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CAS No. : | 4064-06-6 | MDL No. : | MFCD00063225 |
Formula : | C12H20O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 260.28 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.75 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 5.0 |
Molar Refractivity : | 63.41 |
TPSA : | 118.22 Ų |
GI absorption : | High |
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) : | -7.87 cm/s |
Log Po/w (iLOGP) : | -0.36 |
Log Po/w (XLOGP3) : | 0.03 |
Log Po/w (WLOGP) : | -0.74 |
Log Po/w (MLOGP) : | -1.53 |
Log Po/w (SILICOS-IT) : | 0.17 |
Consensus Log Po/w : | -0.49 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.21 |
Solubility : | 16.1 mg/ml ; 0.0619 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.06 |
Solubility : | 2.24 mg/ml ; 0.00861 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | 0.51 |
Solubility : | 842.0 mg/ml ; 3.24 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 4.18 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
99% | With methanesulfonic acid In neat (no solvent) at 30 - 35℃; for 0.25h; Green chemistry; | |
98% | With iodine for 0.0833333h; ice-bath temperature; | |
98% | With 4 A molecular sieve at 20℃; for 4h; |
98% | With 1,4-diaza-bicyclo[2.2.2]octane at 20℃; for 0.416667h; Neat (no solvent); | Typical procedure: Acetylation of methyl α-d-glucopyranoside. General procedure: 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 2,3-dihydro-5,7-bismethyl-1,4-diazepine monohydroperchlorate In neat (no solvent) at 40℃; for 8h; | |
98% | With ammonium cerium (IV) nitrate at 20℃; for 18h; | |
98% | With 1H-imidazole In acetonitrile at 20℃; for 2h; | |
97% | With phosphoric acid In acetonitrile at 50℃; for 21h; | |
96% | With lithium perchlorate for 48h; Heating; | |
92% | With indium(III) triflate at -15℃; for 0.0166667h; | |
92% | With aminosulfonic acid at 60℃; for 0.0833333h; neat (no solvent); | |
88% | With pyridine at 20℃; for 12h; | |
65% | With triethylammonium acetate at 20℃; for 3h; | Typical Procedure General procedure: To a stirred solution of 2-naphthol (0.2 mmol) in TEAA(2 ml), was added acetic anhydride (0.22 mmol). The solutionwas stirred for 3 hours at room temperature. After consumptionof starting material (TLC monitoring, ethyl acetate/hexane, 2:8), the product formed was diluted with 1 mlH2O and extracted with 3 x 2 ml ether. The combined organiclayer was separated, dried (Na2SO4), and evaporatedunder reduced pressure to afford the desired product. 1H and13C NMR spectra were in full accordance with the structureproposed. The water in the aqueous layer was distilled under reduced pressure leaving behind the TEAA which was furtherrecycled. |
With pyridine | ||
In ethyl acetate at 60℃; for 0.5h; | ||
With 6C2F3O2(1-)*(x)C2HF3O2*Zn4O(6+) In toluene at 70℃; for 12h; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In dichloromethane at 0 - 20℃; | (3aR,5S,5aS,8aS,8bR)-5-(Azidomethyl)-2,2,7,7-tetramethyltetrahydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]pyran (N3-Prot-Gal): A solution of ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol (1 g, 3.8 mmol) and NEt3 (0.8mL, 5.8 mmol, 1.5 equiv.) in CH2Cl2 (20 mL) was stirring at room temperature 30min. Then it was cooled to 0C with an ice-bath, after which methanesulfonylchloride (MsCl) (0.5 mL, 5.8 mmol, 1.5 equiv.) dissolved in 5 mL of CH2Cl2 wasadded dropwise within 20 min. After the addition was finished, the ice-bath wasremoved, and the mixture was stirred at room temperature overnight. Thereaction was quenched with aqueous NH4Cl sat. (20 mL) and the organic phasewas separated. The aqueous phase was extracted with CH2Cl2 (3×10 mL). Afterthe organic phase was dried over anhydrous MgSO4, the solvent was removedby a rotary evaporator to give the crude product, which was purified by silica gelchromatography, using hexane:AcOEt (5:1) and (1:1) as eluents, to furnish thedesired ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methyl methanesulfonate (1.4 g, 98%yield) as a pale yellow oil.1H NMR (CDCl3, 400 MHz) δ: 5.92-5.91 (d, J= 4 Hz, 1H, CH), 4.95-4.94 (d, J= 4Hz, 1H, CH), 4.77-4.76 (d, J= 4 Hz, 1H, CH), 4.22-4.17 (m, 1H, CH), 4.13-4.12(m, 2H, CH2+CH), 4.00-3.97 (m, 1H, CH2), 3.07 (s, 3H, CH3), 1.48 (s, 3H, CH3),1.40 (s, 3H, CH3), 1.29 (s, 3H, CH3).13C APT NMR (CDCl3, 100 MHz) δ: 112.8, 109.7, 105.3, 83.8, 82.8, 79.9, 72.2,67.7, 38.1, 27.0, 26.7, 26.2, 25.3 |
98% | With triethylamine In dichloromethane at 0 - 20℃; | (3aR,5S,5aS,8aS,8bR)-5-(Azidomethyl)-2,2,7,7-tetramethyltetrahydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]pyran (N3-Prot-Gal): A solution of ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol (1 g, 3.8 mmol) and NEt3 (0.8mL, 5.8 mmol, 1.5 equiv.) in CH2Cl2 (20 mL) was stirring at room temperature 30min. Then it was cooled to 0C with an ice-bath, after which methanesulfonylchloride (MsCl) (0.5 mL, 5.8 mmol, 1.5 equiv.) dissolved in 5 mL of CH2Cl2 wasadded dropwise within 20 min. After the addition was finished, the ice-bath wasremoved, and the mixture was stirred at room temperature overnight. Thereaction was quenched with aqueous NH4Cl sat. (20 mL) and the organic phasewas separated. The aqueous phase was extracted with CH2Cl2 (3×10 mL). Afterthe organic phase was dried over anhydrous MgSO4, the solvent was removedby a rotary evaporator to give the crude product, which was purified by silica gelchromatography, using hexane:AcOEt (5:1) and (1:1) as eluents, to furnish thedesired ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methyl methanesulfonate (1.4 g, 98%yield) as a pale yellow oil.1H NMR (CDCl3, 400 MHz) δ: 5.92-5.91 (d, J= 4 Hz, 1H, CH), 4.95-4.94 (d, J= 4Hz, 1H, CH), 4.77-4.76 (d, J= 4 Hz, 1H, CH), 4.22-4.17 (m, 1H, CH), 4.13-4.12(m, 2H, CH2+CH), 4.00-3.97 (m, 1H, CH2), 3.07 (s, 3H, CH3), 1.48 (s, 3H, CH3),1.40 (s, 3H, CH3), 1.29 (s, 3H, CH3).13C APT NMR (CDCl3, 100 MHz) δ: 112.8, 109.7, 105.3, 83.8, 82.8, 79.9, 72.2,67.7, 38.1, 27.0, 26.7, 26.2, 25.3 |
89% | With pyridine at 20℃; for 2h; |
81% | With pyridine at 20℃; for 12h; | |
70% | With pyridine In dichloromethane at 20℃; | |
With pyridine | ||
With pyridine In dichloromethane at -10℃; Yield given; | ||
With triethylamine In dichloromethane at -40℃; for 0.5h; | ||
With triethylamine In dichloromethane for 2h; | 4. General Procedure for Sulfonation. 3-phenylpropyl methanesulfonate General procedure: In a 50 mL round-bottomed flask, 3-phenylpropan-1-ol (0.136 ml 1 mmol) and triethylamine (0.140 ml, 3 mmol) were added to DCM (25 ml). The methanesulfonyl chloride (0.090 ml, 1.2 mmol) was added slowly and allowed to stir for 2 hours, After the completion of reaction, Add water and reaction mixture was extracted with DCM. Organic layer washed with brine and dried over Na2SO4 and concentrated in vacuo. The title compound was isolated using column chromatography (0-20% EtOAc: hexane) gave 0.192 mg 90% colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; dmap at 20℃; for 0.1h; sonication; | |
99% | With dmap; triethylamine; 1-amino-3-(dimethylamino)propane In dichloromethane at 20℃; for 2h; | |
98% | With pyridine |
94% | With pyridine at 20 - 60℃; | |
92% | With pyridine In dichloromethane for 5h; | |
92% | Stage #1: ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol With pyridine; dmap In dichloromethane at 0℃; for 0.25h; Stage #2: p-toluenesulfonyl chloride In dichloromethane at 20℃; for 5h; | 3.5 Example 3 Synthesis of 3,4',5-tri-[N-(6-deoxy-galactosyl)-carbamoyl]-resveratrol (Resv(DGAL-C)3) (1,2:3,4-di-O-isopropylidene-6-O-(p-toluensulfonate))-D-galactopiranose (10; DIG-OTs) Example 3 Synthesis of 3,4',5-tri-[N-(6-deoxy-galactosyl)-carbamoyl]-resveratrol (Resv(DGAL-C)3) [0064] [0065] (1,2:3,4-di-O-isopropylidene-6-O-(p-toluensulfonate))-D-galactopiranose (10; DIG-OTs): Pyridine (3.1 mL, 38.4 mmol, 2 eq.) and DMAP (3.51 g, 28.7 mmol, 1.5 eq.) were added to a solution of 1,2:3,4-di-O-isopropylidene-D-galactopiranose (DIG-OH) (5.0 g, 19.2 mmol, 1 eq.) in CH2Cl2 (20 mL), and the mixture was stirred at 0 °C for 15 min. A solution of tosyl chloride (5.49 g, 28.7 mmol, 1.5 Eq) in CH2Cl2 (20 mL) was then added dropwise and the mixture was stirred at room temperature for 5 hours. After adding H2O (30 mL), the mixture was diluted in CH2Cl2 (150 mL) and washed with 0.5 N HCl (5 × 100 mL). The organic layer was dried over MgSO4 and filtered. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography using CH2Cl2:EtOAc 9:1 as eluent to afford 7.33 g of 10 (92 % yield). 1H-NMR (250 MHz, CDCl3) δ (ppm): 1.26 (s, 3H, -C-CH3), 1.30 (s, 3H, -C-CH3), 1.33 (s, 3H, -C-CH3), 1.49 (s, 3H, -C-CH3), 2.43 (s, 3H, Ar-CH3), 4.00-4.20 (m, 4H, H-4, H-5, H-6), 4.28 (dd, 1 H, 3J3-2 = 2.5 Hz, 3J3-4 = 2.5 Hz, H-3), 4.57 (dd, 1 H, 3J2-1 = 2.5 Hz, H-2), 5.44 (d, 1 H, 3J1-2 = 5 Hz, H-1), 7.32 (d, 2H, Ar-H, 3JH-H = 10 Hz), 7.80 (d, 2H, 3JH-H = 7.5 Hz); 13C-NMR (250 MHz, CDCl3) δ (ppm): 144.7, 132.7, 129.7, 128.0, 109.5, 108.9, 96.0, 70.4, 70.3, 70.3, 68.1, 65.8, 25.9, 25.7, 24.9, 24.3, 21.6; ESI-MS (ion trap): m/z 415 [M+H]+. |
91% | With dmap; triethylamine In dichloromethane at 40℃; | Preparation of compound 1 Compound (XII) is treated with tosylchloride in dichloromethane with triethylamine and dimethylamino pyridine to give the corresponding tosylate in 91% yield. The tosylate is treated with potassium phthalimide in DMSO with tetrabutylammonium iodide to give the corresponding phthalimide in approximately 100% yield. The phthalimide is treated with acetyl chloride in methanol to cause deprotection of the alcohols and formation of the methyl glycoside in 87% yield. The amine is then liberated by treating the phthalimide with hydrazine in ethanol. The amine is protected in the presence of acetic anhydride and pyridine and the alcohols are deprotected by treating the resulting compound with sodium methylate in methanol. The alcohol moieties are then protected with benzyl groups to yield compound 1. |
90% | With pyridine; dmap for 24h; | 4.1.4. 1,2:3,4-Di-O-isopropylidene-6-O-tosyl-α-D-galactopyranose (6) 0.52 g (1,99 mmol) 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose was dissolved in 2.0 mL pyridine. To this solution, catalytic amount DMAP and 0.46 g (2.41 mmol) p-toluenesulfonyl chloride were addedand stirred for 24 h. The reaction was monitored with TLC (Hexane/Ethyl acetate, 10:1). When TLC indicated the disappearance of thestarting materials, it was poured into ice-crash and extracted withCHCl3. The solvent was removed under reduced pressure and the residuewas purified by silica gel using Hexane/Ethyl acetate, (10:1) aseluent. 0.74 g product was obtained as white solid (90% yield). 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=8.3 Hz, 2H, Ar-H), 7.33 (d, J=8.0 Hz,2H, Ar-H), 5.45 (d, J = 4.9 Hz, 1H, H-1), 4.59 (dd, J = 7.9, 2.5 Hz, 1H,H-3), 4.29 (dd, J = 5.0, 2.5 Hz, 1H, H-2), 4.23-4.16 (m, 2H, H-4, H-5),4.13-4.00 (m, 2H, H-6a, H-6b), 2.43 (s, 3H, Ar-CH3), 1.49 (s, 3H, -CH3),1.34 (s, 3H, -CH3), 1.31 (s, 3H, -CH3), 1.27 (s, 3H, -CH3); 13C NMR(101 MHz, CDCl3) δ 144.8 (C-SO3), 132.9 (C-Ar) 129.7 (C-Ar), 128.1 (CAr),109.5 (C(CH3)2), 108.9 (C(CH3)2), 96.1 (C-1) 70.5 (C-4) 70.4 (C-3),70.3 (C-2), 68.2 (C-6), 65.9 (C-5), 25.9 (-CH3), 25.8 (-CH3), 24.9 (-CH3),24.3 (-CH3), 21.6 (Ar-CH3). |
89% | With pyridine In dichloromethane | |
88% | With dmap; triethylamine at 20℃; for 0.333333h; | |
84% | With pyridine 1) 0 - 5 deg C, 1 h; 2) room temperature, overnight; | |
84% | With pyridine at 0 - 20℃; for 12h; Inert atmosphere; | General procedure for synthesis of tosyl-sugars (2a-e) General procedure: The stirring solutions of compounds 1a-e in pyridine at 0 °C were added with p-toluene sulphonyl chloride under anhydrous condition. The reactions was allowed to come at room temperature and further stirred for 12 h. After completion (monitered by TLC), the reaction mixtures were in vacuo concentrated and the crude obtained were purified by flash column chromatography to afford tosyl-sugars 2a-e in good yields. |
81% | With pyridine In N,N-dimethyl-formamide | |
80% | With pyridine In acetonitrile for 6h; | |
76% | With pyridine at 20℃; for 20h; | |
75% | With pyridine Ambient temperature; | |
75% | With pyridine; dmap at 20℃; Cooling; | |
75% | With pyridine; dmap at 0 - 20℃; for 8h; | |
71% | With pyridine | |
65% | With pyridine In dichloromethane at 20℃; | |
With pyridine | ||
In pyridine Ambient temperature; | ||
In pyridine | ||
With pyridine at 20℃; for 1h; | ||
With pyridine In acetonitrile | ||
With triethylamine | ||
With dmap; triethylamine In dichloromethane at 40℃; | Preparation of compound 1 Compound (XII) is treated with tosylchloride in dichloromethane with triethylamine and dimethylamino pyridine to give the corresponding tosylate in 91 % yield. The tosylate is treated with potassium phthalimide in DMSO with tetrabutylammonium iodide to give the corresponding phthalimide in approximately 100% yield. The phthalimide is treated with acetyl chloride in methanol to cause deprotection of the alcohols and formation of the methyl glycoside in 87% yield. The amine is then liberated by treating the phthalimide with hydrazine in ethanol. The amine is protected in the presence of acetic anhydride and pyridine and the alcohols are deprotected by treating the resulting compound with sodium methylate in methanol. The alcohol moieties are then protected with benzyl groups to yield compound 1 . | |
With pyridine In dichloromethane | ||
With pyridine | ||
With pyridine at 25℃; | ||
With pyridine at 20℃; | ||
With pyridine at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With chromium(VI) oxide; periodic acid In water; acetonitrile at 0℃; for 0.25h; | |
97% | With 4-(benzyloxycarbonyl)-2,2,6,6-tetramethylpiperidine-1-oxyl; acetylcholine chloride; sodium hydrogencarbonate; pyridinium hydrobromide perbromide In TETRAHYDROPYRANE; water at 20℃; for 2h; | |
93% | With potassium hydroxide In water at 20℃; electrolysis at 0.4 A; |
92% | With 1-chloro-1λ3-benzo[d][1,2]iodaoxol-3(1H)-one; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In dichloromethane; water at 20℃; for 2.5h; | 3. General Procedure for the TEMPO/CBI Mediated Oxidation General procedure: To a vigorously stirred solution of 0.3 mmol monosaccharide alcohol in DCM-water (3 mL,2:1) was added TEMPO (0.03 mmol,0.1 equiv.) and 0.6 mmol CBI (2.0 equiv.). Stirring was allowed until TLC indicated complete conversion of the starting material. The reaction mixture was quenched by the addition of 10 ml Na2S2O3 solution (10% in H2O). The mixture was then extracted twice with EtOAc (10 ml) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Flash column chromatography using EtOAc/petroleum ether afforded the pure uronic acids. |
90% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hypochlorite; tetrabutylammomium bromide; sodium bromide In dichloromethane at 0 - 20℃; for 1h; Stage #2: With sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene In tetrahydrofuran; water; <i>tert</i>-butyl alcohol at 20℃; Further stages.; | |
86% | With ruthenium(IV) oxide; sodium hydrogencarbonate; sodium chloride In tetrachloromethane; water Ambient temperature; electrooxidation; | |
85% | With sodium hydroxide; potassium permanganate at 60℃; for 2h; | |
85% | With sodium hydroxide; potassium permanganate; tetrabutylammomium bromide In dichloromethane; water at 45℃; for 2h; | |
85% | With potassium permanganate; sodium hydroxide In water at 45℃; for 12.25h; | 1.2. Oxidation of DAGA, synthesis of 2 DAGA (3.66 g, 14 mmol) and 61mL of a solution containing 1.67 g of NaOH(42 mmol) were mixed together. When the sugar is solubilizing (ca. 30 minutes),dropwise and under stirring 57 mL of an aqueous solution of KMnO4 (58g/L, 21mmol, 0.37M) has been added during 15 minutes at ambient temperature.The solution was kept stirring at 45 °C for 12 hours. Brown MnO2 precipitatedwas filtered off and the solution washed whit EtOAc 2 x 50mL. H2SO41M was added until pH~2 was reached and the product was extracted in EtOAc3x50mL. The reunite organic layers were washed with distilled water 2x50mL. Thesolution was dried over Na2SO4 and solvent evaporatedunder vacuum. The resulting slurry was strongly sonicating with a solution ofHexane/EtOAc (9:1 v/v) to give a white solid that, washed abundantly withHexane/EtOAc 95:5,afford 2 as a brightwhite solid. Yield = 3.3g (85%). mp= 159-161 °C. 1HNMR (400 MHz, CDCl3) δ: 7.70 (bs, 1H); 5.63 (d, 1H); 4.58-4.72 (m,2H); 4.36-4.45 (m, 2H); 1.50 (s, 3H); 1.43 (s, 3H); 1.32 (m, 6H). |
82% | With ruthenium trichloride; sodium periodate; water In chloroform; acetonitrile | |
81% | With jones reagent In acetone for 6h; | |
81% | With chromium(VI) oxide In acetone at 20℃; for 5h; | |
81% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane; water at 19℃; for 18h; Inert atmosphere; | |
68% | With m-iodosylbenzoic acid In water; acetonitrile at 20℃; | |
65% | With ruthenium trichloride; sodium periodate In chloroform; acetonitrile for 20h; | |
65% | With sodium periodate In chloroform; water; acetonitrile for 20h; | l,2:3,4-Diisopropylidene-α-D-gaIacturonic acid (x); 1Ruthenium trichloride hydrate (14.1 mg, 0.07 mmol, 0.02 eq) and sodium periodate (2.98 g, 13.9 mmol, 4.5 eq) were added to a solution of l,2:3,4-diisopropylidene-α- D-galactose (800 mg, 3.07 mmol, 1.0 eq) in a mixture of CHCl3 (32 mL), water (48 mL) and MeCN (32 mL) and the reaction mixture vigorously stirred under Ar. After 20 h stirring, TLC (EtOAc) indicated consumption of SM (Rf 0.7) and formation of a major product (Rf 0.1). The reaction mixture was diluted with CH2Cl2 (70 mL) and the organic layer separated. The aqueous phase was extracted with CH2Cl2 (2 x 70 mL) and the combined organic extracts were dried (MgSO4) and concentrated to yield an oil. Purification by flash column chromatography on a short plug of silica gel (EtOAc) yielded x as a white solid (547 mg, 65%). m.p. 152-153 °C {lit.:3b m.p. 157 °C; lit:.3a m.p. 149-151 °C); [α]D20 = -86.0 (c = 1.0 in CHCl3) {lit.:3b [α]D = - 92.0 (c = 1.11 in CHCl3)); 1H NMR (300 MHz, CDCl3): δ = 1.36 (m, 6H; C(CH3)2), 1.46, 1.54 (2 x s, 2 x 3H; 2 x C(CH3)), 4.41 (dd, 3J(H,H) = 4.9 Hz, 3J(H,H) = 2.6 Hz, 1H; H-2), 4.47 (d, 3J(H,H) = 1.9 Hz, 1H; H-5), 4.62-4.71 (m, 2H; H-3, H-4), 5.66 (d, EPO 3J(H,H) = 4.9 Hz, 1H; H-I), 6.74 (br s, 1H; CO2H); MS (APCT): m/z (%): 273 (100) [M - H]- |
50% | With ruthenium(IV) oxide; potassium metaperiodate; acetone In water for 2.5h; Ambient temperature; | |
22% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With C29H44Cl2N2Ru; sodium hydroxide In water for 24h; Reflux; Stage #2: With hydrogenchloride In water | |
With potassium hydroxide; potassium permanganate | ||
With sodium periodate; N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In chloroform; water for 2h; Heating; | ||
With tetrapropylammonium perruthennate; 4-methylmorpholine N-oxide In acetonitrile at 20℃; for 2h; | ||
With potassium permanganate; sodium hydroxide In water for 12h; | ||
387 mg | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In water; acetonitrile at 20℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,4-diaza-bicyclo[2.2.2]octane In methanol Irradiation; direct evidence for electron transfer by examining flash photolysis; | ||
With sodium hydroxide In methanol Irradiation; Yield given; | ||
With 1,4-diaza-bicyclo[2.2.2]octane In methanol for 3h; Irradiation; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sulfuric acid; copper(II) sulphate | |
97% | With sulfuric acid; anhydrous zinc chloride at 20℃; for 16h; | |
95% | With nano n-propylsulfonated magnetic γ-Fe2O3 for 2h; Reflux; |
93% | With sulfuric acid for 4h; Ambient temperature; | |
93% | With sulfuric acid; anhydrous zinc chloride at 23℃; for 15h; Inert atmosphere; | |
92% | With sulfuric acid; anhydrous zinc chloride at 20℃; for 24h; Inert atmosphere; | |
92% | With sulfuric acid at 20℃; for 7h; | |
90% | With sulfuric acid; anhydrous zinc chloride at 20℃; for 3h; Cooling with ice; | 2 The reaction equation is as follows The galactose (1,10 g, 56 mmol) was dissolved in dry acetone (300 mL).Concentrated sulfuric acid (10 mL) was gradually added under ice bath.The ice bath was removed and stirred at room temperature for 3 h.After completion of the reaction, water (10 mL) and sodium carbonate (20 g, 189 mmol) were quenched.The reaction was terminated by sulfuric acid.Filtration using celite, concentration by rotary evaporation, purification by flash column (PE: EtOAc = 1:5 to 1:10).The saccharide compound 2 (13.0 g, 90%) was obtained. |
89% | With anhydrous zinc chloride | |
89% | With 4 A molecular sieve; toluene-4-sulfonic acid for 8h; Heating; | |
89% | With tetrapropylammonium tribromide at 20℃; for 8h; diastereoselective reaction; | |
85% | In acetonitrile at 20℃; for 10h; | |
85% | With bromo-dimethylsulfonium bromide at 20℃; for 10h; | |
85% | With sulfuric acid; copper(II) sulphate | |
83.5% | for 0.75h; Heating; | |
82% | With indium trifluoromethanesulfonate for 6h; Reflux; | |
81% | With sulfuric acid; anhydrous zinc chloride at 20℃; for 6h; | |
80% | With iodine at 20℃; for 24h; | |
78% | With sulfuric acid; copper(II) sulphate at 20℃; for 40h; | |
78% | With sulfuric acid for 3h; Heating; | |
77% | With iodine; toluene-4-sulfonic acid for 3h; Heating; | |
77.1% | With sulfuric acid; anhydrous zinc chloride at 20℃; for 4h; Inert atmosphere; | |
75% | With sulfuric acid; anhydrous zinc chloride | |
74.3% | With sulfuric acid; copper(II) sulphate | |
72% | With sulfuric acid; copper(II) sulphate at 20℃; for 24h; | |
72% | With sulfuric acid; copper(II) sulphate at 20℃; for 24h; | |
66% | With sulfuric acid; anhydrous zinc chloride | |
63% | With iodine for 3h; Reflux; | |
63.8% | With phosphoric acid; anhydrous zinc chloride at 20℃; Molecular sieve; | |
58% | With sulfuric acid; anhydrous zinc chloride | |
54% | With sulfuric acid; anhydrous zinc chloride for 5h; Ambient temperature; | |
51% | With K 10 clay at 50℃; for 72h; | |
51% | With sulfuric acid at 0 - 20℃; | (3aR,5S,5aS,8aS,8bR)-5-(Azidomethyl)-2,2,7,7-tetramethyltetrahydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]pyran (N3-Prot-Gal): In a round-bottom flask wasadded acetone (175 mL) and H2SO4 (5 mL) and the reaction mixture put at 0Cusing an ice-bath. D-Galactose (5 g) was added at small portions. The reactionmixture was left stirring at room temperature overnight. Under an ice-bath, thereaction mixture was neutralized with NaHCO3 sat. aq. solution until pH= 8-9. Theacetone was evaporated under reduced pressure and the aqueous phaseextracted with AcOEt (3×20 mL). The combined organic phases were washedwith brine solution, dried with MgSO4 and filtered. The solvent was evaporatedunder reduced pressure and the corresponding ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol5(3.51 g, 51% yield) was obtained as a white solid.1H NMR (CDCl3, 400 MHz) δ: 5.94-5.93 (m, 1H, CH), 4.53-4.52 (m, 1H, CH),4.32-4.31 (m, 1H, CH), 4.18-4.14 (m, 1H, CH2), 4.07-4.05 (m, 1H, CH2), 4.00-3.96 (m, 1H, CH), 3.40 (s, 1H, CH), 2.66 (s br, 1H, OH), 1.49 (s, 3H, CH3), 1.44(s, 3H, CH3), 1.35 (s, 3H, CH3), 1.31 (a, 3H, CH3).13C APT NMR (CDCl3, 100 MHz) δ: 111.9, 109.8, 105.4, 85.2, 81.2, 75.3, 73.6,67.8, 27.0, 26.9, 26.3, 25.3 |
51% | With sulfuric acid at 0 - 20℃; | (3aR,5S,5aS,8aS,8bR)-5-(Azidomethyl)-2,2,7,7-tetramethyltetrahydro-5Hbis([1,3]dioxolo)[4,5-b:4',5'-d]pyran (N3-Prot-Gal): In a round-bottom flask wasadded acetone (175 mL) and H2SO4 (5 mL) and the reaction mixture put at 0Cusing an ice-bath. D-Galactose (5 g) was added at small portions. The reactionmixture was left stirring at room temperature overnight. Under an ice-bath, thereaction mixture was neutralized with NaHCO3 sat. aq. solution until pH= 8-9. Theacetone was evaporated under reduced pressure and the aqueous phaseextracted with AcOEt (3×20 mL). The combined organic phases were washedwith brine solution, dried with MgSO4 and filtered. The solvent was evaporatedunder reduced pressure and the corresponding ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol5(3.51 g, 51% yield) was obtained as a white solid.1H NMR (CDCl3, 400 MHz) δ: 5.94-5.93 (m, 1H, CH), 4.53-4.52 (m, 1H, CH),4.32-4.31 (m, 1H, CH), 4.18-4.14 (m, 1H, CH2), 4.07-4.05 (m, 1H, CH2), 4.00-3.96 (m, 1H, CH), 3.40 (s, 1H, CH), 2.66 (s br, 1H, OH), 1.49 (s, 3H, CH3), 1.44(s, 3H, CH3), 1.35 (s, 3H, CH3), 1.31 (a, 3H, CH3).13C APT NMR (CDCl3, 100 MHz) δ: 111.9, 109.8, 105.4, 85.2, 81.2, 75.3, 73.6,67.8, 27.0, 26.9, 26.3, 25.3 |
In solid matrix | ||
With sulfuric acid; potassium carbonate 1.) sonicated, 75 min, 2.) sonicated, 30 min; var. reagents,; Yield given. Multistep reaction; | ||
With sulfuric acid; copper(II) sulphate | ||
With sulfuric acid; copper(II) sulphate | ||
Acidic conditions; | L-arabino-Hexos-5-ulose derivatives; Since substitution reactions of the primary hydroxyl functions of unprotected methyl glycosides with iodine work very well in the previously reported cases, Garegg's procedure is applied to methyl β-D-galactopyranoside 21 (Figure 10(a)). Unfortunately, analysis after standard acetylation shows, that 3,6-anhydro compound 23 is the exclusive reaction product. Formation of the desired 6-deoxy-6-iodo-compound 22 is not observed. As the hydroxyl function at C-3 has proven to be too reactive for direct reaction of the unprotected methyl glycoside 21, 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose 25 is prepared from D-galactose 24 by acid catalyzed reaction with acetone (Figure 10(b)). | |
With sulfuric acid at 0 - 20℃; | ||
With sulfuric acid; anhydrous zinc chloride at 20℃; for 24h; | ||
With sulfuric acid Green chemistry; | ||
With sulfuric acid; copper(II) sulphate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sulfuric acid; zinc(II) chloride Ambient temperature; | |
95% | With diphenylphosphinopolystyrene; iodine at 20℃; for 0.5h; | |
75.6% | With sulfuric acid; zinc(II) chloride at 20℃; for 4h; Inert atmosphere; | 2.3 Synthesis of 1,2;3,4-di-O-isopropylidene-D-galactose (IpGal) (2) D-galactose (7g, 38.8mmol) and anhydrous ZnCl2 (7.14g, 52.4mmol) were added to acetone (150mL) followed by H2SO4 (0.84mL) dropwise to the solution. It was allowed to react at room temperature for 4h under nitrogen atmosphere until the starting material completely disappeared. The solution was neutralized with saturated Na2CO3 solution after the reaction. After filtration, the solvent was removed under reduced pressure on a rotary evaporator. It was further extracted with diethyl etherand dried over anhydrous Na2SO4. The organic solvent was evaporated, and the product 2 was obtained as a pale-yellow viscous oil in 75.6% yield which was used for the next step without further purification. 1H NMR (400MHz, CDCl3) δ 5.57 (1H, d, J=5.2Hz, anomeric proton CH), 4.62 (1H, dd, J=8.0Hz, 2.4Hz, CH), 4.34 (1H, dd, J=5.2Hz, 2.4Hz, CH), 4.28 (1H, dd, J=8.0Hz, 1.7Hz, CH), 3.87-3.75 (3H, m, CH+CH2), 2.14 (1H, m, OH), 1.45 (3H, s, CH3), 1.33 (3H, s, CH3), 1.25 (6H, s, 2CH3); 13C NMR (100MHz, CDCl3) δ 108.9, 96.5, 71.8, 71.0, 70.8, 68.4, 62.5, 26.2, 26.1, 25.1, 24.5; FTIR (ν ν (cm-1) 3489 (br, O-H stretch), 2985, 2933 (C-H stretch), 1069 (C-O stretch). |
71% | With iodine | |
70% | With iodine at 20℃; for 18h; | |
54% | With sulfuric acid | |
With sulfuric acid | ||
Stage #1: acetone With sulfuric acid at 0 - 20℃; Inert atmosphere; Stage #2: α-D-galactopyranose for 18h; Inert atmosphere; | ||
With iodine | ||
With copper(ll) sulfate pentahydrate In sulfuric acid at 20℃; for 24h; | ||
With sulfuric acid; zinc(II) chloride | ||
With sulfuric acid; copper(II) sulfate | ||
With sulfuric acid; copper(II) sulfate at 25℃; | ||
With sulfuric acid at 0 - 20℃; | ||
With sulfuric acid at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With malonic acid; choline chloride; for 0.333333h;Reflux; Green chemistry; | General procedure: A mixture of the free sugar (2.5 g, 13.8 mmol), dry acetone (15 mL) and a DES(15 g) prepared from choline chloride (6.0 g) and malonic acid (9.0 g) was boiled under reflux for the required time (Table 2). After completion of the reaction as indicated by TLC analysis the resulting mixture was cooled to rt and extracted with ethyl acetate (3 × 20 mL). The combined ethyl acetate layer was evaporated under vacuum to afford the corresponding O-isopropylidene derivative. The DES was treated with (5.0 mL) water and dehydrated under vacuum on a rotary evaporator at 70C for 1 h. |
74% | With sulfonated polystyrene cation exchange resin CAT600; at 40℃; for 10h;Green chemistry; | General procedure: To asuspension of the substrate (2 mmol) in dry acetone (10 mL),CAT600 (100 mg) was added. Then the mixture was stirred at 40 C till the TLC (n-hexane-EtOAc 2:1) showed the completion of the reaction. The catalyst was separated by filtration, washed with acetone, dried, and reused for a consecutive run under the same reaction conditions. The filtrate was condensed to dry in vacuum, and the residue was dissolved in CH2Cl2 (10 mL) and washed with 3 × 5 mL brine.The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to afford the crude product. Then the desired pure product was obtained by recrystallization from n-hexane. While, the silica gel column chromatography was used if the product existed in the liquid form. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With bismuth(III) chloride In acetonitrile at 20℃; for 0.166667h; | |
95% | With iodine(I) bromide at 20℃; for 0.0833333h; chemoselective reaction; | |
93% | Stage #1: 1,2:3,4-di-O-isopropylidene-6-O-trityl-α-D-galactopyranose With indium(III) triflate for 3.5h; Milling; Stage #2: With water; sodium carbonate In ethyl acetate | 3 3.2. General procedure for the solvent-free detritylation General procedure: Method A-using a planetary ball mill: The tritylated compound(1 mmol; typically 563 mg for 4) and In(OTf)3 (141 mg, 0.25 mmol)were allowed to mix in a stainless steel (SS) jar (capacity, 50 mL)containing SS balls (10 numbers, 10 mm o.d.) for 3.5 h (TLC,EtOAc:Hex, 1:1 for 4) in a planetary ball mill (PM-100) at550 rpm. EtOAc was added to the reaction mixture and the solutionwas transferred to a separatory funnel (50 ml 3). It was thenwashed successively with aq Na2CO3 solution (10%, w/v, 50 ml 2)and water (50 ml), dried (Na2SO4), and concentrated underreduced pressure to afford the respective crude de-O-tritylated product. The crude product was purified by flash chromatography to free it from the by-product, TrOH (yield, 305 mg, 95.2%, for 5from 4). It was crystallized from diethyl ether-n-Hex to obtain analytically pure product. The spectral data were in accordance with the expected structure and in agreement with the literature values. Method B-using a vibratory ball mill: The tritylated compound(1 mmol; typically 563 mg for 4) and In(OTf)3 (141 mg, 0.25 mmol)were allowed to mix in a SS jar (capacity, 10 mL) containing SSballs (20 numbers, 3 mm o.d.) for 15 min (TLC, EtOAc/Hex, 1:1 inthe case of 4) in a vibratory ball mill (MM-400) at 30 Hz. Theworkup and isolation of the product were carried out as describedin Method A above. Yield, 308 mg, 96.2% for 5 from 4. |
90% | Stage #1: 1,2:3,4-di-O-isopropylidene-6-O-trityl-α-D-galactopyranose With carbon tetrabromide In methanol for 0.5h; Irradiation; Stage #2: In methanol at 20℃; for 8.5h; | |
90% | With carbon tetrabromide In methanol at 20℃; for 9h; Irradiation; | |
88% | With vanadyl trifluoromethanesulfonate In methanol; dichloromethane at 55℃; for 16h; | |
83% | With silica-supported H2SO4 In dichloromethane for 0.333333h; | |
79% | With chlorine In chloroform at 4℃; for 2.5h; | |
With triethyl ether; trityl tetrafluoroborate In dichloromethane | ||
With iron(III) chloride In dichloromethane for 1h; Ambient temperature; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With tetrabutylammomium bromide; sodium hydroxide In tetrahydrofuran; water at 0℃; for 0.666667h; Stage #2: epichlorohydrin In tetrahydrofuran; water at 0 - 30℃; for 24h; | 2.1.1.1. Preparation of 6-O-[(2R,S)-2,3-epoxypropyl]-1,2:3,4-di-O-isopropylidene-a-D-galactopyranose 7. To a solution of 1,2:3,4-di-Oisopropylidene-a-D-galactopyranose (18.4 mmol) in THF (25 mL)were added tetrabutylammonium bromide (5.3 mmol) and 40% w/w aqueous sodium hydroxide (40 mL). The mixture was magnetically stirred at 0 C for 40 min. Racemic epichlorohydrin(32.3 mmol) was slowly added to this mixture and stirring wascontinued at 0 C for 1 h, then at room temperature (30 C) for 23 h.The progress of the reaction was monitored by thin layer chromatography (1:1 EtOAc/hexane). After completion of the reaction, themixture was extracted twice with dichloromethane. The combinedorganic phases were dried over anhydrous magnesium sulphate,filtered and evaporated to dryness furnishing the compound 3 as abrown oil (27.08 mmol, 94% yield) which was used without furtherpurification. |
90% | Stage #1: epichlorohydrin With sodium hydroxide; tetrabutylammomium bromide In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose In tetrahydrofuran at 0 - 30℃; for 12h; | |
85% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Stage #2: epichlorohydrin In N,N-dimethyl-formamide; mineral oil at 0 - 80℃; for 16h; | 6.2. Synthesis of 6-O-(2,3-epoxypropyl)-1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (6) To a solution of 5 (5 g, 20 mmol) in anhydrous DMF (50 mL) maintained over an ice-bath was added NaH (1.5 g, 60% suspension in mineral oil) with stirring. After 15 min, epichlorohydrin (15 mL, 50 mol equiv) was added and the mixture was stirred at 80 °C overnight (16 h). After the completion of the reaction a few drops of methanol were added and the solvent was evaporated off under reduced pressure. The crude product was taken up in CH2Cl2 (200 mL) and was washed successively with water and brine. The organic layer was then dried over anhydrous sodium sulfate and was concentrated under reduced pressure. The crude product was purified by column chromatography to get pure 6 (5.15 g) as a colorless solid.CommentYield 85%; mp 67.0-68.5 °C; [α]D -77 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 5.54, 5.53 (2xd, J = 5Hz, 1H, H-1, R-, S-), 4.61, 4.59 (2xdd, J1 = 7.8 Hz, J2 = 2.4 Hz 1H, H-3, R-, S-), 4.31 (dd, J1 = 5 Hz, J2 = 2.4 Hz, 1H, H-2, R-, S-), 4.26, 4.24 (2xdd, J1 = 7.8 Hz, J2 = 1.9 Hz, 1H, H-4, R-, S-), 4.01-3.97 (m, 1H, H-5, R-, S-), 3.84-3.62 (m, 3H, H-6a, b and H-1'a, R-, S-), 3.50, 3.43 (2xdd, J1 = 11.6, J2 = 5.6, H-1'b, R-, S-), 3.20-3.15 (m, 1H, H-2' R-, S-), 2.79 (pt, J = 4.7, J = 4.4, 1H, H-3'a, R-, S-), 2.63, 2.60 (2xdd, J1 = 5 Hz, J2 = 2.6 Hz, 1H, H-3'b R-, S-), 1.54, 1.44 (2s, 2x3H, -C(CH3)2, R-, S-), 1.33 (s, 6H, -C(CH3)2, R-, S-); 13C NMR (100 MHz, CDCl3) δ 109.22, 108.53, 96.34, 72.25, 71.84, 2x71.15, 2x70.64, 2x70.58, 70.23, 70.06, 67.02, 66.69, 50.8, 50.7, 44.42, 44.3, 2x26.03, 2x25.94, 2x24.91, 2x24.42 (R-, S-); IR (Neat) νmax 2988, 2930, 1382, 1255, 1211, 1169, 1105, 1069, 1004 cm-1; MALDI-TOF MS: m/z calculated for C15H24O7: 316.347. Found: 339.407 [M + Na]+, 357.419 [M + K]+. |
85% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: epichlorohydrin In N,N-dimethyl-formamide at 80℃; Inert atmosphere; | 1.3. Functionalization of DAGA with epichlorohydrin, synthesis of 4 DAGA (5.3 g, 20 mmol) was dissolved in 16 mL of anhydrous DMF and NaH (0.954 g, 40 mmol) has been added at ambient temperature. After 15 minutes, (±)-epichlorohydrin (16mL, 18.9g, 20.5mmol) was added dropwise and the reaction was kept at 80 °C overnight under argon atmosphere. Then the mixture was diluted with DCM (100mL) and washed with water 3x50mL. The organic layer was dried with Na2SO4 and the solvent removed under vacuum. The crude product 4 was obtained by purification through a flash column chromatographic with Hexane/EtOAc 7/3 as a colorless solid. Yield =5.1g (85%). mp = 69-70°C. Rf 0.31 (Hexane/EtOAc 7/3). 1H NMR (400 MHz, CDCl3) δ 5.56 (m, 1H); 4.62 (d, 1H); 4.34 (m, 1H); 4.28 (m, 1H); 4.01 (m, 1H); 3.91 - 3.62 (m, 3H), 3.49 (m, 1H )3.19 (m, 1H); 2.81 (m, 1H); 2.64 (m, 1H); 1.56 (s, 1H), 1.46 (s, 1H), 1.35 (s, 1H). |
57% | With sodium hydride In tetrahydrofuran for 9h; Heating; | |
With sodium hydroxide In dimethyl sulfoxide; toluene | ||
Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Inert atmosphere; Stage #2: epichlorohydrin In N,N-dimethyl-formamide at 0 - 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 2-methoxyacetic acid; ytterbium(III) triflate In 1,2-dichloro-ethane at 53℃; for 36h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With pyridine In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at 0℃; for 0.666667h; Inert atmosphere; | |
96% | With pyridine In dichloromethane for 0.666667h; Inert atmosphere; | 7 The reaction was performed following general procedure B with diacetone D-galactopyranose 12 (1 g, 3.8 mmol, 1.0 eq.), pyridine (600 μL, 7.7 mmol, 2.0 eq.) and Tf2O (770 μL, 4.6 mmol, 1.2 eq.) in 20 mL of anhydrous DCM (0.19 M). The solution was stirred for 40 min under an argon atmosphere, after which, the crude mixture was subjected to column chromatography on silica (20:80 EtOAc:hexanes) to afford the triflate (1.43 g, 3.65 mmol, 96%). |
94% | With 2,6-dimethylpyridine In dichloromethane at -20 - 0℃; for 0.583333h; Inert atmosphere; | 4.4.1. 1,2:3,4-Di-O-isopropylidene-6-O-trifluoromethane-sulfonyl-α-d-galactopyranose (15) Under argon atmosphere, to a solution of 2,6-lutidine (1.1 mL, 4.5 mmol) in dry dichloromethane (35 mL) was added trifluoromethanesulfonic anhydride (Tf2O, 1.8 mL, 4.5 mmol) at -20 °C. After 5 min, a solution of 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (14, 780 mg, 3.0 mmol) in dichloromethane (40 mL) was added dropwise to the solution at -20 °C. The resulting solution was stirred at -20 °C for 5 min, and then at 0 °C for another 30 min. The mixture was poured into ice-cooled water and extracted with dichloromethane. The extract was condensed under reduced pressure to give a pale yellow oil (1.9 g), which on column chromatography (n-hexane/AcOEt, 20:1) gave title compound (15) as a colorless oil (1.10 g, 94%), inlMMLBox -44.6 (c 1.8, CHCl3). IR (neat): 1416, 1385, 1250, 1211, 1150, 1119, 1073, 1015 cm-1. 1H NMR (500 MHz, CDCl3) δ: 1.337/1.343/1.45/1.53 [each 3H, s, (CH3)2C], 4.11 (1H, ddd, J = 7.2, 4.7, 2.0, H-5), 4.25 (1H, dd, J = 8.0, 2.0, H-4), 4.36 (1H, dd, J = 5.0, 2.6, H-2), 4.58 (1H, dd, J = 10.5, 7.2, H-6a), 4.64 (1H, dd, J = 10.5, 4.7, H-6b), 4.66 (1H, dd, J = 8.0, 2.6, H-3), 5.54 (1H, d, J = 5.0, H-1). 13C NMR (125 MHz, CDCl3) δ: 24.4/24.8/25.8/25.9 [(CH3)2C], 66.0 (C-5), 70.2 (C-2), 70.4 (C-4), 70.6 (C-3), 74.6 (C-6), 96.1 (C-1), 109.1/110.1 [(CH3)2C], 118.6 (q, J = 318, CF3SO3-). FABMS m/z: 393 [M+H]+ (pos). |
93% | With 2,4,6-trimethyl-pyridine In dichloromethane at 20℃; for 4.5h; Schlenk technique; Inert atmosphere; | Intermediate 8: 1.2:3.4-di-O-isopropylidene-6-deoxy-α-D-galactopyranosyl-6-triflate The title compound was prepared according to M. Brackhagen, H. Boye and C. Vogel, J. Carbohydrate Chem. 2001 , 20(1), 31 -43.7.50 g (28.80 mmol, 1.0 eq.) 1 ,2:3,4-di-0-isopropylidene-a-D-galactopyranose (see M. Brackhagen, H. Boye and C. Vogel, J. Carbohydrate Chem. 2001 , 20(1), 31 -43) were mixed with 7.6 ml (6.98 g, 57.60 mmol, 2.0 eq.) dry 2,4,6-collidine. The mixture was dissolved in 300 ml dry DCM. 7.7 ml (13.00 g, 46.08 mmol, 1.6 eq.) trifluoromethanesulfonic anhydride were added dropwise over 30 minutes at ambient temperature to this solution. The reaction mixture turned deep yellow during the addition. Over a stirring period of 4 hours at ambient temperature, the mixture turned orange. The reaction was stopped by pouring the mixture onto 300 ml of iced water. The phases were separated and the water phase was extracted two times with 100 ml chloroform. The combined organic phases were washed two times with 250 ml of an aqueous 17% solution of potassium bisulfate. The organic phase was washed two times with 200 ml of iced water, two times with 250 ml of a saturated aqueous solution of sodium bicarbonate, once with 300 ml iced water and finally once with 300 ml of a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate. The solution was concentrated by reduced pressure. TLC showed the product at an Rf-value of Rf= 0.46 (n-hexane/ethyl acetate = 3/1 v/v). The crude product was purified by column chromatography over silica using an isocratic n-hexane/ethyl acetate = 3/1 mixture (v/v) as eluent, yielding 10.54 g (26.80 mmol, 93%) of the title compound as a yellow oil, which slowly solidified in the fridge.1H-NMR (400 MHz, CDCI3): d = 1 .34 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1 .53 (s, 3H, CH3), 4.12 (ddd,3JHH = 7.0 Hz,3JHH = 4.7 Hz,3JHH = 2.0 Hz, 1 H, CH5), 4.25 (dd,JHH = 7.8 Hz,3JHH = 2.0 Hz, 1 H, CH4), 4.36 (dd,3JHH = 5.0 Hz, JHH= 2.6 Hz, 1 H, CH2), 4.55 - 4.68 (m, 3H, CH3, CH62), 5.54 (d,3JHH = 4.9 Hz, 1 H, CH1) ppm.13C{1H}-NMR (100 MHz, CDCI3): d = 24.4 (s, C9'11H3), 24.8 (s, C9'11H3), 25.8 (s, C9'11H3), 25.9(s, C9'11H3), 66.1 (s, C5H), 70.2 (s, C2H), 70.4 (s, C4H), 70.6 (s, C3H), 74.6 (s, C6H2), 96.1 (s, C1H), 109.1 (s, C8’10(CH3)2), 1 10.1 (s, C8’10(CH3)2), 1 18.6 (q,1JCF= 320 Hz, C7F3) ppm. |
93% | With 2,4,6-trimethyl-pyridine In dichloromethane at 20℃; for 4.5h; Inert atmosphere; | 14 Ex 14: l,2:3,4-Di-0-isopropylidene-6-deoxy-a-D-galactopyranosyl-6-triflate (14) The compound is prepared according to the literature [M. Brackhagen, H. Boye, C. Vogel, J. Carbohydrate Chem. 20, 31 (2001).]. (0107) The reaction is performed under nitrogen. (0108) 7.50 g (28.80 mmol, 1.0 eq.) l,2:3,4-di-0-isopropylidene-a-D-galactopyranose are mixed with 7.6 ml (6.98 g, 57.60 mmol, 2.0 eq.) dry 2,4,6-collidine. The mixture is dissolved in 300 ml dry DCM. 7.7 ml (13.00 g, 46.08 mmol, 1.6 eq.) trifluoromethanesulfonic anhydride are added dropwise over 30 minutes at ambient temperature to this solution. The reaction mixture turns deep yellow during the addition. Over a stirring period of 4 hours at ambient temperature, the mixture turns orange. The reaction is quenched by pouring it onto 300 ml of iced water. The phases are separated and the water phase is extracted two times with 100 ml chloroform. The combined organic phases are washed two times with 250 ml of an aqueous 17% KHSO4 solution. The organic phase is washed two times with 200 ml of iced water, two times with 250 ml of a saturated NaHC03 solution, once with 300 ml iced water and finally once with 300 ml of a saturated NaCI solution. The organic phase is dried over Na2S04. The solution is concentrated by reduced pressure. TLC shows the product at an Rf-value of Rf = 0.46 (n-hexane/ethyl acetate = 3/1 v/v). The crude product is purified by column chromatography over silica using an isocratic n-hexane/ethyl acetate = 3/lmixture (v/v) as eluent, yielding 10.54 g (26.80 mmol, 93%) of a yellow oil, which slowly solidifies in the fridge. (0109) l,2:3,4-Di-0-isopropylidene-6-deoxy-a-D-galactopyranosyl-6-triflate is a yellow, thick oil which is stable under dry nitrogen. It degrades slowly in moist air. It is stored under dry nitrogen at minus twenty degrees. It reacts readily with nucleophiles like thiolates, amines, alcoholates. (0110) FontWeight="Bold" FontSize="10" H-NM R (400 MHz, CDCI3) : d = 1.34 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.53 (s, 3H, CH3), 4.12 (ddd, 37HH = 7.0 HZ, 3JHH = 4.7 HZ, 37HH = 2.0 HZ, lH, CH5), 4.25 (dd, JHH = 7.8 Hz, I/HH = 2.0 Hz, 1H, CH4), 4.36 (dd, 37HH = 5.0 HZ, 7HH = 2.6 Hz, 1H, CH2), 4.55 - 4.68 (m, 3H, CH3, CH62), 5.54 (d, 3 HH = 4.9 Hz, 1H, CH1) ppm. (0111) 13C{1H}-NMR (100 MHz, CDCI3): d = 24.4 (s, C9' H3), 24.8 (s, C9' H3), 25.8 (s, C9' H3), 25.9 (s, C9,11H3), 66.1 (s, C5H), 70.2 (s, C2H), 70.4 (s, C4H), 70.6 (s, C3H), 74.6 (s, C6H2), 96.1 (s, ^H), 109.1 (s, C8'10(CH3)2), 110.1 (s, C8'10(CH3)2), 118.6 (q, ^CF = 320 Hz, C7F3) ppm. |
93% | With 2,4,6-trimethyl-pyridine In dichloromethane at 20℃; for 4.5h; | Intermediate 7: 1,2:3,4-Di-0-isopropylidene-6-deoxy-a-D-qalactopyranosyl-6- triflate (CAS 71001-09-7) The title compound was prepared according to M. Brackhagen, H. Boye and C. Vogel, J. Carbohydrate Chem. 2001 , 20(1), 31 -43. (0705) 7.50 g (28.80 mmol, 1.0 eq.) 1 ,2:3,4-di-0-isopropylidene-a-D-galactopyranose (see M. Brackhagen, H. Boye and C. Vogel, J. Carbohydrate Chem. 2001 , 20(1), 31 -43) were mixed with 7.6 ml (6.98 g, 57.60 mmol, 2.0 eq.) dry 2,4,6-collidine. The mixture was dissolved in 300 ml dry (0706) DCM. 7.7 ml (13.00 g, 46.08 mmol, 1.6 eq.) trifluoromethanesulfonic anhydride were added dropwise over 30 minutes at ambient temperature to this solution. The reaction mixture turned deep yellow during the addition. Over a stirring period of 4 hours at ambient temperature, the mixture turned orange. The reaction was stopped by pouring the mixture onto 300 ml of iced water. The phases were separated and the water phase was extracted two times with 100 ml chloroform. The combined organic phases were washed two times with 250 ml of an aqueous 17% solution of potassium bisulfate. The organic phase was washed two times with 200 ml of iced water, two times with 250 ml of a saturated aqueous solution of sodium bicarbonate, once with 300 ml iced water and finally once with 300 ml of a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate. The solution was concentrated by reduced pressure. TLC showed the product at an Rf-value of Rf = 0.46 (n- hexane/ethyl acetate = 3/1 v/v). The crude product was purified by column chromatography over silica using an isocratic n-hexane/ethyl acetate = 3/1 mixture (v/v) as eluent, yielding 10.54 g (26.80 mmol, 93%) of the title compound as a yellow oil, which slowly solidified in the fridge. (0707) 1H-NMR (400 MHz, CDCI3): d = 1.34 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.45 (s, 3H, CH3), 1.53 (s, 3H, CH3), 4.12 (ddd, 3JHH = 7.0 Hz, 3JHH = 4.7 Hz, 3JHH = 2.0 Hz, 1H, CH5), 4.25 (dd, (0708) JHH = 7.8 Hz, 3JHH = 2.0 Hz, 1H, CH4), 4.36 (dd, 3JHH = 5.0 Hz, JHH = 2.6 Hz, 1 H, CH2), 4.55 - 4.68 (m, 3H, CH3, CH62), 5.54 (d, 3JHH = 4.9 Hz, 1H, CH1) ppm. (0709) 13C{1H}-NMR (100 MHz, CDCI3): d = 24.4 (s, C9'11H3), 24.8 (s, C9'11H3), 25.8 (s, C9'11H3), 25.9 (s, C9'11H3), 66.1 (s, C5H), 70.2 (s, C2H), 70.4 (s, C4H), 70.6 (s, C3H), 74.6 (s, C6H2), 96.1 (s, C1H), 109.1 (s, C8’10(CH3)2), 1 10.1 (s, C8’10(CH3)2), 1 18.6 (q, 1JCF = 320 Hz, C7F3) ppm. |
93% | With 2,4,6-trimethyl-pyridine In dichloromethane at 20℃; for 4h; Schlenk technique; Inert atmosphere; | |
90% | With collidine In dichloromethane at 20℃; for 2h; | |
83% | With 2,6-dimethylpyridine In dichloromethane | |
82% | With pyridine In dichloromethane at 0 - 20℃; | |
76% | With pyridine In dichloromethane at 0 - 23℃; for 2.5h; | |
69% | With 2,3,4-O-(PhCO)3-1,6-dideoxy-1,6-[S(=O)]-β-D-glucopyranose In diethyl ether at 0℃; for 0.0833333h; | |
68% | With potassium carbonate In dichloromethane at -20℃; for 6h; | |
With pyridine In dichloromethane at -15℃; for 0.333333h; | ||
Yield given. Multistep reaction; | ||
With pyridine In dichloromethane | ||
With pyridine In dichloromethane for 0.166667h; | ||
With pyridine In dichloromethane at -30℃; Yield given; | ||
With pyridine In dichloromethane at 0℃; for 0.166667h; | ||
With pyridine In dichloromethane at 0℃; for 0.5h; Inert atmosphere; | ||
With pyridine In dichloromethane at 0℃; for 1h; Inert atmosphere; | 3.2.9.15. 6-Azido-6-deoxy-1,2,3,4-di-O-isopropylidene-α-Dgalactopyranose(35). To a solution of 34 (0.91 g, 3.5 mmol) in dryCH2Cl2 (15 mL) and dry pyridine (6 mL), stirred at 0 °C under N2, was added triflic anhydride (1.2 mL, 7.1 mmol, 2 equiv) dropwise, and thereaction mixture was stirred for 1 h under the same conditions. Aftercompletion, the mixture was diluted with DCM (70 mL), washed withcold saturated NaHCO3 (40 mL) and cold brine (40 mL), dried overMgSO4, filtered and evaporated, co-evaporated twice with toluene, anddried under vacuum for 1 h to afford a brownish foam. To this foamwere added dry DMF (10 mL) and NaN3 (0.7 g, 10.8 mmol, 3 equiv),and the reaction mixture stirred vigorously for 1.5 h at roomtemperature under N2. The reaction mixture was diluted with EtOAc(100 mL), washed with water (2×50 mL) and brine (50 mL), driedover MgSO4, filtered and concentrated. The resulting residue waspurified by flash column chromatography (9:1, petroleum ether-EtOAc with 1% Et3N) to afford 35 as a colorless syrup (748 mg,75%). 1H NMR (CDCl3, 400 MHz): δ 5.53 (d, 1H, J1,2 5.2 Hz, H-1),4.62 (dd, 1H, J3,4 7.6 Hz, H-3), 4.32 (dd, 1H, J2,3 2.4 Hz, H-2), 4.18 (dd,1H, J4,5 2.0 Hz, H-4), 3.90 (m, 1H, H-5), 3.50 (dd, 1H, J5,6a 8.0 Hz,J6a,6b 12.8 Hz, H-6a), 3.35 (dd, 1H, J5,6b 5.4 Hz, H-6b), 1.54 (s, 3H,CH3C), 1.45 (s, 3H, CH3C), 1.333 (s, 3H, CH3C), 1.327 (s, 3H, CH3C).13C NMR (CDCl3, 75 MHz): δ 109.7, 108.9, 96.5, 71.3, 70.9, 70.5, 67.1,50.8, 26.14, 26.05, 25.0, 24.5. ESI-HRMS: Calcd for[C12H19N3O5 + Na]+: 308.1222; Found m/z: 308.1227. | |
With pyridine In dichloromethane at 0 - 20℃; for 0.666667h; | 109.I Step I; Scheme: Pyridine (0.53 mL, 0.007 mol) is added to a stirred solution of l,2:3,4-di-O-isopropylidene-D- galactopyranose( 1.0 g, 0.004 mol) in dichloromethane (10 mL) at room temperature. Reaction mixture is cooled to 0-50C, trifluoromethanesulphonic anhydride (0.76 mL, 0.005 mol) is introduced drop wise over a period of 10 minutes and then stirred at room temperature for 30 minutes. D. M. water (10 mL) is added, organic layer is separated and aqueous layer is extracted with dichloromethane (2x10 mL). Combined dichloromethane layer is washed with brine solution (1x10 mL) and dried over anhydrous sodium sulphate. Removal of dichloromethane under reduced pressure furnish triflate derivative of l,2:3,4-di-O- isopropylidene-D-galactopyranose which is used directly for the next step.N,N-Diisopropylethylamirie (1.66 mL, 0.010 mol) is added to a stirred solution of (4-methyl piperidin-4- yl)carbamic acid benzyl ester (1.31 g, 0.005 mol) in acetonitrile (8 mL) at room temperature and stirred for 15 minutes. A solution of the triflate derivative of l,2:3,4-di-O-isopropylidene-D-galactopyranose in acetronitrile (2 mL) is introduced and heated at 65-700C for 2 hrs. Reaction mixture is concentrated under reduced pressure, D. M. water (10 mL) is added and exctrated with ethyl acetate (3x15 mL). Combined ethyl acetate layer is washed with brine solution (1x10 mL) and dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gives viscous liquid which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate) to get l,2:3,4-di-O-isopropylidene-6-[piperidin- {(4-benzyloxycarbonyIamino)-4-methyl}-l-yl]-6-deoxy-D-galactopyranose. | |
With pyridine In dichloromethane at -20℃; for 1.33333h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride In tetrahydrofuran | |
96% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 25℃; for 18h; Inert atmosphere; | |
94% | With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In water; toluene at 100℃; for 3h; | 1,2;3,4-Di-O-isopropylidene-6-O-benzyl-D-galactose 10: To a solution of commercial 1,2;3,4-di-O-isopropylidene-d-galactose (Acros, αD-56.8° c 5.9 CHCl3) (20.8 g; 80 mmol) in toluene (100 mL) was added KOH (30 g; crushed in a mortar under protective layer of hexane), benzyl bromide (16.6 mL; 24 g; 140 mmol), and Bu4NHSO4 (0.5 g). This mixture was magnetically stirred on an oil bath at ca 100°. After ca 30 min most of KOH formed lumps. Water (30 mL) was added to solubilize KOH and to change a mode of catalysis from solid-liquid to liquid-liquid. After a total time of 3 h, TLC showed that all substrate Rf 0.21 formed the product Rf 0.64 (hexane-EtOAc 3:1). Organic phase was separated and washed with dil. HCl, and twice with water. Evaporation and chromatography (gradient hexane-EtOAc 20:1→20:2→20:3) furnished 10 as an oil, (26.3 g; 94%) αD -68° (c 6.7; CHCl3), αD was not mentioned in Ref. 45. 1H(300 MHz, CDCl3): 7.36-7.25(H aromatic), 5.54 (d, J = 5.0 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H), 4.60(dd, J = 2.4 Hz, 7.8 Hz, 1H), 4.55(d, J = 12.1 Hz, 1H), 4.31(dd, J = 2.3 Hz, 5.0 Hz, 1H), 4.27(dd, J = 2.0 Hz, 8.0 Hz, 1H), 4.01(dt, J = 1.7 Hz, 6.1 Hz, 6.1 Hz, 1H), 3.70(dd, J = 5.9 Hz, 10.0 Hz, 1H), 3.61 (dd, J = 6.7 Hz, 10.0 Hz, 1H), 1.54, 1.44, 1.34, 1.33(four s, 12H total). 13C (75 MHz, CDCl3): 138.56, 128.51, 127.91, 127.74, 109.43, 108.74, 96.59, 73.52, 71.40, 70.88, 70.83, 69.10, 67.11, 26.31, 26.20, 25.15, 24.66. |
87% | With sodium hydride In N,N-dimethyl-formamide for 24h; | |
86% | With potassium hydroxide; 18-crown-6 ether In tetrahydrofuran at 20℃; for 12h; | |
69% | With potassium hydroxide; 18-crown-6 ether In tetrahydrofuran at 20℃; for 0.666667h; | |
With potassium hydroxide In toluene at 100℃; for 5h; Yield given; | ||
With sodium hydride | ||
With sodium hydride In N,N-dimethyl-formamide | ||
34.2 g | With sodium hydride In N,N-dimethyl-formamide Ambient temperature; | |
With tetra-(n-butyl)ammonium iodide; sodium hydride In N,N-dimethyl-formamide Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Inert atmosphere; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 2.5h; Enzymatic reaction; Inert atmosphere; | 2 1,2;3,4-di-O-isopropylidene-6-O-propargyl-D-galactopyranose (Scheme 2.2) galactopyranose (Scheme 2.2) . 10 a solution containing 0.27g (1.Ommol) 1 in 5m1 dry DMF (under an argon atmosphere) was added 75mg (2.0 equiv.) NaH at 0°C. Ihe resulting mixture was stirred for 20 mm. and l7lil (1.5 equiv.) of propargyl bromide was added. After 20 mm. the mixture was brought to RI and stirred for an additional 2.5 hours. The mixture was cooled on an ice bath and quenched by the addition of MeOH (0.5m1) . The reaction mixture was brought to RT, diluted with 20m1 CH2C12 and washed with20m1 saturated NaHCO3-solution. The water phase was extractedwith 20m1 CH2C12. The combined organic phase was washed with 20m1H2Q, dried over Na2SO4, filtered and concentrated. The crudeproduct was purified by column chromatography (Hexane:EtOAc 2:1)to give (Scheme 2.2) as a white solid (0.27g. 91%) . TLC: Rf =0.77 (Hexane:EtOAc 1:1) . H NMR (600 MHz, CDC13, 22°C) : 6 = 5.54(d, 1 H, J = 5.1 Hz, H-i), 4.61 (dd, 1 H, J3,2 = 2.5, J3,4 = 8.0Hz, H-3), 4.32 (dd, 1 H, H-2), 4.26 (dd, 1 H, J4,5 = 1.9 Hz, H-4),4.25 (dd, 1 H, JCH2a,CH = 2.4, JCH2a,CH2b = -15.9 Hz, CH2aCCH), 4.20(dd, 1 H, JCH2b,CH = 2.4 Hz, CH2bCCH) , 4.00 (ddd, 1 H, J5,6a = 5.4,J5,6b = 7.1 Hz, H-5), 3.78 (dd, 1 H, J6a,6b = -10.1 Hz, H-6a) , 3.67(dd, 1 H, H-6b), 2.43 (dd, 1 H, CH2CCH), 1.55, 1.45, 1.34 and1.33 (each s, each 3 H, 02C(CH3)2) ppm. |
93% | With potassium hydroxide In acetonitrile at 20℃; for 21h; Inert atmosphere; | |
91% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 3h; |
86% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 0℃; for 0.25h; Stage #2: propargyl bromide In N,N-dimethyl-formamide; paraffin oil at 20℃; for 8h; | |
85% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide; paraffin oil Inert atmosphere; Stage #2: propargyl bromide With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide; paraffin oil at 0℃; Inert atmosphere; | |
83% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; | |
73% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 12.5h; | |
70% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In tetrahydrofuran for 2h; Heating; Stage #2: propargyl bromide With tetraethylammonium iodide In tetrahydrofuran; toluene at 20℃; for 16h; | |
67% | With potassium hydroxide In acetonitrile at 20℃; for 24h; | |
With tetra-(n-butyl)ammonium iodide; sodium hydride 1.) THF, reflux, 90 min; 2.) THF, toluene, r.t., 150 min; Yield given. Multistep reaction; | ||
With sodium hydride | ||
With sodium hydride In tetrahydrofuran | ||
Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sodium hydride In N,N-dimethyl-formamide at 0℃; Inert atmosphere; Stage #2: propargyl bromide With tetrabutylammomium bromide In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | ||
With tetrabutylammomium bromide; sodium hydride In N,N-dimethyl-formamide at 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.4% | With 1H-imidazole; iodine; triphenylphosphine In toluene; acetonitrile at 90℃; for 24h; | |
97% | With 1H-imidazole; iodine; triphenylphosphine In toluene at 70℃; for 15h; | |
95% | With 1H-imidazole; iodine; chloro-diphenylphosphine In toluene for 0.0833333h; Ambient temperature; |
94% | With 1H-imidazole; iodine; triphenylphosphine In toluene for 4h; Heating; | |
94% | With 1H-imidazole; iodine; triphenylphosphine In toluene at 80℃; for 10h; | |
93% | With 1H-imidazole; iodine; triphenylphosphine In toluene at 80℃; Inert atmosphere; | |
90% | With 1H-imidazole; iodine; triphenylphosphine In toluene Heating; | |
90.8% | With 1H-imidazole; iodine; triphenylphosphine In toluene at 70℃; for 2h; | |
86% | With 1H-imidazole; iodine; triphenylphosphine In toluene at 20 - 80℃; for 3h; | |
85% | With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 90℃; for 1h; Inert atmosphere; | 4.7. Methyl 6-deoxy-6-iodo-α-d-galactopyranoside (12) To a mixture of 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose[57] and [58] (2.6 g, 10 mmol), PPh3 (3.93 g, 15 mmol) and imidazole (1.36 g, 20 mmol) in dry THF (100 mL), was added iodine (3.81 g, 15 mmol) in small portions. After refluxing for 1 h, the reaction mixture was cooled to room temperature, and quenched by the addition of 10% aq Na2S2O4. The product was extracted with EtOAc, and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Distillation of the residue gave 6-deoxy-6-iodo-1,2:3,4-di-O-isopropylidene-α-d-galactopyranose as a yellow oil (3.14 g, 8.48 mmol, 85%). |
85% | With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran for 1h; Reflux; | Methyl 6-deoxy-6-iodo-α-D-galactopyranose (6). To a mixture of1,2:3,4-O-di-isopropyl-α-D-galactopyanose (2.6 g, 10 mmol), PPh3 (3.93 g,15 mmol) and imidazole (1.36 g, 20 mmol) in dry THF (100 mL), was addediodine (3.81 g, 15 mmol) in small portions. After refluxing for 1h, thereaction mixture was cooled to rt, and quenched by the addition of 10% aq. Na2S2O4. Theproduct was extracted with EtOAc, and the combined organic layers were washed with brine,dried (MgSO4), filtered and concentrated. Distillation of the residue gave 6-deoxy-6-iodo-1,2:3,4-O-di-isopropyl-α-D-galactopyanose as a yellow oil (3.14 g, 8.48 mmol, 85%). |
84% | With benzimidazole; iodine; triphenylphosphine In toluene | |
82% | With 1H-imidazole; iodine; triphenylphosphine In toluene for 0.25h; Heating; | |
80% | With 1H-imidazole; iodine; triphenylphosphine In toluene for 24h; Heating; | |
78% | With 1H-imidazole; iodine; triphenylphosphine In toluene Heating; | |
70% | Stage #1: ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol With 1H-imidazole; triphenylphosphine In toluene at 60℃; for 0.5h; Stage #2: With iodine at 56 - 62℃; for 3h; | |
With pyridine; trifluoromethylsulfonic anhydride; N,N,N-tributyl-1-butanaminium iodide 1.) CH2Cl2, 2.) benzene, reflux; Yield given. Multistep reaction; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene; acetonitrile other solvent and reagents; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene Heating; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene Heating; | ||
With 1H-imidazole; triphenylphosphine; sodium iodide In toluene Heating; | ||
With 1H-imidazole; iodine; triphenylphosphine | ||
Multi-step reaction with 2 steps 1: 82 percent / sulfuryl chloride / dimethylformamide / 1 h / Ambient temperature 2: 81 percent / sodium iodide / dimethylformamide / 6 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 82 percent / sulfuryl chloride / dimethylformamide / 1 h / Ambient temperature 2: 78 percent / imidazole / 8 h | ||
Multi-step reaction with 2 steps 1: 1.) sodium hydride / 1.) DMF, RT, 30 min, 2.) DMF, -40 deg C, 30 min 2: 81 percent / sodium iodide / dimethylformamide / 6 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 1.) sodium hydride / 1.) DMF, RT, 30 min, 2.) DMF, -40 deg C, 30 min 2: 78 percent / imidazole / 8 h | ||
Multi-step reaction with 2 steps 2: 94 percent / tetrabutylammoninum iodide / benzene / 2 h / Heating | ||
Multi-step reaction with 2 steps 1: SO2Cl2 / 1.) DMF, -40 deg C - 25 deg C, 2.) 1-24 h, 25 deg C 2: 81 percent / NaI / dimethylformamide / 6 h / 25 °C | ||
Multi-step reaction with 2 steps 1: pyridine 2: acetone; sodium iodide | ||
Now the corresponding 6-deoxy-6-iodo-compound 26 can be synthesized with the Garegg method. Elimination with silver(I)fluoride in pyridine proves to be very slow and more than 4 equivalents of this expensive reagent are required during a reaction time of 5 days. This synthetic step furnishes not only the desired enol ether 27, but also the corresponding 6-deoxy-6-fluoxo-compound 28, the latter in a yield of about 10% by conversion. Epoxidation of 27 with 3-chloroperbenzoic acid in CH2Cl2 in the presence of aqueous sodium bicarbonate furnishes the unstable oxirane 29, which turns out to be too reactive to be purified by chromatographic means. Therefore, the crude product is treated with aqueous trifluoroacetic acid for deprotection and simultaneous epoxide hydrolysis. The resulting L-arabino-hexos-5-ulose 30, akin to all the other previously described ketoaldoses, exists in various tautomeric forms. In order to establish the formation of the postulated reaction product, crude ketoaldose 30 is subjected to a reductive amination procedure using aqueous ammonia, catalytic amounts of Pearlman's catalyst and hydrogen at ambient pressure. The desired iminosugar 1-deoxygalactonojirimycin 31 can be isolated in an overall yield of 24% over the last three synthetic steps. The formation of the corresponding L-altro-configured iminosugar is not observed. | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene for 4h; Reflux; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene at 80℃; for 24h; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene | ||
Multi-step reaction with 2 steps 1: 4-dimethylaminopyridine; triethylamine / 0.33 h / 20 °C 2: potassium iodide; N,N,N-tributyl-1-butanaminium iodide / N,N-dimethyl-formamide / 22 h / 120 °C | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene | ||
18.9 g | With 1H-imidazole; iodine; triphenylphosphine In toluene; acetonitrile at 90℃; for 2h; Cooling with ice; | |
With 1H-imidazole; iodine; triphenylphosphine In toluene at 70℃; | ||
With 1H-imidazole; iodine; triphenylphosphine In toluene; acetonitrile at 80℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In ethyl acetate for 4h; Heating; | |
99% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; polymer-bound {NMe3(1+)*Br(OAc)2(1-)} In dichloromethane at 40℃; for 24h; | |
99% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; bisacetoxybromate(I) resin In dichloromethane at 40℃; for 24h; |
98% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; | |
98% | With Dess-Martin periodane In dichloromethane at 20℃; for 1h; Inert atmosphere; | |
97% | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; Amberlite IRA 900 bisacetoxybromate(I) In dichloromethane at 40℃; for 24h; | |
97% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -55℃; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at -30℃; Inert atmosphere; | |
96% | ||
96% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; | |
95% | With chromium trioxide pyridine In dichloromethane | |
90% | With nicotinium dicromate In pyridine; benzene at 80℃; for 0.333333h; oxidant/pyridine = 1/2, oxidant/sugar = 2/1; | |
89% | With 2,2,6,6-tetramethyl-piperidine-N-oxyl; sodium hydrogencarbonate; potassium bromide In dichloromethane at 0℃; for 0.416667h; | |
88% | In dimethyl sulfoxide oxydation; | |
88% | With Dess-Martin periodane | |
84% | With Dess-Martin periodane In dichloromethane for 1h; | |
82% | With dipyridinium dichromate; sodium acetate In dichloromethane at 20℃; for 6h; Molecular sieve; | |
79% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With oxalyl dichloride; dimethyl sulfoxide In tetrahydrofuran; dichloromethane at -60℃; for 0.25h; Stage #2: With triethylamine In tetrahydrofuran; dichloromethane at -60 - 20℃; | |
79% | With 2-Picolinic acid; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; manganese (II) nitrate tetrahydrate; acetic acid at 25℃; | |
74% | With pyridine hydrochloride; oxalic acid; dicyclohexyl-carbodiimide In methanol; dimethyl sulfoxide at 25℃; for 96h; | |
74% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; for 4h; stereoselective reaction; | |
74% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; | 1,2;3,4-di-O-isopropylidene-α- D -galacto-1,6-dialdo-hexopyranose (13) A mixture of 1,2:3,4-diisopropylidene-α- D -galactopyranose (12) (14.99 g, 57.6 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy TEMPO (900 mg, 5.76 mmol, 10 mol %) was stirred in dichloromethane (62 mL, anhydrous) at room temperature as diacetoxyiodobenzene (BAIB) (20.42 g, 63.4 mmol, 1.1 eq) was added to the reaction mixture. After several minutes of stirring, all the BAIB dissolved in the clear, bright orange reaction mixture. After stirring 4 h the reaction mixture was diluted with dichloromethane (35 mL), washed with saturated aq Na2S2O3 (100 mL), and the aqueous layer was extracted with dichloromethane (4*50 mL). The combined organic layers were then washed with saturated aq NaHCO3 sol'n (100 mL) followed by brine (100 mL), dried via sodium sulfate (anhydrous) and concentrated via rotary evaporation to yield a bright orange liquid that was purified by flash chromatography (40:60 ethyl acetate/hexanes) yielding 10.99 (74%) of (13) as a bright yellow oil that was stored at -23° C. Rf=0.67 (1:1 ethyl acetate/hexanes). The 1H NMR spectra of 1,2:3,4-di-O-aldehyde (13) matched that reported (Brunjes, M., et al., Adv. Synth. Catal., 345: 635-642 (2003)). |
71% | With dipyridinium dichromate; acetic anhydride In dichloromethane; N,N-dimethyl-formamide at 40℃; for 2h; | |
70% | With pyridinium chlorochromate In dichloromethane at 20℃; | |
70% | With oxalyl dichloride; triethylamine In dichloromethane; dimethyl sulfoxide at -78 - 0℃; | |
67.6% | With dipyridinium dichromate; acetic anhydride | |
67% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -70℃; | |
67% | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In ethyl acetate | |
61% | With Dess-Martin periodane In dichloromethane at 20℃; | |
61% | With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane at 0℃; for 2h; Inert atmosphere; | |
60% | With pyridinium chlorochromate In dichloromethane for 4h; Molecular sieve; Reflux; | |
58% | With dipyridinium dichromate; acetic anhydride In N,N-dimethyl-formamide Heating; | |
56.4% | With 4 A molecular sieve; pyridinium chlorochromate In dichloromethane for 2h; | |
56% | With pyridinium chlorochromate In dichloromethane for 16h; Inert atmosphere; Schlenk technique; Molecular sieve; | 4.2.1 Precursor P2 A solution of 1,2:3,4-Di-O-isopropylidene-α-d-galactopyranose (1.30 g, 5.0 mmol) in CH2Cl2 (10 mL) was added to a suspension of PCC (2.50 g, 11.5 mmol) and powder molecular sieves 4 (5.00 g) in CH2Cl2 (20 mL). After 16 h stirring, AcOEt (40 mL) was added. The mixture was filtered through celite and the solvent removed under reduced pressure. The crude was purified by column chromatography (eluent: hexane to AcOEt:hexane 1:4), affording pure product P2 (0.72 g, 56%) as a colourless oil. FTIR (KBr, cm-1): 1742 (νC=O). 1H NMR (CDCl3, 400 MHz): 1.30, 1.33, 1.42, 1.49 (four s, 12H, -C(CH3)2), 4.17 (d, 1H, J = 2.0, H5), 4.36 (dd, 1H, J = 5.0, 2.6, H2), 4.58 (dd, 1H, J = 7.6, 2.0, H4), 4.63 (dd, 1H, J = 7.6, 2.4, H3), 5.65 (d, 1H, J = 5.2, H1), 9.62 (s, 1H, CHO). 13C NMR (CDCl3, 100 MHz): 24.3, 24.9, 25.9, 26.1 (-C(CH3)2), 70.5 (C3), 70.6 (C2), 71.8 (C4), 73.3 (C5), 96.4 (C1), 109.1, 110.1 (-C(CH3)2), 200.4 (CHO). Anal. Calcd. for C12H18O6: C, 55.81; H, 7.02. Found: C, 54.25; H, 7.13. |
With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; | ||
With pyridine; chromium(VI) oxide; acetic anhydride In dichloromethane for 2h; Yield given; | ||
Swern oxydation; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1.) CH2Cl2, -60 deg C, 30 min, 2.) CH2Cl2, from -60 deg C to RT; Multistep reaction; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1.) CH2Cl2, -55 deg C, 30 min, 2.) -55 deg C, 20 min; 20 min; Yield given. Multistep reaction; | ||
With pyridinium chlorochromate | ||
With swern reagent In dichloromethane; dimethyl sulfoxide at -78℃; for 0.5h; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; | ||
With Dess-Martin periodane In dichloromethane at 20℃; for 1h; Inert atmosphere; | Representative experimental procedure: Galactopyranose derivative 24: To 1,2:3,4-di-O-isopropylidene-d-galactopyranose (23) (64 mg, 0.25 mmol) in dry CH2Cl2 (5 mL) at rt under argon was added DMP (209 mg, 0.49 mmol) and the mixture stirred for 1 h. Montmorillonite K10 (50 mg) was then added followed by potassium allyl trifluoroborate (73 mg, 0.49 mmol) and the mixture stirred for 1 h before adding a further portion of DMP (261 mg, 0.62 mmol). After stirring for a further 1 h, the reaction was quenched with sat. aq NaHCO3 (5 mL) and sat. aq Na2S2O3 (5 mL) and allowed to stir for 1 h before diluting with brine (10 mL) and CH2Cl2 (10 mL). The mixture was filtered and then the layers separated. The aqueous portion was further extracted with CH2Cl2 (2 × 5 mL) and the combined organic extracts dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% acetone in CH2Cl2) to give the compound 24 (55 mg, 75%) as a colourless micro-crystalline solid, mp 47-49 °C; Rf (CH2Cl2) = 0.15; vmax/cm-1 (thin film) 2988, 2936, 1723 (CO), 1383; [α]D -144 (c 0.4, CH2Cl2); δH (400 MHz, CDCl3) 5.97 (1H, ddt, J = 17.0, 10.5, 7.0, H-8), 5.64 (1H, d, J = 5.0, H-1), 5.20-5.08 (2H, m, H-9), 4.63 (1H, dd, J = 8.0, 2.5, H-3), 4.56 (1H, dd, J = 8.0, 2.0, H-4), 4.35 (1H, dd, J = 5.0, 2.5, H-2), 4.22 (1H, d, J = 2.0, H-5), 3.50 (1H, ddt, J = 18.5, 7.0, 1.5, H-7a), 3.33 (1H, ddt, J = 18.5, 7.0, 1.5, H-7b), 1.49 (3H, s), 1.44 (3H, s), 1.33 (3H, s), 1.30 (3H, s); δC (100 MHz, CDCl3) 207.2 (C-6), 130.0 (C-8), 118.7 (C-9), 109.6, 109.0, 96.4 (C-1), 73.5 (C-5), 72.3 (C-4), 70.6 (C-3), 70.4 (C-2), 44.6 (C-7), 25.9, 25.8, 24.8, 24.2; m/z (ESI) 321 [M+Na]+; [HRMS (ESI): Calcd for C15H22NaO6, 321.1309. Found: [M+Na]+, 321.1317 (-2.7 ppm error)]; [C15H22O6 requires C, 60.39; H, 7.43. Found C, 60.35; H, 7.35]. | |
With Dess-Martin periodane In dichloromethane at 20℃; | ||
Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With phosgene; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5h; Inert atmosphere; Sealed tube; Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 6h; Inert atmosphere; Sealed tube; | ||
With Dess-Martin periodane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1H-imidazole; dichlorotriphenylphosphorane In pyridine; acetonitrile at 50℃; for 1h; | |
93% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With sulfuryl dichloride In dichloromethane at -5 - 0℃; for 0.666667h; Inert atmosphere; Stage #2: With 1,2,3-Benzotriazole In dichloromethane at 20℃; for 6.5h; Inert atmosphere; | 1 General procedure General procedure: First approach: Freshly distilled sulfuryl chloride (1.5 mmol) was added to the stirred solution of carbohydrate (1 mmol) in DCM (10 ml) in an RB flask under nitrogen atmosphere at -5°-0 °C using NaCl ice bath. The stirring was continued for 40 min at 0 °C and benzotriazole (6.0 mmol) in DCM (10 ml) was added. The reaction mixture was stirred at room temperature for 6.5 h and precipitated salt was filtered. The filtrate was washed with water (3×50 ml) and the organic layer was then washed with saturated solution of Na2CO3 to remove excess of benzotriazole. The combined organic extract was dried over Na2SO4, and filtered. The filtrate was dried under vacuum to give chloro derivative. |
70% | With 2-Sulfanylpyridine; N-chloro-succinimide In dichloromethane at 0℃; for 3h; |
Multi-step reaction with 2 steps 2: 87 percent / tetrabutylammoninum chloride / benzene / 2 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol With dmap; methanesulfonyl chloride In dichloromethane at 0 - 20℃; for 0.0208333h; Stage #2: With Caswell No. 744A; tetrabutylammonium bromide In N,N-dimethyl-formamide at 110℃; for 120h; Further stages.; | |
82% | With zinc azide * 2 pyridine; di-isopropyl azodicarboxylate; triphenylphosphine In toluene Ambient temperature; | |
79% | With di-isopropyl azodicarboxylate; diphenyl phosphoryl azide; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | Compound 1 (3.00 g, 11.3 mmol) was dissolved in dry THF (20 mL), cooled to O0C, and PPh3 (5.95g, 22.6 mmol) was added to the solution, followed by DIAD (5 mL, 22.6 mmol), then DPPA (3.7 ml, 22.6 mmol). The mixture was allowed warm to room temperature and stir overnight. The mixture was concentrated under reduce pressure, then dissolved in EtOAc (200ml), washed with 5% HCI (80ml), continued to washed it with saturated NaHCO3, the extracts were concentrated in vacuo, and the product was purified by column chromatography (SiO2, 1 :5 EtOAc: hexanes) giving a clear glass (2.61 g, 79% yield). NMR (1 H, CDCI3) d 5.55 (d, J = 5.0 Hz, 1 H), 4.63 (dd, J = 2.5, 8.0 Hz, 1 H), 4.34 (dd, J = 2.5,5.0 Hz, 1 H), 4.20 (dd, J = 2.0, 8.0 Hz, 1 H ), 3.93-3.90 (m, 1 H), 3.51 (dd, J = 9.0, 12.5 Hz, 1 H), 3.36 (dd, J = 5.5, 13.0 Hz, 1 H), 1.55 (s, 3 H), 1.46 (s, 3 H), 1.34 (s, 3H); 13C NMR (500 Hz, CDCI3) d 109.8, 108.9, 96.5, 77.2, 77.0, 67.17, 50.8, 26.2,26.1 , 25.1 , 24.6. |
56% | Stage #1: ((3aR,5R,5aS,8aS,8bR)-2,2,7,7-tetramethyltetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran-5-yl)methanol With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 0.25h; Stage #2: With diphenyl phosphoryl azide In tetrahydrofuran | |
Multi-step reaction with 2 steps 1: 92 percent / pyridine / CH2Cl2 / 5 h 2: 99 percent / NaN3 / dimethylsulfoxide / 2 h / 160 °C | ||
Multi-step reaction with 2 steps 1: 76 percent / pyridine / 20 h / 20 °C 2: 92 percent / sodium azide / dimethylformamide / 16 h / 130 °C | ||
Multi-step reaction with 2 steps 1: 65 percent / CBr4; PPh3 / pyridine / 35 - 50 °C 2: 72 percent / NaN3 / dimethylformamide / 60 h / 80 °C | ||
Multi-step reaction with 2 steps 1: 89 percent / pyridine / 2 h / 20 °C 2: 55 percent / NaN3 / dimethylformamide / 100 - 120 °C | ||
Multi-step reaction with 2 steps 1: 82 percent / sulfuryl chloride / dimethylformamide / 1 h / Ambient temperature 2: 81 percent / sodium azide / dimethylformamide / 6 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: 1.) sodium hydride / 1.) DMF, RT, 30 min, 2.) DMF, -40 deg C, 30 min 2: 81 percent / sodium azide / dimethylformamide / 6 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: SO2Cl2 / 1.) DMF, -40 deg C - 25 deg C, 2.) 1-24 h, 25 deg C 2: 81 percent / NaN3 / dimethylformamide / 6 h / 25 °C | ||
Multi-step reaction with 2 steps 1: triethylamine 2: Caswell No. 744A / N,N-dimethyl-formamide | ||
Multi-step reaction with 2 steps 1: pyridine / 10 h / 20 °C 2: Caswell No. 744A / N,N-dimethyl-formamide / 10 h | ||
Multi-step reaction with 2 steps 1: pyridine / dichloromethane 2: Caswell No. 744A / N,N-dimethyl-formamide / 18 h / 120 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: pyridine / 12 h / 0 - 20 °C / Inert atmosphere 2: Caswell No. 744A / N,N-dimethyl-formamide / 18 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: pyridine; dmap / dichloromethane / 0.25 h / 0 °C 1.2: 5 h / 20 °C 2.1: Caswell No. 744A / dimethyl sulfoxide / 1.5 h / 160 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: pyridine; dmap / 8 h / 0 - 20 °C 2: N,N,N-tributyl-1-butanaminium iodide; Caswell No. 744A / N,N-dimethyl-formamide / 72 h / 110 °C | ||
Multi-step reaction with 2 steps 1: pyridine 2: Caswell No. 744A / N,N-dimethyl-formamide / 120 °C | ||
Multi-step reaction with 2 steps 1: pyridine / N,N-dimethyl-formamide 2: Caswell No. 744A / toluene | ||
Multi-step reaction with 2 steps 1: pyridine / 25 °C 2: Caswell No. 744A / N,N-dimethyl-formamide / 120 °C | ||
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 0 °C / Inert atmosphere 2: Caswell No. 744A / N,N-dimethyl-formamide / 1.5 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1.33 h / -20 °C / Inert atmosphere 2: Caswell No. 744A / N,N-dimethyl-formamide / 1 h / 80 °C | ||
Multi-step reaction with 2 steps 1: pyridine; dmap / 24 h 2: Caswell No. 744A / N,N-dimethyl-formamide / 4 h / Reflux | ||
Multi-step reaction with 2 steps 1: p-toluenesulfonyl chloride / pyridine / 20 °C / Inert atmosphere; Cooling with ice 2: Caswell No. 744A / N,N-dimethyl-formamide / 120 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: pyridine / 20 °C 2: Caswell No. 744A / N,N-dimethyl-formamide / 150 °C | ||
Multi-step reaction with 2 steps 1: pyridine / 24 h / 20 °C 2: Caswell No. 744A / dimethyl sulfoxide / 24 h / 115 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 12% 2: 32% 3: 12% | With copper(l) iodide; allylmagnesium bromide In diethyl ether for 48h; Ambient temperature; Title compound not separated from byproducts; | |
1: 12% 2: 12% 3: 32% | With copper(l) iodide; allylmagnesium bromide In diethyl ether for 48h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4 A molecular sieve; lithium perchlorate In diethyl ether at 25℃; for 24h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With 4 A molecular sieve; samarium(III) trifluoromethanesulfonate In acetonitrile at -25℃; for 1h; | ||
With 4 A molecular sieve; samarium(III) trifluoromethanesulfonate In 1,4-dioxane; diethyl ether at -15 - 0℃; for 1h; Title compound not separated from byproducts; |
With 4 A molecular sieve; samarium(III) trifluoromethanesulfonate In acetonitrile at -25℃; for 1h; Title compound not separated from byproducts; | ||
In dichloromethane at 25℃; for 3h; | ||
With bis(benzonitrile)palladium(II) dichloride; silver trifluoromethanesulfonate In dichloromethane at -78℃; for 1h; Inert atmosphere; optical yield given as %de; | ||
62.264 % de | With oligomeric (salen)Co complex In acetonitrile at 20℃; for 2h; Inert atmosphere; Overall yield = 94 %; Overall yield = 45 mg; stereoselective reaction; | |
62 % de | With 1,3-bis(3,5-bis(trifluoro-ethyl)phenyl)thiourea In diethyl ether at 35℃; for 4h; Molecular sieve; Irradiation; Overall yield = 75 %; Overall yield = 12.9 mg; stereoselective reaction; | |
76 % de | With 1,3-bis(3,5-bis(trifluoro-ethyl)phenyl)thiourea In acetonitrile at 35℃; for 4h; Irradiation; Overall yield = 85 %; Overall yield = 58.3 mg; stereoselective reaction; | |
13.043 % de | Stage #1: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl trichloroacetimidate; 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With 1,3-bis(3,5-bis(trifluoro-ethyl)phenyl)thiourea In dichloromethane at 20℃; for 0.166667h; Molecular sieve; Inert atmosphere; Green chemistry; Stage #2: With 3,5-di(methoxycarbonyl)-N-(cyanomethyl)pyridinium bromide In dichloromethane at 20℃; for 3h; Molecular sieve; Inert atmosphere; Green chemistry; Overall yield = 72 %; Overall yield = 85 mg; | (a) Normal procedure: General procedure: To a stirred suspension of trichloroacetimidate donor (0.15 mmol, 1.0equiv), acceptor (0.165 mmol, 1.1 equiv) and 4 Å MS (200 mg) in dry DCM (3 ml) was added aryl thiourea 4 (0.015 mmol, 0.1 equiv) at room temperature. The mixture was stirred for 10 min at room temperature under a nitrogen atmosphere. Then, electron-deficient pyridinium salt (0.015 mmol, 0.1 equiv) was added and the resulting reaction mixture was stirred at room temperature until total consumption of glycosyl donor monitored by TLC. After completion of reaction, the mixture was concentrated in vacuo and purified by column chromatography using different fractions of acetone in hexane as eluting solvent to afford the desired glycosides. |
Stage #1: 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl trichloroacetimidate; 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose In dichloromethane at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: With tris(pentafluorophenyl)borate In dichloromethane at -10℃; for 1.5h; Overall yield = 84 %; Overall yield = 85 mg; stereoselective reaction; | ||
23.077 % de | With eosin y In dichloromethane at 20℃; Molecular sieve; Irradiation; Overall yield = 69 percent; | 1.2.3. Experimental procedures in Scheme 3 General procedure: An oven-dried heavy wall cylindrical vessels equipped with amagnetic stir bar, was charged with the galactosyl and mannosyl trichloroacetimidates 21 and 22 (34.3 mg, 0.05 mmol), cyclohexanol 3(6.2 μL, 0.06 mmol), eosin Y (0.01 mmol), powdered activated 4 Å molecular sieves (34.3 mg), and CH2Cl2(1 mL). The reaction mixture was exposed to visible light irradiation (two blue LED lamps, 24 W intotal) at room temperature. After disappearance of the glycosyl donors detected by TLC, the precipitate was filtered off, and the filtrate was concentrated. The crude product was purified by column chromatographyon silica gel (eluting with petroleum ether/ethyl acetate) to give the desired corresponding glycosides 23 and 24. |
60 % de | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -40℃; Molecular sieve; Inert atmosphere; Overall yield = 80 percent; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With ytterbium(III) triflate In methanol at 25℃; for 0.2h; | |
79% | With sodium tetrahydroborate In ethanol at 20℃; for 1h; | Typical procedure for MAc deprotection General procedure: To a solution of protected alcohol(1.0 mmol) in 4 ml of ethanol, sodium borohydride (0.5-2.0 equiv) was addedand stirred for 1-4 h at rt. The solvent was evaporated and ice-cold water wasadded to the residual solid. The reaction mixture was extracted with ethylacetate, washed with brine and purified by flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With triethylamine In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: acryloyl chloride In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | |
95% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With triethylamine In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: acryloyl chloride In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | 6.1-6.2 (1) Under argon protection and room temperature, add diacetone galactose to the dichloromethane solution, add triethylamine at 0°C, and stir for 0.5h. Then the dichloromethane solution of acryloyl chloride was dropped into the above reaction solution at 0, and the reaction was stirred at room temperature for 12hThe reaction mixture is obtained; wherein the molar ratio of the diacetone galactose, triethylamine, and acryloyl chloride is 1.2:2:1; the reaction equation is:(2) The reaction mixture was quenched by adding saturated ammonium chloride solution, extracted with ether three times, combined the organic phases, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the column silica gel chromatography was performed with petroleum ether and ethyl acetate (PE /EA) Purify the residue,A white solid diacetone galactose acrylate was obtained with a yield of 95%. |
75% | With triethylamine In dichloromethane at -20 - 20℃; for 6.5h; |
74% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | |
56% | With aluminum oxide In acetonitrile at 20℃; for 72h; | |
45% | With triethylamine In dichloromethane at 0 - 20℃; for 16h; | |
With aluminum oxide In ethyl acetate; acetonitrile at 23℃; for 72h; Inert atmosphere; | 12 Synthesis of 1,2;3,4-di-O-isopropylidene-6-O-acryloyl-α-D-galactopyranose (AIpGP) Example 12 Synthesis of 1,2;3,4-di-O-isopropylidene-6-O-acryloyl-α-D-galactopyranose (AIpGP) In this example, 1,2;3,4-di-O-isopropylidene-6-O-acryloyl-α-D-galactopyranose (AIpGP) was synthesized. For example, to a 100-mL round bottom flask were added 1,2,3,4-di-O-isopropylidene-α-D-galactopyranose (1.39 g, 5.20 mmol), basic alumina (2.44 g, 23.92 mmol), 20 mL of dry acetonitrile, and acryloyl chloride (2.26 mL, 27.04 mmol), dropwise. After stirring under argon for 3 days at ambient temperature, the mixture was filtered through a thin layer of celite, and the solids were washed with 50 mL of acetonitrile. The combined organic layers were concentrated under reduced pressure. The resulting pale yellow residue was purified through a flash column using 1:2 ethyl acetate:hexanes as eluents, and its molecular structure was verified by 1H-NMR and compared with the reported data. | |
With triethylamine In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With phosphomolybdic acid hydrate; silica gel In tetrahydrofuran at 20℃; for 0.5h; | |
96% | With sodium tetrachloroaurate(III) dihydrate In methanol at 20℃; for 11h; | Deprotection of TBS Ethers; General Procedure General procedure: A solution of the TBS ether (2 mmol) in MeOH (4 mL) was treated with NaAuCl4·2H2O (4.0 mg, 0.01 mmol, 0.005 equiv) at r.t. When the starting material had disappeared (TLC), mixture was diluted with EtOAc (10 mL) and filtered through activated alumina. The solution was then concentrated in vacuo and the resulting residue was purifiedby flash column chromatography. |
93% | With ethane-1,2-dithiol; nickel dichloride In methanol; dichloromethane at 20℃; for 0.75h; |
87% | With acetyl chloride In methanol for 0.666667h; | |
83% | With zirconium(IV) chloride In acetonitrile at 20℃; for 0.75h; | |
80% | With acetonyltriphenylphosphonium bromide In methanol; dichloromethane at 20℃; for 0.5h; | |
With iodine(I) bromide In methanol; dichloromethane for 1h; Ambient temperature; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; | 12.A Example 12; flR, 2R-Cyclohexanediamme-N, NM f{3-(α, 3-D-GaIactopyranos-6- yIamido)propyl|propanedioato(2-)-Q, O'l Platinum (ID (54); Step A: 6-PhthaIimido-l,2:3,4-Di-O-Isopropylidene-α-D-Galactopyranose (55); [00119] l,2:3,4-Di-0-isopropylidene-α-D-galactopyranose (0.27 mmol), phthalimide (0.3 mmol), and triphenylphosphine (0.3 mmol) were stirred together in THF under a nitrogen atmosphere, then diethylazodicarboxylate (0.3 mmol) was added dropwise and the mixture stirred at room temperature overnight. The solvent was removed in vacuo, the residue dissolved in CH2Cl2 and washed with NaHCO3, and the organic phase purified by column chromatography on silica gel, eluting with 30% v/v ethyl acetate in hexane to afford the title compound (55) in 97% yield. 1H NMR (CD3OD, 400 MHz): δ 7.8 (m, 4H), 5.4 (d, IH), 4.65 (dd, IH) 4.3 (m, 2H), 4.2 (m, 2H), 3.6 (dd, IH), 1.5 (s, 3H), 1.4 (s, 3H), 1.35 (s, 3H), 1.25 (s, 3H). MS (ESI) m/z: 390.2 (M+H)+. |
92% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 25℃; for 1h; | |
90.4% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20 - 25℃; for 5h; Cooling with ice; | 15.1 Step 1 A 250 mL three-necked flask was filled with nitrogen gas and loaded with Compound 15-1 (2.5 g, 9.605 mmol), Compound 15.1 (1.41 g, 9.583 mmol), and 60 mL of tetrahydrofuran, and triphenylphosphine (7.55 g, 28.785 mmol), respectively, cooled in an ice bath, and added dropwise with DIAD (5.83 g, 28.83 mmol), after which it was allowed to warm to room temperature and react for 5 hours. The reaction was monitored by LC-MS until completion. The reaction solution was concentrated and purified by combiflash (0-30% EA in n-hexane) to give Compound 15-2 (3.76 g, 90.4%) as a colorless oil. MS m/z (ESI): 390.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 15% 2: 15% | With [Mg2Cl3(THF)y]+*[AlH4-nCln]- In tetrahydrofuran at 70℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; water Photolysis; | ||
In tetrahydrofuran; water Photolysis; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In tetrahydrofuran at 20℃; for 1h; | |
70% | With dmap; triethylamine In tetrahydrofuran at 0 - 27℃; for 2h; Schlenk technique; Inert atmosphere; | 2.4 Synthesis of 6-O-methacryloyl-1,2;3,4-di-O-isopropylidene-D-galactose (MAIpGal) (3) 2 (5g, 19.2mmol), TEA (8mL, 57.6mmol) and DMAP (2.35g, 19.2mmol) were added to anhydrous THF (60mL) in a 250mL round bottom schlenk flask. The mixture was cooled down to 0°C and MACl (2.06mL, 21.1mmol) was added dropwise over a period of 30min. The reaction mixture was kept at 27°C to react under nitrogen atmosphere for 1.5h. The reaction was monitored by thin-layer chromatography (TLC) with 15% ethyl acetate/hexane as the mobile phase. On completion of the reaction, THF was removed on a rotary evaporator, and it was redissolved in ethyl acetate. This was washed successively with 1N HCl (2 × 30mL), water (2 × 20mL), saturated NaHCO3 (2 × 30mL), brine (2 × 20mL), ammonia solution (2 × 20mL) and brine (2 × 20mL). The organic layer was dried over anhydrous Na2SO4 and the crude product obtained on removal of solvent was purified by column chromatography (5% ethyl acetate in hexane as the eluent) to obtain 3 in 70% yield. 1H NMR (400MHz, CDCl3) δ 6.12 (1H, s, HCH=C), 5.56 (1H, s, HCH=C), 5.54 (1H, d, J=4.8Hz, anomeric proton CH), 4.63 (1H, dd, J=8.0Hz, 2.4Hz, CH), 4.32-4.26 (4 H, m, 2 CH+CH2), 4.08-4.06 (1H, m, CH), 1.94 (3H, s, C=C(CH3)), 1.50 (3H, s, CH3), 1.45 (3H, s, CH3), 1.32 (6H, s, 2 CH3); 13C NMR (100MHz, CDCl3) δ 166.20, 135.05, 124.78, 108.62, 107.74, 95.27, 70.10, 69.69, 69.51, 65.09, 62.62, 28.67, 24.94, 24.93, 23.96, 23.44, 17.26; FTIR (ν ν (cm-1) 2978, 2926 (C-H stretch), 1716 (C=O stretch), 1637 (C=C stretch), 1167 (C-O stretch). |
With triethylamine In acetonitrile at 20℃; |
With triethylamine In dichloromethane Cooling with ice; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With KMOPS buffer; water In dimethyl sulfoxide Photolysis; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [ReOCl3(SMe2)(Ph3PO)] In toluene at 0 - 20℃; for 19h; Title compound not separated from byproducts; | ||
In toluene at 20℃; optical yield given as %de; | ||
60 % de | With trimethylsilyl bromide; Triphenylphosphine oxide In neat (no solvent) at 20℃; Inert atmosphere; Green chemistry; Overall yield = 90 %; diastereoselective reaction; | General procedure for preparation of 2-deoxy-D-glycopyranosides. General procedure: Glycals (50.0mg, 1.0 equiv), acceptors (12-24, 2.0 equiv), and triphenylphosphine oxide (TPPO, 1.0 equiv) were mixed in a flame dried flask. After the reagents became homogeneous, TMSBr (1.0 equiv) was slowly added at room temperature under ambient atmosphere. After stirring for 1 to 2 hours, the mixture was directly purified by flash column chromatography on silica gel and then volatiles were removed in vacuo to affordexpected products. The products and yields are shown in Tables 2-4. |
88.889 % de | With eosin y; diphenyldisulfane In dichloromethane at 20℃; Sealed tube; Irradiation; Overall yield = 66 %; Overall yield = 35 mg; stereoselective reaction; | |
66.667 % de | With 2-thiouracil In dichloromethane for 18h; Reflux; stereoselective reaction; | |
75 % de | With 2,4,6-tri-tertiary-butylpyridinium hydrochloride salt In 1,2-dichloro-ethane at 40℃; for 24h; Inert atmosphere; Overall yield = 76 %; Overall yield = 62 mg; stereoselective reaction; | |
75 % de | With 1-(Trimethylsilyl)imidazole; triphenylphosphine In dichloromethane at 40℃; for 10h; Inert atmosphere; Overall yield = 79 %; diastereoselective reaction; | Typical procedure for preparing 2-deoxyglycoside derivatives 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b General procedure: To a stirred solution of glycal (1a and 1b, 1.0 equiv) in CH2Cl2 (2.0 mL) were added glycosyl acceptor (1.5 equiv), PPh3 (0.20 equiv), and TMSI (0.20 equiv). The mixture was stirred at 40 °C for 10 h, concentrated under reduced pressure, and purified by silica gel chromatography with EtOAc/PE (1:8) to give the products in 67-86% yields. The 1H NMR and 13C NMR of the known compounds are listed in the Supplementary data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With bis(benzonitrile)palladium(II) dichloride; silver trifluoromethanesulfonate In dichloromethane at 25℃; for 0.25h; Inert atmosphere; | |
97% | With bismuth(lll) trifluoromethanesulfonate; 4 A molecular sieve In 1,4-dioxane; 1,2-dimethoxyethane; toluene at -70 - -50℃; | |
90% | With 4 A molecular sieve; ytterbium(III) triflate In 1,2-dimethoxyethane at -15℃; for 2h; |
84% | With tris(pentafluorophenyl)borate In dichloromethane at -10℃; for 1.5h; | General procedures for glycosylation: General procedure: A solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranosyltrichloroacetimidate (1aa) (110 mg, 0.16 mmol, 1 equiv.) andacceptor, non-sugar 3a (25 mg, 0.24 mmol, 1.5 equiv.) andsugar 3b (42 mg, 0.16 mmol, 1.0 equiv.) in freshly driedCH2Cl2 were stirred at room temperature for 5 min. The reactionmixture was cooled to -10C and further stirred for 5min. To this reaction mixture activator BCF (tris(pentafluorophenyl)borane) (0.1 equiv.) was added and stirred for 1.5 hat the same temperature. After the completion of reaction through TLC monitoring, quenched using Et3N (0.1 mL) anddiluted with CH2Cl2. The organic layer was washed with brineand dried over anhydrous Na2SO4. The combined organiclayer was evaporated under reduced pressure and residuewas purified by column chromatography (SiO2, hexane:ethylacetate) to provide glycosylated product 4a (92%) and 4b(84%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With ytterbium(III) triflate In dichloromethane for 24h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tris(pentafluorophenyl)borate In toluene at 75℃; for 2h; Sealed tube; stereoselective reaction; | |
72% | With trimethylsilyl trifluoromethanesulfonate; 1-(n-butyl)-3-methylimidazolium triflate at 20℃; for 1.66667h; stereoselective reaction; | |
66% | With carbon immobilized iron (III) chloride hexahydrate In dichloromethane at 20℃; for 3h; stereoselective reaction; | General Experimental Procedure for the Synthesis of2,3-Unsaturated Galactosides General procedure: To a stirred solution of tri-O-acetyl-D-galactal (50 mg, 0.185 mmol) in DCM(1 mL) were added the corresponding alcohol (0.204 mmol, 1.1 equiv) andFeCl3·6H2O/C (50 mol%) at ambient temperature. After the reaction was completed(monitored by TLC), the reaction mixture was filtered and the catalystwas washed with dichloromethane. After evaporation of the solvent under vacuum,the crude products were purified by silica gel column chromatography(petroleum ether/EtOAc = 10/1). |
62% | With perchloric acid; silica gel In acetonitrile at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In acetonitrile at 20℃; for 2h; | |
92% | With sulfuric acid for 24h; | |
91% | With dimethylbromosulphonium bromide In acetonitrile at 20℃; for 4h; |
87% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)] In acetonitrile at 40℃; for 1h; Inert atmosphere; | General procedure: To a suspension of the sugar/glycoside (1 mmol) in dry acetonitrile (3 mL) and 2,2-dimethoxypropane (2 mmol), the organoiridium catalyst (0.03 mmol) was added and the mixture was allowed to stir at 40 °C under argon atmosphere till the TLC (n-hexane-EtOAc 2:1) showed complete conversion of the starting material. The work-up and purification of the product was as above. |
85% | With phosphotungstic acid In acetone at 20℃; for 7h; Inert atmosphere; | Typical procedure for isopropylidenation of 1,2-diols General procedure: A suspension of the substrate (1 mmol) in dry acetone (5 mL)/2,2-dimethoxypropane (2 mmol) in dry acetone (5 mL) was added 5 mol % of phosphotungstic acid and was stirred at room temperature under nitrogen atmosphere for the specific time given in Table 2. After completion of the reaction, the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (3 × 20 mL) and water and the combined organic layer was dried with Na2SO4 and concentrated in vacuum to give the crude product. The crude product was purified by column chromatography on Silica gel (60-120 mesh) with 15-30% ethylacetate in hexane as eluent. |
78% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; for 0.0833333h; sonication; | |
Stage #1: D-Galactose; 2,2-dimethoxy-propane With toluene-4-sulfonic acid at 80℃; for 8h; Stage #2: With triethylamine for 0.25h; Stage #3: In methanol; water at 80℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With ytterbium(III) triflate In acetonitrile at -30℃; for 1h; | |
85% | With iron(III) chloride In dichloromethane at -60 - 20℃; for 0.666667h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.2% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | |
75% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | Synthesis of Diacetone 6'-O-ketorolac-D-galactopyranoside (1a) 1 g of ketorolac 1 (3.9 mmol), 1.015 g of 1,2,3,4-di-O-isopropylidene-D-α-galactopyranose (3.9 mmol), 748 mg of N-ethyl-N'-(3-dimethyl aminopropyl)carbodiimide (EDC) HCl (3.9 mmol) and 24 mg of 4-(dimethyl amino)pyridine (DMAP) (0.19 mmol) were dissolved in anhydrous dichloromethane (10 mL). The reaction mixture was kept under electromagnetic stirring at room temperature for 12 hours. The organic phase was extracted several times with water and dehydrated with anhydrous sodium sulphate, filtered, and dried in vacuo. The reaction crude was purified on a chromatography column with silica gel using as eluent CHCl3, to obtain 1.45 g of 1a as a white solid (yield 75%). 1H-NMR (CDCl3): δ 1.30, 1.31, 1.40, 1.41 (4 s, 12H, ketals); 2.80, 2.90 (m, 2H, 2-H); 3.30 (m, 1H, 1-H); 4.05 (m, 1H, 4'-H); 4.15 (m, 1H, 5'-H); 4.20 (m, 2H, 6'-H); 4.40 (m, 1H, 2'-H); 4.50 (m, 1H, 3'-H); 4.60 (m, 2H, 3-H); 5.35 (m, 1H, 1'-H); 5.90 (d, 1H, 7-H); 6.80 (d, 1H, 6-H); 7.45 (m, 2H, 2,6-Ph); 7.55 (m, 1H, 4-Ph); 7.85 (m, 2H, 3,5-Ph). 13C-NMR (CDCl3): δ 20 and 22 (4-CH3-ketals); 30 (C-2); 44 (C-3); 48 (C-1); 65 (C-6'); 66.7 (C-4'); 71 (C-5'); 71.5 (C-2'); 72 (C-3'); 97 (C-1'); 105 (C-7); 109 and 111 (C-ketals); 125 (C-6); 127 (C-5); 129 (3,5-Ph); 130 (2,6-Ph); 133 (4-Ph); 140 (C-8); 142 (1-Ph); 175 (ketonic CO); 185 (esteric CO). m/z: 498 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 2-methoxy-2-(S)-phenyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-β-D-glucopyranoso)[1,2-e]-1,4-oxathiane (R)-S-oxide With 2,6-di-tert-butyl-4-methylpyridine; 1,2,3-trimethoxybenzene; trifluoromethylsulfonic anhydride In 1,2-dichloro-ethane at -30 - -10℃; for 0.166667h; 4 Å molecular sieves; Inert atmosphere; Stage #2: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose In 1,2-dichloro-ethane at -10 - 50℃; Inert atmosphere; Stage #3: With methanol; boron trifluoride diethyl etherate In dichloromethane at 20℃; for 0.5h; Inert atmosphere; | |
85% | Stage #1: 2-methoxy-2-(S)-phenyl-(3,4,6-tri-O-acetyl-1,2-dideoxy-β-D-glucopyranoso)[1,2-e]-1,4-oxathiane (R)-S-oxide With 1,2,3-trimethoxybenzene; trifluoromethylsulfonic anhydride; N-ethyl-N,N-diisopropylamine In dichloromethane at -30 - 20℃; for 0.166667h; Inert atmosphere; Molecular sieve; Stage #2: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With N-ethyl-N,N-diisopropylamine In dichloromethane at 37℃; for 24h; Inert atmosphere; Stage #3: With boron trifluoride diethyl etherate In methanol; dichloromethane at 20℃; for 0.5h; Inert atmosphere; optical yield given as %de; | 3.8. General procedure for glycosylation reactions with oxathiane spiroketal-S-oxides(20)19 General procedure: Tf2O (1.1 equiv) was added to a solution of oxathiane spiroketal-S-oxide 13-R or 14-R (1 equiv), 1,3,5-trimethoxybenzene (1.1 equiv) or 1,3-dimethoxybenzene (1.1 equiv), DIPEA (1.2 equiv) and 4 Å molecular sieves in CH2Cl2 or C2H4Cl2 (initial donor concentration 0.26 M), cooled to -30 °C. The reaction mixture was warmed to room temperature over 10 min and then DIPEA (1.3 equiv), followed by a solution of the glycosyl acceptor (1.5 equiv) in CH2Cl2 or C2H4Cl2 (final donor concentration 0.11 M) was added, and the reaction mixture was stirred for 24 h at 37 °C or 50 °C (when using donor 13-R), or room temperature (when using donor 14-R). The reaction mixture was then diluted with CH2Cl2 (5 mL), washed with 1 M HCl (2 × 5 mL), aq NaHCO3 (2 × 5 mL) and aq NaCl (2 × 5 mL), dried (MgSO4) and concentrated to afford the crude product. The crude product was then redissolved in CH2Cl2 (1 mL) and cat. BF3·OEt2 and MeOH (1.5 equiv) were added. After stirring for 30 min at room temperature the reaction mixture was diluted with CH2Cl2 (5 mL), washed with aq NaCl (5 mL), dried (MgSO4) and concentrated to afford the crude O-2 unprotected glycoside. The crude glycoside was purified by size-exclusion chromatography (Sephadex LH-20 resin; eluted with MeOH (50 mL/h)) to afford the desired O-2 unprotected glycoside. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrabutylammomium bromide; sodium hydrogencarbonate In acetonitrile at 20℃; Molecular sieve; | |
90% | With tetrabutylammomium bromide; sodium acetate In acetonitrile at 20℃; for 6h; Molecular sieve; ultrasound irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 2,6-dimethylpyridine In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; | 4.2.3. Representative procedure for the synthesis of TFE-protected sulfocarbohydrates using reagent 20 and 2,6-lutidine (Table 3, compound 36) To a solution of carbohydrate 26 (0.25 g, 0.95 mmol) in CH2Cl2 (4.2 mL) at 0 °C (ice bath) was added 2,6-lutidine (0.123 mL, 1.05 mmol, 1.1 equiv) followed by reagent20 (0.19 g, 0.48 mmol, 0.5 equiv). The reaction was stirred for 1 h at 0 °C and gradually allowed to warm to room temperature. After every 2 h another 0.19 g of reagent 20 was added until the total was equal to 2 equiv and the reaction was stirred overnight for a total of 24 h. The reaction was quenched with water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated to a crude brown oil. Flash chromatography (1:4, EtOAc/hexanes) gave compound 36 as a white solid (0.28 g, 88%): mp 34-35 °C; 1H NMR (300 MHz, CDCl3) δ 1.30 (s, 6H, 2CH3), 1.41 (s, 3H, CH3), 1.49 (s, 3H, CH3), 4.09 (br d, 1H, J=5.6 Hz, H5), 4.15 (dd, 1H, J=7.7, 1.8 Hz, H4), 4.32 (t, 1H, J=4.8 Hz, H2), 4.41 (dd, 2H, J=5.8, 2.5 Hz, H6, H6'), 4.52-4.63 (m, 3H, CH2CF3, H3), 5.49 (d, 1H, J=4.6 Hz, H1); 13C NMR (75 MHz, CDCl3) δ 24.3, 24.7, 25.8, 25.5, 65.6, 66.6 (q, 1C, JCF=150 Hz, CH2CF3), 70.1, 70.4, 70.6, 72.5, 96.1, 109.1, 110.1, 121.6 (q, 1C, JCF=303 Hz, CF3); 19F NMR (282 MHz, CDCl3) δ -73.8; HRMS (ESI) m/z calcd for [C14H22F3O9S]+: 423.0937 [M+H]+; found: 423.0952. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1,2-dimethyl-1H-imidazole In dichloromethane at 0 - 20℃; Inert atmosphere; | 4.2.4. Representative procedure for the synthesis of TFE-protected sulfocarbohydrates using reagent 21 and DMI (Table 3, compound 40) General procedure: To a solution of carbohydrate 3021 (0.3 g, 0.62 mmol) in CH2Cl2 (5 mL) at 0 °C (ice bath) were added DMI (0.15 g, 1.56 mmol) and reagent 21 (0.51 g, 1.25 mmol). The ice bath was removed and the reaction allowed to warm to room temperature and then stirred for 30 h. The reaction was diluted with CH2Cl2, washed with brine, dried (MgSO4) and concentrated to crude brown oil. Flash chromatography (1:4, EtOAc/hexanes) gave compound 40 as a white solid (0.32 g, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1-methyl-1H-imidazole In dichloromethane at 0 - 20℃; Inert atmosphere; | 4.2.7. Representative procedure for synthesis of phenyl-protected sulfocarbohydrates using sulfuryl imidazolium salt 23 (Table 4, compound 50) To a solution of carbohydrate 26 (0.25 g, 0.96 mmol) in CH2Cl2 (4.2 mL) at 0 °C (ice bath) was added 2-methylimidazole (0.23 mL, 2.4 mmol) followed by reagent 23 (0.77 g, 1.92 mmol). The reaction was stirred for 1 h at 0 °C and gradually allowed to warm to room temperature. The reaction was stirred overnight (24 h), then diluted with CH2Cl2, washed with brine, dried (MgSO4) and concentrated to a crude brown oil. Flash chromatography (1:4, EtOAc:hexanes) gave compound 50 as a white solid (0.38 g, 95%): mp 77-79 °C; 1H NMR (300 MHz, CDCl3) δ 1.30 (2s, 6H, 2CH3), 1.42 (s, 3H, CH3), 1.51 (s, 3H, CH3), 4.15 (t, 1H, J=6.6 Hz, H5), 4.21 (dd, 1H, J=7.8, 1.8 Hz, H4), 4.32 (dd, 1H, J=4.8, 2.4 Hz, H2), 4.47-4.56 (dd, 2H, J=5.8, 2.5 Hz, H6, H6'), 4.62 (dd, 1H, J=7.7, 2.2 Hz, H3), 5.51 (d, 1H, J=4.9 Hz, H1), 7.32 (m, 5H, ArH); 13C NMR (75 MHz, CDCl3) δ 24.3, 24.8, 25.9, 25.9, 65.7, 70.2, 70.5, 70.6, 72.3, 96.1, 109.0, 109.8, 121.4, 127.4, 129.8, 150.3; HRMS (EI) m/z calcd for [C17H21O9S]+: 401.0906 [M-CH3]+; found: 401.0905. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With phosphotungstic acid; water In acetonitrile at 20℃; for 3h; | Typical procedure for deprotection of isopropylidenes The substrate (1 mmol) was dissolved in acetonitrile/water mixture (2 mL, 9:1 v/v) and to it was added phosphotungstic acid (5 mol %). The mixture was stirred at room temperature for the appropriate time. After completion of the reaction, the solvent was removed under reduced pressure. The residue was directly purified by using column chromatography on silica gel (60-120 mesh) with 50-100% ethylacetate in hexane as eluent to get the product. |
Multi-step reaction with 3 steps 1.1: sodium hydride; tetrabutylammomium bromide / N,N-dimethyl-formamide; mineral oil / 0.75 h / 0 - 20 °C 1.2: 16 h / 0 - 20 °C 2.1: trifluoroacetic acid / water / 0 - 20 °C 3.1: water / 0.33 h / Irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 20℃; for 12h; | Synthesis of Diacetone 6'-O-<strong>[5104-49-4]Flurbiprofen</strong>-D-galactopyranoside (2a) 1 g of flurbiprofen 2 (4.1 mmol), 1.067 g of 1,2,3,4-di-O-isopropylidene-D-alpha-galactopyranose (4.1 mmol), 786 mg of N-ethyl-N'-(3-dimethyl aminopropyl)carbodiimide (EDC) HCl (4.1 mmol), and 25.2 mg of 4-(dimethyl amino)pyridine (DMAP) (0.205 mmol) were dissolved in anhydrous dichloromethane (10 mL). The reaction mixture was kept under electromagnetic stirring at room temperature for 12 hours. The organic phase was extracted several times with water and dehydrated with anhydrous sodium sulphate, filtered and dried in vacuo. The reaction crude was purified on a chromatography column with silica gel using CH2Cl2 as eluent, to obtain 1.21 g of 2a as a white solid (yield 61%) m/z: 487 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h; | Synthesis of Diacetone 6'-O-Ketoprofen-D-galactopyranoside (3a) 1 g of ketoprofen 3 (3.9 mmol), 1.014 g of 1,2,3,4-di-I-isopropylidene-D-α-galactopyranose (3.9 mmol), 747 mg of N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) HCl (3.9 mmol), and 24 mg of 4-(dimethyl amino)pyridine (DMAP) (0.195 mmol) were dissolved in anhydrous dichloromethane (10 mL). The reaction mixture was kept under electromagnetic stirring at room temperature for 12 hours. The organic phase was extracted several times with water and dehydrated with anhydrous sodium sulphate, filtered and dried in vacuo. The reaction crude was purified on a chromatography column with silica gel using CH2Cl2 as eluent, to obtain 990 mg of 3a as a white solid (yield 51%). m/z: 497 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,3-bis(3,5-bis(trifluoro-ethyl)phenyl)thiourea In dichloromethane for 18h; Inert atmosphere; Reflux; diastereoselective reaction; | |
92% | With copper(I) bromide In dichloromethane at 25℃; for 2h; Inert atmosphere; stereoselective reaction; | General procedure for Glycosylation Reactions General procedure: Under nitrogen atmosphere, the glycal donor (0.100 mmol) and nucleophile acceptor (0.12 mmol) were dissolvedin 1mL dry DCM. Meanwhile CuBr2 (0.005 mmol) was added to the system quickly. The reaction mixture wasstirred at 25 °C until the reaction was determined to be complete by TLC. Then the reaction mixture was quenchedwith sat. aq. NaHCO3, extracted with DCM, the combined organic phases washed with sat. aq. NaHCO3 and brine,dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gelcolumn chromatography. |
82% | With 2-thiouracil In dichloromethane for 18h; Reflux; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 3,5-di(methoxycarbonyl)-N-(cyanomethyl)pyridinium bromide In dichloromethane at 20℃; for 24h; Inert atmosphere; | |
85% | With copper(I) bromide In dichloromethane at 25℃; for 1.5h; Inert atmosphere; stereoselective reaction; | General procedure for Glycosylation Reactions General procedure: Under nitrogen atmosphere, the glycal donor (0.100 mmol) and nucleophile acceptor (0.12 mmol) were dissolvedin 1mL dry DCM. Meanwhile CuBr2 (0.005 mmol) was added to the system quickly. The reaction mixture wasstirred at 25 °C until the reaction was determined to be complete by TLC. Then the reaction mixture was quenchedwith sat. aq. NaHCO3, extracted with DCM, the combined organic phases washed with sat. aq. NaHCO3 and brine,dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gelcolumn chromatography. |
72% | With 1,3-bis(3,5-bis(trifluoro-ethyl)phenyl)thiourea In dichloromethane for 48h; Inert atmosphere; Reflux; diastereoselective reaction; |
68% | With 2-thiouracil In 2-methyltetrahydrofuran at 83℃; for 18h; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-Bromosuccinimide In acetonitrile at 20℃; for 0.666667h; stereoselective reaction; | 23 To a solution of tri-O-acetyl-d-glucal (1; 545 mg, 2.0 mmol) in CH3CN (5 mL) were added alcohol (4.0 mmol) or monosaccharide acceptor (2.5 mmol), diphenyl diselenide (750 mg, 2.40 mmol), and NBS (550 mg, 3.09 mmol) and the reaction mixture was allowed to stir at room temperature for appropriate time as mentioned in Table 1. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic layer was successively washed with satd. NaHCO3, water, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified over SiO2 using hexane-EtOAc as eluant to give pure individual isomer. Spectral data of the isolated products are presented below. 4.2.23 3,4,6-Tri-O-acetyl-2-deoxy-2-phenylselenyl-α-d-talopyranosyl-(1→6)-1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (35) Colorless oil; +1 (c 1.0, CHCl3); 1H NMR (CDCl3, 500 MHz): δ 7.53-7.24 (m, 5H, Ar-H), 5,46 (d, J = 5.0 Hz, 1H, H-1A), 5.43 (dd, J = 5.0, 3.0 Hz, 1H, H-3B), 5.33 (br s, 1H, H-4B), 5.22 (br s, 1H, H-1B), 4.54 (dd, J = 7.5, 2.0 Hz, 1H, H-4A), 4.35-4.33 (m, 1H, H-5B), 4.27-4.26 (m, 1H, H-2A), 4.20-4.16 (m, 1H, H-6aB), 4.13-4.09 (m, 2H, H-3A, H-6bB), 3.91-3.86 (m, 1H, H-5A), 3.76-3.61 (m, 2H, H-6abA), 3.56-3.55 (m, 1H, H-2B), 2.22, 2.08, 2.07 (3 s, 9H, 3 COCH3), 1.48, 1.34, 1.30, 1.24 (4 CH3); 13C NMR (CDCl3, 125 MHz): δ 170.1, 169.9, 169.7 (3 COCH3), 133.7-127.6 (Ar-C), 109.3, 108.6 (2 C(CH3)2), 101.8 (C-1B), 96.1 (C-1A), 70.9 (C-3A), 70.6 (C-4A), 70.5 (C-2A), 76.1 (C-3B), 66.9 (C-5B), 66.5 (C-4B), 66.4 (C-5A), 66.2 (C-6A), 62.0 (C-6B), 46.2 (C-2B), 26.1, 25.9, 24.9, 24.5, (4 CH3), 21.0, 20.9, 20.7 (3 COCH3); ESI-MS: 551.1 [M+Na]+; Anal. Calcd for C30H40O13Se (688.16): C, 52.40; H, 5.86. Found: C, 52.22; H, 6.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane; acetonitrile at -40℃; for 1h; Molecular sieve; Inert atmosphere; | 1 General procedure for sialylation of sialyl donors (D1-D5) with galactosyl acceptors (A1-A4) General procedure: A mixture of sialyl donor (D1-D5, 1.0 equiv), galactosyl acceptor (A1-A4, 1.0 equiv) and activated 4 Å molecular sieves (2.0 g/mmol) in dry MeCN (for D1, D2 and D5) or CH2Cl2/MeCN (2:1, v/v, for D3) or CH2Cl2/MeCN (3:2, v/v, for D4), making the final concentration 50 mM, was stirred under argon atmosphere at room temperature for 1 h to remove any trace amounts of water. The reaction mixture was then cooled to -40 °C (MeCN in liquid N2). N-Iodosuccinimide (2.0 equiv) was added followed by catalytic amount of triflic acid (0.20 equiv) to promote the sialylation process (0.30 equiv TMSOTf for D4). After being stirred at -40 °C for 1 h, the mixture was quenched with triethylamine, diluted with CH2Cl2, and filtered through a pad of Celite. The resulting filtrate was washed with 1 M aqueous Na2S2O3 solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The α/β ratio was determined by 1H NMR analysis of the crude reaction mixture. The residue was purified by column chromatography on silica gel with toluene/acetone or hexane/EtOAc as eluent to give the respective disaccharide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane; acetonitrile at -40℃; for 1h; Molecular sieve; Inert atmosphere; | 1 General procedure for sialylation of sialyl donors (D1-D5) with galactosyl acceptors (A1-A4) General procedure: A mixture of sialyl donor (D1-D5, 1.0 equiv), galactosyl acceptor (A1-A4, 1.0 equiv) and activated 4 Å molecular sieves (2.0 g/mmol) in dry MeCN (for D1, D2 and D5) or CH2Cl2/MeCN (2:1, v/v, for D3) or CH2Cl2/MeCN (3:2, v/v, for D4), making the final concentration 50 mM, was stirred under argon atmosphere at room temperature for 1 h to remove any trace amounts of water. The reaction mixture was then cooled to -40 °C (MeCN in liquid N2). N-Iodosuccinimide (2.0 equiv) was added followed by catalytic amount of triflic acid (0.20 equiv) to promote the sialylation process (0.30 equiv TMSOTf for D4). After being stirred at -40 °C for 1 h, the mixture was quenched with triethylamine, diluted with CH2Cl2, and filtered through a pad of Celite. The resulting filtrate was washed with 1 M aqueous Na2S2O3 solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The α/β ratio was determined by 1H NMR analysis of the crude reaction mixture. The residue was purified by column chromatography on silica gel with toluene/acetone or hexane/EtOAc as eluent to give the respective disaccharide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose With potassium <i>tert</i>-butylate In 1,4-dioxane for 1h; Stage #2: methyl 4,6-O-benzylidene-β-D-galactopyranoside 2,3-di-O-p-toluenesulfonate In 1,4-dioxane for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With triphenylphosphine; diethylazodicarboxylate; In toluene; at 110℃; for 24h;Inert atmosphere; | A solution of 27.40 mL (60 mmol) DEAD (40% in toluene) was addeddropwise over a period of 5 min to a suspension of 3.20 g (20 mmol) 2,3-dicyanohydroquinone[40] and 15.70 g (60 mmol) PPh3 in 180 mL of dry toluene.The mixture was stirred at rt until all solids were dissolved. Next, 15.60 g(60 mmol) 1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranose dissolved in drytoluene was added to the deeply red solution and the mixture was heated to110C for 24 h. The solution was cooled to rt and the solvent was evaporatedunder reduced pressure. The viscous oily residue was purified by column chromatographyusing a mixture of chloroform and methanol (250:1). Compound3 was obtained by crystallization from acetone. Colorless solid (5.90 g, 47%);m.p. 180-182C (acetone); [alpha]D20 = -98.8 (c 1.0, CHCl3); 1H NMR (400 MHz,CDCl3) delta 7.25 (s, 2 H, Ar-H), 5.52 (d, J1,2 = 5.1 Hz, 2 H, H-1), 4.67 (dd, J3,4= 7.8 Hz, 2 H, H-3), 4.42 (d, J4,5 = 8 Hz, 2 H, H-4), 4.35 (dd, J2,3 = 2.3 Hz, 2H, H-2), 4.26-4.18 (m, 6 H, H-5, H-6a, H-6b), 1.54, 1.43, 1.34, 1.33 (4s, 12H,-CH3); 13C NMR (100.6 MHz, CDCl3) delta 155.2 (2 C, Ar-C), 119.2 (2 C, Ar-C),112.8 (2 C, Ar-C), 109.5 (2 C, 2 × -C(CH3)2), 109.0 (2 C, 2 × -C(CH3)2), 105.5 (2C, 2 × -CN), 96.2 (2 C, C-1), 70.6 (2 C, C-2), 70.5 (2 C, C-4), 70.5 (2 C, C-3),68.8 (2 C, C-6), 66.3 (2 C, C-5), 26.2, 26.1, 25.0, 24.4 (8 C, 8 × -CH3); IR (Neat)vmax 2988, 2938, 2232, 1579, 1488, 1454, 1385, 1214, 1009, 920, 810, 514 cm-1;Anal. calcd. for C32H40N2O12: C 59.62; H 6.25; N 4.35; Found: C 59.52; H 6.41;N 4.11.Signals could be reversed.3,6- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; ammonium acetate In water; acetonitrile at 20℃; for 0.75h; | Oxidative Conversion of Alcohols into Nitriles; GeneralProcedure: General procedure: To a solution of alcohol (1 mmol) in MeCN-H2O (9:1, 3 mL) were successively added TEMPO (7.8 mg,5 mol%), NH4OAc (0.308 g, 4 equiv), and PhI(OAc)2 (0.708g, 2.2 equiv). The suspension was stirred at roomtemperature (progress of the reaction was monitored byTLC) for the reaction time indicated in Table 2. The resultantclear two-phase reaction mixture was concentrated, dilutedwith H2O and Et2O, and the organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure.The residue was purified by flash column chromatography(PE-Et2O or PE-CH2Cl2) to give 2. |
Multi-step reaction with 2 steps 1.1: pyridinium chlorochromate / dichloromethane / 16 h / Inert atmosphere; Schlenk technique; Molecular sieve 2.1: pyridine; hydroxylamine hydrochloride / water / 1 h / Inert atmosphere; Schlenk technique 2.2: 2 h / Inert atmosphere; Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With tetrakis(μ-trifluoroacetamidato)dirhodium(II); iodosylbenzene In chlorobenzene at 5 - 20℃; Molecular sieve; Inert atmosphere; stereoselective reaction; | |
74% | Stage #1: 2,2,2-trichloroethyl sulfamate; 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose; triacetyl-D-galactal With tetrakis(μ-trifluoroacetamidato)dirhodium(II) In chlorobenzene Molecular sieve; Inert atmosphere; Stage #2: With iodosylbenzene In chlorobenzene at 5 - 20℃; Molecular sieve; Inert atmosphere; stereoselective reaction; | General procedure for one-pot amidoglycosylation General procedure: To a mixture of glycal 1a,b,c (0.2 mmol), alcohol (0.4 mmol),TcesNH2 (80 mg, 0.35 mmol), Rh2(NHCOCF3)4 (12 mg, 0.02 mmol),and activated powdered molecular sieves 4 Å (160 mg) under nitrogen was added PhCl (3 mL), and the resulting light-purple suspension was cooled with an ice-water bath. PhIO (80 mg,0.36 mmol) was added in several portions for 1 h, and the resulting light-brown suspension was stirred at 5°C for 1 h and then at rt for 5-15 h with monitoring the reaction by TLC. The reaction mixture was filtered, washed with CH2Cl2, and the combined filtrates were concentrated under reduced pressure to remove CH2Cl2. The residue was purified by silica gel chromatography, usually eluting with hexane-EtOAc mixture |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 0℃; for 12h;Inert atmosphere; | 3,4,5,6-<strong>[1835-65-0]Tetrafluorophthalonitrile</strong> (4, 768.7 mg, 3.84 mmol) and potassium carbonate (531.0 mg, 3.84 mmol) were dissolved into dry DMF (5 mL) under nitrogen atmosphere. To this solution, 1,2,3,4-di-O-isopropylidene-alpha-D-galactopyranose (5, 1.00 g, 3.84 mmol) in DMF (5 mL) was slowly dropwised at 0 °C and stirred for 12 h. Water was added into the mixture and solids were filtered. The solids were purified by silica gel column chromatography (benzene:AcOEt = 98:2) to furnish 3a as white powder (588.2 mg, 35percent). The product 3a contained a trace amount of regioisomer 3b (3a:3b = 17:1, determined by 19F NMR). This was used for the next reaction without further purification. Major component: 1H NMR (CDCl3, 200 MHz) delta 5.38 (1 H, d, J 4.8 Hz), 4.65-4.59 (1 H, m), 4.58-4.54 (2 H, m), 4.33-4.23 (2 H, m), 4.14-4.09 (1 H, m) 1.50 (3 H, s), 1.42 (3 H, s), 1.32 (6 H, s); 19F NMR (CDCl3, 188 MHz) delta -118.7 (1F, dd, J 10.2 Hz, J 13.2 Hz), -127.6 (1F, dd, J 10.2 Hz, J 20.0 Hz), -132.8 (1F, dd, J 13.2 Hz, J 20.0 Hz); 13C NMR (CDCl3, 151 MHz) delta 154.7, 153.0, 151.0, 149.2, 148.5, 146.7, 142.7, 142.6, 142.5, 109.9, 109.3, 109.0, 96.0, 74.3, 70.7, 67.5, 25.9, 25.8, 24.8, 24.4; IR (KBr) nu 2989, 2933, 2245, 1620, 1583, 1504, 1486, 1541, 1403, 1386, 1309, 1290, 1255, 1215, 1165, 1110, 1092, 1067, 1011, 974, 925, 913, 884, 854, 796, 774, 696, 650, 632 cm-1; element. anal. Found: C, 54.55; H, 4.35; N, 6.36. Requires: C, 54.61; H, 4.53; N, 6.36percent; MS (EI) m/z 425 (M+-Me); minor component: 19F NMR (CDCl3, 188 MHz) delta -128.7 (1F, dd, J 8.6 Hz, J 19.7 Hz), -134.6 (1F, dd, J 8.5 Hz, J 19.7 Hz), -143.5 (1F, t, J 19.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 3,5-di(methoxycarbonyl)-N-(cyanomethyl)pyridinium bromide In dichloromethane at 40℃; for 24h; Inert atmosphere; | |
77% | With copper(I) bromide In dichloromethane at 25℃; for 2h; Inert atmosphere; stereoselective reaction; | General procedure for Glycosylation Reactions General procedure: Under nitrogen atmosphere, the glycal donor (0.100 mmol) and nucleophile acceptor (0.12 mmol) were dissolvedin 1mL dry DCM. Meanwhile CuBr2 (0.005 mmol) was added to the system quickly. The reaction mixture wasstirred at 25 °C until the reaction was determined to be complete by TLC. Then the reaction mixture was quenchedwith sat. aq. NaHCO3, extracted with DCM, the combined organic phases washed with sat. aq. NaHCO3 and brine,dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gelcolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | General procedure: To a solution of 1.00 eq. of saccharide in benzene was added at rt 5.00 eq.of sodium hydroxide (50% in water) as well as 100 mg of benzyl triethylammoniumchloride. The suspension was stirred for an additional hour before 4.00eq. of tosylate was added at once and stirring was continued for 18 h. The solutionwas neutralized with a saturated aqueous solution of ammonium chlorideand the aqueous phase was extracted three times using DCM. The combinedorganic layers were dried over magnesium sulfate, the solvents were removedunder reduced pressure, and the residue was purified by column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 16h;Inert atmosphere; | To a stirred solution of the commercially available galactose his-acetonide (260 mg, 1.00 rnmol) in dichloromethane (10 mL) at room temp under argon was added linolenic acid (278 mg, 1.0 rnmol), dicyclohexylcarbodiimide (206 mg, 1.0 mmol) and DMAP (24 mg, 0.2 mmoi), the reaction mixture was stirred overnight (ca 16 hours) at room temp. The reaction was cooled to -20 C, and filtered, the filtrated, was and evaporated under reduced pressure and the mixture was purified by silica gel chromatography (8:1 to 2:1 Petrol:Et2O) to afford the compound 146 (438 mg, 0.84 mmol, 84 %) as a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With trifluorormethanesulfonic acid In 1,2-dichloro-ethane at 40℃; for 12h; | 3.3. General Procedure for the Glycosylation with GlcNAc Donors General procedure: To a mixture of GlcNAc donor (1.00 mmol) and acceptor (1.50 mmol) in 1,2-dichloroethane(5.0 mL) was added TMSOTf (36 L, 0.2 mmol) at 40 °C. After the reaction was stirred at the same temperature for 12 h, it was quenched by the addition of satd. aq. NaHCO3 (50 mL). The resulting mixture was then extracted with CHCl3 (50 mL x 3) and washed with brine (50 mL). The combined extracts were dried over Na2SO4, filtered off, and concentrated in vacuo. The crude product was purified by flash column chromatography to give the desired GlcNAc glycoside. Additional purification using Sephadex LH-20 (MeOH/CHCl3 = 1:1) was performed if needed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;Inert atmosphere; Cooling with ice; | To a cold (ice-bath) solution of <strong>[78967-07-4]2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetic acid</strong> (<strong>[78967-07-4]mofezolac</strong>, 300 mg, 0.885 mmol) and 1,2:3,4-Di-O-isopropylidene-D-galactose (230 mg, 0.885 mmol) in CH2Cl2 (5 mL) , 4-(dimethylamino)pyridine (DMAP) (27 mg, 0.22 mmol), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC HCl, 680 mg, 3.56 mmol) were added in portions under argon atmosphere. The reaction mixture was stirred at room temperature for 24h and then quenched by adding distilled water. The aqueous phase was extracted three times with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and the solvent removed under reduced pressure. The product (375 mg) was isolated by column chromatography (silica gel; CHCl3/MeOH 95:5) of the reaction crude. 73% Yield. NMR (300 MHz, CDCl3, delta) : 7.41-7.36 (m, 2H, aromatic protons) ; 7.19-7.14 (m, 2H, aromatic protons) ; 6.94-6.89 (m, 2H, aromatic protons) ; 6.85-6.81 (m, 2H, aromatic protons) ; 5.53 (d, 1H, J = 4.95 Hz) ; 4.61 (dd, 1H, J = 8.0 Hz, J = 2.5 Hz) ; 4.34-4.25 (m, 2H) ; 4.18 (dd, 2H, J = 8.0 Hz, J = 1.9 Hz) ; 4.05-3.99 (m, 1H) ; 3.83 (s, 3H OCH3) ; 3.80 (s, 3H, OCH3) ; 3.79 (s, 2H, CH2) ; 1.45 (s, 6H, 2CH3) ; 1.32 (s, 3H) ; 1.31 (s, 3H) . ESI-MS m/z (%) : C31H35NO10 (M + Na)+: 604. |
73% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;Inert atmosphere; Cooling with ice; | General procedure: The procedure to prepare 2 is described. 12 and 13 synthesisfollowed the same procedure used to obtain 2. The exact amountsof reagents are reported in Table 5.To a cold (ice-bath) solution of <strong>[78967-07-4]2-(3,4-bis(4-methoxyphenyl)isoxazol-5-yl)acetic acid</strong> (1, <strong>[78967-07-4]mofezolac</strong>, 300 mg, 0.885 mmol) and1,2:3,4-di-O-isopropylidene-D-galactose (230 mg, 0.885 mmol) inCH2Cl2 (5 mL), 4-(dimethylamino)pyridine (DMAP) (27 mg,0.22 mmol), and N-(3-dimethylaminopropyl)-N0-ethylcarbodiimidehydrochloride (EDC HCl, 680 mg, 3.54 mmol) wereadded in small aliquots under argon atmosphere. The reactionmixture was stirred at room temperature for 24 h and thenquenched by adding distilled water. The aqueous phase wasextracted three times with EtOAc. The combined organic phaseswere dried over anhydrous Na2SO4, filtered, and the solventremoved under reduced pressure. The product (375 mg, 73% yield)was isolated by column chromatography (silica gel; CHCl3/MeOH95:5) of the reaction crude. 4.3.1 1,2:3,4-Di-O-isopropylidene-6-O-{2-[3,4-bis(4-methoxyphenyl)isoxazol-5-yl]acetyl}-d-galactopyranose (2) 1H NMR (300MHz, CDCl3, delta): 7.41-7.36 (m, 2H, aromatic protons); 7.19-7.14 (m, 2H, aromatic protons); 6.94-6.89 (m, 2H, aromatic protons); 6.85-6.81 (m, 2H, aromatic protons); 5.53 (d, 1H, J=4.9Hz); 4.61 (dd, 1H, J=8.0Hz, J=2.5Hz); 4.34-4.25 (m, 2H); 4.18 (dd, 2H, J=8.0Hz, J=1.9Hz); 4.05-3.99 (m, 1H); 3.83 (s, 3H, OCH3); 3.80 (s, 3H, OCH3); 3.79 (s, 2H, CH2); 1.45 (s, 6H, 2CH3); 1.32 (s, 3H); 1.31 (s, 3H). ESI-MS m/z (%): C31H35NO10 (M+Na)+: 604. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With diphenylphosphoranyl azide; triethylamine; In 1,4-dioxane; for 24h;Reflux; | General procedure: To a solution of the corresponding (±)-trans-2-phenylcyclopropane-1-carboxylic acid, 21-25 (2.0 mmol) in 5 cm3 dry tert-butyl alcohol (for 1-4) or 5 cm3 dry toluene (for 5-7) or 5 cm3 dry 1,4-dioxane (for 8) corresponding alcohol (2.4 mmol) (except for 1-4), 0.43 cm3 diphenylphosphoryl azide (2.0 mmol) and 0.33 cm3 TEA (2.4 mmol) were added. The mixture was heated to reflux for 24 h, and then the solvent was removed under reduced pressure. The residue was dissolved in 20 cm3 CH2Cl2 and the solution was washed with 2*25 cm3 saturated sodium bicarbonate and 2*25 cm3 brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography on silica gel [EtOAc/n-hexane (1/1)]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(I) bromide In dichloromethane at 25℃; for 5h; Inert atmosphere; stereoselective reaction; | General procedure for Glycosylation Reactions General procedure: Under nitrogen atmosphere, the glycal donor (0.100 mmol) and nucleophile acceptor (0.12 mmol) were dissolvedin 1mL dry DCM. Meanwhile CuBr2 (0.005 mmol) was added to the system quickly. The reaction mixture wasstirred at 25 °C until the reaction was determined to be complete by TLC. Then the reaction mixture was quenchedwith sat. aq. NaHCO3, extracted with DCM, the combined organic phases washed with sat. aq. NaHCO3 and brine,dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gelcolumn chromatography. |
66% | With eosin y; diphenyldisulfane In dichloromethane at 20℃; Sealed tube; Irradiation; stereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With ammonium cerium (IV) nitrate In water; acetonitrile at 20℃; for 0.25h; | 1,2:3,4-di-O-isopropylidene--D-galactopyranose (2) General procedure: To a solution of the compound 3 (12.0 mg, 32.8 μmol) in MeCN/H2O = 9/1 (3.3 mL) were added CAN(180 mg, 328 μmol) at rt for 15 min. The reaction was quenched by 100 mM aqueous ascorbic acidand the aqueous layer was extracted with AcOEt. The organic phase was washed with satd. aqueousNaHCO3, brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude productwas purified by flash column chromatography on silica gel (Toluene/AcOEt = 2/1) to give compound2 (7.5 mg, 88%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With 2-methyl-1,2-epoxypropane; dmap In tert-butyl methyl ether at 50℃; for 24h; | Results and discussion. Reaction development. The realization of the stereoretentive glycosylation concept outlined above is influenced by the anomeric configuration of the electrophilic substrate. In the current reaction development, a-configured glycosyl bromide 1 was chosen as a model electrophilic partner and galactopyranoside 2 as a glycosyl nucleophile to simplify the analysis of coupling product mixtures 22k). Previous reports have documented the ability of glycosyl bromides to function as one of the most common electrophiles under various glycosylation conditions and to generate as a-configured substrates (Koenig, W., et al., Ber. Dtsch. Chem. Ges. 34, 957-981 (1901); Lanz, et al., Eur. J. Org. Chem., 31 19-3125 (2016)). The reaction of 2 with glucosyl electrophile 1 , having a C(2)-non-participatory benzyl (Bn) group (Nigudkar, et al., Chem. Sci. 6, 2687-2704 (2015)), often proceeds via an SN1 -like pathway to provide the coupling product with poor anomeric selectivity. As expected, use of the conventional Lewis acid, silver triflate (AgOTf), provided a 4: 1 (a:b) mixture of the desired product 3. Upon exploring a range of reaction parameters (FIGs. 23- 28), coupling of 2 with 1 was discovered in the presence of 15 mol% of 4,7-diphenyl-1 , 10-phennathroline (4) as a catalyst and isobutylene oxide (I BO) as a hydrogen bromide scavenger in tert- butyl methyl ether (MTBE) at 50 °C for 24 h and that this provided the highest yield and a-selectivity of 3 (73% yield, a:b > 30: 1). In the absence of catalyst 4, no reaction was apparent after 24 h. The reaction was conducted with other catalysts (5 - 8), and three trends were observed. First, the yield of 3 is correlated with the ability of the catalyst to displace the anomeric bromide. The C(2)- and C(9)-methyl groups of catalyst 5 reduce the accessibility of the pyridine nitrogen atom for displacing the bromide leaving group. Second, the conformation of the catalyst can influence the efficiency and selectivity of the coupling event. For instance, 2,2’-bipyridine (6) is less a-selective than catalyst 4 potentially due the two nitrogen atoms being disrupted by the free-rotation about the bond linking the pyridine rings. Third, the a-selectivity is correlated with the efficiency of the catalyst to promote glycosylation. As expected, pyridine (7) is not as a-selective as phenanthroline catalyst 4. Since 4- (dimethylamino)pyridine (8) is known to be a more effective catalyst than pyridine (7) (Koenig, W., et al., Ber. Dtsch. Chem. Ges. 34, 957-981 (1901)), the product 3 was obtained in higher yield (25% vs. 51 %) (FIG. 22A).[0315] A primary roadblock that hinders study of the role of carbohydrates in many biological processes remains the limited availability of reproducible and predictable glycosylation conditions to allow for routine oligosaccharide synthesis in large and pure quantities. In addition, current techniques are limited to specialists who can produce these constructs. Since the phenanthroline- catalyzed reaction is air- and moisture-tolerant and operationally simple by combining coupling partners 1 and 2 with catalyst 4 and IBO in MTBE under an open air in the flask (FIG. 20B), this system could be suitable for a large-scale synthesis. Accordingly, the reaction was conducted on a 4 mmol scale of 1 and 4.4 mmol of 2 (FIG. 22C). Because the reaction was performed on a gram scale at a relatively high concentration (2 M), a catalyst loading of 5 mol% proved sufficient. The product 3 was attained without any effect on the yield and selectivity. |
86.667 % de | With 2-methyl-1,2-epoxypropane; dmap In tert-butyl methyl ether at 50℃; for 24h; Schlenk technique; Sealed tube; Inert atmosphere; Overall yield = 51 %; stereoselective reaction; | |
85.714 % de | With copper(l) iodide; 2,6-di-tert-butyl-4-methylpyridine; bathophenanthroline; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In [D3]acetonitrile at 25℃; for 24h; Irradiation; Overall yield = 70 percent; diastereoselective reaction; |
88.889 % de | With 2-isopropyloxirane; 2,2':6,2''-terpyridine In tert-butyl methyl ether at 50℃; for 24h; Schlenk technique; Overall yield = 43 percent; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With copper(I) bromide In dichloromethane at 25℃; for 2h; Inert atmosphere; stereoselective reaction; | General procedure for Glycosylation Reactions General procedure: Under nitrogen atmosphere, the glycal donor (0.100 mmol) and nucleophile acceptor (0.12 mmol) were dissolvedin 1mL dry DCM. Meanwhile CuBr2 (0.005 mmol) was added to the system quickly. The reaction mixture wasstirred at 25 °C until the reaction was determined to be complete by TLC. Then the reaction mixture was quenchedwith sat. aq. NaHCO3, extracted with DCM, the combined organic phases washed with sat. aq. NaHCO3 and brine,dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gelcolumn chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With dmap; triethylamine In dichloromethane at 0 - 20℃; | 3. Preparation of 4-iodoarenes 2 General procedure: General Procedure: The preparation of 2 is according to the literature.1 The corresponding alkylamine (5.0 mmol, 1.0 equiv) or alkyl alcohol (5.0 mmol, 1.0 equiv), triethylamine (1.5 mL, 11.0 mmol,2.2 equiv), DMAP (61 mg, 0.5 mmol, 0.1 equiv), and CH2Cl2 (10 mL) were added to a round-bottomedflask. The reaction mixture was cooled to 0 oC with an ice-water bath. 4-Iodobenzoyl chloride (2.0 g,7.5 mmol, 1.5 equiv) dissolved in CH2Cl2 (10 mL) was added dropwise to the reaction mixture withstirring. The reaction was slowly warmed to room temperature. The reaction was monitored by TLC.After the reaction was completed, the reaction mixture was diluted with EtOAc and washed withsaturated ammonium chloride, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated,the residue was purified with silica gel chromatography (petroleum) to afford compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 2,6-di-tert-butyl-4-methylpyridinium trifluoromethanesulfonate In dichloromethane at 20℃; for 40h; Molecular sieve; | General Procedure A: ylide 2i mediated benzylation General procedure: To the mixture of nucleophile 5 and ylide 2i in CH2Cl2 (c = 0.1 M) in the presence of 4 Å MS (50 mg/mL), TfOH·DTBMP in CH2Cl2 was added. The reaction mixture was stirred at room temperature until the reaction was completed. The reaction mixture was quenched with saturated aqueous NaHCO3, filtered through Celite and extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel flash column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With C29H28F6N4OS In fluorobenzene at 80℃; for 48h; Schlenk technique; Inert atmosphere; | 1 General procedure: Put compound 2 (133mg, 0.25mmol), compound 43 (77mg, 0.166mmol) and compound 29 (10mg, 0.0166mmol) in a Schlenk tube. After vacuuming with oil pump for 1 hour, they were replaced with nitrogen and protected under a nitrogen atmosphere. 0.5mL of dry fluorobenzene was added, the reaction system was reacted at 80 for 48h and then cooled to room temperature, concentrated by rotary evaporation, and purified by silica gel column chromatography (PE/EA=10:1) to obtain compound 43'α/43' β (121 mg, 0.122 mmol, 73%, α/β=8.3:1) white solid. |
88% | With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea In toluene at 80℃; for 48h; Inert atmosphere; Sealed tube; stereoselective reaction; | General procedure for organo-catalysis stereoselective glycosylation usingconformation-restrained 2-nitroglucal 5 as the donor General procedure: 2-Nitroglucal donor 5 (1.5 eq) and an acceptor (1.0 eq) were co-evaporatedtwice with toluene, and together with catalyst C4 (0.1 eq, according todonor) were then added to the sealed tube. The sealed tube was evacuatedand flushed with N2 for three times. Dry fluorobenzene (0.5M for donors)was added to the sealed tube under N2 atmosphere at room temperature.The sealed tube was stirred at 80 C for 48 hours and monitored by TLCanalysis. The resulting mixture was transferred into a round-bottomed flaskand concentrated in vacuo. The residue was purified by silica gel columnchromatography to deliver the products. |
88% | With 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea In fluorobenzene at 80℃; for 48h; Inert atmosphere; Sealed tube; stereoselective reaction; | General procedure for organo-catalysis stereoselective glycosylation usingconformation-restrained 2-nitroglucal 5 as the donor General procedure: 2-Nitroglucal donor 5 (1.5 eq) and an acceptor (1.0 eq) were co-evaporatedtwice with toluene, and together with catalyst C4 (0.1 eq, according todonor) were then added to the sealed tube. The sealed tube was evacuatedand flushed with N2 for three times. Dry fluorobenzene (0.5M for donors)was added to the sealed tube under N2 atmosphere at room temperature.The sealed tube was stirred at 80 C for 48 hours and monitored by TLCanalysis. The resulting mixture was transferred into a round-bottomed flaskand concentrated in vacuo. The residue was purified by silica gel columnchromatography to deliver the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With fac-tris(2-phenylpyridinato-C<SUP>2</SUP>,N)iridium(III); cyanomethyl bromide In dichloromethane at 20℃; Molecular sieve; Irradiation; Inert atmosphere; Sealed tube; stereoselective reaction; |
Tags: 4064-06-6 synthesis path| 4064-06-6 SDS| 4064-06-6 COA| 4064-06-6 purity| 4064-06-6 application| 4064-06-6 NMR| 4064-06-6 COA| 4064-06-6 structure
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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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