% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 40 - 80℃; for 5h; | |
81% | With DL-10-camphorsulphonic acid In acetonitrile for 0.75h; Reflux; Inert atmosphere; | |
81% | With DL-10-camphorsulphonic acid In acetonitrile at 50℃; | |
80% | With DL-10-camphorsulphonic acid In acetonitrile at 80℃; for 0.333333h; | |
80% | With DL-10-camphorsulphonic acid In acetonitrile at 80℃; for 0.333333h; | |
80% | With toluene-4-sulfonic acid | |
78% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide for 1h; | |
76% | With CSA In acetonitrile at 85℃; for 6h; | |
75% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 55℃; Inert atmosphere; | |
75% | With iodine In N,N-dimethyl-formamide at 20℃; for 12h; | |
74% | With DL-10-camphorsulphonic acid In acetonitrile at 20℃; for 0.75h; Inert atmosphere; Reflux; | |
73% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 50℃; for 2h; | |
73% | With toluene-4-sulfonic acid In water monomer; N,N-dimethyl-formamide at 84℃; for 1.5h; Inert atmosphere; | |
73% | With DL-10-camphorsulphonic acid In acetonitrile for 0.333333h; Reflux; Dean-Stark; | |
73.6% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide | Preparation of methyl 4,6-O-benzylidene-α-D-glucopyranoside (Glc-1) Following the reported method. [1] To a solution of methyl α-D-glucopyranoside (Glc,6.0 g, 30.9 mmol) in anhydrous DMF (25 mL) was added PhCH(OMe)2 (7.0 ml,46.3 mmol) and the solution was acidified with p-TsOHH2O (0.7 g, 3.1 mmol) topH 3. The reaction was stirred at 50°C for 4 h and was neutralized with 3 mL of TEA.Then, the reaction mixture was poured into saturated solution of NaHCO3 and extracted with 300 mL of EtOAc. The resulting extract was washed with H2O. Theorganic extracts were dried over anhydrous Na2SO4 and then concentrated underreduced pressure. The residue was lyophilized to dryness overnight to afford Glc-1as a white solid (6.3 g, 73.6%; Rf = 0.6, CHCl3: MeOH = 9: 1). 1H NMR data (400MHz, CD3OD): δ 7.51 - 7.49 (2H, H-2Ar and H-6Ar, overlap), 7.37 - 7.33 (3H, H-3Ar,H-4Ar, H-5Ar, overlap), 5.56 (1H, s, PhCHO2), 4.73 (1H, d, J = 3.8 Hz, H-1), 4.20(1H, dd, J = 15.3, 5.5 Hz, H-6a), 3.82 (1H, t, J = 9.4 Hz, H-3), 3.78 - 3.70 (2H, H-5and H-6b, overlap), 3.52 (1H, dd, J = 9.3, 3.8 Hz, H-2), 3.43 (1H, m, H-4), 3.42 (3H,s, OCH3). 13C NMR data (101 MHz, CD3OD): δ 139.2 (Ar-C), 129.9, 129.0(2),127.5(2) (Ar-CH), 103.0 (PhCHO2), 102.0 (C-1), 82.9 (C-4), 74.1 (C-2), 72.0 (C-3),70.0 (C-5), 63.9 (C-6), 55.8 (OCH3). ESI-MS: (m/z) [M+Na]+ 305.5. |
73% | With camphor sulfuric acid In acetonitrile Reflux; Inert atmosphere; | |
72% | With dodeca-tungstophosphoric acid In acetonitrile at 0℃; Molecular sieve; Inert atmosphere; | |
70% | With DL-10-camphorsulphonic acid In chloroform at 350℃; for 9h; Dean-Stark; Molecular sieve; Reflux; | |
65% | With DL-10-camphorsulphonic acid In acetonitrile for 0.333333h; Reflux; | 8 0236| Mi hyl-4,6- -beBaEySi(Jee--I -gcopyraiiosiile (41). To a solution containing 1 .0 g (51 ,5 mmoi) of a-D-raethyl glueopyranoside in 200 mL of acetonitriie was added 14.0 mL (14.2 g, 92.7 tnmo) of benxaldehyde dimethyl acetai and 600 rag (2,57 mmoi) of camphor si Ionic acid. The reaction mixture was heated to reflux for 20 mm and then allowed to cool to room temperature and neutralized by the addition of 400 uJL of triethySamine. The reaction mixture vvas diluted with 800 mL of ethyl acetate. The organic layer was washed with three 250-mL portions of water and dried (MgSQ ). The organic laye was concentrated under diminished pressure to afford a crude residue. The residue was crystallized from 1 :7 dichloroniethane-hexanes to afford acetai 41 as a colorless solid: yield. 9.48 g (65%); silica gel TLC Rf 0.1 (2: i ethyl acetate-hexanes); fH NMR (CDC ) 5 3.45-3.47 (m, 4H), 3.63 (dd, IH, J" 9.1 and 3.9 Hz), 3.71-3.85 (m5 2H), 3.93 (t, 1H, J '= 9.2 .z), 4.29 (dd, 1H, J= 9.7 and 4.3 Hz), 4.80 (d, JH, = 3.9 Hz), 3.53 (s, I H) aad 7.33-7.53 (m, 5H); : NMR (CDCfe) δ 55.7, 62.5, 69. L 72.0, 73.0, 81.0, 99.9, 102.1 , 126.4, 137.2. |
63% | With pyridinium 4-toluenesulfonate In N,N-dimethyl-formamide at 80℃; | |
60% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 60℃; | |
53% | With DL-10-camphorsulphonic acid In acetonitrile at 20℃; for 2h; | |
42% | Stage #1: methyl-α-D-glucopyranoside With DL-10-camphorsulphonic acid for 1h; Stage #2: benzaldehyde dimethyl acetal In acetonitrile at 20℃; for 11h; | |
34% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide for 0.116667h; Sonication; | 1.1.6 (1.6) 5 ml of DMF was added to (+)-α-methyl-D-glucose (7) (500 mg, 2.58 mmol), benzaldehyde dimethylacetal (412 mg, 2.71 mmol) and p-toluenesulfonic acid monohydrate (491 mg, 2.58 mmol), and the mixture was subjected to a sonication treatment for 7 minutes. Triethylamine was added to the reaction mixture, and the mixture was filtered and concentrated under a reduced pressure to give a crude product. The crude product was purified by separating by silica gel column chromatography (elution solvent: chloroform/methanol = 20/1) to give (+)-(4,6-O-benzylidene)methyl-α-D-glucopyranoside (8) (yield amount: 248 mg, yield: 34%), as shown in the following chemical reaction formula. The result of the physical and chemical analysis of this by 1H NMR is shown below. 1H NMR (CDCl3) δ = 7.48 (dd, J = 3.6 Hz, J = 3.0 Hz, 2H), 7.35-7.39 (m, 3H), 5.49 (s, 1H), 4.71 (d, J = 4.0 Hz, 1H), 4.26 (dd, J = 5.6 Hz, J = 4.2 Hz, 1H), 3.89 (t, J = 9.6 Hz, 1H), 3.69-3.80 (m, 2H), 3.56 (dd, J = 5.2Hz, J = 3.8 Hz, 1H), 3.44 (t, J = 9.4 Hz, 1H), 3.40 (s, 3H) |
29% | With DL-10-camphorsulphonic acid In acetonitrile Reflux; | 5 As shown in Scheme 5, the benzylidene was formed on compound 38 with benzaldehyde diemthyl acetal (49) and catalytic camphorsulfonic acid (CSA). Diol 50 was protected as benzyl ethers to give compound 51a 84% yield. |
With DL-10-camphorsulphonic acid In N,N-dimethyl-formamide at 100℃; for 2h; | ||
With toluene-4-sulfonic acid | ||
With DL-10-camphorsulphonic acid In chloroform Heating; | ||
With perchloric acid on silica gel In acetonitrile at 20℃; for 0.5h; | ||
With toluene-4-sulfonic acid In N,N-dimethyl-formamide | ||
With toluene-4-sulfonic acid In acetonitrile at 20℃; for 5h; | ||
With toluene-4-sulfonic acid | ||
With toluene-4-sulfonic acid In aceonitrile for 17h; Inert atmosphere; Reflux; | ||
With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 40℃; | ||
With 10-camphorsufonic acid In chloroform at 68℃; for 2h; | ||
With iodine In acetonitrile at 20℃; for 3h; | ||
With DL-10-camphorsulphonic acid In acetonitrile at 35℃; for 4h; Inert atmosphere; | ||
With DL-10-camphorsulphonic acid In acetonitrile at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With (1S)-10-camphorsulfonic acid; In N,N-dimethyl-formamide; at 20℃; under 30.003 Torr; for 2h; | 2) Synthesis of [6-Methoxy-3,4,5-Tris(4-Methoxy-Benzyloxy)Tetrahydropyran-2-yl]Methanol of Formula (V)a) Step 1: Synthesis of 6-methoxy-2-(4-methoxyphenyl)-hexahydropyrano[3,2-D][1,3]dioxine-7,8-diol of formula (VII)The synthesis begins with the protection of the primary alcohol (VIII) (3,4,5-trihydroxy-6-methoxytetrahydro-pyran-2-ylmethanol) in the form of an acetal (VII) (6-methoxy-2-(4-methoxyphenyl)hexahydropyrano[3,2-D]-[1,3]dioxine-7,8-diol) through the action of p-anisaldehyde dimethyl acetal (III) in the presence of camphorsulfonic acid in DMF (dimethylformamide).The reaction is carried out at ambient temperature under an industrial vacuum (pressure=40 mbar) (evaporation of the methanol form) for 2 hours, so that a significant advancement in the formation of the desired product is observed, such that only traces of the starting product remain.After an aqueous treatment in a basic medium, the traces of starting product are eliminated by washing with cyclohexane; this makes it possible to isolate the compound (VII) in the form of a white solid with yields of between 60% and 80% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2.5h; | |
96% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | A. Synthesis of Methyl 2,3,4,6-Tetra-O-benzyl-α-D-glycopyranosides 3-2, 5-2 and 11-2 General procedure: To a stirred solution of methyl α-D-glycopyranosides 3-1, 5-1or 11-1 (1.94 g, 10 mmol) in 30 mL of dried DMF cooled with an ice-water bath was added portionwise NaH (2.40 g, 60 mmol, 60% in mineral oil). After addition, the reaction mixture was stirred at this temperature until the evolution of gas subsided (typically within 30 min). Benzyl bromide (10.26 g, 60 mmol) was added portionwise to the reaction mixture over 5 min. After addition, the reaction mixture was stirred at this temperature for 30 min and then at room temperature overnight, when TLC analysis indicated that the 3 reaction completed. The reaction mixture was carefully poured into 300 mL of ice-water while stirring, and the resulting mixture was extracted with three 100-mL portions of dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated on a rotary evaporator to afford an oily residue, which was purified by column chromatography to yield the pure methyl 2,3,4,6-tetra-O-benzyl-α-D-glycopyranosides 3-2, 5-2 and 11-2. |
96.6% | With potassium hydroxide In cyclohexane at 80 - 85℃; | 5 Example 5 In a 250ml three-necked flask with a reflux trap, methylglucoside 19.4g (100 mmol), Potassium hydroxide solid 26.8g (430mmol), cyclohexane 60ml, 80 ~ 85 °C reflux dehydration reaction to anhydrous distillation,71.8 g (420 mmol) of benzyl bromide was added dropwise, and the reaction was continued at 80-85° C. under reflux and dehydration. The reaction was monitored by HPLC and the reaction solution was washed with water until neutral (20 ml×4).After washing with water, the solvent was distilled off under reduced pressure to obtain 54.3 g of pale yellow oil. The content was 98.6% as measured by HPLC and the yield was 96.6%. |
95% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: benzyl bromide With tetrabutylammonium bromide In N,N-dimethyl-formamide at 0 - 20℃; for 20h; | |
94% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2.5h; Inert atmosphere; Stage #2: benzyl bromide With N,N,N-tributyl-1-butanaminium iodide In N,N-dimethyl-formamide; mineral oil for 18.75h; Inert atmosphere; | |
94% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; Inert atmosphere; Stage #2: benzyl bromide With tetra-n-propylammonium iodide In N,N-dimethyl-formamide at 20℃; for 18.75h; Inert atmosphere; | |
94% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; | 2 Preparation of intermediate D-3 25 g of the compound D-2 was dissolved in 500 mL of DMF, and 60 g of 60% sodium hydride was added at 0 ° C. After 1 h of reaction, 92 mL of benzyl bromide was added, and the mixture was reacted at room temperature overnight. The saturated ammonium chloride solution was quenched and extracted with ethyl acetate.The solution was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. Evaporation on a silica gel column chromatography under reduced pressure to give a colorless oil D-3 67g, yield 94%. |
93% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere; | 4.2. General procedure A: O-benzylation General procedure: The starting material (1 equiv) was dissolved in dry DMF (15 mLper 1 g of sugar) under inert atmosphere and the mixture wascooled to 0C. Sodium hydride (1.5 equiv per OH group) was addedand the mixture stirred for 30 min. Benzyl bromide (1.5 equiv perOH group) was added dropwise over 30 min. The reaction mixturewas then allowed to reach room temperature and stirred untilcompletion (ca. 3 h). Methanol was then added (1.0 mL per 1 g ofsodium hydride added) and the resulting solution was allowed tostir for a further 10 min. The solvents were removed under reducedpressure and the residue was diluted with water and ethyl acetate.The organic phase was separated, washed with water and brine,dried with magnesium sulfate. The solvents were then removedunder reduced pressure and the residue puried using silica gelcolumn chromatography. |
90% | With potassium hydroxide In tetrahydrofuran for 0.5h; Ambient temperature; | |
90% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 12h; | |
90% | With N,N,N-tributyl-1-butanaminium iodide; sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 12h; | |
90% | With N,N,N-tributyl-1-butanaminium iodide; sodium hydride In N,N-dimethyl-formamide | |
87% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; | |
87% | With sodium hydride In N,N-dimethyl-formamide at 0℃; | For the construction of polysaccharides and complex glycans, a set of common building block materials and for use in iterative glycosylation reactions is essential. Using this pragmatic tenet, a variety of glycosyl donors have been prepared. As can be seen in Scheme 7, the method is straightforward and applies standard chemistry. The strategy was to prepare the trichloroacetimidates and then convert them to the hydroquinone adducts, which have all been stable solids. Following this general route, donors 15, 40-42, and 32 have been prepared. |
87% | With sodium hydride In N,N-dimethyl-formamide | |
85% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | 6.1.1. Methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside (2a) Benzyl bromide (9.19 mL, 77 mmol) was added to a stirred solution of methyl α-D-glucopyranoside (3.0 g, 15 mmol) in anhydrous DMF (30 mL). The reaction mixture was cooled to 0 °C and sodium hydride (3.6 g, 90 mmol, 60% dispersion in oil) was then added portion-wise. The mixture was then allowed to warm to room temperature. After 17 h, TLC (petroleum ether/ethyl acetate = 5:1) indicated complete conversion of starting material to a major product (Rf = 0.50). The reaction mixture was quenched with methanol, diluted with diethyl ether (200 mL) and washed with water (100 mL). The aqueous phase was extracted with diethyl ether (200 mL) and the combined organic was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 20:1) to give 2a (7.2 g, 85%). 1H NMR (400 MHz, CDCl3): δ 3.37 (s, 3H, OCH3), 3.54-3.65 (m, 3H), 3.70-3.75 (m, 2H), 3.98 (t, J = 9.6 Hz, 1H), 4.45-4.48 (m, 2H), 4.58-4.67 (m, 3H), 4.78-4.84 (m, 3H), 4.98 (d, J = 10.8 Hz, 1H), 7.12-7.36 (m, 20H); 13C NMR (100 MHz, CDCl3): δ 55.20, 68.51, 70.08, 73.42, 73.51, 75.06, 75.78, 77.70, 79.87, 82.16, 98.24, 127.61, 127.71, 127.88, 127.93, 128.00, 128.17, 128.38, 128.42, 128.47, 137.95, 138.20, 138.29, 138.83; HRMS (ESI) calcd for [C35H38O6+Na]+ 577.2561, found 577.2564. |
84% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere; | |
81% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 3.5h; | |
81.4% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 8h; | Methyl 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranoside (11) To a solution of methyl α-D-glucopyranoside 10 (10.0 g, 51.5 mmol) in anhydrous DMF (30 mL) and the reaction mixture was cooled to 0°C, then sodium hydride (12.4 g, 0.31 mol) and benzyl bromide (36.7 mL, 0.31 mol) were added successively.The mixture was then allowed to warm to room temperature. After 8 h, the reaction was analyzed by TLC (petroleum ether/ethyl acetate = 5:1) which indicating that the starting material was consumed and conversed to a major product. The reaction mixture was quenched with methanol, diluted with ethyl acetate (350 mL), the organic layer washed with water (100 mL), NaHCO3 (100 mL) and saturated brine(100 mL) in sequence, then collected the organic layer and dried over anhydrous Na2SO4, the solvent was removed in vacuo and the residue was purified by flash column chromatography to give 11 (23.2 g, 81.4%). 1H NMR (400 MHz, CDCl3)δ 7.46-7.18 (m, 18H), 7.14-7.12 (m, 2H), 4.97 (d, J = 10.8 Hz, 1H), 4.84-4.77 (m,3H), 4.67-4.58 (m, 3H), 4.47 (d, J=11.6Hz, 2H), 3.98 (t, J=9.2Hz, 1H), 3.75-3.69(m, 2H), 3.63 (d, J = 9.2 Hz, 2H), 3.56 (dd, J = 9.6, 3.6 Hz, 2H), 3.37 (s, 3H); 13CNMR (100 MHz, CDCl3) δ 138.86, 138.32, 138.22, 137.98, 128.48, 128.39, 128.17,128.00, 127.93, 127.87, 127.71, 127.61, 98.25, 82.17, 79.91, 77.73, 75.78, 75.05, 73.52,73.42, 70.11, 68.55, 55.20. HRMS(ESI) calcd for [C35H38O6 +Na]+ 577.2566, found 577.2563 |
80% | With sodium hydroxide In lithium hydroxide monohydrate; dimethyl sulfoxide for 1h; Ambient temperature; | |
80% | Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide at 0℃; Stage #2: benzyl bromide With N,N,N-tributyl-1-butanaminium iodide at 20℃; for 20h; | |
72% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 24h; Inert atmosphere; | |
71% | Stage #1: benzyl bromide; methyl-α-D-glucopyranoside With tetrabutylammonium bromide; di-n-butyltin(IV) oxide; N-ethyl-N,N-diisopropylamine In neat (no solvent) at 140℃; for 2h; Stage #2: benzyl bromide With N-ethyl-N,N-diisopropylamine In neat (no solvent) at 140℃; for 5h; | |
65% | With potassium hydroxide; tri-n-octylmethylammonium chloride at 50℃; for 48h; in presence of alumina; var. bases; var. temps and time; | |
65% | With potassium hydroxide; tri-n-octylmethylammonium chloride at 50℃; for 48h; | |
With sodium hydride In N,N-dimethyl-formamide at 0℃; upto r.t.; | ||
With sodium hydride In N,N-dimethyl-formamide | ||
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; | ||
With sodium hydride | ||
With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; | ||
Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; Stage #2: benzyl bromide With tetrabutylammonium bromide In N,N-dimethyl-formamide; mineral oil at 20℃; | 39.A methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside To a suspension of NaH (5.19 g of a 60% dispersion in oil, 130 mmol) in DMF (150 mL) was added portionwise methyl-α-D-glucopyranoside (4.2 g, 21.6 mmol). The resulting mixture was stirred at rt for 2 hr, to which tetrabutyl ammonium bromide (800 mg, 2.16 mmol) was and followed by dropwise addition of benzyl bromide (11.58 mL, 97 mmol). After stirring at rt overnight, the mixture was concentrated and the residue was suspended in water and extracted with ether (3*150 mL). The combined ether layers were washed with brine (200 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (330 g), eluting with 0-30% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 3.44 (s, 3H), 3.62 (dd, J=9.6, 3.5, 1H), 3.66-3.72 (m, 2H), 3.75-3.82 (m, 2H), 4.04 (t, J=9.3, 1H), 4.51-4.55 (m, 2H), 4.66 (d, J=12.1, 1H), 4.69 (d, J=3.5, 1H), 4.72 (d, J=12.1, 1H), 4.83-4.90 (m, 3H), 5.04 (d, J=11.0, 1H), 7.19 (m, 2H), 7.30-7.43 (m, 18H). | |
With sodium hydride In N,N-dimethyl-formamide for 12h; | ||
With sodium hydride In N,N-dimethyl-formamide | ||
Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 2h; Inert atmosphere; Stage #2: benzyl bromide With N,N,N-tributyl-1-butanaminium iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 18h; Inert atmosphere; | ||
Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; Stage #2: benzyl bromide With N,N,N-tributyl-1-butanaminium iodide In N,N-dimethyl-formamide; mineral oil at 20℃; | 39.A Step A: methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside To a suspension of NaH (5.19 g of a 60% dispersion in oil, 130 mmol) in DMF (150 mL) was added portionwise methyl-α-D-glucopyranoside (4.2 g, 21.6 mmol). The resulting mixture was stirred at rt for 2 hr, to which tetrabutyl ammonium bromide (800 mg, 2.16 mmol) was and followed by dropwise addition of benzyl bromide (11.58 mL, 97 mmol). After stirring at rt overnight, the mixture was concentrated and the residue was suspended in water and extracted with ether (3x150 mL). The combined ether layers were washed with brine (200 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (330 g), eluting with 0-30% EtOAc in hexanes to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 3.44 (s, 3H), 3.62 (dd, J = 9.6, 3.5, 1H), 3.66-3.72 (m, 2H), 3.75-3.82 (m, 2H), 4.04 (t, J = 9.3, 1H), 4.51-4.55 (m, 2H), 4.66 (d, J = 12.1, 1H), 4.69 (d, J = 3.5, 1H), 4.72 (d, J = 12.1, 1H), 4.83-4.90 (m, 3H), 5.04 (d, J = 11.0, 1H), 7.19 (m, 2H), 7.30-7.43 (m, 18H). | |
Stage #1: methyl-α-D-glucopyranoside With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5h; Cooling with ice; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 12h; | Preparation of 2,3,4,6-tetra-O-benzyl-α-D-methyl glucoside: The first compound (methyl α-D-glucopyranoside) (20.00 g, 103.00 mmol) was added to a 1000 mL round bottom flask and dried.DMF (N, N-Dimethylformamide, DMF, N, N-dimethylformamide) (500 mL) was stirred and dissolved, argon gas was added, and 60% NaH (18.50 g, 463.50 mmol) was slowly added in portions in an ice water bath. Gradually changed from clear to viscous, kept stirring for 30 min, then added benzyl bromide (56.80 mL, 463.50 mmol)Then, it was moved to room temperature for 12 h. After the reaction was completed, distilled water (300 mL) was added.Extract with dichloromethane (300 mL) and dry with saturated sodium bicarbonate (300 mL)Wash twice, then wash twice with distilled water (300 mL) and saturated brine (300 mL).Concentrate the organic phase to give a light yellow oily second compound2,3,4,6-tetra-O-benzyl-α-D-methyl glucoside, | |
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 20h; | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 16h; Inert atmosphere; | ||
With sodium hydride In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: methyl-alpha-D-glucopyranoside With di(n-butyl)tin oxide In methanol; toluene at 100℃; for 3h; Inert atmosphere; Stage #2: benzyl bromide With tetrabutylammomium bromide; N-ethyl-N,N-diisopropylamine In toluene at 100℃; for 44h; Inert atmosphere; regioselective reaction; | |
85% | Stage #1: methyl-alpha-D-glucopyranoside With di(n-butyl)tin oxide In toluene for 1h; Reflux; Inert atmosphere; Stage #2: benzyl bromide With tetrabutylammomium bromide In toluene at 100℃; for 10h; Inert atmosphere; regioselective reaction; | 6 Methyl 2, 6-di-O-benzyl-α-D-glucopyranoside (9) Methyl α-D-glucopyranoside (200 mg, 1.03 mmol) and dibutyltin oxide (566 mg, 2.266 mmol) was dissolved in 40 mL anhydrous toluene, and refluxed for 1 h. After evaporation of the solvent till 4 mL remained, benzyl bromide (490 μl, 4.412 mmol) was added dropwise, and then allowed to react at 100 °C for 10 h. The resulting mixture was directly purified by flash column chromatography (hexane/ethyl acetate, 2:1). To give 327 mg of product (85%). 1H NMR (DMSO-d6, 400 MHz): δ=7.26-7.39 (m, 10H, 2×Ph), 5.11 (d, J=6, 1H, 4-OH), 5.07 (d, J=5.2, 1H, 3-OH), 4.71 (d, J=3.6, 1H, 1-H), 4.59-4.68 (m, 2H, PhCH2), 4.50 (s, 2H, PhCH2), 3.67-3.69 (d, J=9.2, 1H, 6a-H), 3.50-3.56 (m, 3H, 3-H, 5-H, 6b-H), 3.26 (s, 3H, OMe), 3.18-3.21 (dd, J1=3.6, J2=9.6, 1H, 2-H), 3.11-3.13 (m, 1H, 4-H) ppm. |
68% | Stage #1: methyl-alpha-D-glucopyranoside With di(n-butyl)tin oxide In toluene at 110℃; for 2h; Stage #2: benzyl bromide With tetrabutylammomium bromide In toluene at 100℃; for 12h; |
66% | Stage #1: methyl-alpha-D-glucopyranoside With di(n-butyl)tin oxide In toluene at 137℃; Inert atmosphere; Stage #2: benzyl bromide In toluene at 147℃; Inert atmosphere; | 4.2.13. Methyl 2,6-di-O-benzyl-α-d-glucopyranoside (17)23 Methyl α-d-glucopyranoside (5.04 g, 25.9 mmol) and dibutyltin oxide (9.69 g, 38.9 mmol) in anhydrous toluene (100 mL) were heated at reflux at 137 °C overnight, under argon. The contents were evaporated to dryness in vacuo. Benzyl bromide (15 mL) and anhydrous toluene (15 mL) were added to the resultant yellow solid, and the reaction was set to reflux overnight at 147 °C, under argon. Upon completion, the reaction was cooled and the solvent removed in vacuo. The contents were partitioned between water (100 mL) and CH2Cl2 (100 mL). The aqueous phase was further extracted with CH2Cl2 (2 × 100 mL). The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography on silica gel (1:1 toluene/EtOAc) yielded (17) as a white solid (6.40 g, 66%). Mp 81-83 °C (lit.23 85-87 °C); +65.8 (c 1.0, CHCl3) (lit.35 +59.8 (c 1.1, CHCl3)); νmax (NaCl disc/cm-1) 3428 (br, s, OH), 2914 (s, CH), 1497 (m, CC (arom)), 1454 (m, CC (arom)),1054 (s, C-O), 738 (s, CH (arom)), 698 (s, CH (arom)); δH (400 MHz, CDCl3) 2.92 (1H, d, J = 2.5 Hz, H-3), 2.94 (1H, d, J 3.0, C(4)OH), 3.33 (3H, s, OCH3), 3.37 (1H, dd, J = 9.5, 3.5 Hz, H-2), 3.57 (1H, dt, J = 9.0, 3.0 Hz, H-4), 3.66-3.71 (3H, m, H-5,6), 3.90 (1H, dt, J = 9.0, 2.5 Hz, H-3), 4.54 (1H, d, J = 12.0 Hz, OCH2Ph), 4.58-4.66 (3H, m, H-1, OCH2Ph), 4.70 (1H, d, J = 12.0 Hz, OCH2Ph), 7.32-7.35 (10H, m, Ar-H); δC (101 MHz, CDCl3) 55.0 (OCH3), 69.2 (C-6), 69.5 (C-5), 70.8 (C-4), 72.8 (C-3), 72.8 (OCH2Ph), 73.4 (OCH2Ph), 78.9 (C-2), 97.5 (C-1), 127.4-128.3 (ArC), 137.7 (ArC); m/z (ESI) 397 ([M+Na]+, 100%). Found [M+Na]+ 397.1638, C21H26NaO6 requires 397.1622. |
With di(n-butyl)tin oxide 1.) toluene, reflux, 12 h, 2.) 80-90 deg C, 24 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide; benzene for 48h; Inert atmosphere; Dean-Stark; | |
92% | With trimethyl orthoformate In neat (no solvent) at 90℃; for 1.5h; | |
87% | With formic acid at 0℃; for 24h; |
80% | With zinc(II) chloride for 0.333333h; | |
72% | With zinc(II) chloride at 20℃; for 16h; | 1 Preparation of Methyl-4,6-O-benzylidene-α-D-glucopyranoside (Ia) To a solution of benzaldehyde (400 mL, 3.94 mol, 5.9 eq.) was added zinc chloride (100.3 g, 0.74 mol, 1.1 eq.) under vigorous stirring. After homogenization of the solution methyl-a-D-glucopyranoside (129.6 g, 0.67 mol, 1.0 eq.) was added portionwise. After 16 hours stirring at room temperature the reaction mixture was diluted with diethyl ether (100 mL). The mixture was then poured dropwise and under vigorous stirring in a solution containing ice water (1.5 L) and hexane (350 mL). The precipitate was filtered, washed with diethyl ether (3 x 300 mL) and dried under vacuum over KOH. The product was then recrystallised from CH2Cl2 (720 mL) and washed with a Et2O/CH2Cl2 solution (75:25, 2 x 200 mL). The filtrate was repeatedly recrystallised five times from CH2Cl2 to afford compound Ia as white crystals (136.97 g, 0.49 mol, 72%).; 1H NMR (CDCl3, 250 MHz): δ 2.35 (d, JCH-OH = 9.2 Hz, 1 H, OH), 2.83 (d, JCH-OH = 2.2 Hz, 1 H, OH), 3.46 (s, 3H, -OCH3), 3.43-3.46 (m, 1 H, H-4), 3.63 (td, JCH-OH = J 2,3 = 9.2 Hz, J 1,2 == 3.9 Hz, 1 H, H-2), 3.70-3.81 (m, 2H, H-5, H-6), 3.93 (td, J= 9.2 Hz, JCH-OH = 2.2 Hz, 1 H, H-3), 4.29 (m, 1 H, H-6), 4.79 (d, J 1,2 = 3.9 Hz, 1 H, H-1), 5.54 (s, 1 H, Ph-CH), 7.35-7.38 (m, 3H, HAr), 7.47-7.51 (m, 2H, HAr).; 1 3C NMR (CDCl3, 62.9 MHz): δ 55.6 (-OCH3), 62.5 (C-5), 69.0 (C-6), 71.1 (C-3), 72.9 (C-2), 81.0 (C-4), 99.9 (C-1), 102.0 (Ph-CH), 126.4, 128.5, 129.4, 137.1 (6xCAr).; IR (film) v (cm-1): 3369 (O-H). |
71% | With zinc(II) chloride for 0.666667h; Ambient temperature; ultrasonication; | |
63% | With zinc(II) chloride for 36h; Ambient temperature; | |
52% | With zinc(II) chloride for 3h; | |
Yield given; | ||
With zinc(II) chloride | ||
With zinc(II) chloride Inert atmosphere; | ||
With zinc(II) chloride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With zinc(II) chloride at 12℃; for 6h; | |
91% | With vanadyl triflate In methanol; acetonitrile at 20℃; for 36h; | |
85% | With dimethyl sulfate for 10h; Ambient temperature; |
81% | With 3,4-bis((3,5-bis(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione; orthoformic acid triethyl ester In acetonitrile at 20℃; for 5h; Inert atmosphere; | |
81% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In N,N-dimethyl-formamide at 40℃; for 2h; | |
78% | With zinc(II) chloride In dichloromethane at 20℃; for 6h; | |
75% | With zinc(II) chloride In chloroform | |
72% | With zinc(II) chloride for 72h; | |
72% | With zinc(II) chloride at 20℃; for 16h; | 1 Preparation of methyl-4,6-O-benzylidene-α-D-glucopyranoside (Ia) To a solution of benzaldehyde (400 mL, 3.94 mol, 5.9 eq.) was added zinc chloride (100.3 g, 0.74 mol, 1 .1eq.) under vigorous stirring. After homogenization of the solution methyl-α-D-glucopyranoside (129.6 g, 0.67 mol, 1.0 eq.) was added portionwise.After 16 hours stirring at room temperature the reaction mixture was diluted with diethyl ether (100 mL). The mixture was then poured dropwise and under vigorous stirring in a solution containing ice water (1 .5 L) and hexane (350mL). The precipitate was filtered, washed with diethyl ether (3 x 300 mL) and dried under vacuum over KOH. The product was then recrystallised from CH2CI2 (720 mL) and washed with a Et20/CH2CI2 solution (75:25, 2 x 200 mL). The filtrate was repeatedly recrystallised five times from CH2CI2 to afford compound la as white crystals(136.97 g, 0.49 mol, 72%).1H NMR (CDCI3, 250 MHz): δ 2.35 (d, JCH-OH= 9.2 Hz, 1 H, OH), 2.83 (d, JCH-OH = 2.2 Hz, 1 H, OH),3.46 (s, 3H, -OCH3), 3.43-3.46 (m, 1 H, H-4), 3.63 (td, JCH-OH= ^2,3 = 9.2 Hz, J1 2 = 3.9 Hz, 1 H, H-2), 3.70-3.81 (m,2H, H-5, H-6), 3.93 (td, J = 9.2 Hz, JCH-OH = 2.2 Hz, 1H, H-3), 4.29 (m, 1 H, H-6 ), 4.79 (d, J1i2 = 3.9 Hz, 1 H, H-1 ),5.54 (s, 1 H, Ph-CH), 7.35-7.38 (m, 3H, HAr), 7.47-7.51 (m, 2H, HAr).13C NMR (CDCI3, 62.9 MHz): δ 55.6 (-OCH3), 62.5(C-5), 69.0 (C-6), 71.1 (C-3), 72.9 (C-2), 81 .0 (C-4), 99.9 (C-1 ), 102.0(Ph-CH), 126.4, 128.5, 129.4, 137.1 (6xCAr).IR(film) v (cm"1): 3369 (O-H) |
72% | With zinc(II) chloride | |
72% | With trichloroacetonitrile In N,N-dimethyl-formamide at 20℃; for 10h; Inert atmosphere; | |
68% | With zinc(II) chloride at 20℃; for 24h; | |
66% | With zinc(II) chloride for 72h; | |
63% | With zinc(II) chloride at 20℃; for 48h; | |
53% | With zinc(II) chloride for 5h; Ambient temperature; | |
With toluene-4-sulfonic acid; orthoformic acid triethyl ester | ||
With zinc(II) chloride at 20℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.1% | With sodium hydride In toluene; paraffin oil at 90 - 95℃; | 2 Methyl-2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside In a 250ml three-necked flask equipped with a stirrer, thermometer, and condenser tube,Methyl-α-D-glucopyranoside 9.7 g (50.0 mmol), sodium hydride paraffin oil dispersion (55% sodium hydride) 9.16 g (209.9 mmol), toluene 60 ml,Benzyl chloride 26.56 g (210.0 mmol), heated to approximately 90-95°C, followed by liquid chromatography,Keep warm until reaction is complete.After completion of the heat preservation reaction, cool down to about 60°C, slowly add water, and react with residual sodium hydride until no bubbles are formed. The solid matter was removed by filtration, and the filter cake was washed with 15 ml x 2 toluene, and the organic layers were combined.The organic layer was heated up to 65-70°C, washed until neutral, each time using 20 ml of water, and washed 3 to 4 times (the first wash was discarded, and the other wash water was successively used for the next batch of water wash).After the organic layer is dehydrated by the reflux water separation method, the toluene is decompressed and recovered until no fraction is distilled (Toluene can be directly applied to the next batch).After cooling and letting go, paraffin oil was removed and 29.03 g of a light red syrupy viscous liquid was obtained.That is methyl-2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside, with a content of 93.6% and a yield of 98.1%. |
94% | With sodium hydride In N,N-dimethyl-formamide at 75℃; for 24h; | |
85% | With sodium hydroxide; potassium carbonate In dimethyl sulfoxide; benzene for 5h; Ambient temperature; |
63% | With sodium hydride for 5h; Heating; | |
With sodium methylsulfinylmethanide In dimethyl sulfoxide for 0.5h; | ||
With sodium hydride at 120℃; for 3h; Yield given; | ||
11.10 g | With sodium hydride at 140℃; for 5h; | |
With potassium hydroxide for 2h; Heating; | ||
With potassium hydroxide In 1,4-dioxane | 1 EXAMPLE 1 Methyl 2,3,4,6-tetra-O-benzyl α-D-glucopyranoside 10 (acc. to Methods in Carbohydrate Chemistry, 1972) Batch: 50 g methyl α-D-glucopyranoside (257 mmoles) 250 g KOH (powdered) 150 ml dioxane 318 ml benzylchloride (2.76 moles) Yield: 116 g 10 (81.3% of theory) as highly-viscous, yellow, clear oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; for 1h; | |
96% | With 1H-imidazole In N,N-dimethyl-formamide for 5h; | |
92% | With 1H-imidazole In N,N-dimethyl-formamide for 24h; Ambient temperature; |
84% | With pyridine; tetrabutylammomium bromide at 20℃; for 3h; regioselective reaction; | Typical procedure for the regioselective mono-O-silylation: General procedure: To a mixture of the polyol substrate(0.5-1 mmol), TBAB and the silylating agent, pyridine was added under air (see Tables 1 and 2 for stoichiometric proportions). The mixture was kept under stirring at room temperature until consumption of the starting material as revealed by TLC analysis (1.5-3 hours). The mixture was concentrated under vacuum and then submitted to silica-gel flash cromatography (eluents: ethylacetate or ethyl acetate/hexane mixtures) to afford the mono-O-silylated products in the yields indicated in Tables 1 and 2. |
82% | With 1H-imidazole In N,N-dimethyl-formamide for 16h; | |
62% | With pyridine; dmap at 50℃; for 16h; regioselective reaction; | |
In N,N-dimethyl-formamide electroreductive silylation at platinized Pt electrode with LiBr as conducting agent, electrode potential -2 V against Ag/Ag(+); Yield given; | ||
With 1H-imidazole In N,N-dimethyl-formamide | ||
With 1,4-diaza-bicyclo[2.2.2]octane for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: methyl-alpha-D-glucopyranoside With di-n-octyltin dichloride In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: phenylcarbonochloridothioate With 1,2,2,6,6-pentamethylpiperidine; tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 6h; regioselective reaction; | |
97% | Stage #1: methyl-alpha-D-glucopyranoside With dibutyltin chloride; methyl β-D-arabinofuranoside In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: phenylcarbonochloridothioate With 1,2,2,6,6-pentamethylpiperidine; tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 6h; chemoselective reaction; | |
97% | With 1,2,2,6,6-pentamethylpiperidine; tetra-(n-butyl)ammonium iodide; di-n-octyltin dichloride In tetrahydrofuran at 20℃; for 6h; | 12 194.2 mg (1.0 mmol) of methyl α-D-glucopyranoside, 41.6 mg (0.10 mmol) of dioctyl dichloro tin, tetrabutylammonium iodide36.9 mg (0.10 mmol) and 10 ml of tetrahydrofuran were added and stirred. To this mixed solution, 0.175 ml (1.3 mmol) of phenyl chlorothionoformate was added, then 0.271 ml (1.5 mmol) of 1,2,2,6,6-pentamethylpiperidine was added and the mixture was stirred at 20 ° C. for 6 hours.After completion of the reaction, 20 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and extraction operation was carried out three times with 20 ml of ethyl acetate. The organic phase (ethyl acetate phase) was washed with 20 ml of water and 20 ml of an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the solvent (ethyl acetate) was distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent n-hexane: ethyl acetate = 5:: 1), 319.5 mg (yield: 97%) of methyl 2-O-phenoxythiocarbonyl-α-D-glucopyranoside was obtained. |
21% | Stage #1: methyl-alpha-D-glucopyranoside With di(n-butyl)tin oxide; methyl beta-D-glucopyranoside In tetrahydrofuran at 20℃; for 0.166667h; Stage #2: phenylcarbonochloridothioate With 1,2,2,6,6-pentamethylpiperidine; tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 6h; chemoselective reaction; | |
With di(n-butyl)tin oxide 1.) methanol, reflux, 3 h; 2.) dioxane; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: methyl-alpha-D-glucopyranoside With pyridine; sulfuryl dichloride In chloroform at -78 - 50℃; for 42h; Stage #2: With sodium iodide In methanol; water at 20℃; for 0.166667h; | 1 Sulfuryl chloride (16.7 mL, 206 mmol, 8.0 equiv) was added dropwise over 1 h to a solution of methyl a-D-glucopyranoside (5.0 g, 25.7 mmol) in pyridine (30 mL) and chloroform (30 mL) at -78 °C. The yellow suspension was stirred at -78 °C for 2 h and warmed to rt. The reaction mixture was heated to 50 °C and stirred for 40 h. After cooling to rt, the solution was diluted with methanol (15 mL) and water (15 mL) and subsequently neutralized by slow addition of solid sodium carbonate. A solution of sodium iodide (1.9 g, 12.7 mmol) in water (5 mL) and methanol (5 mL) was added to the reaction mixture, and the mixture was stirred an additional 10 min. The resulting mixture was filtered to remove insoluble matter and washed with chloroform (50 mL). The filtrate was separated into two layers and the aqueous layer was extracted with five 25-mL portions of chloroform. The combined organic layers were concentrated under reduced pressure. The residue was recrystallized from chloroform to provide methyl 4,6-dideoxy-4,6-dichloro-a-D- galactopyranoside (3.55 g, 60%) as a colorless solid. 1H NMR (CDC13, 500 MHz) δ = 4.85 (d, 1H, J = 3.8 Hz, H-l), 4.53 (d, 1H, J = 3.1 Hz, H-4), 4.14 (t, 1H, J = 6.5 Hz, H-5), 3.99 (dd, 1H, J = 9.8 Hz, 3.1 Hz, H-3), 3.85 (dd, 1H, J = 9.8 Hz, 3.8 Hz, H-2), 3.67 (d, 2H, J = 6.5 Hz, H-6), 3.48 (s, 3H, OCH3); 1JC NMR (CDC13, 100 MHz) δ = 99.4, 70.0, 69.8, 69.4, 62.6, 55.9, 42.8; HRMS (ESI) Calcd for C7Hi2Cl2Na04 [M+Na]+: 253.0010. Found: 253.0020. |
55.8% | With pyridine; sulfuryl dichloride In chloroform at -78 - 50℃; for 7h; | |
55% | With pyridine; sulfuryl dichloride In chloroform at -78℃; for 2.5h; |
With 1H-imidazole; dichlorotriphenylphosphorane In pyridine; acetonitrile at 70℃; for 3.5h; | ||
With sulfuryl dichloride; potassium iodide In pyridine at -78℃; for 2h; | ||
Multi-step reaction with 2 steps 1: sulfuryl chloride; pyridine; chloroform 2: ammonia; methanol / Eindampfen des Reaktionsprodukts mit wss. Natronlauge unter vermindertem Druck und Erhitzen des erhaltenen Natrium-Salzes mit Kupfer(II)-sulfat in Wasser |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; sodium hydrogencarbonate In water; acetonitrile at 0 - 20℃; for 15h; | 3.2. General Procedure for the Oxidation General procedure: Methyl glycoside (methyl α-D-glucopyranoside, methyl β-D-galactopyranoside, or methyl α-D-mannopyranoside) (4-15 g) was firstly dissolved in deionized water (10 mL/g) and acetonitrile(10 mL/g) was added. TEMPO (0.3 eq.), BAIB (2.2 eq.), and NaHCO3 (1 eq.) were subsequently addedand the mixture was stirred at 0 °C for 2 h and at room temperature. The reaction was monitored byTLC. After completion, the reaction was quenched by the addition of ethanol, followed by evaporationand decantation with H2O/EtOAc. The aqueous phase was concentrated and the resultant syrup wasevaporated to dryness overnight to quantitatively give the corresponding sodium uronate as a whitecrystalline solid. For methyl α-D-glucopyranoside, the reaction was finished after 15h; for the methyl β-D-galactopyranoside, a second addition of TEMPO (0.3 eq.) and BAIB (2.2 eq.) was necessary andthe reaction was finished after 48 h; for methyl α-D-mannopyranoside, two supplementary additionsof TEMPO (0.3 eq.) and BAIB (2.2 eq.) and 8 days were necessary to oxidize all of the mannoside. |
90% | With oxygen; sodium hydrogencarbonate In water at 55℃; for 3h; pH 6-7; | |
90% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; sodium hydrogencarbonate In water; acetonitrile at 0 - 20℃; for 2h; regioselective reaction; | General procedure for TEMPO-mediated oxidation using PhI(OAc)2: General procedure: TEMPO (0.2 equiv per 1o-OH group) and bis(acetoxy)iodobenzene (3 equiv per 1o-OH group) were added to a stirred solution of sugar/nucleoside (0.1 - 0.5 mmol) and NaHCO3 (2 equiv per 1o -OH group) in a MeCN:H2O (1:1, 2 mL) at 0 oC; stirring was continued at the same temperature for 5 min. After that the resulting mixture was warmed to room temperature and stirred for 15 min to complete one cooling-warming cycle. Again, the temperature of the reaction mixture was lowered to 0 oC for 5 minutes and then warmed to room temperature for 15 minutes to complete the second warming-cooling cycle and so on until most of the starting material was consumed (by mass/TLC analysis). After completion the reaction mixture was diluted with H2O and washed with EtOAc (to remove TEMPO). Aqueous layer was concentrated under vacuum to afford the crude product which was further purified by silica gel flash chromatography/ion exchange resin to afford the pure acid product as sodium salt/triethyl ammonium salt. |
With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hypochlorite; sodium bromide In water at 2℃; for 0.916667h; selectivity of primary alcohol groups oxidation; pH 10; effect of reagents concentration on the rate of oxidation; also methyl β-glucopyranoside, α,α-trehalose and other glucans; | ||
82 % Chromat. | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hydroxide; sodium hypochlorite In water at 5℃; for 3h; sonication; | |
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; sodium hydrogencarbonate In water; acetonitrile at 0 - 20℃; | 6 Comparative Example 6: Preparation of methyl (2S.3f?.5S.6S)-3,5-dihydroxy-6- methoxy-4-oxotetrahvdro-2H-pyran-2-carboxylate (methyl-0-3-D-3’-ketoglucuronide methyl ester) Methyl-a-D-glucopyranoside (available from the company Sigma-Aldrich) (1.0 g, 5.1 mmol) was dissolved in acetonitrile (10 ml_) and water (10 ml_) and the stirred solution cooled to 0 °C. 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) (0.24 g, 1.5 mmol), iodobenzene diacetate (3.6 g, 11.2 mmol) and sodium bicarbonate (0.43 g, 5.1 mmol) were added. The mixture was allowed to warm to room temp after 1 h and allowed to stir overnight. Ethanol (10 ml_) was added and the solvent removed by distillation under reduced pressure. The residue was dissolved in water 10 ml_), washed with ethyl acetate (2 x 10 ml_) and the aqueous portion concentrated by distillation under reduced pressure to afford the crude methyl-a-D-glucuronide as its sodium salt as a white solid (1.40 g). Data for this compound is available in Lu et ai, Molecules, 2016, 21, 1301. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-Bromosuccinimide; triphenylphosphine In N,N-dimethyl-formamide | |
78% | With bromine; triphenylphosphine In dichloromethane; N,N-dimethyl-formamide for 2h; Ambient temperature; | |
73% | With carbon tetrabromide; triphenylphosphine In acetonitrile for 36h; Ambient temperature; |
64% | With pyridine; carbon tetrabromide; triphenylphosphine at 0 - 65℃; for 4.16667h; | 19 Example 19; Synthesis of (2S,3S,4S,5R,6S)-2-(((3-(dichloroamino)-3-methylbutyl)sulfonyl)methyl)-6- methoxytetrahydro-2H-pyran-3,4,5-triol-141 )Methyl 6-bromo-a-D-glucopyranosid[00216] To a 0°C solution of methyl a-D-glucopyranoside (3.9 g, 20 mmol) in 125 ml_ of anhydrous pyridine was added triphenylphospine (10.5 g, 40 mmol) followed by carbon tetrabromide (9.9 g, 30mmol). The reaction was stirred at 0 °C for 10 minutes then warmed to 65 °C for 4 hours. The reaction was quenched with 20 mL of methanol and concentrated to a crude residue, a portion of which was purified by column chromatography eluting from silica gel with a gradient of 0 to 15% methanol in dichloromethane to give 1 .1 g of an off-white solid (64%). 1 H NMR (400 MHz, d6-DMSO)5 3.00-3.06 (m, 1 H), 3.16-3.23 (m, 1 H), 3.30 (s,3H), 3.30-3.41 (m, H), 3.47-3.57 (m,2H), 3.73-3.76 (dd, J= 1 .6, 10.3 Hz, 1 H), 4.56-4.57 (d, J= 3.6 Hz, 1 H), 4.82-4.83 (d, J=6.4Hz, 1 H), 4.90-4.91 (d, J= 5.0 Hz, 1 H), 5.21 -5.23 (d, J= 5.9 Hz, 1 H). 13C NMR (100MHz, de-DMSO) 5 35.2, 55.0, 71 .0, 71.9, 72.3, 73.0, 99.9. |
With methanesulfonyl bromide; sodium methylate 1.) DMF, 65 deg C, 19 h, 2.) MeOH; Yield given. Multistep reaction; | ||
With N-Bromosuccinimide; triphenylphosphine In N,N-dimethyl-formamide 1.) 0 deg C, 20 min, 2.) 55 deg C, 3 h; | ||
With pyridine; carbon tetrabromide; triphenylphosphine | ||
With N-Bromosuccinimide; triphenylphosphine In N,N-dimethyl-formamide at 0 - 55℃; for 3.33333h; | 7 Methyl α-D-glucopyranoside (1) (13.0 g, 66.95 mmol) and Ph3P (35.18 g, 133.8 mmol) were dissolved in dry DMF (280 mL). The mixture was cooled in an ice bath. NBS (24.1 , 135 mmol) was added and the mixture was stirred at 0° C. for 20 min. The ice bath was replaced with an oil bath and the mixture was heated at 55° C. for 3h. Methanol (15 mL) was added and the mixture was stirred for a further 10 min. Sodium azide (26.0 g, 400 mmol) was added and the mixture was heated at 85° C. for 4 h. The solvent was removed under vacuum and the residue was dissolved in water (250 mL). The aqueous phase was washed with methylene chloride (3×250 mL) and filtered. The aqueous solution was evaporated in vacuo and the residue was dried under high vacuum to yield a light yellow solid (11.6 g, 79% ); mp 45-47° C.; TLC (SiO2) Rf 0.30 ( eluants 4:4:1 hexanes-ethyl acetate-methanol); IR (KBr) 2102.1 (N3) cm-1; 1H-NMR (D2O, 300 MHz) δ 4.81 (s, H-1), 3.43 (s, 3H, OCH3); 13C-NMR (DMSO-d6, 75 MHz) δ 99.8 (C-1), 72.9 (C-3), 71.7, 71.1(C-2, 5), 7.10 (C-4), 54.5 (OCH3), 51.3 (C-6). | |
With tetrabutylammomium bromide; (chloro-phenylthio-methylene)dimethylammonium chloride In N,N-dimethyl-formamide at 20℃; for 48h; Inert atmosphere; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With tetrakis(tetrabutylammonium)decatungstate(VI); 4-biphenylthiol; dibutylphosphoric acid tetrabutylammonium salt In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; | |
15 % Chromat. | In water Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With (1S)-10-camphorsulfonic acid; In N,N-dimethyl-formamide; at 60℃; for 21h; | 7-Anisaldehyde dimethylacetal (50 mL, 294 mmol, 1.14 equiv) was added to a suspension of a mixture of methyl a-D-glucopyranoside (50 g, 257 mmol) and D- camphorsulfonic acid (1.79 g, 7.72 mmol, 0.03 equiv) in DMF (250 mL). The reaction mixture was stirred at 60 C for 21 h. After cooling to rt, the solution was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution (500 mL) was added to the residue and the resulting mixture was stirred for 1 h. The precipitate was filtered and washed with cold aqueous saturated sodium bicarbonate solution (500 mL) to provide methyl 4,6-O-(4-methoxy)benzylidene-a-D-galactopyranoside (78.5 g, 98%) as a colorless solid, mp: 192-194 C; 1H NMR (CD3OD, 600 MHz) delta = 7.40 (d, 2H, J = 8.4 Hz, CH of Ar), 6.88 (d, 2H, J = 8.4 Hz, CH of Ar), 5.51 (s, IH, ArCH), 4.71 (d, IH, J = 3.8 Hz, H- l), 4.18 (dd, IH, J = 8.1 Hz, 3.3 Hz, H-6?), 3.81-3.78 (m, IH, H-4), 3.78 (s, 3H, OCH3 of An), 3.74-3.68 (m, 2H, H-3, H-6P), 3.50 (dd, IH, J = 9.3 Hz, 3.8 Hz, H-2), 3.43-3.40 (m, IH, H-5), 3.42 (s, 3H, OCH3); 13C NMR (CD3OD, 125 MHz) delta = 161.6, 131.5, 128.8, 114.3, 103.0, 102.0, 82.9, 74.1, 72.0, 70.0, 63.9, 55.8, 55.7; HRMS (ESI) Calcd for Ci5H2107 [M+H]+: 313.1287 |
94% | camphor-10-sulfonic acid; In N,N-dimethyl-formamide; for 0.666667h; | Step a); Methyl 4,6-0-(4-methoxybenzylidene)-alpha-D-glucopyranoside(4); A solution of methyl alpha-D-glucopyranoside (10 g, 51.5 mmol) in dimethylformamide (DMF, 50 ml) was added with a catalytic amount of camphorsulfonic acid (CSA) and anysaldehyde dimethylacetal (ADMA, 10 ml, 51.5 mmol) and the mixture was kept under magnetic stirring and low vacuum to remove the methanol formed during the condensation reaction. After 40 min the solvent was evaporated off. The residue was added with a NaHCO3 saturated solution and the resulting diphasic mixture was kept under vigorous stirring for one hour. The resulting precipitate was filtered and washed with an ice-cold bicarbonate solution (100 ml). The residue was triturated in hexane to afford compound 4 as a white solid (15 g, 94%). 4: Rf = 0,31 (EtOAc/MeOH/H2O 7:2:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With iodine for 40h; Heating; Title compound not separated from byproducts; | ||
1: 30 % de 2: 8 % de | With β-hydroxy-substituted sulfonic acid functionalized silica at 80℃; for 0.0833333h; | 2. General procedure General procedure: A flow reactor system consisting of syringe pump, column (φ 4.0 mm × 50 mm, filledwith HO-SAS (350 mg, , 0.9-1.0 mmol/g loading of SO3H), backpressure regulatorand tubes (inner diameter φ = 50 μm, length L1 = 40 cm, L2 = 10 cm, L3 = 20 cm))was used. A solution of glucose (1, 90 mg, 0.5 mmol) in Methanol (5 mL, 0.10 Mglucose solution) was filled in the syringe. The syringe was pumped using the syringepump at flow rates of 0.1 mL/min (residence time = 5 min) and the reaction solutionwas passed through the column filled with HO-SAS. After the reaction solution cameout from the column end, the solution is discarded for 3 minutes (priming time = 3min). Then, the solution was collected for 10 min. After concentration in vacuo, thecrude mixture was analyzed by NMR. New HO-SAS was used except for theexperiments in Figure 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With proteinase N In water; N,N-dimethyl-formamide at 45℃; for 168h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With Novozym 435 In acetonitrile at 50℃; for 120h; Enzymatic reaction; | |
60% | With Novozym 435 In acetonitrile at 50℃; for 120h; | ii. Synthesis of Methyl 6-O-Methacryloyl-α-D-glucoside(6-O-MMAGlc, 2). 6-O-MMAGlc was synthesized as described previously.40) Briefly, methyl α-D-glucoside (16.0 g, 0.082 mol), Novozym 435 (8.0 g), and vinyl methacrylate (8.8 g, 0.078 mol) were dissolved or suspended in acetonitrile (80 mL). Then the mixture was homogenized for 120 h under 50 °C. The enzyme was filtered off and washed with methanol after the reaction.The filtrate was collected and evaporated under vacuum. The crude product was purified on column chromatography, eluting with ethyl acetate: hexane:ethanol, 7:2:1. Yield: 60%. 1H NMR (600 MHz, DMSO-d6, δ): 6.03 (s, 1H; CH2), 5.69 (s, 1H; CH2), 5.16 (d, J = 5.8 Hz, 1H; CH), 4.87 (d, J = 4.9 Hz, 1H; OH), 4.78 (d, J = 6.4 Hz, 1H; OH), 4.55 (d, J = 3.6 Hz, 1H; OH), 4.37 (dd, J = 11.6, 1.5 Hz, 1H; CH2), 4.11 (dd, J = 11.7, 6.9 Hz, 1H; CH2), 3.62-3.56 (m, 1H; CH), 3.42-3.37 (m, 1H; CH), 3.27 (s, 3H; OCH3), 3.24-3.19 (m, 1H; CH), 3.13-3.07 (m, 1H;CH), 1.89 (s, 3H; CH3). 13C NMR (150 MHz, DMSO-d6, δ): 166.39, 135.86, 125.63, 99.63, 73.19, 71.80, 70.40, 69.52, 64.12, 54.18, 17.89. IR (KBr): 3397, 2927, 2838, 1720, 1635, 1460, 1311, 1182, 1055, 943,901, 814, 752 (Scheme 2). |
With Novozym 435; 2,6-di-tert-butyl-4-methyl-phenol In acetonitrile at 50℃; for 120h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 3,4-bis((3,5-bis(trifluoromethyl)phenyl)amino)cyclobut-3-ene-1,2-dione; orthoformic acid triethyl ester In acetonitrile at 20℃; for 0.17h; Inert atmosphere; | |
87% | Stage #1: 4-methoxy-benzaldehyde; methyl-alpha-D-glucopyranoside With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: With orthoformic acid triethyl ester In N,N-dimethyl-formamide at 20℃; for 2.25h; | |
82% | With toluene-4-sulfonic acid; trimethyl orthoformate In N,N-dimethyl-formamide at 20 - 50℃; Inert atmosphere; | Methyl 4,6-O-[(R)-(4-methoxyphenyl)methylene]-α-D-glucopyranoside (7). To a solution of methylα-D-glucopyranoside (2.14 g, 11.0 mmol) in dry (10.0 mL), p-anisaldehyde (1.36 g, 10.0 mmol), and p-toluenesulfonic acid (0.0476 g, 0.250 mmol) were added andstirred for 5 min at rt under a nitrogen atmosphere. Methyl orthoformate (1.31mL, 12.00 mmol) was added dropwise and the resulting solution was stirred for15 min at rt. Afterwards, the solution was subject to rotary evaporation in a50 °C water bath where the reaction was monitored by TLC until completion.After the reaction is completed, the mixture was diluted with EtOAc (50 mL),and the resulting solution was quenched with saturated aqueous NaHCO3 (150mL). The aqueous layer was washed with EtOAc (3 x 75 mL), and the combinedorganic layers are washed with brine, dried over Na2SO4,and concentrated. The resulting crude product was stirred with hexanes (200 mL)for 16 h and the heterogeneous solutions was filtered to provide the insolublematerial, which was rinsed. The organic solvent was evaporated to afford 7 (2.82 g, 82%) as a white powder. The analyticaldata match previous report by Chen et al.(Org. Lett. 2005, 7, 3343). |
80% | With vanadyl triflate In methanol; acetonitrile at 20℃; for 48h; | |
40% | With perchloric acid adsorbed on silica gel In PEG 600 at 80℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With phosphomolybdic acid hydrate; silica gel In acetonitrile at 20℃; for 0.166667h; | |
95% | With chloro-methylsulfanyl-methane; water; potassium iodide In 1,4-dioxane at 50℃; for 2.4h; | Deprotection of silyl ethers; the desilylation of 1a General procedure: Protected diosgenin 1a (200 mg, 1 equiv.), chloromethyl methyl sulfide (4 mg, 0.1 equiv.), KI (2 mg, 0.03 equiv.), dioxane (4.0 mL)and water (102 mg, 15 equiv.) were added to a 25 mL round-bottom flask. The mixture was then stirred at 50 °C for 2.3 h. The solvent was then removed under reduced pressure for silica gel chromatography to furnish diosgenin 1aa as: White solid; yield 152 mg (>99%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine; N-Bromosuccinimide; sodium azide; acetic anhydride; triphenylphosphine In methanol; [(2)H6]acetone; dichloromethane; water; N,N-dimethyl-formamide | 1 Methyl 2,3,4-tri-O-acetyl-6-azido-6-deoxy-α-D-glucopyranoside (III) Methyl 2,3,4-tri-O-acetyl-6-azido-6-deoxy-α-D-glucopyranoside (III) To a solution of methyl-α-D-glucopyranoside (I, 1.0 g, 5.14 mmol), triphenylphosphine (2.72 g, 10.3 mmol) in DMF (30 mL) and NBS (1.84 g, 10.3 mmol) were added and the mixture was stirred at 60° C. for 2 hr. Methanol (1 mL) was added to quench the reaction and sodium azide (2.0 g, 30 mmol) was added and the mixture was heated at 80° C. for 4 hr. Solvents were removed under the reduced pressure and the resulting residue was dissolved in water and washed with 1:1 chloroform-hexane. The water phase was then evaporated to dryness and the resulting residue was suspended in acetone. Filtration removed the solid and the filtrate was evaporated to dryness. Pyridine (10 mL) and acetic anhydride (2 mL) was added and the mixture was stirred overnight at room temperature (rt). Methanol (2 mL) was added to quench the reaction. Solvents were removed under the reduced pressure and the resulting residue was dissolved in dichloromethane and washed with 5% NaHCO3 and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography, eluting with 2% methanol in dichloromethane, to give III (1.24 g, 70%) as a white foam. 1H NMR (500.1 MHz) (CD3Cl) δ: 5.41 (t, J=12.5 Hz, 1H), 4.81-4.96 (m, 3H), 3.91 (m, 1H), 3.40 (s, 3H), 3.26 (m, 2H), 2.02 (s, 3H), 1.98 (s, 3H), 1.95 (s, 3H). |
Multi-step reaction with 2 steps 1: 1.) Ph3P, CBr4, NaN3, 2.) MeOH / 1.) DMF, room temperature, 24 h, 2.) 120 deg C, overnight 2: pyridine | ||
Multi-step reaction with 3 steps 1: pyridine 2: pyridine 3: sodium azide / N,N-dimethyl-formamide |
With pyridine; sodium azide; carbon tetrabromide; acetic anhydride; triphenylphosphine In N,N-dimethyl-formamide | ||
Multi-step reaction with 3 steps 1: pyridine / 0 °C / Inert atmosphere 2: pyridine / 20 °C 3: sodium azide / N,N-dimethyl-formamide / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With toluene-4-sulfonic acid In pyridine; acetonitrile | 16 Step (A)--Preparation of Methyl 4,6-O-Benzylidene-2,3-di-O-benzoyl-α-D-glucopyranoside (compound 65) Step (A)--Preparation of Methyl 4,6-O-Benzylidene-2,3-di-O-benzoyl-α-D-glucopyranoside (compound 65) To a mixture of 25 g (0.13 mmol) of methyl-α-D-glucopyranoside (64) (commercially available from Aldrich Chemical Co., Milwaukee, Wis., USA) in 750 mL of acetonitrile was added αα-dimethoxytoluene (20 mL) and p-toluenesulfonic acid (600 mg). The resulting mixture was stirred at room temperature for 20 hours and then neutralized with triethylamine and evaporated. The residue was dissolved in pyridine (200 mL) and cooled in an ice bath. Benzoyl chloride (5 eq) was then added and the mixture was stirred overnight at room temperature. After standard work-up procedures, compound 65 (44.2 g, 70%) was crystallized from a mixture of ethyl acetate and ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 20℃; for 24h; | |
90% | With hafnium tetrakis(trifluoromethanesulfonate) In dichloromethane at 20℃; | General Experimental Procedure for the Acylation of alcohols General procedure: To an oven-dried and nitrogen flushed 10 mL round bottom flask was added benzyl alcohol (52µL, 0.5mmol, 1 equiv.) and dichloromethane (0.2mL). To this mixture was added isobutyric anhydride (0.17mL, 1.0mmol, 2 equiv.) followed by Hf(OTf)4 (3.9mg, 0.005mmol, 1 mol%). The reaction mixture was stirred at room temperature, and its progress monitored by TLC. When the reaction was completed, methanol (3mL) was added and the resulting mixture was heated under reflux for 3hrs. The resulting reaction mixture was concentrated in vacuo and purified by flash column chromatography (7/1, hexanes/ethyl acetate) to obtain the purified benzyl isobutyrate 5 as pale yellow |
60% | With 4-(N,N-dimethylamino)pyridine based 1,3,5,7-tetraphenyladamantane polymer In neat (no solvent) at 60℃; for 24h; Schlenk technique; | 2.7. Acylation of alcohols General procedure: The alcohol (1.5 mmol) and anhydride (3 mmol) were mixed in a 50 mL Schlenk tube, and then TPB-DMAP or TPA-DMAP (0.045 mmol) was added. The mixture was stirred at room temperature unless otherwise indicated. After completion of the reaction, the reaction mixture was subjected to centrifugation and the solid catalyst was separated. The liquid phase was harvested by decanting and evaporated, and the residue was purified by column chromatography on silica gel to afford the pure ester product. For recycling the catalyst, the isolated catalyst was washedwith diethyl ether and dried in vacuum, the recovered yellow solid was reused directly for the next run. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hafnium tetrakis(trifluoromethanesulfonate) In dichloromethane at 20℃; | General Experimental Procedure for the Acylation of alcohols General procedure: To an oven-dried and nitrogen flushed 10 mL round bottom flask was added benzyl alcohol (52µL, 0.5mmol, 1 equiv.) and dichloromethane (0.2mL). To this mixture was added isobutyric anhydride (0.17mL, 1.0mmol, 2 equiv.) followed by Hf(OTf)4 (3.9mg, 0.005mmol, 1 mol%). The reaction mixture was stirred at room temperature, and its progress monitored by TLC. When the reaction was completed, methanol (3mL) was added and the resulting mixture was heated under reflux for 3hrs. The resulting reaction mixture was concentrated in vacuo and purified by flash column chromatography (7/1, hexanes/ethyl acetate) to obtain the purified benzyl isobutyrate 5 as pale yellow |
86% | at 20℃; for 0.75h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 29 %Chromat. 2: 20 %Chromat. 3: 6 %Chromat. | With phosphotungstic acid In methanol at 194.84℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 35 %Chromat. 2: 26 %Chromat. | With sulfonated lignin In methanol at 194.84℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With stannous chloride In acetonitrile at 80℃; for 1h; | |
164 mg | With toluene-4-sulfonic acid In acetonitrile for 24h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sulfuric acid; acetic acid In water for 6h; Reflux; | 6.1.2. 2,3,4,6-Tetra-O-benzyl-D-glucopyranoside (3a) A solution of methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside 2a (3.7 g, 6.7 mmol) in 80% AcOH (100 mL) was added 1 M H2SO4 (25 mL). After the solution was refluxed for 6 h, the reaction mixture was neutralized by ice water containing 2.5 g NaOAc. This mixture was concentrated to dryness on the rotoevaporator. Then the mixture was suspended in water (100 mL) and the crude product was extracted using CH2Cl2 (2 × 100 mL), the extracts were washed with saturated aqueous solutions of NaHCO3 (100 mL), followed by saturated aqueous solutions of NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The crude product was recrystallized with EtOAc, affording a white solid 3a (2.2 g, 60%). The white solid was used for the next step. |
Multi-step reaction with 2 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 2.5 h / 0 - 20 °C / Inert atmosphere 1.2: 18.75 h / Inert atmosphere 2.1: acetic acid; hydrogenchloride / water / 6.5 h / 80 - 85 °C | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 2.5 h / 0 - 20 °C / Inert atmosphere 1.2: 18.75 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride; acetic acid / water / 6.5 h / 90 °C |
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 1.2: 0 - 20 °C 2.1: hydrogenchloride; strontium (III) chloride hexahydrate / acetic acid; water / 70 °C | ||
Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide 2: sulfuric acid; acetic acid; water / Reflux | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere 1.2: 18 h / 20 °C / Inert atmosphere 2.1: acetic acid; hydrogenchloride / water / 85 °C | ||
Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 48 h / 0 - 20 °C / Inert atmosphere 2: hydrogenchloride; acetic acid / water / 5 h / 100 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 8 h / 0 - 20 °C 2: acetic acid; sulfuric acid / Reflux | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 1.2: 20 °C / Inert atmosphere 2.1: acetic acid; hydrogenchloride / water / 0.75 h / 85 - 124 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 0 °C 2: acetic acid; sulfuric acid / water / 48 h / 100 °C | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / Cooling with ice 1.2: 12 h / 20 °C 2.1: acetic acid; hydrogenchloride / water / 80 °C / Reflux | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide 2.1: acetic acid 2.2: 125 °C | ||
Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 20 h / 0 - 20 °C 2: sulfuric acid / acetic acid / 36 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C 1.2: 20 h / 0 - 20 °C 2.1: acetic acid; hydrogenchloride; sulfuric acid / water / 20 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In N,N-dimethyl-formamide at 50℃; for 6h; | 1 Synthesis of Compound [5] p-Toluenesulfonic acid monohydrate (190 mg, 1 mmol), triethyl orthoformate (6.7 mE, 40 mmol), and 1-do- decanal (7.4 g, 40 mmol) were added to a suspension solution of methyl a-D-glucopyranoside (7.8 g, 40 mmol) in DMF (50 mE) at room temperature. The flask containing a reaction solution was connected to a rotary evaporatot The bath temperature of the rotary evaporator was set at 50° C. and the flask was rotated for 6 hours while the pressure of the inside of the system was being reduced to 50 hPa. After 6 hours, the mixture was allowed to cool to room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture and the resultant mixture was concentrated under reduced pressure. Toluene (200 mE) and water (200 mE) were added to the residue and the resultant mixture was vigorously shaken in a separating flannel. An organic phase was separated and dried over sodium sulfate. The sodium sulfate was removed by filtration and then the solvent was distilled off under reduced pressure. Hexane (200 mE) was added to the residue and the resultant mixture was stirred. The obtained suspension was filtered to give a white solid. Hexane (100 mE) was added to the obtained white solid and the resultant mixture was stirred while cooling with an ice bath. The obtained suspension was filtered and washed with cold hexane. The obtained powder was dried to give the target product (Compound [5]): Yield63% (9.1 g), ‘H NMR (400 MHz, CDC13): 0 4.76 (1H, d, J=4.1 Hz), 4.54 (1H, t, J=5.0 Hz), 4.13 (1H, dd, J=4.8, 10.3 Hz), 3.84 (1H, t, J=9.2 Hz), 3.68-3.54 (2H, m), 3.51 (1H, t, J=10.3 Hz), 3.43 (3H, s), 3.26 (1H, t, J=9.4 Hz), 2.65 (1H, s), 2.22 (1H, d, J=9.6 Hz), 1.70-1.60 (2H, m), 1.44-1.34 (2H, m), 1.34-1.20 (16H, m), 0.88 (3H, t, J=6.9 Hz). |
61% | With (R)-10-camphorsulfonic acid In N,N-dimethyl-formamide at 90℃; | |
28% | With sodium sulfate In tetrahydrofuran at 66℃; for 3h; Inert atmosphere; | 4.1. General procedure A: acetalisation of methyl pyranosides General procedure: In a dry two-necked round bottom flask, the correspondingmethyl glycopyranoside (2.0 equiv) and sodium sulfate (1.5 equiv)were added in dry THF under argon. Dodecanal (1.0 equiv) wasadded portionwise over a 1-min period, followed by Amberlyst 15(20 wt%/aldehyde). The mixture was stirred at 66 °C for the timestated. After cooling down to room temperature, the reactionmixture was filtered, washed with CH2Cl2 (2 25 mL) and thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography (Cyclohexane: EtOAc) to give thecorresponding methyl pyranoside acetals 6, 12-15. See supportinginformation for characterization details. |
26% | With sodium sulfate In tetrahydrofuran at 66℃; for 3h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 4-ethoxybenzaldehyde dimethyl acetal; methyl-alpha-D-glucopyranoside With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 80℃; Stage #2: With ammonium hydroxide In water; N,N-dimethyl-formamide at 80℃; for 1h; | 4.1.1.4. Compounds 4a-e and 7a-e22 General procedure: Methyl α-d-glucopyranoside (1, 0.97 g, 5 mmol), dimethylacetal derivatives 3a-e or 6a-e (5 mmol), dry N,N-dimethylformanide (4 mL), and p-toluenesulfonic acid monohydrate (p-TSA, 2.5 mg) were mixed and heated at 80 °C for 4-6 h. Then, DMF was evaporated under reduced pressure, and a solution of 2% NH4OH (5 mL) was added to the residue. The resulting suspension was stirred and heated at 80 °C for 1 h, and after that cooled in an ice bath. The final product was filtered off and washed with distilled water (3 × 10 mL), resulting in a white solid which was dried in a high vacuum pump at room temperature. Compounds 4a and 7a were purified by recrystallization from ethyl acetate, and the other ones were purified by column chromatography in silica gel with dichloromethane/ethyl acetate 3:1 (4b and 7b), or alumina with dichloromethane/methanol 95:05 (4c-e and 7c-e).Compound 4a (isolated as white needle-like crystals in 66% yield, mp 188-190 °C,+85 (c 0.5 g/100 mL, MeOH); IR (KBr, cm-1): ν 3180-3616, 2997, 2848, 1617, 1513, 1376, 1255, 1076, 1039, 820; 1H NMR (250 MHz, DMSO-d6, TMS) δ (ppm): 7.34 (d, 2H, J9-10 = 8.7 Hz, H-9), 6.89 (d, 2H, J10-9 = 8.7 Hz, H-10), 5.49 (s, 1H, H-7), 5.16 (d, 1H, JOH-3 = 5.0 Hz, OH), 4.98 (d, 1H, JOH-2 = 6.5 Hz, OH), 4.63 (d, 1H, J1-2 = 3.7 Hz, H-1), 4.13 (dd, 1H, J6B-5 = 4.1 Hz, J6B-6A = 9.5 Hz, H-6B), 4.01 (q, 2H, J12-13 = 7.5 Hz, H-12), 3.62-3.70 (m, 1H, H-6A), 5.52-3.62 (m, 2H, H-3, H-5), 3.34-3.37 (m, 2H, H-2, H-4), 3.33 (s, 3H, OCH3), 1.31 (t, 3H, H-13); 13C NMR (62.5 MHz, DMSO-d6, TMS) δ (ppm): 158.7, 129.9, 127.6, 113.6, 100.7, 100.4, 81.2, 72.3, 69.8, 68.0, 62.9, 62.3, 54.6, 14.5; TOF-MS, m/z calculated for C16H22O7 326.1366, found: m/z 326.1366. Compound 4b (isolated as a white solid in 75% yield, mp 146-148 °C, +83 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3196-3608, 2987, 2864, 1619, 1516, 1373, 1247, 1071, 1037, 802; 1H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.34 (d, 2H, J9-10 = 8.8 Hz, H-9), 6.90 (d, 2H, J10-9 = 8.8 Hz, H-10), 5.49 (s, 1H, H-7), 5.16 (d, 1H, JOH-3 = 5.2 Hz, OH), 4.98 (d, 1H, JOH-2 = 6.8 Hz, OH), 4.62 (d, 1H, J1-2 = 3.6 Hz, H-1), 4.13 (dd, 1H, J6B-5 = 4.4 Hz, J6B-6A = 9.8 Hz, H-6B), 3.91 (t, 2H, J12-13 = 6.8 Hz, H-12), 3.66 (t, 1H, J6A-6B,6A-5 = 10.0 Hz), 3.53-3.59 (m, 2H, H-3, H-5), 3.31-3.36 (m, 2H, H-2, H-4), 3.33 (s, 3H, OCH3), 1.73 (h, 2H, J13 = 7,2 Hz, H-13), 0.96 (t, 3H, J14 = 7,4 Hz, 8.3 Hz, H-14); 13C NMR (100 MHz, DMSO-d6, TMS) δ (ppm): 158.9, 130.1, 127.7, 113.8, 100.8, 100.5, 81.3, 72.4, 69.9, 68.9, 68.1, 62.4, 54.7, 22.0, 10.3; TOF-MS, m/z calculated for C17H24O7 340.1522, found: m/z 340.1518. Compound 4c (isolated as a white solid in 69% yield, mp 141-142 °C, +84 (c 0.6 g/100 mL, MeOH);IR (KBr, cm-1): ν = 3134-3606, 2962, 2869, 1616, 1516, 1373, 1245, 1079, 1030, 827; 1H NMR (400 MHz, CDCl3, TMS) δ (ppm): 7.41 (d, 2H, J9-10 = 8.8 Hz, H-9), 6.89 (d, 2H, J10-9 = 8.8 Hz, H-10), 5.49 (s, 1H, H-7), 4.78 (d, 1H, J1-2 = 3.9 Hz, H-1), 4.28 (dd, 1H, J6B-5 = 4.3 Hz, J6B-6A = 9.7 Hz, H-6B), 3.96 (t, 2H, J12-13 = 6.5 Hz, H-12), 3.89-3.94 (m, 1H, H-3), 3.70-3.83 (m, 2H, H-5, H-6A), 3.58-3.64 (m, 1H, H-2), 3.45-3.49 (m, 1H, H-4), 3.46 (s, 3H, OCH3), 3.05 (s, 1H, OH), 2.53 (d, 1H, JOH-2 = 9.2 Hz, OH), 1.77 (p, 2H, J13-14 = 6.6 Hz, H-13), 1.49 (h, 2H, J14-15 = 7.5 Hz, H-15), 0.98 (t, 3H, J15-14 = 7.4 Hz, H-15); 13C NMR (100 MHz, CDCl3, TMS) δ (ppm): 159.8, 129.3, 127.6, 114.3, 101.9, 99.8, 80.9, 72.8, 71.7, 68.9, 67.7, 62.4, 55.5, 31.2, 19.2, 13.8; TOF-MS, m/z calculated for C18H26O7 354.1578, found: m/z 354.1663. Compound 4d (isolated as a white solid in 66% yield, mp 137-138 °C, +63 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3154-3615, 2926, 2852, 1622, 1513, 1380, 1251, 1079, 1031, 823; 1H NMR (400 MHz, CDCl3, TMS) δ (ppm): 7.39 (d, 2H, J9-10 = 8.7 Hz, H-9), 6,86 (d, 2H, J10-9 = 8.7 Hz, H-10), 5.46 (s, 1H, H-7), 4.75 (d, 1H, J1-2 = 3.9 Hz, H-1), 4.25 (dd, 1H, J6B-5 = 4.3 Hz, J6B-6A = 9.7 Hz, H-6B), 3.93 (t, 2H, J12-13 = 6.6 Hz, H-12), 3.86-3.89 (m, 1H, H-3), 3.67-3.80 (m, 2H, H-5, H-6A), 3.56-3.61 (m, 1H, H-2), 3.41-3.46 (m, 1H, H-4), 3.43 (s, 3H, OCH3), 3.15 (s, 1H, OH), 2.60 (d, 1H, JOH-2 = 9.6 Hz, OH), 1.75 (p, 2H, J13-14 = 7.3 Hz, H-13), 1.28-1.47 (m, 10H, H-14-18), 0.88 (t, 3H, J19-18 = 7.4 Hz, H-19); 13C NMR (62.5 MHz, CDCl3, TMS) δ (ppm): 160.0, 129.5, 127.7, 114.4, 102.1, 99.9, 81.1, 73.0, 71.8, 69.0, 68.2, 62.5, 55.6, 31.9, 29.5, 29.3, 26.1, 22.7, 14.2; TOF-MS, m/z calculated for C22H34O7 410.2305, found: m/z 410.2305. Compound 4e (isolated as a white solid in 75% yield, mp 130-132 °C, +56 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3145-3605, 2925, 2851, 1620, 1523, 1379, 1252, 1083, 1037, 827; 1H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.33 (d, 2H, J9-10 = 8.6 Hz, H-9), 6.88 (d, 2H, J10-9 = 8.6 Hz, H-10), 5.48 (s, 1H, H-7), 4.90 (d, 1H, J1-2 = 4.9 Hz, H-1), 4.71 (d, 1H, JOH-3 = 6.6 Hz, OH), 4.62 (d, 1H, JOH-2 = 3.6 Hz, OH), 4.12 (dd, 1H, J6B-5 = 4.4 Hz, J6B-6A = 9.8 Hz, H-6B), 3.95 (t, 2H, J12-13 = 6.5 Hz, H-12), 3.59-3.68 (m, 1H, H-6A), 3.54-3.61 (m, 2H, H-3, H-5), 3.32-3.40 (m, 1H, H-4), 3.33 (s, 3H, OCH3), 3.15 (H2O), 1.68 (p, 2H, J13-14 = 6.7 Hz, H-13), 0.85 (t, 3H, J27-26 = 6.2 Hz, H-27); 13C NMR (62.5 MHz, DMSO-d6, TMS) δ (ppm): 158.9, 130.0, 127.6, 113.7, 100.8, 100.5, 81.3, 72.4, 69.9, 68.1, 67.4, 62.3, 54.7, 31.2, 28.9, 28.7, 28.6, 25.4, 22.0, 13.8; TOF-MS, m/z calculated for C30H50O7 522.3557, found: m/z 522.3553. |
50% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 1.16667h; Inert atmosphere; | 1 Synthesis of compound [G1] Synthesis of compound [G1]Under a nitrogen atmosphere, to a solution of methyl α-D-glucopyranoside (2.5 g, 13 mmol) in DMF (10 mL), p-toluenesulfonic acid (59 mg, 0.3 mmol) was added, and the mixed solution was stirred at room temperature for 5 minutes. To the mixed solution, a solution of 4-ethoxybenzaldehyde dimethyl acetal [18] (2.3 g, 12 mmol) in DMF (5 mL) was added dropwise at room temperature. After the dropwise addition, the mixed solution was stirred at room temperature for 10 minutes and stirred under reduced pressure for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated salt solution and then was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with diethyl ether, yielding the target compound as a white solid: Yield 50%; 1H NMR (500 MHz, CDC3): δ 7.40 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.5 Hz), 5.49 (s, 1H), 4.81 (s, 1H), 4.28 (d, 1H, 10.0 Hz), 4.03 (q, 2H, J=6.9 Hz), 3.93 (t, 1H, J=9.2 Hz), 3.80 (t, 1H, J=9.8 Hz), 3.73 (t, 1H, 10.1 Hz), 3.64 (t, 1H, J=9.3 Hz), 3.51-3.46 (m, 4H), 2.63 (s, 1H), 2.21 (d, 1H, J=9.4 Hz), 1.40 (t, 3H, J=6.9 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 4-octyloxybenzaldehyde dimethyl acetal; methyl-alpha-D-glucopyranoside With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 80℃; Stage #2: With ammonium hydroxide In water; N,N-dimethyl-formamide at 80℃; for 1h; | 4.1.1.4. Compounds 4a-e and 7a-e22 General procedure: Methyl α-d-glucopyranoside (1, 0.97 g, 5 mmol), dimethylacetal derivatives 3a-e or 6a-e (5 mmol), dry N,N-dimethylformanide (4 mL), and p-toluenesulfonic acid monohydrate (p-TSA, 2.5 mg) were mixed and heated at 80 °C for 4-6 h. Then, DMF was evaporated under reduced pressure, and a solution of 2% NH4OH (5 mL) was added to the residue. The resulting suspension was stirred and heated at 80 °C for 1 h, and after that cooled in an ice bath. The final product was filtered off and washed with distilled water (3 × 10 mL), resulting in a white solid which was dried in a high vacuum pump at room temperature. Compounds 4a and 7a were purified by recrystallization from ethyl acetate, and the other ones were purified by column chromatography in silica gel with dichloromethane/ethyl acetate 3:1 (4b and 7b), or alumina with dichloromethane/methanol 95:05 (4c-e and 7c-e).Compound 4a (isolated as white needle-like crystals in 66% yield, mp 188-190 °C,+85 (c 0.5 g/100 mL, MeOH); IR (KBr, cm-1): ν 3180-3616, 2997, 2848, 1617, 1513, 1376, 1255, 1076, 1039, 820; 1H NMR (250 MHz, DMSO-d6, TMS) δ (ppm): 7.34 (d, 2H, J9-10 = 8.7 Hz, H-9), 6.89 (d, 2H, J10-9 = 8.7 Hz, H-10), 5.49 (s, 1H, H-7), 5.16 (d, 1H, JOH-3 = 5.0 Hz, OH), 4.98 (d, 1H, JOH-2 = 6.5 Hz, OH), 4.63 (d, 1H, J1-2 = 3.7 Hz, H-1), 4.13 (dd, 1H, J6B-5 = 4.1 Hz, J6B-6A = 9.5 Hz, H-6B), 4.01 (q, 2H, J12-13 = 7.5 Hz, H-12), 3.62-3.70 (m, 1H, H-6A), 5.52-3.62 (m, 2H, H-3, H-5), 3.34-3.37 (m, 2H, H-2, H-4), 3.33 (s, 3H, OCH3), 1.31 (t, 3H, H-13); 13C NMR (62.5 MHz, DMSO-d6, TMS) δ (ppm): 158.7, 129.9, 127.6, 113.6, 100.7, 100.4, 81.2, 72.3, 69.8, 68.0, 62.9, 62.3, 54.6, 14.5; TOF-MS, m/z calculated for C16H22O7 326.1366, found: m/z 326.1366. Compound 4b (isolated as a white solid in 75% yield, mp 146-148 °C, +83 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3196-3608, 2987, 2864, 1619, 1516, 1373, 1247, 1071, 1037, 802; 1H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.34 (d, 2H, J9-10 = 8.8 Hz, H-9), 6.90 (d, 2H, J10-9 = 8.8 Hz, H-10), 5.49 (s, 1H, H-7), 5.16 (d, 1H, JOH-3 = 5.2 Hz, OH), 4.98 (d, 1H, JOH-2 = 6.8 Hz, OH), 4.62 (d, 1H, J1-2 = 3.6 Hz, H-1), 4.13 (dd, 1H, J6B-5 = 4.4 Hz, J6B-6A = 9.8 Hz, H-6B), 3.91 (t, 2H, J12-13 = 6.8 Hz, H-12), 3.66 (t, 1H, J6A-6B,6A-5 = 10.0 Hz), 3.53-3.59 (m, 2H, H-3, H-5), 3.31-3.36 (m, 2H, H-2, H-4), 3.33 (s, 3H, OCH3), 1.73 (h, 2H, J13 = 7,2 Hz, H-13), 0.96 (t, 3H, J14 = 7,4 Hz, 8.3 Hz, H-14); 13C NMR (100 MHz, DMSO-d6, TMS) δ (ppm): 158.9, 130.1, 127.7, 113.8, 100.8, 100.5, 81.3, 72.4, 69.9, 68.9, 68.1, 62.4, 54.7, 22.0, 10.3; TOF-MS, m/z calculated for C17H24O7 340.1522, found: m/z 340.1518. Compound 4c (isolated as a white solid in 69% yield, mp 141-142 °C, +84 (c 0.6 g/100 mL, MeOH);IR (KBr, cm-1): ν = 3134-3606, 2962, 2869, 1616, 1516, 1373, 1245, 1079, 1030, 827; 1H NMR (400 MHz, CDCl3, TMS) δ (ppm): 7.41 (d, 2H, J9-10 = 8.8 Hz, H-9), 6.89 (d, 2H, J10-9 = 8.8 Hz, H-10), 5.49 (s, 1H, H-7), 4.78 (d, 1H, J1-2 = 3.9 Hz, H-1), 4.28 (dd, 1H, J6B-5 = 4.3 Hz, J6B-6A = 9.7 Hz, H-6B), 3.96 (t, 2H, J12-13 = 6.5 Hz, H-12), 3.89-3.94 (m, 1H, H-3), 3.70-3.83 (m, 2H, H-5, H-6A), 3.58-3.64 (m, 1H, H-2), 3.45-3.49 (m, 1H, H-4), 3.46 (s, 3H, OCH3), 3.05 (s, 1H, OH), 2.53 (d, 1H, JOH-2 = 9.2 Hz, OH), 1.77 (p, 2H, J13-14 = 6.6 Hz, H-13), 1.49 (h, 2H, J14-15 = 7.5 Hz, H-15), 0.98 (t, 3H, J15-14 = 7.4 Hz, H-15); 13C NMR (100 MHz, CDCl3, TMS) δ (ppm): 159.8, 129.3, 127.6, 114.3, 101.9, 99.8, 80.9, 72.8, 71.7, 68.9, 67.7, 62.4, 55.5, 31.2, 19.2, 13.8; TOF-MS, m/z calculated for C18H26O7 354.1578, found: m/z 354.1663. Compound 4d (isolated as a white solid in 66% yield, mp 137-138 °C, +63 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3154-3615, 2926, 2852, 1622, 1513, 1380, 1251, 1079, 1031, 823; 1H NMR (400 MHz, CDCl3, TMS) δ (ppm): 7.39 (d, 2H, J9-10 = 8.7 Hz, H-9), 6,86 (d, 2H, J10-9 = 8.7 Hz, H-10), 5.46 (s, 1H, H-7), 4.75 (d, 1H, J1-2 = 3.9 Hz, H-1), 4.25 (dd, 1H, J6B-5 = 4.3 Hz, J6B-6A = 9.7 Hz, H-6B), 3.93 (t, 2H, J12-13 = 6.6 Hz, H-12), 3.86-3.89 (m, 1H, H-3), 3.67-3.80 (m, 2H, H-5, H-6A), 3.56-3.61 (m, 1H, H-2), 3.41-3.46 (m, 1H, H-4), 3.43 (s, 3H, OCH3), 3.15 (s, 1H, OH), 2.60 (d, 1H, JOH-2 = 9.6 Hz, OH), 1.75 (p, 2H, J13-14 = 7.3 Hz, H-13), 1.28-1.47 (m, 10H, H-14-18), 0.88 (t, 3H, J19-18 = 7.4 Hz, H-19); 13C NMR (62.5 MHz, CDCl3, TMS) δ (ppm): 160.0, 129.5, 127.7, 114.4, 102.1, 99.9, 81.1, 73.0, 71.8, 69.0, 68.2, 62.5, 55.6, 31.9, 29.5, 29.3, 26.1, 22.7, 14.2; TOF-MS, m/z calculated for C22H34O7 410.2305, found: m/z 410.2305. Compound 4e (isolated as a white solid in 75% yield, mp 130-132 °C, +56 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3145-3605, 2925, 2851, 1620, 1523, 1379, 1252, 1083, 1037, 827; 1H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.33 (d, 2H, J9-10 = 8.6 Hz, H-9), 6.88 (d, 2H, J10-9 = 8.6 Hz, H-10), 5.48 (s, 1H, H-7), 4.90 (d, 1H, J1-2 = 4.9 Hz, H-1), 4.71 (d, 1H, JOH-3 = 6.6 Hz, OH), 4.62 (d, 1H, JOH-2 = 3.6 Hz, OH), 4.12 (dd, 1H, J6B-5 = 4.4 Hz, J6B-6A = 9.8 Hz, H-6B), 3.95 (t, 2H, J12-13 = 6.5 Hz, H-12), 3.59-3.68 (m, 1H, H-6A), 3.54-3.61 (m, 2H, H-3, H-5), 3.32-3.40 (m, 1H, H-4), 3.33 (s, 3H, OCH3), 3.15 (H2O), 1.68 (p, 2H, J13-14 = 6.7 Hz, H-13), 0.85 (t, 3H, J27-26 = 6.2 Hz, H-27); 13C NMR (62.5 MHz, DMSO-d6, TMS) δ (ppm): 158.9, 130.0, 127.6, 113.7, 100.8, 100.5, 81.3, 72.4, 69.9, 68.1, 67.4, 62.3, 54.7, 31.2, 28.9, 28.7, 28.6, 25.4, 22.0, 13.8; TOF-MS, m/z calculated for C30H50O7 522.3557, found: m/z 522.3553. |
63% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 51135h; Inert atmosphere; | 1 Compound [G6] Compound [G6]Under a nitrogen atmosphere, to a solution of methyl α-D-glucopyranoside (4.3 g, 22 mmol) in DMF (20 mL), p-toluenesulfonic acid (190 mg, 1.0 mmol) was added, and the mixed solution was stirred at room temperature for 5 minutes. To the mixed solution, a solution of 4-octyloxybenzaldehyde dimethyl acetal [23] (5.6 g, 20 mmol) in DMF (10 mL) was added dropwise at room temperature. After the dropwise addition, the mixed solution was stirred at room temperature for 10 minutes and stirred under reduced pressure for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated salt solution and then was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with diethyl ether, yielding the target compound as a white solid: Yield 63%; 1H NMR (500 MHz, CDC3): δ 7.40 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.49 (s, 1H), 4.80 (d, 1H, J=3.5 Hz), 4.28 (dd, 1H, J=10.1, 4.8 Hz), 3.97-3.89 (m, 3H), 3.83-3.70 (m, 2H), 3.67-3.61 (m, 1H), 3.51-3.45 (m, 4H), 2.64 (d, 1H, J=2.2 Hz), 2.22 (d, 1H, J=9.4 Hz), 1.80-1.72 (m, 2H), 1.48-1.22 (m, 10H), 0.93-0.85 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 51135h; Inert atmosphere; | 1 Synthesis of compound [G3] Synthesis of compound [G3]Under a nitrogen atmosphere, to a solution of methyl α-D-glucopyranoside (4.3 g, 22 mmol) in DMF (20 mL), p-toluenesulfonic acid (190 mg, 0.5 mmol) was added, and the mixed solution was stirred at room temperature for 5 minutes. To the mixed solution, a solution of 4-butoxybenzaldehyde dimethyl acetal [20] (4.7 g, 21 mmol) in DMF (10 mL) was added dropwise at room temperature. After the dropwise addition, the mixed solution was stirred at room temperature for 10 minutes and stirred under reduced pressure for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated salt solution and then was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with diethyl ether, yielding the target compound as a white solid: Yield 85%; 1H NMR (500 MHz, CDC3): δ 7.40 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.49 (s, 1H), 4.81 (d, 1H, J=3.8 Hz), 4.28 (dd, 1H, J=9.8, 4.4 Hz), 3.97-3.91 (m, 3H), 3.83-3.70 (m, 2H), 3.64 (dt, 1H, J=9.5, 4.1 Hz), 3.50-3.47 (m, 4H), 2.67 (s, 1H), 124 (d, 1H, J=9.5 Hz), 1.75 (m, 2H), 1.48 (sext, 2H, J=7.6 Hz), 0.96 (t, 3H, J=7.6 Hz). |
69% | Stage #1: methyl-alpha-D-glucopyranoside; 4-butoxybenzaldehyde dimethyl acetal With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 80℃; Stage #2: With ammonium hydroxide In water; N,N-dimethyl-formamide at 80℃; for 1h; | 4.1.1.4. Compounds 4a-e and 7a-e22 General procedure: Methyl α-d-glucopyranoside (1, 0.97 g, 5 mmol), dimethylacetal derivatives 3a-e or 6a-e (5 mmol), dry N,N-dimethylformanide (4 mL), and p-toluenesulfonic acid monohydrate (p-TSA, 2.5 mg) were mixed and heated at 80 °C for 4-6 h. Then, DMF was evaporated under reduced pressure, and a solution of 2% NH4OH (5 mL) was added to the residue. The resulting suspension was stirred and heated at 80 °C for 1 h, and after that cooled in an ice bath. The final product was filtered off and washed with distilled water (3 × 10 mL), resulting in a white solid which was dried in a high vacuum pump at room temperature. Compounds 4a and 7a were purified by recrystallization from ethyl acetate, and the other ones were purified by column chromatography in silica gel with dichloromethane/ethyl acetate 3:1 (4b and 7b), or alumina with dichloromethane/methanol 95:05 (4c-e and 7c-e).Compound 4a (isolated as white needle-like crystals in 66% yield, mp 188-190 °C,+85 (c 0.5 g/100 mL, MeOH); IR (KBr, cm-1): ν 3180-3616, 2997, 2848, 1617, 1513, 1376, 1255, 1076, 1039, 820; 1H NMR (250 MHz, DMSO-d6, TMS) δ (ppm): 7.34 (d, 2H, J9-10 = 8.7 Hz, H-9), 6.89 (d, 2H, J10-9 = 8.7 Hz, H-10), 5.49 (s, 1H, H-7), 5.16 (d, 1H, JOH-3 = 5.0 Hz, OH), 4.98 (d, 1H, JOH-2 = 6.5 Hz, OH), 4.63 (d, 1H, J1-2 = 3.7 Hz, H-1), 4.13 (dd, 1H, J6B-5 = 4.1 Hz, J6B-6A = 9.5 Hz, H-6B), 4.01 (q, 2H, J12-13 = 7.5 Hz, H-12), 3.62-3.70 (m, 1H, H-6A), 5.52-3.62 (m, 2H, H-3, H-5), 3.34-3.37 (m, 2H, H-2, H-4), 3.33 (s, 3H, OCH3), 1.31 (t, 3H, H-13); 13C NMR (62.5 MHz, DMSO-d6, TMS) δ (ppm): 158.7, 129.9, 127.6, 113.6, 100.7, 100.4, 81.2, 72.3, 69.8, 68.0, 62.9, 62.3, 54.6, 14.5; TOF-MS, m/z calculated for C16H22O7 326.1366, found: m/z 326.1366. Compound 4b (isolated as a white solid in 75% yield, mp 146-148 °C, +83 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3196-3608, 2987, 2864, 1619, 1516, 1373, 1247, 1071, 1037, 802; 1H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.34 (d, 2H, J9-10 = 8.8 Hz, H-9), 6.90 (d, 2H, J10-9 = 8.8 Hz, H-10), 5.49 (s, 1H, H-7), 5.16 (d, 1H, JOH-3 = 5.2 Hz, OH), 4.98 (d, 1H, JOH-2 = 6.8 Hz, OH), 4.62 (d, 1H, J1-2 = 3.6 Hz, H-1), 4.13 (dd, 1H, J6B-5 = 4.4 Hz, J6B-6A = 9.8 Hz, H-6B), 3.91 (t, 2H, J12-13 = 6.8 Hz, H-12), 3.66 (t, 1H, J6A-6B,6A-5 = 10.0 Hz), 3.53-3.59 (m, 2H, H-3, H-5), 3.31-3.36 (m, 2H, H-2, H-4), 3.33 (s, 3H, OCH3), 1.73 (h, 2H, J13 = 7,2 Hz, H-13), 0.96 (t, 3H, J14 = 7,4 Hz, 8.3 Hz, H-14); 13C NMR (100 MHz, DMSO-d6, TMS) δ (ppm): 158.9, 130.1, 127.7, 113.8, 100.8, 100.5, 81.3, 72.4, 69.9, 68.9, 68.1, 62.4, 54.7, 22.0, 10.3; TOF-MS, m/z calculated for C17H24O7 340.1522, found: m/z 340.1518. Compound 4c (isolated as a white solid in 69% yield, mp 141-142 °C, +84 (c 0.6 g/100 mL, MeOH);IR (KBr, cm-1): ν = 3134-3606, 2962, 2869, 1616, 1516, 1373, 1245, 1079, 1030, 827; 1H NMR (400 MHz, CDCl3, TMS) δ (ppm): 7.41 (d, 2H, J9-10 = 8.8 Hz, H-9), 6.89 (d, 2H, J10-9 = 8.8 Hz, H-10), 5.49 (s, 1H, H-7), 4.78 (d, 1H, J1-2 = 3.9 Hz, H-1), 4.28 (dd, 1H, J6B-5 = 4.3 Hz, J6B-6A = 9.7 Hz, H-6B), 3.96 (t, 2H, J12-13 = 6.5 Hz, H-12), 3.89-3.94 (m, 1H, H-3), 3.70-3.83 (m, 2H, H-5, H-6A), 3.58-3.64 (m, 1H, H-2), 3.45-3.49 (m, 1H, H-4), 3.46 (s, 3H, OCH3), 3.05 (s, 1H, OH), 2.53 (d, 1H, JOH-2 = 9.2 Hz, OH), 1.77 (p, 2H, J13-14 = 6.6 Hz, H-13), 1.49 (h, 2H, J14-15 = 7.5 Hz, H-15), 0.98 (t, 3H, J15-14 = 7.4 Hz, H-15); 13C NMR (100 MHz, CDCl3, TMS) δ (ppm): 159.8, 129.3, 127.6, 114.3, 101.9, 99.8, 80.9, 72.8, 71.7, 68.9, 67.7, 62.4, 55.5, 31.2, 19.2, 13.8; TOF-MS, m/z calculated for C18H26O7 354.1578, found: m/z 354.1663. Compound 4d (isolated as a white solid in 66% yield, mp 137-138 °C, +63 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3154-3615, 2926, 2852, 1622, 1513, 1380, 1251, 1079, 1031, 823; 1H NMR (400 MHz, CDCl3, TMS) δ (ppm): 7.39 (d, 2H, J9-10 = 8.7 Hz, H-9), 6,86 (d, 2H, J10-9 = 8.7 Hz, H-10), 5.46 (s, 1H, H-7), 4.75 (d, 1H, J1-2 = 3.9 Hz, H-1), 4.25 (dd, 1H, J6B-5 = 4.3 Hz, J6B-6A = 9.7 Hz, H-6B), 3.93 (t, 2H, J12-13 = 6.6 Hz, H-12), 3.86-3.89 (m, 1H, H-3), 3.67-3.80 (m, 2H, H-5, H-6A), 3.56-3.61 (m, 1H, H-2), 3.41-3.46 (m, 1H, H-4), 3.43 (s, 3H, OCH3), 3.15 (s, 1H, OH), 2.60 (d, 1H, JOH-2 = 9.6 Hz, OH), 1.75 (p, 2H, J13-14 = 7.3 Hz, H-13), 1.28-1.47 (m, 10H, H-14-18), 0.88 (t, 3H, J19-18 = 7.4 Hz, H-19); 13C NMR (62.5 MHz, CDCl3, TMS) δ (ppm): 160.0, 129.5, 127.7, 114.4, 102.1, 99.9, 81.1, 73.0, 71.8, 69.0, 68.2, 62.5, 55.6, 31.9, 29.5, 29.3, 26.1, 22.7, 14.2; TOF-MS, m/z calculated for C22H34O7 410.2305, found: m/z 410.2305. Compound 4e (isolated as a white solid in 75% yield, mp 130-132 °C, +56 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3145-3605, 2925, 2851, 1620, 1523, 1379, 1252, 1083, 1037, 827; 1H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.33 (d, 2H, J9-10 = 8.6 Hz, H-9), 6.88 (d, 2H, J10-9 = 8.6 Hz, H-10), 5.48 (s, 1H, H-7), 4.90 (d, 1H, J1-2 = 4.9 Hz, H-1), 4.71 (d, 1H, JOH-3 = 6.6 Hz, OH), 4.62 (d, 1H, JOH-2 = 3.6 Hz, OH), 4.12 (dd, 1H, J6B-5 = 4.4 Hz, J6B-6A = 9.8 Hz, H-6B), 3.95 (t, 2H, J12-13 = 6.5 Hz, H-12), 3.59-3.68 (m, 1H, H-6A), 3.54-3.61 (m, 2H, H-3, H-5), 3.32-3.40 (m, 1H, H-4), 3.33 (s, 3H, OCH3), 3.15 (H2O), 1.68 (p, 2H, J13-14 = 6.7 Hz, H-13), 0.85 (t, 3H, J27-26 = 6.2 Hz, H-27); 13C NMR (62.5 MHz, DMSO-d6, TMS) δ (ppm): 158.9, 130.0, 127.6, 113.7, 100.8, 100.5, 81.3, 72.4, 69.9, 68.1, 67.4, 62.3, 54.7, 31.2, 28.9, 28.7, 28.6, 25.4, 22.0, 13.8; TOF-MS, m/z calculated for C30H50O7 522.3557, found: m/z 522.3553. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: methyl-alpha-D-glucopyranoside; 4-propoxybenzaldehyde dimethyl acetal With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 80℃; Stage #2: With ammonium hydroxide In water; N,N-dimethyl-formamide at 80℃; for 1h; | 4.1.1.4. Compounds 4a-e and 7a-e22 General procedure: Methyl α-d-glucopyranoside (1, 0.97 g, 5 mmol), dimethylacetal derivatives 3a-e or 6a-e (5 mmol), dry N,N-dimethylformanide (4 mL), and p-toluenesulfonic acid monohydrate (p-TSA, 2.5 mg) were mixed and heated at 80 °C for 4-6 h. Then, DMF was evaporated under reduced pressure, and a solution of 2% NH4OH (5 mL) was added to the residue. The resulting suspension was stirred and heated at 80 °C for 1 h, and after that cooled in an ice bath. The final product was filtered off and washed with distilled water (3 × 10 mL), resulting in a white solid which was dried in a high vacuum pump at room temperature. Compounds 4a and 7a were purified by recrystallization from ethyl acetate, and the other ones were purified by column chromatography in silica gel with dichloromethane/ethyl acetate 3:1 (4b and 7b), or alumina with dichloromethane/methanol 95:05 (4c-e and 7c-e).Compound 4a (isolated as white needle-like crystals in 66% yield, mp 188-190 °C,+85 (c 0.5 g/100 mL, MeOH); IR (KBr, cm-1): ν 3180-3616, 2997, 2848, 1617, 1513, 1376, 1255, 1076, 1039, 820; 1H NMR (250 MHz, DMSO-d6, TMS) δ (ppm): 7.34 (d, 2H, J9-10 = 8.7 Hz, H-9), 6.89 (d, 2H, J10-9 = 8.7 Hz, H-10), 5.49 (s, 1H, H-7), 5.16 (d, 1H, JOH-3 = 5.0 Hz, OH), 4.98 (d, 1H, JOH-2 = 6.5 Hz, OH), 4.63 (d, 1H, J1-2 = 3.7 Hz, H-1), 4.13 (dd, 1H, J6B-5 = 4.1 Hz, J6B-6A = 9.5 Hz, H-6B), 4.01 (q, 2H, J12-13 = 7.5 Hz, H-12), 3.62-3.70 (m, 1H, H-6A), 5.52-3.62 (m, 2H, H-3, H-5), 3.34-3.37 (m, 2H, H-2, H-4), 3.33 (s, 3H, OCH3), 1.31 (t, 3H, H-13); 13C NMR (62.5 MHz, DMSO-d6, TMS) δ (ppm): 158.7, 129.9, 127.6, 113.6, 100.7, 100.4, 81.2, 72.3, 69.8, 68.0, 62.9, 62.3, 54.6, 14.5; TOF-MS, m/z calculated for C16H22O7 326.1366, found: m/z 326.1366. Compound 4b (isolated as a white solid in 75% yield, mp 146-148 °C, +83 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3196-3608, 2987, 2864, 1619, 1516, 1373, 1247, 1071, 1037, 802; 1H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.34 (d, 2H, J9-10 = 8.8 Hz, H-9), 6.90 (d, 2H, J10-9 = 8.8 Hz, H-10), 5.49 (s, 1H, H-7), 5.16 (d, 1H, JOH-3 = 5.2 Hz, OH), 4.98 (d, 1H, JOH-2 = 6.8 Hz, OH), 4.62 (d, 1H, J1-2 = 3.6 Hz, H-1), 4.13 (dd, 1H, J6B-5 = 4.4 Hz, J6B-6A = 9.8 Hz, H-6B), 3.91 (t, 2H, J12-13 = 6.8 Hz, H-12), 3.66 (t, 1H, J6A-6B,6A-5 = 10.0 Hz), 3.53-3.59 (m, 2H, H-3, H-5), 3.31-3.36 (m, 2H, H-2, H-4), 3.33 (s, 3H, OCH3), 1.73 (h, 2H, J13 = 7,2 Hz, H-13), 0.96 (t, 3H, J14 = 7,4 Hz, 8.3 Hz, H-14); 13C NMR (100 MHz, DMSO-d6, TMS) δ (ppm): 158.9, 130.1, 127.7, 113.8, 100.8, 100.5, 81.3, 72.4, 69.9, 68.9, 68.1, 62.4, 54.7, 22.0, 10.3; TOF-MS, m/z calculated for C17H24O7 340.1522, found: m/z 340.1518. Compound 4c (isolated as a white solid in 69% yield, mp 141-142 °C, +84 (c 0.6 g/100 mL, MeOH);IR (KBr, cm-1): ν = 3134-3606, 2962, 2869, 1616, 1516, 1373, 1245, 1079, 1030, 827; 1H NMR (400 MHz, CDCl3, TMS) δ (ppm): 7.41 (d, 2H, J9-10 = 8.8 Hz, H-9), 6.89 (d, 2H, J10-9 = 8.8 Hz, H-10), 5.49 (s, 1H, H-7), 4.78 (d, 1H, J1-2 = 3.9 Hz, H-1), 4.28 (dd, 1H, J6B-5 = 4.3 Hz, J6B-6A = 9.7 Hz, H-6B), 3.96 (t, 2H, J12-13 = 6.5 Hz, H-12), 3.89-3.94 (m, 1H, H-3), 3.70-3.83 (m, 2H, H-5, H-6A), 3.58-3.64 (m, 1H, H-2), 3.45-3.49 (m, 1H, H-4), 3.46 (s, 3H, OCH3), 3.05 (s, 1H, OH), 2.53 (d, 1H, JOH-2 = 9.2 Hz, OH), 1.77 (p, 2H, J13-14 = 6.6 Hz, H-13), 1.49 (h, 2H, J14-15 = 7.5 Hz, H-15), 0.98 (t, 3H, J15-14 = 7.4 Hz, H-15); 13C NMR (100 MHz, CDCl3, TMS) δ (ppm): 159.8, 129.3, 127.6, 114.3, 101.9, 99.8, 80.9, 72.8, 71.7, 68.9, 67.7, 62.4, 55.5, 31.2, 19.2, 13.8; TOF-MS, m/z calculated for C18H26O7 354.1578, found: m/z 354.1663. Compound 4d (isolated as a white solid in 66% yield, mp 137-138 °C, +63 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3154-3615, 2926, 2852, 1622, 1513, 1380, 1251, 1079, 1031, 823; 1H NMR (400 MHz, CDCl3, TMS) δ (ppm): 7.39 (d, 2H, J9-10 = 8.7 Hz, H-9), 6,86 (d, 2H, J10-9 = 8.7 Hz, H-10), 5.46 (s, 1H, H-7), 4.75 (d, 1H, J1-2 = 3.9 Hz, H-1), 4.25 (dd, 1H, J6B-5 = 4.3 Hz, J6B-6A = 9.7 Hz, H-6B), 3.93 (t, 2H, J12-13 = 6.6 Hz, H-12), 3.86-3.89 (m, 1H, H-3), 3.67-3.80 (m, 2H, H-5, H-6A), 3.56-3.61 (m, 1H, H-2), 3.41-3.46 (m, 1H, H-4), 3.43 (s, 3H, OCH3), 3.15 (s, 1H, OH), 2.60 (d, 1H, JOH-2 = 9.6 Hz, OH), 1.75 (p, 2H, J13-14 = 7.3 Hz, H-13), 1.28-1.47 (m, 10H, H-14-18), 0.88 (t, 3H, J19-18 = 7.4 Hz, H-19); 13C NMR (62.5 MHz, CDCl3, TMS) δ (ppm): 160.0, 129.5, 127.7, 114.4, 102.1, 99.9, 81.1, 73.0, 71.8, 69.0, 68.2, 62.5, 55.6, 31.9, 29.5, 29.3, 26.1, 22.7, 14.2; TOF-MS, m/z calculated for C22H34O7 410.2305, found: m/z 410.2305. Compound 4e (isolated as a white solid in 75% yield, mp 130-132 °C, +56 (c 0.6 g/100 mL, MeOH); IR (KBr, cm-1): ν 3145-3605, 2925, 2851, 1620, 1523, 1379, 1252, 1083, 1037, 827; 1H NMR (400 MHz, DMSO-d6, TMS) δ (ppm): 7.33 (d, 2H, J9-10 = 8.6 Hz, H-9), 6.88 (d, 2H, J10-9 = 8.6 Hz, H-10), 5.48 (s, 1H, H-7), 4.90 (d, 1H, J1-2 = 4.9 Hz, H-1), 4.71 (d, 1H, JOH-3 = 6.6 Hz, OH), 4.62 (d, 1H, JOH-2 = 3.6 Hz, OH), 4.12 (dd, 1H, J6B-5 = 4.4 Hz, J6B-6A = 9.8 Hz, H-6B), 3.95 (t, 2H, J12-13 = 6.5 Hz, H-12), 3.59-3.68 (m, 1H, H-6A), 3.54-3.61 (m, 2H, H-3, H-5), 3.32-3.40 (m, 1H, H-4), 3.33 (s, 3H, OCH3), 3.15 (H2O), 1.68 (p, 2H, J13-14 = 6.7 Hz, H-13), 0.85 (t, 3H, J27-26 = 6.2 Hz, H-27); 13C NMR (62.5 MHz, DMSO-d6, TMS) δ (ppm): 158.9, 130.0, 127.6, 113.7, 100.8, 100.5, 81.3, 72.4, 69.9, 68.1, 67.4, 62.3, 54.7, 31.2, 28.9, 28.7, 28.6, 25.4, 22.0, 13.8; TOF-MS, m/z calculated for C30H50O7 522.3557, found: m/z 522.3553. |
66% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 1.16667h; Inert atmosphere; | 1 Synthesis of compound [G2] Synthesis of compound [G2]Under a nitrogen atmosphere, to a solution of methyl α-D-glucopyranoside (2.9 g, 15 mmol) in DMF (15 mL), p-toluenesulfonic acid (63 mg, 0.3 mmol) was added, and the mixed solution was stirred at room temperature for 5 minutes. To the mixed solution, a solution of 4-propoxybenzaldehyde dimethyl acetal [19] (2.9 g, 14 mmol) in DMF (8 mL) was added dropwise at room temperature. After the dropwise addition, the mixed solution was stirred at room temperature for 10 minutes and stirred under reduced pressure for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated salt solution and then was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with diisopropyl ether, yielding the target compound as a white solid: Yield 66%; 1H NMR (500 MHz, CDC3): δ 7.40 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.9 Hz), 5.49 (s, 1H), 4.81 (s, 1H), 4.28 (d, 1H, J=9.9 Hz), 3.96-3.89 (m, 3H), 3.80 (t, 1H, J=9.8 Hz), 3.73 (t, 1H, J=10 Hz), 3.64 (t, 1H, J=9.4 Hz), 3.51-3.46 (m, 4H), 2.65 (s, 1H), 2.22 (d, 1H, J=9.4 Hz), 1.84-1.75 (m, 2H), 1.02 (t, 3H, J=7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: methyl-alpha-D-glucopyranoside With di(n-butyl)tin oxide In toluene for 1h; Reflux; Inert atmosphere; Stage #2: benzyl bromide With tetrabutylammomium bromide In toluene at 100℃; for 8h; Inert atmosphere; regioselective reaction; | 4 Methyl 2-O-benzyl-α-D-glucopyranoside (8) Methyl α-D-glucopyranoside (200 mg, 1.03 mmol) and dibutyltin oxide (282 mg, 1.133 mmol) was dissolved in 40 mL anhydrous toluene, and refluxed for 1 h. After evaporation of the solvent till 4 mL remained, benzyl bromide (122 μl, 1.236 mmol) was added dropwise, and then allowed to react at 100 °C for 8 h. The resulting mixture was directly purified by flash column chromatography (hexane/ethyl acetate, 1:1). To give 243 mg of product (83%). 1H NMR (DMSO-d6, 400 MHz): δ=7.24-7.41 (m, 5H, Ph), 5.10 (d, J=6, 1H, 4-OH), 4.97 (d, J=7.2, 1H, 3-OH), 4.78 (s, 2H, PhCH2), 4.51-4.55 (m, 2H, 1-H, 6-OH), 3.62-3.66 (m, 1H, 6a-H), 3.43-3.50 (m, 2H, 3-H, 6b-H), 3.30-3.35 (m, 2H, 2-H, 5-H), 3.29 (s, 3H, OMe), 3.23-3.27 (m, 1H, 4-H) ppm. |
75% | With tris(2,6-dimethylheptane-3,5-dionato)iron(III); potassium carbonate In N,N-dimethyl-formamide; acetonitrile at 80℃; for 24h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 21% 2: 30% | With H-meso-ZSM-5 at 189.84℃; for 12h; Autoclave; | 16.2.3. Catalytic reaction General procedure: The conversions of cellulose and cellobiose were performed ina Teflon-lined stainless-steel autoclave with a volume of 75 cm3.After the catalyst (typically 0.050 g) and cellobiose (typically 0.20 g,equivalent to 1.2 mmol C6H10O5unit) were added into the auto-clave pre-charged with methanol (typically 20 cm3), N2with apressure of 3.0 MPa was introduced. The reaction was started byheating the mixture to a reaction temperature. After a certain time(4 h), the reaction was stopped by cooled water, and the productswere analyzed by HPLC (Shimazu LC-20A) equipped with a RI detec-tor and a ShodexTMSH1011 column (10 m, 6.5 × 300 mm). Theconversion of cellulose was calculated by the change of the weightof cellulose after the reaction. The yield of a product was definedas the percentage of the molar amount of the target product in thetotal molar amount of C6H10O5unit in cellulose or cellobiose. |
With carbon dioxide at 240℃; for 120h; Supercritical conditions; | 1 Example 1 Into a glass container were added 5 g of cellulose (“Avicel”) and 20 ml of methanol, and then the container was placed in a 200 mL stainless-steel pressure resistant reactor equipped with a pressure gauge and a rupture type relief valve (TVS-N2-200 portable reactor, manufactured by Taiatsu Techno) so that the mixture was stirred with a stirrer and allowed to suspend. [0072] After the pressure resistant reactor was sealed, a liquefied CO2 was introduced thereinto, followed by heating with a heater so that the temperature and pressure inside the reactor were 180° C. and 8 MPa thereby allowing the carbon dioxide to be in the supercritical state. [0073] This state was kept for 3 days (72 hours) and 5 days (120 hours). [0074] The supercritical temperature and pressure of methanol are 240° C. and 8 MPa. [0075] (Residue Analysis) [0076] After the predetermined periods of time passed, the glass container was taken out and the content therein was filtered to measure the weight of the residue and carry out a wide-angle X-ray diffraction (WAXD) measurement. The cellulose decomposition rate was calculated using the following formula. Cellulose decomposition rate(%)=[(weight of charged cellulose-residue weight)/(weight of charged cellulose)]×100 [0077] As the result, the decomposition rates of the cellulose after 3 day and 5 day reactions were found to be 13.2% and 20.3 percent, respectively. [0078] The comparison of characteristics of the residue and charged cellulose (“Avicel”) were carried out by comparing their wide-angle X-ray diffraction (WAXD) patterns. The measurement was carried out using RINT-2200 X-ray diffraction device (manufactured by Rigaku Corporation) under conditions where the diffraction angle 2θ=5 to 30°, the X-ray tube voltage was 40 kV, the X-ray tube current was 40 mA, the sampling time was 4 seconds, and the step width was 0.04°. [0079] FIG. 1 shows the X-ray diffraction patterns of the cellulose and the residue after the 3 day reaction and 5 day reaction. [0080] As apparent from FIG. 1, two diffractions at 15.7° and 22.5° assigned to the crystal of the cellulose and the halo patterns of the amorphia overlap those of the residues, and no significant difference in the whole comparison of the patterns was found. Therefore, it is confirmed that in the present invention, a methanol soluble component was produced without giving the cellulose significant change. [0081] (Soluble Matter Analysis 1: NMR Spectrum Analysis) [0082] The methanol was distilled out from the 5 day reaction filtrate with a rotary evaporator and then dried under vacuum with a vacuum pump for 15 hours to give a methanol soluble matter. [0083] Part of the methanol soluble matter was dissolved in deuterated water to carry out the carbon nuclear magnetic resonance (13C-NMR) measurement. The measurement was carried out with a superconducting multinuclear magnetic resonator “JNM-GC400” (manufactured by JEOL Ltd.,) at 100 MHz and cumulated number of 2048 times. FIG. 2 shows 13C-NMR spectra. [0084] The vicinity of δ=100 ppm which corresponds to the anomeric carbon was enlarged (FIG. 3). [0085] As a comparative sample, the same measurement was carried out for a commercially available α-methyl glucoside. [0086] From the comparison of the both shown in FIG. 2, the methanol soluble matter was found to include substantially only methyl glucoside. [0087] From the comparison of the enlarged views of the vicinity of δ=100 ppm of the both shown in FIG. 3, the methanol soluble matter was found to be a mixture including substantially α-methyl glucoside and β-methyl glucoside. [0088] (Soluble Matter Analysis 2: HPLC Analysis) [0089] As an oligosaccharide standard, D-(+)-glucose, cellobiose, cellotriose, cellotetraose, and cellopentaose were each weighed and then dissolved in purified water to prepare oligosaccharide aqueous solutions each containing the respective component at a concentration of 10 mg/mL. Cellohexaose was weighed and dissolved in purified water to prepare an oligosaccharide aqueous solution containing cellohexanose at a concentration of 5 mg/ml. By mixing 20 μL of each of the 10 mg/mL oligosaccharide aqueous solutions, 40 μL of the 5 mg/mL oligosaccharide aqueous solution and 60 μL of acetonitrile was prepared an oligosaccharide standard solution (containing each oligosaccharide standard at a concentration of 1 mg/mL). [0090] The filtrates after 3 day reaction and 5 day reaction were sampled out each in an amount of 500 μL, followed by removal of methanol with a centrifugal evaporator and then were dissolved in 100 μL of purified water to prepare methanol soluble matter aqueous solutions. The aqueous solutions were filtered with a 0.45 μm filter and 30 μL of acetonitrile was mixed with 50 μL of each of the filtrates thereby preparing methanol soluble matter analysis samples. [0091] An analysis test was carried out under the following conditions. [0092] Device: LC-10 Avp system, manufactured by Shimadzu Corporation [0093] Column: COSMOSIL Sugar-D 4.6 mm (I.D)×2, 5 cm, manufactured by Nacalai Tesque [0094] Column temperature: 30° C. [0095] Mobile phase: acetonitrile/water=70 vol %/30 vol % [0096] Mobile phase flow rate: 1 mL/min [0097] Detector: RI detector RI2000, manufactured by LSL Lab System [0098] Charge: 10 μL [0099] (Result) [0100] FIG. 4 shows the result of the HPLC analysis of the oligosaccharide standard solution. [0101] FIG. 5 shows the result of the HPLC analysis of the methanol soluble matter after the 3 day reaction. [0102] FIG. 6 shows the result of the HPLC analysis of the methanol soluble matter after the 5 day reaction. [0103] The 3 day reaction methanol soluble matter or the 5 day reaction methanol soluble matter contains no glucose or oligosaccharides and was found to be a mixture including substantially only α-methyl glucoside and β-methyl glucoside. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 76% 2: 13% | With Lipolase 100T In acetonitrile at 20 - 37℃; for 98h; Enzymatic reaction; regioselective reaction; | 4. General procedure for enzymatic acylation of Me α-D-Glcp General procedure: Me α-D-Glcp (1) (1 mmol), vinyl carboxylate (1.5 mmol, 1.5 equiv.) and Lipolase 100T (3 g) were added to 20 mL of acetonitrile at room temperature. The reaction mixtures were stirred at 37°C for several hours (Table 1) and finished by filtration. The filter cake was washed with acetone and combined organic phases were concentrated under reduced pressure. Crude mixtures were purified by silica-gel chromatography (toluene/ethylacetate, 2:1→0:1) to afford first 2,6-di-O-acyl and next 6-O-acyl products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With (1S)-10-camphorsulfonic acid In tetrahydrofuran at 20℃; for 30h; Reflux; | Methyl 2,3,4,6-Tetrakis-O-(p-methoxybenzyl)-α-D-glucopyranoside (2k) To a solution of methyl α-D-glucopyranoside (58.3 mg, 0.300mmol) and TriBOT-PM (235.0 mg, 0.480 mmol) in THF (4.00 mL), CSA (41.8 mg, 0.180 mmol) was added at r.t. The mixture was heated to reflux and additional TriBOT-PM was added after 1 h (117.5 mg, 0.240 mmol), 5.5 h (33.7 mg, 0.0688 mmol), 12.5 h (58.7 mg, 0.120 mmol), 17 h (58.7 mg, 0.120 mmol), and 21 h (117.5 mg,0.240 mmol), respectively. The mixture was stirred for an additiona l9 h, the mixture was cooled to r.t., diluted with Et2O (12 mL), and washed with H2O (60 mL), 10% K2CO3 (3 × 12 mL), and brine (12mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane-EtOAc, 4:1 to 3:1 to 2:1) followed by recycling preparative HPLC to afford 2k (139.1 mg, 69%) as a clear pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With alpha-galactosidase AgaB; In aq. phosphate buffer; at 37.0℃; for 24.0h;pH 6.5;Enzymatic reaction; | General procedure: The donor component (1equiv), the acceptor substrate (2.5equiv), and alpha-galactosidase AgaB (10U/mmol acceptor) were dissolved in potassium phosphate buffer (100muL, version A or version B) and incubated in a thermomixer for 24h at 65C. For termination the temperature was enhanced to 95C for 15min. Separation and purification of the products were done either on Biogel P2 with water as eluent or on Sephadex LH-20 with water/ethanol 1:5 as eluent. Version A for glycopyranosyl fluoride donors: 0.3M KH2PO4/K2HPO4, pH 6.5. Version B for other donors: 0.1M K2HPO4/K2HPO4, pH 6.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 51135h; Inert atmosphere; | 1 Synthesis of compound [G3] Synthesis of compound [G3]Under a nitrogen atmosphere, to a solution of methyl α-D-glucopyranoside (2.5 g, 13 mmol) in DMF (6 mL), p-toluenesulfonic acid (46 mg, 0.3 mmol) was added, and the mixed solution was stirred at room temperature for 5 minutes. To the mixed solution, a solution of 4-butoxybenzaldehyde diethyl acetal [20′] (2.9 g, 12 mmol) in DMF (6 mL) was added dropwise at room temperature. After the dropwise addition, the mixed solution was stirred at room temperature for 10 minutes and stirred under reduced pressure for 1 hour. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated salt solution and then was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with diisopropyl ether, yielding the target compound as a white solid: Yield 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester; In N,N-dimethyl-formamide; at 20℃; for 102270h;Inert atmosphere; | Synthesis of compound [G3]Under a nitrogen atmosphere, to a solution of methyl alpha-D-glucopyranoside (1.9 g, 10 mmol) in DMF (7 mL), 4-butoxybenzaldehyde [10] (1.8 g, 10 mmol) and p-toluenesulfonic acid (52 mg, 0.27 mmol) were added, and the mixed solution was stirred at room temperature for 10 minutes. To the mixed solution, triethyl orthoformate (1.5 g, 10 mmol) was added dropwise at room temperature. After the dropwise addition, the mixed solution was stirred at room temperature for 20 minutes and stirred under reduced pressure for 2 hours. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated salt solution and then was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with hexane, yielding the target compound as a white solid: Yield 78%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In N,N-dimethyl-formamide at 40℃; for 2h; | |
65% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In N,N-dimethyl-formamide at 20 - 40℃; for 4.33333h; Inert atmosphere; | 1 Synthesis of compound [G13′] Synthesis of compound [G13′]Under a nitrogen atmosphere, to a solution of methyl α-D-glucopyranoside (3.9 g, 20 mmol) in DMF (13 mL), 3-butoxybenzaldehyde [G6′] (3.6 g, 20 mmol) and p-toluenesulfonic acid (92 mg, 0.5 mmol) were added, and the mixed solution was stirred at room temperature for 10 minutes. To the mixed solution, triethyl orthoformate (3.8 g, 26 mmol) was added dropwise at room temperature. After the dropwise addition, the mixed solution was stirred at room temperature for 20 minutes, then stirred under reduced pressure at room temperature for 1 hour, and stirred at 40° C. for 2 hours. To the reaction solution, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated salt solution and then was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained solid was washed with hexane, yielding the target compound as a white solid: Yield 65%; 1H NMR (500 MHz, CDC3): δ 7.30-7.25 (m, 1H), 7.06-7.03 (m, 2H), 6.89 (d, 1H, J=9.2 Hz), 5.50 (s, 1H), 4.81 (d, 1H, J=3.8 Hz), 4.29 (q, 1H, J=4.8 Hz), 3.99-3.91 (m, 3H), 3.84-3.78 (m, 1H), 3.74 (t, 1H, J=10.3 Hz), 3.65 (t, 1H, J=9, 5 Hz), 3.52-3.42 (m, 4H), 2.63 (s, 1H), 121 (d, 1H, J=9.4 Hz), 1.79-1.72 (m, 2H), 1.53-1.44 (m, 2H), 0.97 (t, 3H, J=7.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In tetrahydrofuran at 85℃; for 16h; | Methyl 4,6-O-Benzylidene-α-D-glucopyranoside (14) A mixture of methyl-α-D-glucopyranoside (20 g, 0.10 mol), freshly distilled benzaldehyde (60 mL), triethyl orthoformate (20 mL), p-toluenesulfonic acid monohydrate (1.0 g) and THF (200 mL) was refluxed at 85 °C for 16 h. After cooling the reaction mixture to room temperature, K2CO3 (1.0 g) was added and the mixture was stirred at room temperature for 30 min. The mixture was filtered, and the filtrate was suspended in distilled water (400 mL) and a suitable amount of 95% EtOH was added to dissolve the suspended materials in full. Then, the solution was evaporated under reduced pressure, until a fine crystalline species appeared, and kept at 4 °C for 12 h. The crystals formed in the solution were filtered, washed with water (100 mL ×2) and cyclohexane (100 mL ×3), and dried in vacuo to give pure methyl 4,6-O-benzylidene-α-D-glucopyranoside (14, 20 g, 0.071 mol, 71.0% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In N,N-dimethyl-formamide at 20 - 50℃; for 6h; | 1 Example 1: Synthesis of Saccharide Derivative Synthesis of compound [3]: Triethyl orthoformate (5.0 mL, 30 mmol) was added to a DMF (100 mL) suspension of methyl-a-D-glucopyranoside (8.74 g, 45 mmol), p-(dodecyloxy) benzaldehyde [2] (8.71 g, 30 mmol) and p-toluenesulfonic acid monohydrate (143 mg, 0.75 mmol) at room temperature. The reaction solution was heated to 500 C. and depressurized. After 6 hours, the reaction solution was allowed to cool to room temperature, 200 mL of saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was filtered. The residue on the filter paper was washed with 400 mL of pure water, and to the obtained solid was added pure water and heated at 90° C. for 30 minutes. The resulting suspension solution was filtered and washed with 400 mL of pure watet The obtained solid was dried under reduced pressure, finely pulverized, and then subjected to solid-liquid separation and washing with 300 mL of hexane at room temperature. The suspension was filtered and washed with 400 mL of hexane, and then the white powder was dried under reduced pressure to obtain the target compound.10114] Yield: 83% (11.7 g) ‘H NMR (400 MHz, CDC13):o 7.39 (2H, d, J=8.7 Hz), 6.88 (2H, d, J=8.7 Hz), 5.48 (1H, s), 4.80 (1H, d, J=4.1 Hz), 4.27 (1H, dd, J=4.6, 9.6 Hz), 3.98-3.88 (3H, m), 3.84-3.68 (2H, m), 3.63 (1H, dt, J=4.1,9.2 Hz), 3.52-3.41 (4H, m), 2.72 (1H, s), 2.27 (1H, d, J=9.6 Hz), 1.76 (2H, quintet, J=6.9 Hz), 1.50-1.16 (18H, m), 0.88 (3H, t, J=6.9 Hz). |
76% | Stage #1: 4-n-dodecyloxybenzaldehyde; methyl-alpha-D-glucopyranoside With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: With orthoformic acid triethyl ester In N,N-dimethyl-formamide at 20℃; for 2.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 25% 2: 49% | With H-meso-ZSM-5 at 149.84℃; for 4h; Autoclave; | 16.2.3. Catalytic reaction General procedure: The conversions of cellulose and cellobiose were performed ina Teflon-lined stainless-steel autoclave with a volume of 75 cm3.After the catalyst (typically 0.050 g) and cellobiose (typically 0.20 g,equivalent to 1.2 mmol C6H10O5unit) were added into the auto-clave pre-charged with methanol (typically 20 cm3), N2with apressure of 3.0 MPa was introduced. The reaction was started byheating the mixture to a reaction temperature. After a certain time(4 h), the reaction was stopped by cooled water, and the productswere analyzed by HPLC (Shimazu LC-20A) equipped with a RI detec-tor and a ShodexTMSH1011 column (10 m, 6.5 × 300 mm). Theconversion of cellulose was calculated by the change of the weightof cellulose after the reaction. The yield of a product was definedas the percentage of the molar amount of the target product in thetotal molar amount of C6H10O5unit in cellulose or cellobiose. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 11% 2: 21% 3: 8.3% | With H-meso-ZSM-5 at 189.84℃; for 18h; Autoclave; | 16.2.3. Catalytic reaction General procedure: The conversions of cellulose and cellobiose were performed ina Teflon-lined stainless-steel autoclave with a volume of 75 cm3.After the catalyst (typically 0.050 g) and cellobiose (typically 0.20 g,equivalent to 1.2 mmol C6H10O5unit) were added into the auto-clave pre-charged with methanol (typically 20 cm3), N2with apressure of 3.0 MPa was introduced. The reaction was started byheating the mixture to a reaction temperature. After a certain time(4 h), the reaction was stopped by cooled water, and the productswere analyzed by HPLC (Shimazu LC-20A) equipped with a RI detec-tor and a ShodexTMSH1011 column (10 m, 6.5 × 300 mm). Theconversion of cellulose was calculated by the change of the weightof cellulose after the reaction. The yield of a product was definedas the percentage of the molar amount of the target product in thetotal molar amount of C6H10O5unit in cellulose or cellobiose. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In 1,4-dioxane at 50℃; for 22h; | 2.5.1 Methylglycosidation/acid hydrolysis of Medalose Medalose (15mg) was ref1uxed with absolute MeOH (2ml) at 70°C for 18h in the presence of cation exchange R-l20 (H) resin. The reaction mixture was filtered while hot and filtrate was concentrated. To a solution of methylglycoside of Medalose in 1,4-dioxane (I ml), 0.1NH2S04 (1ml) was added and the solution was warmed for 30min at 50°C. The hydrolysis was complete after 22h. The hydrolysate was neutralized with freshly prepared BaCO3 filtered and concentrated under reduced pressure to afford α-and β-methylglucosides along with the GIc, Gal and GlcNAc. Their identification was confirmed by comparison with authentic samples (TLC, PC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetyl chloride In methanol at 85℃; | 3.7. Absolute Configuration of Compound 4 Approximately 90 g of compound 4 in MeOH (50 L) was treated with 500 L MeOH-acetylchloride (10:1), and heated at 85 C overnight, after which the mixture was dried by nitrogen gas.The residue was redissolved in 500 L (S)-2-butanol-acetylchloride (10:1), and heated at 85 C for3 h. Reference samples consisting of methyl -D-glucopyranoside, treated with both (S)-2-butanoland racemic 2-butanol, were prepared in the same manner. The resulting 2-butyl glycosides weredried by a stream of nitrogen gas, and subsequently silylated by adding 100 L pyridine and 100 LBSTFA-TMSCl, 99:1 (Sylon BFT, Supelco). The solutions were kept at room temperature overnight.Following dilution with ethyl acetate (1 mL) all samples were analyzed by GC-MS using a fused silicacolumn (HP-5MS; 0.25 m, 30 m 0.25 mm, Agilent) with a temperature gradient (80 °C for 5 min,80-250 C at 5 C/min, and a final hold at 250 °C for 5 min). The GC injector was held at 240 °C,and the GC-MS interface at 240 °C. Samples (1 L) were injected in split mode (50:1), and helium wasused as carrier gas (1 mL/min). This derivatization procedure results in a mixture of mainly 2-butyl/-glucopyranosides and the (S)-2-butyl and (R)-2-butyl glycosides of one of these anomeric formsare well separated by GC [26]. The (S)-2-butyl D-glucopyranoside yielded one GC peak at tR 32.82 minand the (R)-2-butyl D-glucopyranoside at tR 33.08. The peak of the (R)-2-butyl D-glucopyranoside ischromatographically equivalent to the enantiomeric (S)-2-butyl L-glucopyranoside, representing astandard for identification of L-glucose. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In dichloromethane; N,N-dimethyl-formamide at 40℃; for 4h; | 1 Synthesis of Compound [7] p-Toluenesulfonic acid monohydrate (25 mg, 0.13mmol) and triethyl orthoformate (0.7 mE, 4 mmol) were added to a suspension solution of methyl a-D-glucopyranoside (0.8 g, 4 mmol) in DMF (5 mE) at room temperature. To the resultant suspension solution, a solution of 1 -hexadecanal (Compound [2]) (1.0 g, 4 mmol) in dichloromethane (5 mE) was added at room temperature. The flask containing a reaction solution was connected to a rotary evaporatot The bath temperature of the rotary evaporator was set at 40° C. and the flask was rotated for 4 hours while the pressure of the inside of the system was being reduced to 50 hPa. After 4 hours, the resultant mixture was allowed to cool to room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture and the obtained precipitate was filtered and washed with watet The residue was purified by column chromatography (silica gel, hexane:ethyl acetate=60:40 to 40:60 (v/v)) to give the target product (Compound [7]): Yield 21% (0.35 g)’H NMR (400 MHz, CDC13): 0 4.76 (1H, d, J=3.7 Hz), 4.54 (1H, t, J=5.0 Hz), 4.12 (1H, dd, J=4.8, 10.3 Hz), 3.85 (1H, t, J=9.4 Hz),3.68-3.54 (2H, m), 3.51 (1H, t, J=10.3 Hz), 3.43 (3H, s),3.26 (1H, t, J=9.4 Hz), 2.72 (1H, s), 2.28 (1H, s), 1.71-1.60 (2H, m), 1.44-1.34 (2H, m), 1.33-1.21 (24H, m), 0.88 (3H, t, J=6.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In N,N-dimethyl-formamide at 70℃; for 5h; | 1 Synthesis of Compound [8]-1 Triethyl orthoformate (14.7 mE, 100 mmol) wasadded to a suspension solution of methyl a-D-glucopyranoside (19.4 g, 100 mmol), 1-octadecanal (Compound [3]) (29.5 g, 110 mmol), and p-toluenesulfonic acid monohydrate (1.05 g, 5.5 mmol) in DMF (130 mE) at room temperature. The flask containing a reaction solution was connected to a rotary evaporatot The bath temperature of the rotary evaporator was set at 70° C. and the flask was rotated for 5 hours while the pressure of the inside of the system was being reduced to 220 hPa. Afier 5 hours, the mixture was allowed to cool to room temperature. 13.3 mE of triethylamine was added to the mixture and the reaction solvent was distilled off under reduced pressure. To the residue, 350 mE of ethanol was added to carry out solid-liquid washing. After filtration, white powder was dried under reduced pressure. This washing operation was carried out two times to give the target product (Compound [8]): Yield 76% (33.7 g)’H NMR (400 MHz, CDC13): 0 4.76 (1H, d, J=3.7 Hz), 4.54 (1H, t, J=4.6 Hz), 4.13 (1H, dd, J=5.0, 10.1 Hz), 3.86 (1H, t, J=9.2 Hz), 3.69-3.54 (2H, m), 3.51 (1H, t, J=10.1 Hz), 3.43 (3H, s), 3.26 (1H, t, J=9.2 Hz), 2.73 (1H, br s), 2.30 (1H, br s), 1.76-1.55 (2H, m), 1.50-1.14 (30H, m), 0.88 (3H, t, J=6.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | With toluene-4-sulfonic acid; orthoformic acid triethyl ester In N,N-dimethyl-formamide at 50℃; for 5h; | 1 Synthesis of Compound [4] p-Toluenesulfonic acid monohydrate (46 mg, 0.24mmol) and triethyl orthoformate (1.7 mE, 10 mmol) were added to a suspension solution of methyl a-D-glucopyranoside (1.9 g, 10 mmol) in DMF (10 mE) at room temperature. To the resultant suspension solution, a suspension solution of 1-undecanal (1.7 g, 10 mmol) in DMF (5 mE) was added at room temperature. The flask containing a reaction solution was connected to a rotary evaporatot The bath temperature of the rotary evaporator was set at 50° C. and the flask was rotated for 5 hours while the pressure of the inside of the system was being reduced to 50 hPa. After 5 hours, the mixture was allowed to cool to room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the mixture. The resultant mixture was extracted with ethyl acetate and the extracted liquid was washed with a saturated aqueous sodium chloride solution. Afier washing, the extracted liquid was dried over sodium sulfate and the sodium sulfate was removed by filtration. Thereafier, the solvent was distilled off under reduced pressure. Hexane was added to the residue and the resultant mixture was stirred while cooling with an ice bath. The obtained suspension was filtered and washed with cold hexane. The obtained powder was dissolved in methanol and recrystallized with water to give the target product (Compound [4]): Yield 33% (1.2 g), ‘H NMR (400 MHz, CDC13):o 4.76 (1H, d, J=4.1 Hz), 4.54 (1H, t, J=5.0 Hz), 4.13 (1H, dd, J=4.8, 10.3 Hz), 3.85 (1H, dt, J=1.8, 9.2 Hz), 3.68-3.54 (2H, m), 3.51 (1H, t, J=10.1 Hz), 3.43 (3H, s), 3.26 (1H, t, J=9.4 Hz), 2.66 (1H, s), 2.23 (1H, d, J=9.6 Hz), 1.72-1.60 (2H, m), 1.45-1.34 (2H, m), 1.34-1.20 (14H, m), 0.88 (3H, t, J=6.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine In neat (no solvent) at 25℃; for 8h; Inert atmosphere; | Trimethylsilylation of Sugars with TEA and TMSOAc; General Procedure 2 General procedure: To a solution of 1a-m (200 mg, 1.0 equiv) and TEA (1.0 equiv/OH) were added TMSOAc (2.0 equiv/OH) and the mixture was stirred for 8 h under N2 atmosphere. The mixture was diluted with hexane and the hexane layer was washed with sat. NaHCO3 (3 x) and brine (3 x). The hexane layer was dried (anhyd MgSO4) and filtered. Evaporating the organic layer in vacuum furnished the desired product 2a-m (Scheme 3). |
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P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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