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CAS No. : | 582-52-5 | MDL No. : | MFCD00005544 |
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 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 60.12 |
TPSA : | 66.38 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.9 cm/s |
Log Po/w (iLOGP) : | 2.61 |
Log Po/w (XLOGP3) : | -0.02 |
Log Po/w (WLOGP) : | 0.38 |
Log Po/w (MLOGP) : | -0.06 |
Log Po/w (SILICOS-IT) : | 0.65 |
Consensus Log Po/w : | 0.71 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.38 |
Solubility : | 11.0 mg/ml ; 0.0422 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.92 |
Solubility : | 31.0 mg/ml ; 0.119 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.6 |
Solubility : | 66.0 mg/ml ; 0.254 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 4.57 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
65% | With poly(4-vinylpyridine) supported iodine In acetone at 50℃; Molecular sieve; Inert atmosphere; | synthesis of (3aR,5S,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-tetrahydrofuro[2,3-d][1,3]dioxol-6-ol D-glucose (10 g, 55.5 mmol) was added to a mixture of P(4-VPI)+I3- (0.6 g, 36.2 mol%) in anhydrous acetone (100 mL) under nitrogen atmosphere. The reaction mixture was refluxed for 6 h and then allowed to room temperature. The reaction mixture was filtered and the catalyst was washed with ethyl acetate (2 x 10 mL). The solvent was evaporated under reduced pressure to getcompound 7as a white solid (9.4 g, 65%). |
With phosphoric acid; acetone; zinc(II) chloride | ||
With sulfuric acid; acetone |
With sulfuric acid; acetone; zinc(II) chloride | ||
With sulfuric acid; acetaldehyde; acetone | ||
With phosphorus pentoxide; acetone | ||
With phosphoric acid; acetone; zinc(II) chloride Reagens 4: Phosphor(V)-oxid; | ||
With sulfuric acid; copper(II) sulfate; acetone |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine In dichloromethane for 2h; | |
81% | With pyridine at 0℃; | |
74% | In pyridine |
68% | With pyridine at 0℃; for 48h; | 1,2:5,6-Di-O-isopropylidene-3-O-methanesulfonyl-α-D-glucofuranose(9) 1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose (3) (2.0 g;7.7 mmol) was dissolved in dry pyridine (6 ml), cooled at 0 °C and methanesulfonyl chloride (0.8 ml) was dropped to the solution. The reaction mixture was allowed to stand for 2 days at 0 °C. After the solution was poured into icewater,the solid crude product was filtered, washed withcold water and recrystallized from methanol (50%) to givewhite crystalline product 9 (1.8 g; 68%). M.p.: 83-84 °C;lit. m.p. (Helferich et al. 1939): 83-84 °C; Rf = 0.44 (hexane-EtOAc 2:1). |
With pyridine | ||
With dmap; triethylamine In dichloromethane | ||
With pyridine In dichloromethane at -10℃; Yield given; | ||
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.9% | With pyridine at 80 - 85℃; for 25h; | |
83% | With pyridine at 0 - 20℃; | 1,2:5,6-Di-O-isopropylidene-3-O-toluenesulfonyl-α-D-glucofuranose(10) (I) 1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose (3)(3.9 g; 15.0 mmol) was dissolved in dry pyridine (15 ml)and p-toluenesulfonyl chloride (5.7; 29.9 mmol) was addedto the solution with stirring at room temperature. The suspensionwas stirred for 1 day and allowed to stand for overnightat 0 °C. The reaction mixture was poured into icewater,the precipitate was filtered, washed with cold water.The cream-coloured crude material was recrystallized fromethanol (95%) to give white crystalline product 10 (5.1 g;83%). M.p.: 125-127 °C; lit. m.p. (Whistler and Doner1972): 122-123 °C; Rf = 0.80 (hexane-EtOAc 2:1).(II) From 3 (19.5 g; 75.0 mmol) the yield was 81% (25.1 g). |
82% | In pyridine |
With pyridine | ||
With potassium hydroxide | ||
With pyridine In dichloromethane Ambient temperature; | ||
With pyridine at 0℃; for 8 - 10h; | 3.a To a solution of diacetoneglucose (8 g) (commercially available) in pyridine (20 ml) was added a solution of p-toluenesulphonyl chloride (4 g) in pyridine (20 ml) at 0° C. The reaction mixture was stirred for 8-10 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was washed with hexane to obtain the title compound (8 g). | |
With pyridine at 0℃; for 8 - 10h; Neat (no solvent); | 3.a To a solution of diacetoneglucose (8 g) (commercially available) in pyridine (20 ml) was added a solution of p-toluenesulphonyl chloride (4 g) in pyridine (20 ml) at 0°C. The reaction mixture was stirred for 8-10 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was washed with hexane to obtain the title compound (8g). | |
With pyridine In pyridine at 0℃; for 8 - 10h; | 3.a To a solution of diacetoneglucose (8 g) (commercially available) in pyridine (20 ml) was added a solution of p-toluenesulphonyl chloride (4 g) in pyridine (20 ml) at 0° C. The reaction mixture was stirred for 8-10 hours. The solvent was evaporated under reduced pressure and the residue thus obtained was washed with hexane to obtain the title compound (8 g). | |
With pyridine at 0℃; for 8 - 10h; | 3.a Example 3: Synthesis of l,2;5,6-Di-O-isopropylidene-3-deoxy-3-([{4-(2-methoxy-2-oxo- ethvD-phenyll-aminol-carbonvD-amino-α-D-glucofuranoside (Compound No. 4)Step a: Synthesis of l,2;5,6-Di-0-isopropylidene-3-0-tosyl-α-D-glucofuranoside To a solution of diacetoneglucose (8 g) (commercially available) in pyridine (20 ml) was added a solution of p-toluenesulphonyl chloride (4 g) in pyridine (20 ml) at 0°C.The reaction mixture was stirred for 8-10 hours. The solvent was evaporated under EPO reduced pressure and the residue thus obtained was washed with hexane to obtain the title compound (8g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With solid catalyst supported on silica gel, sulfuric acid, acetic acid; In dichloromethane; at 30℃; for 14h; | 1) weigh the 0.1 mol of diacetone glucose and 3mol ofdichloromethane and stirred until it mixed evenly; 2) into the above mentioned reaction system added 0.01mol ofSilica-Supported Sulfuric Acid-glacial acetic acid (with the content count of hydrogen titration) and stirred at 30oC for14h; 3) filtering, washing the filter cake methanol and the combined filtrate and washings, 40 C and concentrated under reduced pressure to a solid, was added a molar ratio of 1: 2: 6 tert-butyl methyl ether and iso-hexane, 3 C crystallization 3h, get monopropyl fork glucose 0. 093mol, 97% purity, 93% yield. |
85% | With water; acetic acid; at 25℃; | d-Glucose diacetonide 5 (10 g 38.4 mmol) was dissolved in a mixture of acetic acid (100 mL) and water (50 mL). The mixture was stirred for 12 h at 25 C. The crude was concentrated under vacuum at 50 C. A pure compound was obtained by recrystallization from ethyl acetate to give triol compound 6 (7.2 g, 32.64 mmol, 85%).[alpha]D20 = -11.2 (c 1.1, H2O); IR (KBr): 3420, 2952, 2795, 1434, 1322, 1275, 1235, 1095, 1043 cm-1. 1H NMR (300 MHz, CD3OD): delta 1.32 (s, 3H), 1.47 (s, 3H), 3.62 (dd, J = 6.0, 11.7 Hz, 1H), 3.79 (dd, J = 3.0, 11.8 Hz, 1H), 3.90-3.94 (m, 1H), 4.04 (dd, J = 2.6, 8.3 Hz, 1H), 4.22 (d, J = 2.3 Hz, 1H), 4.51 (d, J = 3.4 Hz, 1H), 5.90 (d, J = 3.4 Hz, 1H). 13C NMR (75 MHz, CD3OD): delta 26.4, 27.0, 65.3, 70.4, 75.5, 81.3, 86.5, 106.4, 112.7. HRMS (ESI-MS): m/z [M+Na]+ calcd for C9H16O6Na: 243.0845; found: 243.0850. |
85% | With silica supported polyphosphoric acid; In acetonitrile; at 55℃; for 0.5h; | General procedure: 3-O-Benzyl-1,2:5,6-di-O-isopropylidene-a-D-allofuranose (1) (100 mg) wasdissolved in CH3CN (2 ml) and PPA-SiO2 (100mg, 0.16 mmol, based uponPPA weight) was added.[3] The reaction mixture was stirred at 55 C for30 min. After completion of the reaction (monitored by TLC), the mixturewas allowed to cool to room temperature. Further, the reaction mixturewas filtered through filter paper, washed with CH3CN (1 x 5 ml).Evaporation of the solvent under reduced pressure yielded 3-O-Benzyl-1,2-O-isopropylidene-a-D-allofuranose (2)[17] as a crude oily compound. Thecrude compound 2 was purified by column chromatography to obtain colorless oily compound (75 mg, 85%); Rf0.31 (petroleum ether: EtOAc 1:1). |
78% | With water; iodine; In acetonitrile; at 20℃; for 7h; | 1,2-O-isopropylidene-alpha-D-glucofuranosewas prepared by a modification of the method of Yadav et al.[32] Iodine (1.47 g, 5.8 mmol, 0.3eq.) was added to a solution of 1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose (5.00 g, 19.2mmol) in MeCN (270 mL). H2O (2 mL) was added, and the reaction mixture was stirred atroom temperature for 7 h. The reaction was quenched with saturated aqueous Na2S2O3 solutionand extracted into EtOAc (5 x 200 mL). The organic layers were dried over anhydrousNa2SO4, the solvent removed and the crude mixture was purified by column chromatography(silica) using EtOAc/hexane 2:1, EtOAc and EtOAc/MeOH 1:0.01 to give the product as awhite powder (3.29 g, 14.9 mmol, 78% yield). Rf 0.23 (EtOAc, silica); [alpha]26D -18.3 (c 1.00, H2O)(lit. [alpha]22D -12.0 (c 1.0, H2O)[33]). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1,3-dimethylbarbituric acid In methanol at 40℃; | |
99% | With tetrakis(triphenylphosphine) palladium(0); p-toluene sulfinic acid In dichloromethane for 0.416667h; Ambient temperature; | |
99% | With 1,3-dimethylbarbituric acid In tetrahydrofuran at 90℃; for 24h; |
95% | With aminomethyl resin-supported N-propylbarbituric acid In tetrahydrofuran at 90℃; for 24h; | |
66% | With oxygen; copper(l) chloride; palladium dichloride In water; N,N-dimethyl-formamide | |
66% | With sodium periodate; osmium(VIII) oxide; 4-methylmorpholine N-oxide In 1,4-dioxane at 60℃; for 18h; | |
With oxygen; copper(l) chloride; palladium dichloride In water; N,N-dimethyl-formamide Ambient temperature; | ||
Multi-step reaction with 2 steps 1: NBS / CCl4 / 0.5 h / Heating; Irradiation 2: 3 M aq. NaOH / CCl4 / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane; water for 1h; Sealed tube; Irradiation; | |
90% | With hydrogen In various solvent(s) at 20℃; for 10h; | |
87.3% | With 3,3-dimethyldioxirane In dichloromethane; acetone for 48h; Ambient temperature; |
81% | With aluminum oxide; tetrabutylammomium bromide; periodic acid In dichloromethane at 20℃; for 1.5h; | General procedure General procedure: Wet alumina was prepared by mixing neutral alumina (50g, Fluka (ref 06300), Brockmann activity 1)with water (10g) and shaking until a free-flowing homogeneous powder was obtained.To a solution of the benzylidene acetal (1mmol) in CH2Cl2 (10 mL) was successively added wet Al2O3(2.2 g), NBu4Br (0.16 g, 0.5 equiv) and H5IO6 (0.68 g, 3 equiv) and the suspension was vigorouslystirred at room temperature for 90 min. The resulting orange suspension was poured to a column ofsilica gel and the hydroxybenzoates was separated with an appropriate mixture of petroleum ether-AcOEt or petroleum ether-ether |
60% | With N-Bromosuccinimide; calcium carbonate In tetrachloromethane; water for 1h; Irradiation; | |
Multi-step reaction with 2 steps 1: ozone / CH2Cl2 / 0.83 h / 0 °C 2: NaOCH3 / methanol / 15 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With iodine | |
93% | With phosphoric acid; zinc(II) chloride | |
89% | In acetonitrile at 20℃; for 10h; |
88% | With tetrapropylammonium tribromide at 20℃; for 8h; diastereoselective reaction; | |
84% | With dimethylbromosulphonium bromide at 20℃; for 10h; | |
80% | With iodine | |
77% | With sulfuric acid; copper(II) sulfate | |
75% | With iodine; acetic anhydride at 20 - 59℃; for 3h; | 1 EXAMPLE 1; 3-Azido-3-deoxy-1,2-di-O-isopropylidene-α-D-ribofuranoside; 13-Azido-3-deoxy-1,2-di-O-isopropylidene-α-D-ribofuranoside (1) was prepared from glucose following procedures based on those described in R. L. Whistler et al., J. Org. Chem., (1972) 37, 3187 and P. Stazewski et al., Tetrahedron (1998) 54. To a mixture of glucose (220 g, 1099 mmol) in acetone (3.6 L) was added iodine (14.1 g, 55.4 mmol) and acetic anhydride (170 g, 1667 mmol) at room temperature. The mixture was refluxed at 59° C. for 3 h and allowed to cool whereupon triethylamine (338 g) was added slowly at ambient temperature, filtered the solid and washed twice with acetone (100 mL). The filtrate was concentrated under vacuum and water was added (600 mL). The organic layer was extracted thrice with toluene (600 mL) and the combined organic phases were concentrated. Heptane (800 mL) was added with stirring, filtered and the solid, washed with heptane-acetone (2:1, 750 mL) to obtain white crystalline solid (217 g, 75%) 1, 2:5,6-di-O-isopropylidene-α-D-glucofuranoside, or diacetone glucose. |
71.5% | for 2h; Heating; | |
68% | With phosphoric acid; zinc(II) chloride at 20℃; for 36h; | |
64% | With K 10 clay at 50℃; for 72h; | |
60% | With iron(III) chloride at 20℃; for 24h; | D-glucose(10.0 g, 55.6 mmol) was dissolved in dry acetone (500 mL). To it FeCl3 (5.4g) was added and the contents were stirred for 24 h at RT. The reaction was quenched by addition of 10% K2CO3 solution (200 mL).Solvent was evaporated under reduced pressure, and residue was extracted withCHCl3 (3 x 100 mL). The combined organic layers were washed withwater, dried over Na2SO4 and concentrated under reduced pressure. Chromatography on silica gel afforded 2 (8.7 g, 60%) as white crystals. 1H NMR (300 MHz, CDCl3,δ, ppm): 1.32 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.45 (s,3H, CH3), 1.50 (s, 3H, CH3), 2.66 (d, J=3.6 Hz, 1H, OH),3.99 (dd, J=8.7 Hz and 5.4 Hz, 1H), 4.08 (dd, J=7.5 Hz and 2.4 Hz, 1H), 4.17(t, J=8.4 Hz, 1H), 4.35 (dd, J=12.3 Hzand 5.7 Hz, 2H), 4.54 (d, J=3.3 Hz, 1H, H-2), 5.95 (d, J=3.3 Hz, 1H, H-1).13C NMR (75 MHz, CDCl3, δ ppm): 25.2 (CH3),26.2 (CH3), 26.7 (CH3), 26.8 (CH3), 67.6(C-6), 73.2 (C-5), 75.0 (C-4), 81.3 (C-3), 85.1 (C-2), 105.3 (C-1), 109.6(C-8), 111.8 (C-7). HRMS (ESI-TOF) m/z: [M+Na]+ calcd for C12H20O6Na283.1152; Found 283.1158. |
47% | With iodine at 20℃; for 3.5h; | |
43.4% | With phosphoric acid; zinc(II) chloride | |
43% | With phosphoric acid; zinc(II) chloride for 36h; Reflux; | |
42% | With sulfuric acid at 20℃; for 24.5h; Cooling with ice; | 1,2:5,6-Di-O-isopropylidene-a-D-glucofuranose. A suspension of D-glucose (50.1 g, 278mmol) in acetone (1000 ml) was stirred vigorously on an ice bath. Sulfuric acid(40.0 ml) was added dropwise for 30 min. After the reaction mixture was stirredfor 24 h at room temperature, NaOH aq. was added to the solution to neutralize.After removal of insoluble materials by filtration, the filtrate wasconcentrated in vacuo. The residue was dissolved in CHCl3 andwashed with water, sat. NaHCO3 aq., and brine. The CHCl3layer was dried over MgSO4 and concentrated in vacuo. Theresidue was purified by crystallization from AcOEt and hexane to give colorlessneedles (29.9 g, 42%).1H-NMR (600 MHz, CDCl3) d 6.44 (1H, s, H-1),5.02 (1H, s, H-2), 4.86-4.79 (2H, m, H-4, H-5), 4.66 (1H, dd, Jgem = 9.5 Hz, J6a,5 = 6.5 Hz, H-6a), 4.56(1H, d, J3,4 = 7.5 Hz,H-3), 4.51 (1H, dd, Jgem =9.5 Hz, J6b,5 = 6.8 Hz,H-6b), 3.62 (1H, bs, 3-OH), 2.00 (3H, s, CH3), 1.95 (3H, s, CH3),1.87 (3H, s, CH3), 1.82 (3H, s, CH3); 13C-NMR(150 MHz, CDCl3) d 111.7, 109.4, 105.1, 85.0, 81.1, 74.7, 73.0,67.5, 26.7, 26.7, 26.1, 25.1; HRMS (positive mode); Found: m/z 283.1153[(M+Na)+], Calcd. for C12H20O6Na: 283.1152. |
In solid matrix | ||
With sulfuric acid; potassium carbonate 1.) sonicated, 60 min, 2.) sonicated, 30 min; var. reagents,; Yield given. Multistep reaction; | ||
With phosphoric acid; zinc(II) chloride for 18h; Ambient temperature; | ||
With phosphoric acid In water at 20℃; for 30h; | 1.1E IE. Preparation of l,2:5,6-Di-0-isopropylidene-α-D-glucofuranose: A suspension of 150 grams (0/83 mol) of dry D-glucose, 120 grains (0.83 mol) of anhydrous zinc chloride and 7.5 grams of phosphoric acid (88% v/v) in 1 L of dry acetone was stirred at ambient temperature for 30 hours. Unchanged glucose was removed by filtration, and inorganic salts were precipitated by the addition of a solution of 58 grams of sodium hydroxide in 85mL of water. The resulting suspension was filtered, the residue washed with acetone and the acetone layer evaporated. The mass was dissolved in 200 mL of water and extracted with five 100-mL portions of dichloromethane. The organic phase was dried and evaporated on rotary evaporator. Recrystallisation from light petroleum (b.p. 80-100°C) gave 70 grams of product, m.p. 109-1100C, [α]20D -18.5° (c 5 in H2O). | |
With phosphoric acid; zinc(II) chloride | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyridine In toluene at -78℃; | |
87% | With pyridine In tetrahydrofuran at -78℃; Yields of byproduct given; | |
87% | With pyridine at -78℃; for 1h; Inert atmosphere; diastereoselective reaction; |
With pyridine In tetrahydrofuran at -78℃; other bases and solvents: diastereoselectivity; | ||
With pyridine In tetrahydrofuran at -78℃; | ||
With N-ethyl-N,N-diisopropylamine In toluene at -78℃; | ||
With pyridine In tetrahydrofuran at -78℃; Yield given; Yields of byproduct given. Title compound not separated from byproducts; | ||
With pyridine In tetrahydrofuran at 70℃; for 5h; Title compound not separated from byproducts; | ||
With pyridine In tetrahydrofuran at -78℃; for 1h; Title compound not separated from byproducts; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine In toluene at -78℃; | |
90% | With N-ethyl-N,N-diisopropylamine In toluene at -78℃; | |
90% | With N-ethyl-N,N-diisopropylamine In toluene at -78℃; for 1h; Inert atmosphere; diastereoselective reaction; |
With N-ethyl-N,N-diisopropylamine In toluene at -78℃; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine In dichloromethane at -20℃; for 2h; | |
100% | With pyridine In dichloromethane at -0.16℃; for 2h; | 2.1.1. Synthesis of isopropyl 3-deoxy-a-D-ribo-hexopyranoside,(I) (Scheme 1). Anhydrous pyridine (2.48 ml, 30.7 mmol)was added to a solution of 1,2:5,6-di-O-isopropylidene--dglucofuranose,(V) (2.00 g, 7.7 mmol), in anhydrous CH2Cl2(60 ml) at 273 K. Triflic anhydride (2.6 ml, 15.4 mmol) wasadded dropwise and the resulting mixture was stirred at 273 Kfor 2 h. The reaction was quenched by pouring the reactionmixture into ice-cold 5% aqueous NaHCO3 solution (50 ml).After isolating the organic phase, the aqueous phase was extracted twice with CH2Cl2 (2 50 ml). The organic phaseswere combined and concentrated at 303 K in vacuo to give1,2:5,6-di-O-isopropylidene-3-O-triflyl--d-ribo-hexofuranose,(VI), as a yellow solid in nearly quantitative yield (3.0 g,7.7 mmol). NMR spectral data obtained for (VI) were consistentwith those reported previously (Dias et al., 2019; Russell etal., 1990). |
99% | With pyridine In dichloromethane at -17℃; for 4.5h; | 4.2. 1,2:5,6-di-O-isopropylidene-3-O-trifluoromethanesulfonyl-α-D-glucofuranose (3) 3 was prepared by a 1-step reaction using a literature method [27]as follows: 14 (1042 mg, 4 mmol) and pyridine (1249 μL, 15.5 mmol) were dissolved in CH2Cl2 (83 mL), and the mixture was cooled to -17 °C. Trifluoromethanesulfonic anhydride (808 μL, 4.8 mmol) was added to the solution, and the mixture was stirred for 4.5 h. The reaction mixture was poured to mixture of ice (20 g) and saturated aqueous NaHCO3 (20 mL), and the mixture was extracted with CH2Cl2 (50 mL×2). The combined organic layer was dried over Na2SO4, and the mixture was filtered. The filtrate was concentrated under reduced pressure at <37 °C, and pyridine was azeotropically removed by toluene(100 mL×3). The residue was dissolved in hexane (160 mL), and supernatant was filtered. The filtrate was concentrated under reduced pressure at <37 °C, 3 (1548 mg, 99%) was obtained: colorless powder; mp 70 °C (dec., from hexane; lit. 70.0 °C from light petroleum [27]); 1HNMR (600 MHz, CDCl3): δ 5.99 (d, 1H, J=4.1 Hz, H-1), 5.26 (d, 1H,J=2.1 Hz, H-3), 4.77 (d, 1H, J=4.1 Hz, H-2), 4.23-4.18 (m, 2H, H-4and H-5), 4.15 (dd, 1H, J=8.9, 5.5 Hz, H-6a), 3.97 (dd, 1H, J=8.9,4.1 Hz, H-6b), 1.52 (s, 3H, Me), 1.43 (s, 3H, Me), 1.34 (s, 3H, Me), 1.33(s, 3H, Me). |
98% | With pyridine In dichloromethane at -10℃; for 1.5h; | |
98% | With pyridine In dichloromethane at -10℃; for 1.5h; | |
98% | With pyridine In dichloromethane at -10℃; for 1.5h; Inert atmosphere; Cooling; | (3aR,5S,6R,6aR)-6-Azido-2,2-dimethyl-5-[(prop-2-en-1-yloxy)methyl]tetrahydro-2Hfuro[2,3-d][1,3]dioxole (2b) The compound S19 was synthesized following literature procedure [SR12]. Thus, to a threenecked flask charged with S9 (3 g, 11.54 mmol) in dichloromethane (30 mL) under argon cooledat -10 °C was slowly added triflic anhydride (6.5 g, 23.08 mmol) and pyridine (3.65 g, 0.384 mmol). After completion (TLC) reaction mixture was poured onto ice water (1 L) and theaqueous phase was extracted with dichloromethane (4 × 100 mL). Pooled organic layers weredried over Na2SO4, and repeatedly co-evaporated with toluene to remove pyridine. The brownresidue was extracted with hexane (3 × 50 mL) and evaporation of hexane yielded the desiredproduct as white crystals (4.25 g, 98%). |
94.5% | With pyridine In dichloromethane at -10℃; for 1h; | 1 The above diacetone glucose (200 g, 786 mmol) was dissolved in dichloromethane (2.7 L) and pyridine (121 g, 1.53 mmol) was added. The mixture was cooled to -10° C. and trifluoromethanesulfonic anhydride (257 g, 911 mmol) was added dropwise and stirred for 1 hour at -10° C. Water (1.6 L) was added to the mixture and allowed to warm to ambient temperature and the organic phase was separated. The aqueous layer was extracted twice with 300 mL dichloromethane and the combined organic phases were washed twice with 450 mL water and evaporated in vacuo at a temperature below 35° C. The residue was taken up in diethyl ether (1 L) and extracted with cold 2 N hydrochloric acid (1 L). The organic phase was separated and the aqueous layer was extracted with diethyl ether (100 mL) and the combined organic phases were washed with water, brine (400 mL each) and saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was filtered through 250 g silica gel and the silica gel was eluted with 2 L diethyl ether. Evaporation of the solution and drying under high vacuum afforded 285.0 g (94.5%) of 1, 2:5,6-Di-O-isopropylidene-3-O-trifluoromethanesulfonyl-α-D-glucofuranoside. |
90% | With pyridine In dichloromethane at -10℃; for 2h; Inert atmosphere; | 1,2:5,6-Di-O-isopropylidene-3-O-trifluoromethanesulfonyl-α-d-glucofuranose(8) 1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose (3) (3.0 g;0.01 mol) was dissolved in dichloromethane (30 ml) containingpyridine (2.8 ml). The reaction mixture was cooledat -10 °C and under N2-atmosphere trifluoromethanesulfonicanhydride (2.9 ml) was dropped to the solution. Thereaction mixture was stirred for 2 h. After the solution waspoured into ice-water, the aqueous phase was extractedwith dichloromethane. The organic phase was dried(Na2SO4), filtered and concentrated in vacuo. The whitecrystalline product 8 crystallized from n-hexane (4.1 g;90%). M.p.: 76-77 °C; lit. m.p. (Hall and Miller 1976):70 °C; Rf = 0.61 (hexane-EtOAc 1:2). |
82% | With pyridine In dichloromethane at -10℃; for 0.25h; Inert atmosphere; | |
With pyridine In dichloromethane | ||
With pyridine 1.) -20 deg C, 1 h; 2.) up to RT; Yield given; | ||
With pyridine In dichloromethane at -30℃; Yield given; | ||
With pyridine In dichloromethane at 0℃; for 1h; | ||
With pyridine at 0℃; for 1h; | ||
In pyridine; dichloromethane at -15℃; for 1h; | ||
With pyridine In dichloromethane at -10℃; | ||
Stage #1: trifluoromethylsulfonic anhydride With pyridine In dichloromethane at -15℃; for 0.5h; Stage #2: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose In dichloromethane at -15℃; for 1h; Further stages.; | ||
With pyridine at 0℃; | ||
With pyridine | ||
With pyridine In dichloromethane at 0℃; | ||
With pyridine In toluene at 0 - 10℃; for 6h; Large scale; | 1 Example 1 [(3aR,5R,6S,6aR)-5-[(4R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2,2-dimethyl-3a,5,6,6a- tetrahydrofuro[2,3-d][l,3]dioxol-6-yl] trifluoromethanesulfonate (compound III) To a 1500 L glass-lined reactor was charged with (3aR,5S,6S,6aR)-5-[(4R)-2,2-dimethyl- l,3-dioxolan-4-yl]-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][l,3]dioxol-6-ol (compound (II), 60.0 kg, 231 mol), toluene (600 L) and pyridine (36.4 kg, 460 mol) at 5 °C-15 °C. After cooled to 0 °C-10 °C, the reaction mixture was then charged with Tf20 (78.0 kg, 276 mol) dropwise at 0 °C-10 °C over 2 hours and stirred at 0 °C-10 °C for another 4 hours. The reaction was then quenched by adding water (180 L) at 0 °C-10 °C slowly. After phase separation, the organic phase was washed with 10% AcOH (240 L, three times), sat. NaHC03 (240 L, twice) and water (180 L), dried with Na2S04 (60 kg) for 4 hours. The solid was removed by vacuum filtration and the wet cake was washed with toluene (30 L). The combined organic phase (solution A) was used for next step without further purification. | |
With pyridine In dichloromethane at 0℃; Inert atmosphere; | ||
In dichloromethane at 0℃; for 3h; Inert atmosphere; | Diol 2 Pyridine (38 mL, 0.473 mol) was added to an stirred solution of 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose 1 (50.0 g, 0.192 mol) in CH2Cl2(800 mL) at 0C. Trifluoromethanesulfonic anhydride (33 mL, 0.196 mol)was added to the previous solution during a period of 30 min keeping thetemperature under 5C. The coldbath was removed and the reaction mixturewas stirred for 3 h. The organic phase was washed with 1M HCl(2100 mL) then dried over Na2SO4. The solvent was removed underreduced pressure and coevaporated with toluene (250 mL) to furnish thecorresponding triflate. Crude product was dissolved in anhydrous DMF(250 mL), then mixed subsequently with tetrabutyl ammonium chloride(270 mg, 0.97 mmol) and sodium azide (25 g, 0.38 mol). The reaction mixturewas heated at 60C for 4 h and then cooled down. The organic phasewas partitioned with the addition of water (750 mL) and extracted withdiethyl ether (4100 mL). The combined organic extractions were driedover Na2SO4, filtered and concentrated under reduced pressure. A mixtureof methanol (210 mL), water (260 mL), acetic acid (160 mL) was added tothe crude azide and warmed to 60C for 6 h, then cooled down. The mixturewas neutralized via addition of solid sodium bicarbonate followed byextraction with ethyl acetate (3200 mL). The combined organic extractswere dried over Na2SO4, filtered and concentrated under reduced pressure.The residue was purified by flash chromatography (7:3 ethyl acetate/hexanes)to give diol 2 as an oil (18.6 g, 40% over 3 steps); 1H NMR(400 MHz, CDCl3) d 5.75 (d, J3.7 Hz, 1 H), 4.72 - 4.67 (m, 1 H), 4.00(dd, J9.3, 4.1 Hz, 1 H), 3.92 (dd, J7.2, 3.7 Hz, 1 H), 3.65 (dd, J10.3,5.4 Hz, 2 H), 3.56 (dd, J9.3, 4.8 Hz, 1 H), 1.51 (s, 3H), 1.30 (s, 3 H); 13CNMR (101 MHz, CDCl3) d 113.22, 104.04, 80.57, 77.84, 71.57, 62.96, 60.26,26.41, 26.38; HRMS (ESI) calc’d for C9H15N3NaO5 [MNa] m/z268.09039, found 268.08939; FT-IR (azide) 2109.0 cm1. | |
With pyridine In dichloromethane at 0℃; for 1h; Inert atmosphere; | ||
With pyridine In dichloromethane at -20℃; for 1.33333h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 20℃; for 5h; | |
100% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: benzyl bromide In tetrahydrofuran at 40℃; for 10h; | |
100% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 8h; |
100% | With sodium hydride In N,N-dimethyl-formamide at 0 - 24℃; for 2h; | |
100% | With sodium hydride In N,N-dimethyl-formamide at 25℃; for 6h; | |
99% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 18h; Inert atmosphere; | |
98% | With sodium hydride | |
98% | With sodium hydride In tetrahydrofuran at 50℃; | |
98% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2h; | 3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (17) In a cooled (0 °C) solution of 11 (3.0 g, 11.53 mmol) in anhydrous DMF (45 mL) were added successively 80% NaH (0.829 g, 34.54 mmol) and BnBr (1.78 mL, 15.0 mmol). After 0.5 h, the cooling bath was removed and stirring was continued at room temperature for additional 1.5 h. Methanol (10 mL) was then added to the mixture and the stirring was continued for an additional 20 min. The reaction solution was evaporated and the residue was dissolved in a mixture of CH2Cl2 (3 × 50 mL) and H2O (300 mL). The organic phases were separated and combined, dried and evaporated. The remaining crude 17 was purified by flash chromatography (17:3 light petroleum/ Et2O) whereby pure product 17 (3.946 g, 98%) was obtained in the form of a colourless glass, [α]D = -28.1 (c 1.0, CHCl3), lit.1 [α]D = -26.4 (c 1.2, CHCl3); Rf = 0.26 (9:1 toluene/Et2O).IR (film): νmax 1602 (Ph).1H NMR (250 MHz, CDCl3): δ 1.32, 1.39, 1.45 and 1.51 (4 × s, 3 H each, 2 × Me2C), 3.98-4.07 (m, 2 H, J3,4 = 3.0, J5,6a = 5.9, J6a,6b = 10.5 Hz, H-3 and H-6a), 4.09-4.20 (m, 2 H, J4,5 = 7.0, J5,6b = 6.1, J6a,6b = 10.5 Hz, H-4 and H-6b), 4.39 (m, 1 H, J4,5 = 7.0, J5,6a = 5.9, J5,6b = 6.1 Hz, H-5), 4.60 (d, 1 H, J1,2 = 3.7 Hz, H-2), 4.65 and 4.61 (2 × d, 1 H each, Jgem = 11.8 Hz, PhCH2), 5.91 (d, 1 H, J1,2 = 3.7 Hz, H-1), 7.30-7.40 (m, 5 H, Ph). 13C NMR (62.5 MHz, CDCl3): δ 25.4, 26.2, 26.7 and 26.8 (2 × CMe2), 67.3 (C-6), 72.3 (PhCH2), 72.4 (C-5), 81.2 (C-4), 81.6 (C-3), 82.6 (C-2), 108.2 (C-1), 108.9 and 111.7 (2 × Me2C), 127.8, 128.3, 129.6 and 137.6 (Ph). HRMS (ESI): m/e 373.1618 (M++Na), calcd for C19H26NaO6: 373.1622; m/e 368.2062 (M++NH4), calcd for C19H30NO6: 368.2068. |
97% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2.5h; | |
97% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; | 3-O-Benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (9) To a cooled (0 °C) solution of compound 8 (4.75 g, 18.25 mmol) in dry DMF (100 mL), were added NaH (1.13 g, 47.08 mmol) and BnBr (3.0 mL, 25.22 mmol). The reaction mixture was stirred at 0 °C for 0.5 h, and then at room temperature for an additional 2 h. Methanol (20 mL) was then added to the reaction mixture and the stirring at room temperature was continued for another 20 min. The mixture was evaporated, and the residue was distributed between CH2Cl2 (100 mL) and water (100 mL). The aqueous phase was extracted with CH2Cl2 (2 × 100 mL), the organic layers were combined, dried, and evaporated. The residue was purified by flash column chromatography (19:1 toluene/Et2O), to give pure 9 (6.19 g, 97%) as a colourless syrup, [α]D = -28.1 (c 1.0, CHCl3), lit.1 [α]D = -26.4 (c 1.2, CHCl3), Rf = 0.33 (17:3 light petroleum/Et2O). |
97% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2.5h; | 3-O-Benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (9) To a cooled (0 °C) solution of compound 8 (4.75 g, 18.25 mmol) in dry DMF (100 mL), were added NaH (1.13 g, 47.08 mmol) and BnBr (3.0 mL, 25.22 mmol). The reaction mixture was stirred at 0 °C for 0.5 h, and then at room temperature for an additional 2 h. Methanol (20 mL) was then added to the reaction mixture and the stirring at room temperature was continued for another 20 min. The mixture was evaporated, and the residue was distributed between CH2Cl2 (100 mL) and water (100 mL). The aqueous phase was extracted with CH2Cl2 (2 × 100 mL), the organic layers were combined, dried, and evaporated. The residue was purified by flash column chromatography (19:1 toluene/Et2O), to give pure 9 (6.19 g, 97%) as a colourless syrup, [α]D = -28.1 (c 1.0, CHCl3), lit.1 [α]D = -26.4 (c 1.2, CHCl3), Rf = 0.33 (17:3 light petroleum/Et2O). |
96% | With sodium hydride In acetonitrile at 180℃; for 0.0166667h; microwave irradiation; | |
95% | With barium dihydroxide; barium(II) oxide In dimethyl sulfoxide for 16h; | |
95% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With potassium hydroxide In dimethyl sulfoxide for 0.5h; Stage #2: benzyl bromide In dimethyl sulfoxide at 20℃; for 14h; | 4.4.7 3-O-Benzyl-1,2-5,6-O-diisopropylidene-α-d-glucofuranose (30) [42,43] Diacetonide-d-glucose (5g, 19.2mmol) was added to a suspension of KOH (4.3g, 76.8mmol) in anhydrous DMSO (32mL). After 30min stirring, BnBr (4.6mL, 38.4mmol) was added. The reaction mixture was stirred for 14h at room temperature, diluted with water (20mL), extracted three times with diethyl ether. The organic layers were dried over Na2SO4, concentrated under reduced pressure. The oil obtained was purified on silica gel chromatography column (hexane/ethyl acetate, 9/1 then 8/2, v/v) to give the corresponding protected compound as yellow oil (6.4g, 95%). Rf (Hexane/EtOAc, 8/2, v/v) 0.28. 1H NMR (400MHz, DMSO-d6) δ=7.40-7.25 (m, 5H, H-Ar), 5.85 (d, J=3.76Hz, 1H, H-1), 4.72 (d, J=3.8Hz, 1H, H-2), 4.69 (d, J=11.9Hz, 1H, H-7), 4.54 (d, J=11.86Hz, 1H, H-7′), 4.28 (dd, J=6.14-6.78Hz, 1H, H-5), 4.1 (dd, J=3.14-6.78Hz, 1H, H-4), 3.98 (dd, J=6.14-8.35Hz, 1H, H-6), 3.93 (d, J=3.14Hz, 1H, H-3), 3.8 (dd, J=6.38-8.35Hz, 1H, H-6′), 1.4-1.1 (4s, 12H, C(CH3)2). 13C NMR (100MHz, DMSO-d6) δ=138.3, 128.7, 128.1, 128.0 (C-Ar), 111.3 (C(CH3)2), 108.5 (C(CH3)2), 105.2 (C-1), 82.0 (C-2), 81.6 (C-3), 80.9 (C-4), 72.7 (C-5), 71.5 (C-7), 66.6 (C-6), 27.1, 27.0, 26.5, 25.7 (C(CH3)2). |
95% | With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; | |
94% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.25h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0℃; for 0.5h; | |
94% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 23h; Inert atmosphere; | |
93% | With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 0 - 25℃; for 20h; | |
92% | With sodium hydride In N,N-dimethyl-formamide for 5h; | |
92% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 6h; | |
89% | With sodium hydride In N,N-dimethyl-formamide | |
86% | With sodium hydride | |
85% | With potassium hydroxide In tetrahydrofuran for 0.25h; Ambient temperature; | |
85% | With potassium hydroxide; 18-crown-6 ether In tetrahydrofuran at 20℃; for 3h; | |
83% | ||
83% | With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 0 - 20℃; | 2 Preparation of 3-O-benzyl-1,2,5,6-O-diisopropylidene-D-glucose (2) Diacetone-D-glucose 1 (5.0 g, 32.7 mmol) was dissolved in DMF (30 mL), and sodium hydride (NaH, 1.9 g, 39 mmol, 50%) was added dropwise to the solution at 0 °C. In liquid paraffin),A mixed solution of benzyl bromide (BnBr, 2.5 mL, 35.6 mmol) and DMF (30 mL). After stirring at room temperature for 2-10 hours,Pour the reaction solution into cold water (300 mL).Extracted with ethyl acetate (3×200 mL), and the combined organic layer was washed with brine.Dry over anhydrous sodium sulfate, concentrate,Separation by column (hexane/ethyl acetate: 15/1)A colorless oil 2 (5.6 g, 16 mmol, 83%). |
80% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 0 - 20℃; Stage #2: benzyl bromide In dichloromethane at 20℃; | |
78% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane at 20℃; for 12h; | |
75% | With sodium hydride In tetrahydrofuran | |
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran for 0.75h; Heating; | ||
With sodium hydride 1.) DMF, 0 deg C, 30 min, 2.) DMF, RT, 30 min; Yield given. Multistep reaction; | ||
With sodium hydride; N,N-dimethyl-formamide 1.) mineral oil, rt, 1 h 2.) rt, 3 h; Multistep reaction; | ||
With Lithium dimsyl 1) DMSO, 2 h, 2) overnight; Yield given. Multistep reaction; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride 1.) THF, from 0 deg C to RT, 2.) THF, 50 deg C, 2 h; Multistep reaction; | ||
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide Yield given; | ||
With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide | ||
With potassium hydroxide at 130℃; for 4h; | ||
With sodium hydride 1.) THF, 30 min, 2.) THF, DMF, room temperature, 2 h; Yield given. Multistep reaction; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran for 48h; Ambient temperature; | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 20℃; for 14h; | ||
With sodium hydride In N,N-dimethyl-formamide at 90℃; for 2h; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 20℃; for 6h; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 20℃; for 24h; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran Stage #2: benzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 10h; Further stages.; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran | ||
With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 20℃; for 16h; | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; | 1.3 Commercially available diacetoneglucose, solubilized in anhydrous dimethylformamide (0.5 M concentration), is treated with 1.2 equivalents of benzyl bromide and 1.3 equivalents of NaH. After 1 h at 20° C., the excess NaH is destroyed with isopropanol. The reaction mixture is then diluted with ethyl ether and the organic phase is washed three times with water. After evaporation, the residue is taken up with 60% acetic acid so as to achieve a concentration of 0.1 M. After two hours at 50° C., the mixture is evaporated and then coevaporated with toluene under reduced pressure. Chromatography on silica gel (eluent: 9/1 to 2/8 petroleum ether/ethyl acetate) makes it possible to obtain the desired diol with a 98% yield. This diol is solubilized in dichloromethane (0.25 M concentration), and then the same volume of water, 0.5 equivalent of tetrabutyl-ammonium hydrogen sulphate, and 0.5 equivalent of NaHCO3 are added, followed, after having lowered the temperature to 0° C., by 2 equivalents of NaIO4, in small portions. The temperature is then allowed to return to ambient temperature and the mixture is then left stirring for 1 h. After separation by settling out, the organic phase is recovered and is evaporated and then taken up with ethyl ether. The organic phase is washed three times with water, dried over magnesium sulphate, filtered and evaporated. The residue is filtered on silica gel (eluent: ethyl acetate) and the compound 12, obtained quantitatively, is directly used, after evaporation and coevaporation with toluene, in the subsequent step. A solution of trisphenylthiomethyl-lithium is prepared in the following way: 1.2 equivalents (relative to the aldehyde) of trisphenylthiomethane are solubilized in the amount of THF required to obtain a concentration of 0.8 M, the temperature is lowered to -78° C. and the mixture is stirred mechanically, and then 1.1 equivalents (relative to the aldehyde) of n-butyllithium in solution in hexane are added. A yellow precipitate appears and the stirring is maintained at -78° C. for 1 h 30 min. The aldehyde, solubilized in THF (0.6 M concentration) is then added dropwise. The mixture is stirred at -78° C. for one hour and then the temperature is allowed to return to ambient temperature over 16 h and the reaction is stopped by adding a saturated ammonium chloride solution. The resulting solution is extracted three times with ethyl ether, and the organic phase is dried over magnesium sulphate, evaporated, and then chromatographed on silica gel (eluent: 9/1 to 6/4 petroleum ether/ethyl acetate). The compound 13c is thus obtained with a 92% yield. | |
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0℃; for 3h; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Inert atmosphere; Stage #2: benzyl bromide In methanol; N,N-dimethyl-formamide; mineral oil at 90℃; Inert atmosphere; | ||
With sodium hydride In tetrahydrofuran | 2 Synthesis of Compound 6 of FIG. 13; Compound 6 was obtained from diacetone glucose (Compound I) through a series of chemical transformations as detailed in Lohman, G. J. S. et. al. J. Org. Chem. 2003, 68 (19), 7559-7561. | |
With sodium hydride In N,N-dimethyl-formamide | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran at 0℃; for 0.333333h; Inert atmosphere; Stage #2: benzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 2h; Reflux; | 3; 4 Sodium hydride (in the form of a dispersion at 60% in mineral oil) (2.5 g; 62 mmol; 1.2 eq.) is added at 0° C., under a nitrogen atmosphere, to a solution of commercial 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (13.5 g; 52 mmol) in anhydrous THF (100 ml). The mixture is stirred for 20 minutes at 0° C. After the addition, at ambient temperature (approximately 20° C.) of tetrabutylammonium iodide (149 mg; 0.4 mmol; 0.008 eq.), benzyl bromide (9 ml; 76 mmol; 1.3 eq.) is added dropwise. The mixture is refluxed for 2 h, and then methanol (10 ml) is added slowly. The mixture is diluted with dichloromethane (100 ml) and water (40 ml). The aqueous phase is extracted 3 times with dichloromethane (50 ml). The organic phases are combined, dried, and concentrated under vacuum. The crude product is purified by silica gel chromatography (cyclohexane/Et2O 4/1+0.4% of Et3N), to give the compound 26 in the form of a yellow oil.C19H26O6 (M=350.42 g/mol).1H NMR (400 MHz, CDCl3): δ 1.31 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.49 (s, 3H, CH3), 4.00 (d, 1H, H6A, J6A-5=5.6, J6A-6B=8.4 Hz), 4.02 (d, 1H, H3, J4-3=3.0 Hz), 4.11 (d, 1H, H6B, J6B-5=6.0 Hz), 4.15 (d, 1H, H4, J4-5=7.6 Hz), 4.37 (m, 1H, H5), 4.58 (d, 1H, H2, J2-1=3.6 Hz), 4.66 (AB, 2H, CH2Ph), 5.90 (d, 1H, H1), 7.27.35 (m, 5H, CHar).13C NMR (101 MHz, CDCl3): δ 25.57 (CH3), 26.37 (CH3), 26.92 (CH3), 26.97 (CH3), 67.53 (C6'), 72.50 (CH2Ph), 72.65 (C5'), 81.45 (CV), 81.83 (C3'), 82.79 (C2'), 105.42 (C1'), 109.10 (Cq), 111.90 (Cq), 127.77, 127.96, 128.52, 137.77.SI-MS m/z M calculated: 350.17; found: 351.0 [M+H]+, 373.0 [M+Na]+. | |
With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide at 20℃; for 8h; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 70℃; for 10h; | ||
With sodium hydride In tetrahydrofuran at 0 - 20℃; for 8h; Inert atmosphere; | 3-O-benzyl 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose a solution of 7 (1 ,2:5,6, -di-O-isopropylidene-a-D-glucofuranose, commercially available, 50.0 g, 192 mmol) in THF (500 mL) was consecutively added benzyl bromide (39.4 g, 230 mmol) and NaH (11.5 g, 288 mmol) at 0 °C under nitrogen. After stirring for 8 h at room temprature, the reaction was quenched with MeOH, and the solvent was evaporated at reduced pressure. The mixture was dissolved in EtO Ac, and the solution was sequentially washed with water, and brine. The organic layer was dried over anhydrous MgS04, filtered, and concentrated in vacuo to afford compound 8. 1H NMR (400 MHz, CDC13) δ 7.36-7.25 (m, 5H, Ar-H), 5.88 (d, J= 3.7 Hz, 1H, H-l), 4.66, 4.62 (ABq, J= 11.8 Hz, 2H, CH2Ph), 4.57 (d, 1H, J= 3.7 Hz, H-2), 4.35 (m, 1H, H-5), 4.13 (dd, J= 7.8, 3.0 Hz, 1H, H-4), 4.10 (dd, J= 8.6, 6.0 Hz, 1H, H-6a), 4.01 (d, J= 3.0 Hz, 1H, H-3) , 3.99 (dd, J = 8.5, 6.0 Hz, 1H, H-6b), 1.48 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.29 (s, 3H, CH3). | |
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 70℃; for 10h; | ||
With sodium hydride In tetrahydrofuran Inert atmosphere; Schlenk technique; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran at 0 - 10℃; for 5h; Inert atmosphere; Stage #2: benzyl bromide With tetrabutylammomium bromide In tetrahydrofuran at 0 - 20℃; | 1.a Step a: preparing 3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose Step a: preparing 3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose Under argon atmosphere, 1 L of tetrahydrofuran, 64 g of sodium hydride (60%) were successively added into a 5 L four-necked reaction flask, then the reactants were cooled down to 0∼5 °C with an ice-water bath. A mixture solution of 315 g of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose and 1 L of tetrahydrofuran was added dropwise. The temperature was maintained at 0∼10 °C. The reaction was conducted at about 0 °C for 5 hours. 220 mL Benzyl bromide was added dropwise, and the temperature was maintained at 0∼10 °C, and then 20 g of tetrabutylammonium bromide was added. The ice-water bath was removed, and the temperature climbed up to room temperature naturally. Continue stirring till the reaction was completed. A small amount of methanol was added dropwise to quench the reaction. The solvent was concentrated and removed under a reduced pressure. The reaction was dissolved by adding ethyl acetate, and washed 3 times with water, dried over anhydrous sodium sulfate, and concentrated to provide 540 g of crude product which was used in the next step directly. |
|
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran; mineral oil at 0 - 5℃; for 5h; Inert atmosphere; Stage #2: benzyl bromide With tetrabutylammomium bromide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 1a Step a: preparing 3-O-benzyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose Under argon atmosphere, 1 L of tetrahydrofuran, 64 g of sodium hydride (60%) were successively added into a 5 L four-necked reaction flask, then the reactants were cooled down to 0-5 ° C. with an ice-water bath. A mixture solution of 315 g of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose and 1 L of tetrahydrofuran was added dropwise. The temperature was maintained at 0-10° C. The reaction was conducted at about 0° C. for 5 hours. 220 mL Benzyl bromide was added dropwise, and the temperature was maintained at 0-10° C., and then 20 g of tetrabutylammonium bromide was added. The ice-water bath was removed, and the temperature climbed up to room temperature naturally. Continue stirring till the reaction was completed. A small amount of methanol was added dropwise to quench the reaction. The solvent was concentrated and removed under a reduced pressure. The reaction was dissolved by adding ethyl acetate, and washed 3 times with water, dried over anhydrous sodium sulfate, and concentrated to provide 540 g of crude product which was used in the next step directly. | |
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 50℃; | 2.5 4.2.5 3-O-(Phenylmethyl)-α/β-D-glucopyranose (10) A mixture of 60% sodium-hydrogen (20.8 g, 0.52 mol) and TBAI (7.4 g, 0.02 mol) in tetrahydrofuran (300.0 ml) was stirred in ice bath for 30 min. A solution of Diacetone-D-Glucose 8 (104.1 g, 0.40 mol) in tetrahydrofuran (300.0 ml) and Benzyl Bromide (82.1 g, 0.48 mol) was added dropwise to the reaction successively. The reaction was stirred for 8 h at 50 °C and quenched with methanol (20.0 ml) and filtrated through Celite, the filtrate was concentrated to get crude product 9. Compound 9 in the mixture of trifluoroacetic acid (150.0 ml) and water (150.0 ml) was stirred overnight. The reaction was diluted with brine (300.0 ml), washed with mixture of ether (80.0 ml) and ethyl acetate (400.0 ml). The water layer was concentrated and purified by crystallization from ethyl acetate to give derivative 10 (51.6 g, 44%). 1H NMR (400 MHz, DMSO-d6) δ 7.42-7.24 (m, 5H, -ArH), 6.67 (d, J = 6.4 Hz, 1H, 1-CH), 5.05 (dd, J = 5.4, 3.7 Hz, 2H, 2-OH and 4-OH), 4.85-4.73 (m, 2H, OCH2Ar), 4.51 (t, J = 5.8 Hz, 1H, 1-OH), 4.39-4.25 (m, 1H, 6-OH), 3.69 (m, 1H, 2-CH), 3.46 (m, 1H, 4-CH), 3.26-3.03 (m, 4H, 3-CH, 5-CH and 6-CH2). 13C NMR (150 MHz, DMSO-d6) δ 139.68, 127.88, 127.40, 126.96, 96.90, 85.30, 76.70, 74.75, 73.61, 69.86, 61.05. HRMS calcd for C13H18O6 m/z [M+Na]+: 293.0996, found 293.1001. | |
With sodium hydride at 20℃; Inert atmosphere; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 14h; Inert atmosphere; | 17 l,2,4,6-tetra-i?-benzoyI-3-i?-benzyI-p-D-gIucopyranoside (7-23) l,2,4,6-tetra-0-benzoyI-3-0-benzyl-P-D-glucopyranoside (7-23) The synthesis was accomplished with the modified procedure followed in Carbohydr. Res, 1998, 305, 293-303. To an ice-cooled solution of l,2;5,6-di-0-isopropylidene-a-D-glucofuranose (7-20) (30.0 g, 115.3 mmol) in dry DMF (100 mL) was added 60 wt% NaH (9.2 g, 230.6 mmol) and stirred at 0 °C for 30 min. Then benzyl bromide (29.5 g, 173 mmol) was added dropwise and the solution was warmed at room temperature. After stirring for 14 h, crushed ice was added and the mixture was diluted with water, extracted with ether and washed with water and brine successively. The solution was dried over Na2S04, filtered, concentrated to obtain 7-21. The crude was taken for next step without further purification. A solution of 7-21 in a mixture of EtOH: THF: H20 (2:2:5 /v, 130 mL) was stirred with Dowex 50 resin (Ff form, 25 g) for 12 h at 75 °C. Then, the resin was filtered off and the filtrate was quenched with trimethylamine. The solvent was evaporated and further coevaporated twice with toluene to obtain 7-22 as a white solid. The solid was then dissolved in DCM (150 mL) and were added trimethylamine (83 g, 821.6 mmol), DMAP (6.25 g, 51.3 mmol) and then cooled at 0 °C. Benzoyl chloride (60 mL, 616.2 mmol) was added slowly and stirred for additional 14 h at room temperature. The mixture was diluted with DCM, washed with 2 M HC1, saturated NaHC03 solution and brine, and dried over Na2S04. Evaporation of the solvent and dissolution of the residue in MeOH resulted in crystallized product 7-23 (47.5 g, 60% over 2 steps). 'H NMR (400 MHz, CDC13): d 8.02-7.97 (m, 8H), 7.60-7.49 (m, 4H), 7.45-7.35 (m, 8H), 7.07-7.00 (m, 5H), 6.17 (d, 1H, J= 7.6 Hz), 5.73 (dd, 1H, J = 7.6 Hz, 7.6 Hz), 5.7l(dd, 1H, J = 8.8 Hz, 8.8 Hz), 4.67 (d, 1H, J = 11.6 Hz), 4.64 (dd, 1H, J= 11.6 Hz), 4.61 (dd, 1H, J= 12 Hz, 3.2 Hz), 4.43 (dd, 1H, J= 12 Hz, 4.8 Hz), 4.25 (ddd, 1H, J= 12 Hz, 4.8 Hz, 3.2 Hz), 4.19 (dd, 1H, J= 8.4 Hz, 8.4 Hz). | |
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide at 0℃; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride In tetrahydrofuran for 24h; Ambient temperature; | |
98% | With potassium hydroxide In acetonitrile at 150℃; for 0.0333333h; microwave irradiation; | |
97% | With sodium hydride In water; N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; | 3 To a solution of 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose,(100 g, 0.38 mol) and benzyl chloride (50.024 g, 45.47 mL,0.395 mol) in DMF (300 mL), NaH (14.59 g, 0.608 mol) was addedportion-wise over 10 min at 0 C. The reaction mixture was stirredat rt for 30 min before water (500 mL) was added. The solutionwasdiluted with EtOAc (2200 mL) and washed with water(2200 mL). The organic layer was dried (Na2SO4), filtered,concentrated, and the resulting crude product was pure enough togive 2 (130.6 g, 97%) as a yellowish oil, which was carried to thenext step without further purification: Rf 0.56 (5:1 hexaneeEtOAc);[a]D 24.3 (c 6.8, CHCl3); 1H NMR (500 MHz, CDCl3): d 7.38e7.25(m, 5H, AreH), 5.89 (d, 1H, J3.7 Hz, H-1), 4.69e4.62 (m, 2H,AreCH2), 4.58 (d, 1H, J3.7 Hz, H-2), 4.37 (dt, 1H, J7.7, 6.0 Hz, H-3),4.17e4.08 (m, 2H, H-5, H-6), 4.03e3.98 (m, 2H, H-4, H-6), 1.49 (s,3H, CH3), 1.42 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.30 (s, 3H, CH3)); 13CNMR (125 MHz, CDCl3): d 137.7, 128.4, 127.9, 127.7, 111.8 ((CH3)2C),109.0 ((CH3)2C), 105.3, 82.7, 81.7, 81.4, 72.6, 72.4, 67.4, 26.9, 26.3,26.3, 25.5. HRMS (ESI) calcd (MNa) C19H26O6Na: 373.1622.Found: 373.1614. |
96% | With sodium hydroxide; tetrabutyl-ammonium chloride In benzene at 80℃; for 2h; | |
95% | With sodium hydride In tetrahydrofuran; dimethyl sulfoxide for 3h; Heating; | |
71% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide; benzene at 20℃; for 2h; Stage #2: benzyl chloride In N,N-dimethyl-formamide; benzene at 20℃; for 16h; Further stages.; | |
With sodium hydride In dimethyl sulfoxide | ||
With sodium hydride 1.) THF, DMSO, RT, 15 min, 2.) THF, DMSO, RT, 35 min; Multistep reaction; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: benzyl chloride In N,N-dimethyl-formamide at 20℃; for 2h; Further stages.; | ||
With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In tetrahydrofuran; water for 3h; Heating / reflux; | b To 377 g (1.45 mol) of l,2:5,6-Di-(9-isopropylidene-α-D-glucose is added 180 mL (1.56 mol) of BnCl, 17 g Bu4NHSO4, 200 g NaOH dissolved in 200 mL of water and 800 mL THF. The mixture is stirred for 3 hrs at reflux. The phases were separated and the aqueous phase extracted with diethylether. The organic phase was dried with MgSO4 and evaporated. | |
With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In tetrahydrofuran for 2h; Reflux; | ||
149 g | With tetrabutylammomium bromide; potassium hydroxide In toluene at 80 - 85℃; | 1 Example 1 : Process for the Preparation of 3-O-Benzyl diacetone-d-glucose To a solution of diacetone-D-glucose (100 g) in toluene (500 ml) at ambient temperature, pulverized potassium hydroxide (43.11 g), tetrabutyl ammonium bromide (12.4 g) and benzyl chloride (58.4 g) were added. The reaction mixture was slowly heated to 80°C to 85°C. At the same temperature, the reaction mixture was stirred for 2 hours to 3 hours and then cooled to 25°C to 30°C. Methanol (20 ml) was added to the mixture and the resultant reaction mixture was stirred for 30 minutes. Water (500 ml) was added to the reaction mixture under stirring and the mixture was allowed to settle. The organic layer so formed was separated and washed twice with water (500 ml x 2). The solvent was recovered under vacuum at 60°C from the resultant organic layer to obtain the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran for 24h; | |
98% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran at 0 - 20℃; Stage #2: allyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 16h; | |
98% | With sodium hydride In N,N-dimethyl-formamide at 0 - 23℃; for 1h; |
97% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; | 6-(Allyloxy)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole (S10) To a solution of the S9 (6 g, 23.08 mmol) in DMF (30 mL) was added sodium hydride (0.96 g,46.15 mmol) at 0 °C, and allyl bromide (2.9 mL,27.69 mmol) and stirred at room temperature for12 hours. After completion (TLC), the reaction mixture was diluted with water (30 mL) andextracted in ethyl acetate (3 × 60 mL). Pooled organic layers were washed with brine, dried overNa2SO4 and solvent was removed under reduced pressure and residue was purified by silica gelcolumn chromatography to afford S10 (6.75 g, 97%) as colourless oil. |
96% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane for 3h; | |
96% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1h; | |
95% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane at 20℃; for 24h; | |
95% | With potassium carbonate In acetone for 4h; Reflux; | |
93% | With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 20℃; for 2h; | |
90% | With potassium hydroxide In tetrahydrofuran for 0.166667h; Ambient temperature; | |
90% | With tetrabutylammomium bromide; sodium hydride In tetrahydrofuran for 18h; Ambient temperature; | |
90% | With sodium hydride In tetrahydrofuran; dimethyl sulfoxide at 20℃; for 8h; | |
88% | With sodium hydride In acetonitrile at 190℃; for 0.0166667h; microwave irradiation; | |
87% | With sodium hydride | |
83% | With sodium hydride In tetrahydrofuran | |
78% | With sodium hydride In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide | |
78% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h; | |
61% | With potassium hydroxide In acetone for 3h; Heating; | |
With potassium hydride 1.) THF, 0 deg C, 5 min, 2.) rt, 1 h; Yield given. Multistep reaction; | ||
With sodium hydride for 2h; Heating; | ||
With sodium hydride In N,N-dimethyl-formamide at 0℃; | ||
With sodium hydride 1.) DMF, 0 deg C, 15 min, 2.) DMF, room temperature; Multistep reaction; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide Stage #2: allyl bromide In N,N-dimethyl-formamide | ||
188 g | With sodium hydride In N,N-dimethyl-formamide at 0℃; for 3.5h; | |
With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 2h; | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h; | ||
In N,N-dimethyl-formamide | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 20℃; for 16h; | 5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-6-(prop-2-yn-1-yloxy)tetrahydrofuro[2,3-d][1,3]dioxole (S16) To a solution of S9 (6 g, 23.1 mmol) in DMF (30 mL) was added sodium hydride (1.107 g, 46mmol) at 0 °C and stirred for 10 min. Then, propargyl bromide (2.39 mL, 28 mmol) was addedand stirred at room temperature for 16 hours. After completion (TLC), reaction mixture wasdiluted with water (50 mL) and extracted in ethyl acetate (3 × 50 mL). Pooled organic layerswere washed with brine (50 mL), dried over Na2SO4 and solvent was removed under reducedpressure and crude was purified by silica gel column chromatography to furnish S16 ascolourless oil (6.8 g, 99%). |
97% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 20℃; for 15h; | |
95% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 13h; |
92% | With sodium hydroxide; tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 96h; | |
92% | With sodium hydroxide; tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; | |
90% | With sodium hydroxide; tetrabutylammomium bromide; water In dichloromethane; toluene at 25℃; for 15h; | |
90% | With sodium hydride In N,N-dimethyl-formamide; toluene at 0 - 20℃; for 12.5h; | Sodium hydride (13 mg. 5.8 mmol) was added to a solution of,2 :5 ,6-Di-O-isopropylidene-a-D-glucofbranose (Compound SI, 500 tug, 1 .92 mmol. Aldrich 1)7600) in 10 mL dry DMF at 0 °C. The solution was stirred at 0 O( for 30 mm before propargyl bromide (80% in toluene. 0.43 mL, 3,84 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 12 h before quenched with saturated ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (2 x 25 mL). and th.e organic layer was combined, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by column chromatographysilica gel (0-50% Ethyl acetate in Hexanes) to give Compound S2 (51 8 mg, 90%) as a colorless oil. The 1H NMR spectrum is in accordance with previously published values (A. Hausherr et al., SvnthesL, 2001. 1377).101971 lii NMR (400 MHz, CDCI3) 3 588 (d. J 3.6 Hz. I H), 4.30 - 42 (ni, 3 H), 414 (dd. J:::: 7.6, 2.8 Hz, lI-i), 4.11 - 406 (m, 2 ii), 199 (dd, J &8, 56 Hz, I H), 147 (t, 3:::: 2.4 Hz, il-ILI iO (s, 3 H). 1.42 (s, 3 H), 1.35 (s, 3 H), 1.31 (s, 3 H).[0198] HRMS (FAL3+) nVz Calcd. fbr C15H204 [M±H] 299.1495. Found: 299. 1496 |
90% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h; Cooling with ice; | |
89% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 8h; | |
87% | With benzyltriethylammonium bromide In sodium hydroxide; dichloromethane for 4h; | |
83% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane at 20℃; for 12h; | |
82% | With tetrabutylammomium bromide; sodium hydride In tetrahydrofuran at 0℃; for 12h; | |
82% | With tetrabutylammomium bromide; sodium hydroxide In dichloromethane; water at 20℃; Inert atmosphere; | 3. Preparation of aryl/alkyl substituted terminal acetylenes 5 On the other hand, acetylenic substrate 5d (see Table 1 in text) was synthesized from commercially available diacetone-D-glucose as shown in Scheme 2. To a well stirred solution of diacetone-D-glucose (500 mg, 1.9 mmol) in dry dichloromethane (25 mL) were successively added propargyl bromide (343 mg, 1.5 eqv.), 25 mL of 50% sodium hydroxide solution (aqueous) and a catalytic amount (10 mg) of tetrabutyl ammonoum bromide (TBAB). The reaction mixture was allowed to stir at room temperature for overnight. The crude product was isolated using standard work-up and separated through silica gel (100-200 mesh) column chromatography using 15% ethyl acetate in petroleum ether as eluent to obtain the the desired propargylated diacetone-D-glucose (5d) with 82% yield (448 mg). |
80% | With sodium hydride In tetrahydrofuran; dimethyl sulfoxide at 20℃; for 8h; | |
80% | With tetrabutylammomium bromide; sodium hydroxide In dichloromethane; water at 0 - 20℃; | |
76% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran; mineral oil at 20 - 70℃; for 2h; Stage #2: propargyl bromide With tetraethylammonium iodide In tetrahydrofuran; toluene; mineral oil at 20℃; for 16h; | |
72% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2.5h; | |
72% | With sodium hydride In tetrahydrofuran | |
66% | With tetrabutylammomium bromide; sodium hydroxide In dichloromethane; water at 20℃; for 12h; | Compound 2 (5.0 g, 19.2 mmol) was dissolved in CH2Cl2(200 mL). The resulting solution was treated with an aqueous solution of NaOH(50% w/w, 200 mL), propargyl bromide (2.6 mL, 28.6 mmol) and Bu4NBr(343.7 mg, 1.1 mmol). After stirring for 12 h at RT, the reaction mixture wasextracted with CH2Cl2. Combined organic layers werewashed with brine, dried and concentrated in vacuo. Purification of the productwas carried out by chromatography using hexane and ethylacetate to yield 3 (3.8 g, 66%). 1H NMR (300MHz, CDCl3, δ, ppm): 1.32-1.35 (2s, J=10.2 Hz, 6H, 2 x CH3),1.42 (s, 3H, CH3), 1.49 (s, 3H, CH3), 2.50 (t, J=2.4 Hz,1H), 3.98 (dd J=8.4 Hz, and 5.4 Hz, 1H), 4.06-4.15 (m, 3H), 4.24-4.29 (m, 3H),4.63 (d, J=3.6 Hz, 1H, C-2), 5.87 (d, J=3.6 Hz, 1H, C-1). 13C NMR(75 MHz, CDCl3, δ ppm): 25.3 (CH3), 26.2 (CH3),26.7 (CH3), 26.8 (CH3), 58.1 (O-CH2), 67.2 (C-6), 72.5 (C-5), 74.9 (C-4), 79.3(CH), 81.0 (C-3), 81.6(-C), 82.8 (C-2), 105.2 (C-1), 109.0 (C-8), 111.8 (C-7). HRMS(ESI-TOF) m/z: [M+Na]+ calcd for C15H22O6Na321.1309; Found 321.1325. |
62% | With potassium hydroxide In acetonitrile at 20℃; for 24h; | |
With sodium hydride 1.) DMF, 0 deg C, 30 min, 2.) DMF, -10 deg C, 60 min; Yield given. Multistep reaction; | ||
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 In tetrahydrofuran | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 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; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 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 24h; | Synthesis of 1,2,4,6-tetra-O-acetyl-3-O-propargyl-D-glucopyranose (4) A solution ofsodium hydride (240 mg, 10 mmol) in dry DMF (10 mL) in a 100-mL round bottom flask wascooled to 0 °C and a solution of diacetone glucose (1.3 g, 5.0 mmol in 10 mL DMF) wasadded. The reaction was continued at that temperature for 30 min and then propargyl bromide(10 mmol) was added under stirring. The reaction mixture was allowed to come to room temperatureand the reaction continued for 24 h at room temperature. After completion of thereaction, as indicated by TLC, ethyl acetate (50 mL) was added followed by water (50 mL)and the two layers were separated. The organic layer was washed with distilled water (3×30mL) followed by brine solution (30 mL), dried over anhydrous sodium sulphate and concentratedto dryness. The crude product was dissolved in a mixture of THF and water (9:1).To this solution, Dowex H+ (30 wt. %) resin was added. The reaction mixture was stirred for24 h at room temperature. After disappearance of the starting material, confirmed by TLCanalysis, the reaction mixture was filtered through filter paper. After filtration of the resin, thefiltrate was then concentrated and repeatedly washed with ethyl acetate to give a syrup.Acetylation of the hydroxyl groups of the syrupy product was realised using acetyl chloridealong with sodium acetate as base to obtain 1,2,4,6-tetra-O-acetyl-3-O-propargyl-Dglucopyranose.28 The crude product was purified by column chromatography to give anoverall yield of 80 %. | |
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Inert atmosphere; Stage #2: propargyl bromide In N,N-dimethyl-formamide; toluene at 0 - 20℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | (I) 1,2:5,6-Di-O-isopropylidene-alpha-D-glucofuranose (3)(1.0 g; 4.0 mmol) was dissolved in DMF (20 ml), cooledat 0 C and under N2-atmosphere NaH (0.14 g; 6.0 mmol)was added to the solution. The suspension was stirred for30 min and cooled to -35 to -40 C. After N?,N-sulfonyldiimidazole(1.2 g; 6.0 mmol) in DMF (12 ml) was droppedto the reaction mixture and stirred for 30 min again at-40 C. MeOH was added (0.8 ml) to the solution andstirred for 30 min at -40 C. The solution was poured intoice-water (200 ml). The precipitate was filtered, washedwith cold water to get the white crystalline product 11(1.2 g; 80%). M.p.: 97-98 C; lit. m.p. (Vatle and Hanessian1996): 98-99 C; Rf = 0.70 (EtOAc-hexane 1:1).(II) From 3 (25.0 g; 96.0 mmol) the yield was 84% (31.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: 2-bromomethylnaphthyl bromide In N,N-dimethyl-formamide at 20℃; for 20h; | |
90% | In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 6h; | 1 4.1.1 1,2:5,6-Di-O-isopropylidene-3-O-(2-naphthyl)methyl-α-d-glucopyranose (3) 1,2:5,6-Di-O-isopropylidene-α-d-glucofuranose 2 (10 g, 38 mmol) and 2-methylnaphtyl bromide (9.25 g, 1.1 equiv) was introduced in a round-bottomed flask. Dry dimethylformamide (35 mL) was poured into the mixture and sodium hydride 60% in oil dispersion (1.54 g, 1.2 equiv) was slowly added at 0 °C. Then, the mixture was allowed to reach room temperature. After 6 h of stirring, excess NaH was neutralized with methanol. The product was precipitated by adding 300 mL of crushed ice. The upper layer was transferred to a separation funnel, diluted with dichloromethane and washed with water. The organic layer was dried over MgSO4 and concentrated to dryness to give after purification by column chromatography (Toluene/EtOAc 10:1, Rf=0.4) 13.8 g of yellow oil (90%). 1H NMR (CDCl3, 25 °C, 400 MHz): δ 7.85-7.80 (m, 4H, H-Ar), 7.49-7.45 (m, 3H, H-Ar), 5.93 (d, JH1,H2 3.74, 1H, H-1), 4.85 (d, Jgem 12.03, 1H, NapCH2), 4.80 (d, Jgem 12.03, 1H, NapCH2), 4.63 (d, JH1,H2 3.74, 1H, H-2), 4.42 (ddd, JH4,H5 7.80, JH5,H6a 5.86, JH5,H6b 6.13, 1H, H-5), 4.16 (dd, JH3,H4 3.10, JH4,H5 7.80, 1H, H-4), 4.14 (dd, JH5,H6b 6.13, Jgem 8.75, 1H, H-6b), 4.08 (d, JH3,H4 3.10, 1H, H-3), 4.03 (dd, JH5,H6a 5.86, Jgem 8.75, 1H, H-6a), 1.49, 1.43, 1.40, 1.31, (4 s, 12H, CH3). 13C NMR (CDCl3, 25 °C, 100 MHz): δ 135.2, 133.4, 133.2 (3*C-ipso), 128.4, 128.0, 127.9, 126.6, 126.3, 126.1, 125.8 (7 C-Ar), 112.0, 109.2 (23*(CH3)2CH), 105.48 (C-1), 82.9 (C-2), 81.8 (C-3), 81.5 (C-4), 72.7 (C-5), 72.6 (NapCH2), 67.6 (C-6), 27.0, 26.4, 25.6 (4 CH3). ESI-HRMS: [M+Na]+ m/z calcd for C23H28O6Na 423.1784, found 423.1788. |
88% | With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran for 1h; Ambient temperature; |
84% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1h; Stage #2: 2-bromomethylnaphthyl bromide With tetra-(n-butyl)ammonium iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 12h; | |
With sodium hydride In DMF (N,N-dimethyl-formamide) at 2℃; for 2.5h; | 1.2 117.7 g (1 eq.) of commercial 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (M=260.28) and 100 g of 2-methylnaphthyl bromide (1 eq.) are introduced into a 2 L reactor at a temperature of 2° C. 400 mL of dimethylformamide are then added (dilution 1 in 2) and 21.7 g (1.2 eq.) of 60% sodium hydride are added to the reaction progressively over 10 minutes. The temperature is then allowed to rise slowly. After 2 hours 20 minutes, the excess of NaH is neutralised with methanol and the product is precipitated out by the addition of 2 L of iced water under vigorous agitation. 2 hours later, the supernatant is removed and the precipitate taken up into dichloromethane (1 L). After decanting, the organic phase is dried and concentrated. The crude product (M=400.5) is used directly for the following step.TLC: Rf=0.5 [toluene/ethyl acetate (9/1; v/v)]. White solid.13C NMR (CDCl3, 100 MHz): 135.12; 133.29; 133.11 (C quat. arom.); 128.29, 127.95, 127.78, 126.54, 126.25, 126.07, 125.71 (C arom.); 111.89, 109.011 (C quat. acetal.); 105.39 (C1); 82.73 (C2); 81.65 (C3); 81.41 (C4); 72.59 (C5); 72.49 (C7); 67.50 (C6); 26.90, 26.32, 25.54 (CH3).1H NMR (CDCl3, 400 MHz): 7.84-7.80 (m, 4H, H arom.); 7.49-7.45 (m, 3H, H arom.); 5.93 (d, 1H, H1, JH1-H2=3.7 Hz); 4.85 (d, 1H, H7a, JH7a-H7b=12.0 Hz); 4.79 (d, 1H, H7b, JH7b-H7a=12.0 Hz); 4.63 (d, 1H, H2, JH2-H1=3.7 Hz); 4.42 (td, 1H, H5, JH5-H4=7.8 Hz, JH5-H6a=JH5-H6b=6.0 Hz); 4.16 (dd, 1H, H4, JH4-H3=3.0 Hz, JH4-H5=7.7 Hz); 4.14 (dd, 1H, H6a, JH6a-H5=6.1 Hz, JH6a-H6b=8.6 Hz); 4.08 (d, 1H, H3, JH3-H4=3.0 Hz); 4.03 (dd, 1H, H6b, JH6b-H5=5.8 Hz; JH6b-H6a=8.6 Hz); 1.49, 1.43, 1.40, 1.31 (4s, 12H, CH3). | |
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1.5h; Cooling with ice; Stage #2: 2-bromomethylnaphthyl bromide In N,N-dimethyl-formamide at 20℃; for 16.5h; Cooling with ice; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran at 0 - 20℃; for 3h; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h; Stage #2: 2-bromomethylnaphthyl bromide for 16h; Inert atmosphere; | A.A.1.a Example A.1 Synthesis of the d glucose 23 Diacetone glucose 21 (16.2 g, 62.2 mmol) was dissolved in anhydrous dimethylformamide (80 ml_) at 0 °C. To this solution, sodium hydride (1 .17 g, 74.7 mmol, 60% in mineral oil) was added and the solution was stirred until all gas evolution has ceased (2 h). To this solution, 2-(bromomethyl)naphthalene (40.8 g, 184 mmol) was added and the reaction was stirred for 16 h under argon. The reaction was quenched by slow addition of sat. aq. NH CI solution. The mixture was extracted with diethyl ether and the organic layer was washed with brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give a viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridine at 0 - 20℃; | |
90% | With pyridine In methanol; dichloromethane at 20℃; for 14.5h; Inert atmosphere; Cooling with ice; | |
87% | With pyridine at 0℃; for 2h; |
85% | With dmap In dichloromethane at 20℃; for 48h; | |
With pyridine; 1-hydroxy-pyrrolidine-2,5-dione In benzene at 80℃; | ||
With dmap In acetonitrile for 6h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: carbon disulfide; 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With 1H-imidazole; sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 0.5h; Further stages.; | |
99% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran at 20℃; for 1h; Stage #2: carbon disulfide; methyl iodide In tetrahydrofuran for 1h; | O-((3aR,5R,6S,6aR)-5-((R)-2,2-climethvl-1,3-dioxolan-4-vl)-2,2-dimethyltetrahydrofuro[2,3-tfl 11.31 dioxol-6-yl) S-methyl carbonodithioate Diacetone-D-elucose (20s, 76.8 mmol) was dissolved in dry THF (320 ml) at room temperature and 95% NaH (2.77g, 115,3 mmol) was added in two portions within 15 minutes wit vigorous stirring and gas evolution observed. The reaction mixture was then stirred at room temp lor 30 minutes and to the resulting cloudy yellow solution was added CS2 (9.28 mL, 153,7 mmol) dropwise via syringe. This mixture was stirred for 30 minutes and then Mel (8.13 mL, 130.6 mmol) was added dropwise via syringe. Stirring was continued for another 30 minutes, at which point TLC (1 : 1 Hexanes EtOAc - Mn04 stain) indicated complete conversion. The resulting brown solution, containing a white precipitate, was evaporated in vacuo to a thick brown syrup, dissolved in EtOAc (300 mL) and washed with water (300 mL). The aqueous layer was then back extracted twice with EtOAc (200 mL) and the combined organic layers dried over MgSCu, filtered and concentrated in vacuo to a thick dark orange oil. Purification was performed in 2 batches using Teledyne Isco with a normal phase 120 g ediS'e j column as the stationary phase. Hexanes and EtOAc were used as the mobile phase. Column conditions: 100% hexanes for 2 column volumes (CVs) followed by 0→ 35% EtOAc over 14 CVs. The title compound was isolated in 99% yield (26.8 g, 76.75 mmol) as a thick yellow oil with spectra matching previously reported values.1 |
98% |
98% | With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; | |
94% | Stage #1: carbon disulfide; 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With 1H-imidazole; sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Stage #2: methyl iodide In tetrahydrofuran at 20℃; for 0.5h; | |
89% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With 1H-imidazole; sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 0.25h; Stage #2: carbon disulfide In tetrahydrofuran; mineral oil at 20℃; for 1h; Stage #3: methyl iodide In tetrahydrofuran; mineral oil at 0 - 20℃; for 2h; | 1.1 Step-1: O-((3aR,5R,6S,6aR)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl) S-methyl carbonodithioate (1S) To a suspension of NaH (60% in mineral oil, 36 g, 0.961 mol) in THF (500 mL) at 0° C. was added a solution of commercially available (3aR,5S,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol [582-52-5](100 g, 0.384 mol) and imidazole (1.3 g, 1.92 mmol) in THF (500 mL) dropwise. The reaction mixture was stirred at 10° C. for 15 min. To this mixture was added carbon disulfide (121 mL, 1.92 mol) and the reaction mixture was stirred at RT for 1 h, followed by iodomethane (118 mL, 1.92 mol) at 0° C. Stirring was continued at RT for 2 h whereupon the reaction mixture was quenched with sat. NH4Cl solution (1 L) and extracted with EtOAc (2*1.5 L). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (100-200 mesh, eluting with 5% EtOAc in Pet-ether) to afford 120 g (89%) of O-((3aR,5R,6S,6aR)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl) S-methyl carbonodithioate (1S) [1667-96-2] as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 5.92-5.91 (m, 2H), 4.68-4.67 (m, 1H), 4.34-4.29 (m, 2H), 4.12-4.04 (m, 2H), 2.59 (s, 3H), 1.61 (s, 3H), 1.54 (s, 3H), 1.33-1.32 (m, 6H). |
86% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With 1H-imidazole; sodium hydride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: carbon disulfide In tetrahydrofuran for 2h; Inert atmosphere; Stage #3: methyl iodide In tetrahydrofuran for 1h; Inert atmosphere; | |
83% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With 1H-imidazole; sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.333333h; Inert atmosphere; Stage #2: carbon disulfide In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #3: methyl iodide In tetrahydrofuran; mineral oil at 20℃; for 0.25h; Inert atmosphere; | |
With sodium hydride 1, 2) THF, r.t.; Multistep reaction; | ||
With 1H-imidazole; sodium hydride In tetrahydrofuran; paraffin Yield given; | ||
With sodium hydride Yield given. Multistep reaction; | ||
Stage #1: carbon disulfide; 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran Stage #2: methyl iodide | ||
With sodium hydride In tetrahydrofuran | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With 1H-imidazole; sodium hydride In tetrahydrofuran; mineral oil for 0.333333h; Inert atmosphere; Stage #2: carbon disulfide In tetrahydrofuran; mineral oil for 0.5h; Inert atmosphere; Stage #3: methyl iodide In tetrahydrofuran; mineral oil for 0.25h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dipyridinium dichromate; acetic anhydride In dichloromethane | |
100% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; water at 0℃; | |
99% | With Dess-Martin periodane In dichloromethane at 0 - 20℃; |
98% | With dipyridinium dichromate; 4 A molecular sieve; acetic acid In dichloromethane for 24h; Ambient temperature; | |
98% | With pyridinium dichromate; acetic anhydride In dichloromethane | |
97% | With dipyridinium dichromate; acetic anhydride In dichloromethane for 2h; Heating; | |
97% | With cetyltrimethylammonium bromochromate In dichloromethane at 20℃; for 1.75h; | |
96% | With dipyridinium dichromate; acetic anhydride | |
96.7% | With dipyridinium dichromate; acetic anhydride | |
95% | With dipyridinium dichromate; acetic anhydride In dichloromethane for 2h; | |
93% | With oxalyl dichloride; TEA; dimethyl sulfoxide In dichloromethane at -78 - 20℃; for 0.666667h; | |
93% | With pyridinium chlorochromate In dichloromethane at 0 - 20℃; Inert atmosphere; Molecular sieve; | |
93% | With dipyridinium dichromate; acetic anhydride In dichloromethane at 0 - 20℃; for 17h; Molecular sieve; Inert atmosphere; Schlenk technique; | |
92% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃; for 1h; | |
92% | With 3 A molecular sieve; pyridinium chlorochromate In dichloromethane for 3h; Ambient temperature; | |
91% | With dipyridinium dichromate; acetic anhydride In dichloromethane at 75℃; for 4h; | |
88% | With dipyridinium dichromate; 4 A molecular sieve; acetic acid In dichloromethane | |
88% | With dipyridinium dichromate In dichloromethane; acetic anhydride | |
87% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.75h; Stage #2: With triethylamine In dichloromethane at -78 - 25℃; | |
86% | With quinolinium monofluorochromate(VI) In dichloromethane for 1.5h; Ambient temperature; | |
86% | With dipyridinium dichromate; acetic anhydride In dichloromethane at 78℃; for 3h; | |
86% | With Dess-Martin periodane In dichloromethane at 0 - 20℃; | |
85% | With aluminum oxide; 3 A molecular sieve; pyridinium chlorochromate In dichloromethane at 20℃; for 15h; | |
85% | With dipyridinium dichromate; acetic anhydride In dichloromethane at 20℃; Molecular sieve; | synthesis of (3aR,5R,6aS)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethylfuro[2,3-d][1,3]dioxol-6(3aH,5H,6aH)-one To a solution of compound 5-(2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (7)(7 g, 26.9mmol) in anhydrous DCM (135 mL) was added PDC (20.2 g, 53.8mmol) portion wise at 0 oC followed by freshly activated molecular sieves powder (3 g) and drop wise addition of acetic anhydride (0.4 mL). The reaction mixture was stirred for 4 h at room temperature, then filtered through celite (5 g) and the solvent was evaporated under reduced pressure using toluene for the azeotropic removal of pyridine/AcOH. The resulting dark brown residue was filtered through a small bed of silica gel with diethyl ether to give the product 8 (5.9 g, 85%). m.p. 40 oC; [a]D +139o (c, 1.0, CHCl3); Rf = 0.65 (Silica, 95:5 DCM-MeOH); IR (KBr): u 2856, 1748, 1232, 859 cm-1; 1H NMR (CDCl3, 300 MHz): d5.65 (d, J = 3.8 Hz, 1H), 4.33-4.41 (m, 3H), 4.05 (d, J = 3.6 Hz, 2H), 1.45 (d, J = 6.2 Hz, 6H), 1.35 (s, 6H);13C NMR (CDCl3, 50 MHz): d203.5, 116.5, 108.1, 103.2, 78.1, 72.6, 68.4, 65.1, 25.9; FABMS: m/z: 259 [M+];Elemental Anal C12 H18 O6Calcd: C, 55.81, H, 7.02 Found: C, 55.78, H, 7.11. |
85% | With dipyridinium dichromate; acetic anhydride In dichloromethane for 3h; Reflux; | |
84% | With hydrogenchloride; 2,2,6,6-tetramethyl-piperidine-N-oxyl; Amberlite IRA 900 chlorite In dichloromethane at 20℃; for 18h; | |
84% | With pyridine; chromium(VI) oxide; acetic anhydride In dichloromethane for 0.75h; | |
83% | With Dess-Martin periodane In 1,2-dichloro-ethane at 65℃; for 2h; | |
83% | With acetic anhydride; pyridinium chlorochromate In dichloromethane at 25℃; for 0.5h; | |
83% | With oxalyl dichloride; C4F9CH2CH2S(O)CH3 In dichloromethane at -30℃; | |
83% | With phosgene; triethylamine In dichloromethane at -78 - 20℃; for 1.5h; | |
82% | With dipyridinium dichromate; acetic anhydride In dichloromethane for 3.5h; Heating; | |
82% | With pyridine; chromium(VI) oxide In dichloromethane | |
81% | With dipyridinium dichromate; acetic anhydride In dichloromethane at 75℃; for 3h; | |
81% | With Dess-Martin periodane In dichloromethane at 20℃; for 14h; | |
81% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide In dichloromethane; water at 25 - 35℃; for 1h; Inert atmosphere; | |
80% | With pyridinium chlorochromate | |
80% | With dipyridinium dichromate; acetic anhydride | |
80% | With dipyridinium dichromate; acetic anhydride In dichloromethane regioselective reaction; | |
79% | With 3 A molecular sieve; pyridinium chlorochromate In dichloromethane at 20℃; for 17h; | |
77% | With pyridinium chlorochromate | |
76% | With molecular sieve; pyridinium chlorochromate In dichloromethane | |
70% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In dichloromethane; water at -10 - 0℃; for 0.583333h; Alkaline conditions; Stage #2: In dichloromethane at 100 - 105℃; | 1,2:5,6-Di-O-isopropylidene-α-D-ribo-3-hexofuranose-3-ulose (6) In an open-mouth beaker equipped with mechanical stirrer, a solution of NaBr (4.20g, 0.04 mol, 0.1 equiv) in water (20 mL) was added to a solution of diacetone-α-D-glucose(5) (104 g, 0.4 mol, 1.0 equiv) in CH2Cl2 (400 mL), followed by TEMPO(0.300 g, 1.9 mmol, 0.5 mol-%). The resulting mixture was cooled to -5 - -10°C(internal temperature) and vigorously stirred, and aqueous solution of NaClO (~1.6 mol/L, pH 9.5, 360 mL, 0.58 mol, 1.45 equiv) 3 was added dropwise in 30 minutes while keeping the internal temperature in the range of -10 - 0°C. After addition of the bleach solution, the resulting reaction mixture was stirred for 5 minutes.4 The organic layer was separated and washed successively with solution of KI (1.60 g, 0.01 mol, 2.5 mol-%) in 0.5 M aqueous hydrochloric acid (100 mL), 10% aqueous solution of Na2S2O3 (100 mL), saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL). After drying (Na2SO4), filtration and evaporation under reduced pressure, the crude product (93.0 g, ~90%) contained a mixture of ketone hydrate 7 and ketone 6 in various proportions with the latter being the major component.If required,5 product can be purified by vacuum distillation: The foregoing mixture was diluted with CH2Cl2 (10-20 mL) and transferred into a flask suitable for vacuum distillation6 and the residual CH2Cl2 was distilled of at 1-5 torr (bath temperature 40-50 oC). Then, the vacuum was adjusted to 0.2-0.4 torr, and ketone 6 was distilled at 100-105 oC (bath temperature 125-135 oC). Fraction I: 2 g (2%, purity by NMR 90%); fraction II: 72 g (70%, purity by NMR 96%); fraction III: 7 g (6%, purity by NMR: 85%). The product from fraction II is considered to be sufficiently pure and is used for full characterization. Yield 72 g (70%). |
60% | With dipyridinium dichromate; acetic anhydride In dichloromethane | |
58% | With pyridinium dichromate; acetic anhydride In dichloromethane at 20℃; for 18.5h; Inert atmosphere; Reflux; | |
55.2% | With 9-benzyl-9-norazaadamantane N-oxyl; sodium hypochlorite; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at 0℃; for 1h; | 1 (Compounds 1 to 3) 1,2: 5,6-di-O-isopropylidene-α-D-glucofuranose (50.0 g, 0.192 mol), potassium bromide (2.29 g, 19.2 mmol) in dichloromethane (50 mL),It was dissolved in a saturated aqueous sodium hydrogen carbonate solution (130 mL).After cooling to 0 ° C., Nor-AZADO (1.3 mg) and aqueous sodium hypochlorite solution (203 mL) were added dropwise, and the mixture was stirred at the same temperature for 1 hr. Saturated sodium thiosulfate was added and the mixture was stirred and then extracted 5 times with chloroform.The organic layer was dried over magnesium sulfate, concentrated under reduced pressure to dryness,Crude compound 2 was obtained.Next, the crude compound 2 was dissolved in tetrahydrofuran (370 mL), paraformaldehyde (11.1 g) and potassium carbonate (51.0 g) were added, and the mixture was stirred at 40 ° C. for 24 hours. The insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure.The residue was dissolved in tetrahydrofuran (370 mL) and deionized water (74.5 mL) and cooled to 0 ° C.Sodium borohydride (14.0 g, 0.370 mol) was added, and the mixture was stirred at the same temperature for 3 hours.The reaction solution was concentrated under reduced pressure and then extracted 5 times with chloroform.The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure.The residue was dissolved in ethyl acetate, hexane was added, and the mixture was stirred.The precipitated solid was collected by filtration and dried to obtain compound 3 (30.7 g, 0.106 mol, 55.2%). |
25% | With 4,4'-bis-(dichloroiodo)-biphenyl; tetraethylammonium bromide In chloroform at 20℃; for 0.5h; | |
15% | With benzalacetophenone In various solvent(s) at 110℃; for 6h; | |
6% | With potassium carbonate In water at 20℃; electrolysis; | |
With acetic anhydride; dimethyl sulfoxide for 24h; Ambient temperature; | ||
3.20 g | With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 1h; | |
With 4 A molecular sieve; pyridinium chlorochromate In dichloromethane | ||
With pyridine; chromium(VI) oxide | ||
With pyridinium chlorochromate | ||
With sodium periodate | ||
With 3 A molecular sieve; pyridinium chlorochromate In dichloromethane | ||
With acetic anhydride In dimethyl sulfoxide at 70℃; for 2h; | ||
With molecular sieve; pyridinium chlorochromate In dichloromethane | ||
With molecular sieve; pyridinium chlorochromate In dichloromethane | ||
With oxygen | ||
With ruthenium(IV) oxide; potassium metaperiodate; potassium carbonate In dichloromethane at 30℃; Yield given; | ||
With N-chloro-succinimide; dimethyl sulfoxide; triethylamine; triphenylphosphine 1.) CH2Cl2, -50 deg C to -40 deg C, 1.5 h, 2.) CH2Cl2, from -50 deg C to RT, 100 min; Yield given. Multistep reaction; | ||
With 3 A molecular sieve; pyridinium chlorochromate In dichloromethane for 24h; | ||
With pyridinium chlorochromate In dichloromethane | ||
With dipyridinium dichromate; acetic acid In dichloromethane Ambient temperature; | ||
With dipyridinium dichromate; acetic anhydride In dichloromethane at 50℃; for 2h; | ||
With pyridinium chlorochromate In dichloromethane for 3h; Ambient temperature; | ||
With dipyridinium dichromate; acetic anhydride In dichloromethane | ||
With molecular sieve; pyridinium chlorochromate In dichloromethane | ||
With pyridinium chlorochromate In dichloromethane | ||
With pyridine; chromium(VI) oxide; acetic anhydride In dichloromethane | ||
With dipyridinium dichromate | ||
With dipyridinium dichromate; acetic anhydride In dichloromethane for 2h; Heating; | ||
With dipyridinium dichromate | ||
With dipyridinium dichromate; acetic anhydride In dichloromethane | ||
With N-methyl-2-indolinone; tetrapropylammonium perruthennate; 4 A molecular sieve In acetonitrile | ||
With dipyridinium dichromate; 3 A molecular sieve; acetic acid In dichloromethane at 20℃; for 16h; | ||
With pyridine; chromium(VI) oxide; acetic anhydride In dichloromethane at 0 - 20℃; for 2.5h; | ||
With acetic anhydride; dimethyl sulfoxide at 75℃; for 3h; | ||
With pyridine; chromium(VI) oxide; acetic anhydride In dichloromethane at 0 - 20℃; for 2.5h; | ||
With dipyridinium dichromate; acetic anhydride In dichloromethane Heating; | ||
With pyridine; chromium(VI) oxide; acetic anhydride In dichloromethane at 0℃; for 1h; | ||
With chromium(VI) oxide In pyridine; acetic anhydride | ||
With acetic anhydride; dimethyl sulfoxide at 50 - 60℃; for 24h; | A.a; B.a To diacetoneglucose (25 g) (commercially available) was added dimethyl sulphoxide (100 ml) and acetic anhydride (50 ml). The reaction mixture was stirred at 50-60° C. for 24 hours. Dimethyl sulphoxide was evaporated under reduced pressure and water (2.5 ml) was added with vigorous stirring followed by the addition of ether (10 ml) and hexane. The mixture was kept in refrigerator for overnight. The solid thus separated was filtered to obtain the title compound (16 g).To diacetone glucose (25 g) (commercially available) was added dimethyl sulphoxide (100 ml) and acetic anhydride (50 ml). The reaction mixture was stirred at 50-60° C. for 24 hours. Dimethyl sulphoxide was evaporated under reduced pressure and water was added with constant stirring followed by the addition of ether (10 ml) and hexane. The mixture was kept in refrigerator for overnight and the solid thus separated was filtered to obtain the title compound (16 g). | |
With pyridine; chromium(VI) oxide; acetic anhydride | ||
With pyridinium chlorochromate In dichloromethane Molecular sieve; | ||
With dipyridinium dichromate In dichloromethane; acetic anhydride Reflux; | ||
With pyridine; chromium(VI) oxide; acetic anhydride In dichloromethane at 20℃; for 1h; | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -80℃; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at -80℃; Inert atmosphere; | ||
With acetic anhydride; dimethyl sulfoxide at 50 - 60℃; for 24h; Neat (no solvent); | A.a To diacetoneglucose (25g) (commercially available) was added dimethyl sulphoxide (100ml) and acetic anhydride (50ml). The reaction mixture was stirred at 50-60°C for 24 hours. Dimethyl sulphoxide was evaporated under reduced pressure and water (2.5ml) was added with vigorous stirring followed by the addition of ether (10ml) and hexane. The mixture was kept in refrigerator for overnight. The solid thus separated was filtered to obtain the title compound (16g). | |
With sodium acetate; pyridinium chlorochromate In dichloromethane Inert atmosphere; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine | ||
Inert atmosphere; | ||
With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 18.25h; | ||
With pyridine; chromium(VI) oxide; acetic anhydride In dichloromethane at 20℃; | ||
With sodium hypochlorite solution; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium bromide | ||
With dipyridinium dichromate In dichloromethane; acetic anhydride Reflux; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; water; sodium acetate; sodium bromide In ethyl acetate at 3 - 7℃; for 8.5h; Large scale; | Alternative procedure To l,2:5,6-di-0-isopropylidene-a-D-glucofuranose, II (112 kg, 430 mol) solubilized in a mixture of ethyl acetate (504 L) were added demineralized water (168 L), NaBr (35.0 kg, 340 mol), NaOAc (53.0 kg, 646 mol) and further demineralized water (56 L) at 27 °C. The reaction mixture was cooled to 0 °C then TEMPO (1.0 kg, 6.45 mol) and further ethyl acetate (56 L) added. To a separate vessel sodium hypochlorite (9-12% w./w, 1000 L, ca. 1649 mol) was added and the pH adjusted to 11.5 to 12.5 with a 1:1 mixture of concentrated sulphuric acid: water (ca. 67 L) at 2.5°C. The sodium hypochlorite solution was filtered and added to the reaction mixture at 7 °C over 7.5 hours. The mixture was stirred for 1 hour at 3 °C then 20% w/w aq. sodium sulfite (135 kg) was added at 3 °C. The mixture was warmed to 29 °C and the phases separated. The organic phase was checked for absence of sodium hypochlorite. To the aqueous phase, solid NaCl (56 kg) was added, and then it was extracted with ethyl acetate (225 L). To the aqueous phase solid NaCl (28 kg) was added, and then it was extracted with ethyl acetate (224 L). The combined organic phases were washed with 9 % w/w aqueous sodium chloride (112 kg) at 30 °C, the layers separated and the aqueous layer back-extracted with ethyl acetate (112 L). The combined organic layers were dried with MgSCb (56 kg), filtered, the filter cake washed with ethyl acetate (56 L), and the combined filtrates were concentrated in vacuo at up to 45 °C to 392 L. Three further ethyl acetate addition (225, 225 and 112 L), distillation cycles were performed to control water to < 0.3 % w/w and the assay of the solution determined. l,2:5,6-di-0-isopropylidene-a-D-glucofuran-3-ulose hydrate III was progressed to the next step of the process as an ethyl acetate solution with an assumed 119 kg, 100% th yield. |
85% | With ruthenium(IV) oxide; sodium periodate; N-benzyl-N,N,N-triethylammonium chloride; water; potassium carbonate In chloroform for 22h; | |
With ruthenium(IV) oxide; potassium metaperiodate; potassium carbonate 1.) 12 h; 2.) 12 h; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose In 1,2-dichloro-ethane Stage #2: With tri-n-butyl-tin hydride In toluene Further stages.; | |
62% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With carbon disulfide; sodium hydride; methyl iodide In tetrahydrofuran Stage #2: With tri-n-butyl-tin hydride In toluene Heating; Further stages.; | |
61% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With 1H-imidazole; sodium hydride In tetrahydrofuran; mineral oil for 0.333333h; Stage #2: With carbon disulfide In tetrahydrofuran; mineral oil for 0.5h; Further stages; | 3-deoxy-1 ,2:5,6-di-0-isopropylidene-a-D-ribo-hexofuranose (FH8473) To a solution of diacetone glucose (26.0 g, 100 mmol), under nitrogen flow, was added imidazole (0.1 g, catalytic) and NaH (60% dispersion in mineral oil, 6.0 g, 150 mmol, 1 .5 eq.) portionwise over a 5 - 10 min period. The resulting mixture was stirred for 20 min afther which CS2 (18.0 mL, 300 mmol, 3 eq.) was added in one portion. After stirring for 30 min, Mel (1 1 .21 mL, 180 mmol, 1 .8 eq.) was added in one portion. The reaction mixture was further stirred for 20 min, after which TLC indicated full conversion of the starting material. Next, 5 mL of acetic acid was added to quench residual NaH. The mixture was afterwards filtered, and the filtrate evaporated till a semi-solid. Diethylether and water were added, layers separated, and the diethylether layer sequentially washed with sat. aq. NaHC03 solution (2x), water (1 x) and brine (1 x). The organic layer was dried over Na2S04, evaporated and used without further purification. The residue was dissolved in anhydrous toluene (1000 mL, 10 mL / mmol), and to this was added AIBN (1 .97 g, 12 mmol, 0.12 eq.), followed by (nBu)3SnH (32 mL, 120 mmol, 1 .2 eq.) and the resulting solution refluxed till TLC analysis showed full conversion (~3 to 5 H). Next, the mixture was cooled to room temperature and the solvent removed in vacuum and the residue partitioned between MeCN/hexanes. The MeCN layer was additionally washed with hexanes (2x) and then evaporated. Purification by column chromatography (gradient: 5→ 15 % EA/PET), gave 15 g (61 mmol) of FH8473 as a yellowish oil (Yield = 61 %). 1H NMR (300 MHz, CDCI3) δ: 1 .32 (s, 3H, CH3), 1 .36 (s, 3H, CH3), 1 .43 (s, 3H, CH3), 1 .51 (s, 3H, CH3), 1 .72 - 1 .81 (m, 1 H, H-3'), 2.19 (dd, J = 13.5, 4.2 Hz, 1 H, H-3), 3.80 - 3.86 (m, 1 H), 4.07 - 4.20 (m, 3H), 4.75 (t, J = 4.2 Hz, 1 H, H-2), 5.82 (d, J = 3.6 Hz, 1 H, H-1 ). HRMS (ESI): no corresponding signal detected. |
With 1H-imidazole; tri-n-butyl-tin hydride; sodium hydride; methyl iodide 1.) THF, CS2, RT, 2.) toluene, reflux, 3 h; Yield given. Multistep reaction; | ||
With tri-n-butyl-tin hydride; sodium hydride; methyl iodide 1.) CS2; 2.) toluene, reflux; Yield given. Multistep reaction; | ||
With 1H-imidazole; carbon disulfide; tri-n-butyl-tin hydride; sodium hydride; methyl iodide 1.) THF, 2.) toluene, reflux, 3 h; Yield given; Multistep reaction; | ||
Multi-step reaction with 2 steps 1: 93 percent / 1,2-dichloro-ethane / Heating 2: 74 percent / n-Bu3SnH / toluene / Heating | ||
Multi-step reaction with 2 steps 1: 76 percent / N-hydroxysuccinimide, pyridine / tetrahydrofuran / 2 h / Ambient temperature 2: 100 percent Spectr. / PhSiH3, benzoyl peroxide / toluene / 1.33 h | ||
Multi-step reaction with 2 steps 1: N-hydroxysuccinimide, pyridine / benzene / 80 °C 2: tributyltin hydride, AIBN / benzene-d6 / competition experiments between reagents in different reaction time and temperature | ||
Multi-step reaction with 2 steps 1: 1H-imidazole; iodine; triphenylphosphine / toluene / 3 h / Reflux 2: (1,3-dimethylimidazol-2-ylidene)borane; triethyl borane / hexane; benzene / 2 h / 20 °C | ||
Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 0.33 h / 20 °C 1.2: 0.5 h / 20 °C 2.1: thiophenol / 0.25 h / 20 °C 3.1: tri-n-butyl-tin hydride / toluene / 17 h / Reflux | ||
Multi-step reaction with 2 steps 1.1: 1H-imidazole; sodium hydride / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 1.2: 2 h / Inert atmosphere 1.3: 1 h / Inert atmosphere 2.1: tri-n-butyl-tin hydride / toluene / Reflux | ||
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 0 °C 2: tetra-(n-butyl)ammonium iodide / toluene / 80 °C 3: fac-tris(4-methyl-(2-pyridinyl-κN)phenyl-κ2C)iridium(III); N-ethyl-N,N-diisopropylamine; para-thiocresol / acetonitrile / 1 h / 20 °C / Irradiation; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: dmap / dichloromethane / 20 °C / Inert atmosphere; Darkness 2: N-ethyl-N,N-diisopropylamine; tris[2-phenylpyridinato-C2,N]iridium(III) / acetonitrile / Photolysis; Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 1 h / 20 °C 1.2: 1 h 2.1: tri-n-butyl-tin hydride; 2,2'-azobis(isobutyronitrile) / toluene / 2 h / 90 °C | ||
Multi-step reaction with 2 steps 1: pyridine / toluene / 6 h / 0 - 10 °C / Large scale 2: tetrabutylammonium borohydride / toluene / 65 - 75 °C / Large scale | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 4 h / Heating / reflux 2: tri-n-butyl-tin hydride / 2,2'-azobis(isobutyronitrile) / toluene / 6.5 h / Heating / reflux | ||
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 0.25 h / -10 °C / Inert atmosphere 2: tetrabutylammonium borohydride / toluene / 4 h / Inert atmosphere; Reflux | ||
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 0 °C / Inert atmosphere 2: tetrabutylammonium borohydride / toluene / 7 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1.1: 1H-imidazole; sodium hydride / mineral oil; tetrahydrofuran / 0.25 h / 0 - 10 °C 1.2: 1 h / 20 °C 1.3: 2 h / 0 - 20 °C 2.1: 2,2'-azobis(isobutyronitrile); tri-n-butyl-tin hydride / toluene / 6 h / 120 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 2 h / -0.16 °C 2: tetrabutylammonium borohydride / 4 h / 99.84 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With i-PrEtN In tetrahydrofuran at -78℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 20h; | |
98% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 20h; | 3-O-Cinnamoyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (9) A solution of 4 (1.0g, 3.84mmol), cinnamic acid (1.253g, 8.46mmol), DCC (1.903g, 9.22mmol) and DMAP (1.878g, 15.37mmol) in dry CH2Cl2 (100mL) was stirred at room temperature for 20h. The mixture was poured in water (300mL) and extracted with CH2Cl2 (2×50mL), the combined organic solutions were washed with 10% aqueous NaCl (250mL), dried and evaporated. Flash column chromatography of the residue (3:1 light petroleum/Et2O) gave pure 9 (1.476g, 98%) as a colourless syrup, [α]D25 =-48.7 (c 1, CHCl3), Rf=0.32 (3:1 light petroleum/Et2O). IR (neat): 1720, 1637, 1578 1162cm-1. 1H NMR (250MHz, CDCl3): δ 1.31, 1.32, 1.42, 1.54 (4×s, 3H each, 2×CMe2), 4.03-4.05 (m, 2H, 2×H-6), 4.26-4.37 (m, 2H, H-4 and H-5), 4.58 (d, 1H, J1,2=3.7Hz, H-2), 5.39 (d, 1H, J3,4=2.2Hz, H-3), 5.93 (d, 1H, J1,2=3.7Hz, H-1), 6.44 (d, 1H, J2′,3′=16.0Hz, H-2′), 7.35-7.59 (m, 5H, Ph), 7.72 (d, 1H, J2′,3′=16.0Hz, H-3′). 13C NMR (62.9MHz, CDCl3): δ 25.2, 26.1, 26.6, 26.8 (2×CMe2), 67.0 (C-6), 72.4 (C-5), 76.1 (C-3), 79.7 (C-4), 83.3 (C-2), 105.0 (C-1), 109.2 and 112.2 (2×CMe2), 117.0 (C-2′), 128.1, 128.9, 130.6, 133.9 (Ph), 146.0 (C-3′), 165.4 (C-1′). HRMS (ESI) calcd for C21H26NaO7 413.1571, found 413.1577 (M++Na). |
72% | With dmap; dicyclohexyl-carbodiimide In dichloromethane for 4h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane at 25℃; for 12h; | |
72% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 20℃; for 12h; | |
72% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane at 20℃; for 12h; |
70.5% | With sodium hydroxide In dichloromethane at 25℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 0 - 20℃; Stage #2: 1-Bromo-2-bromomethyl-benzene In dichloromethane at 20℃; | |
70.5% | With sodium hydroxide In dichloromethane at 25℃; for 12h; | |
70% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 20℃; for 12h; |
70% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 0 - 20℃; | |
70.5% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane at 25℃; for 12h; | |
70% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride In N,N-dimethyl-formamide at 0 - 25℃; for 2.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine In dichloromethane at 0 - 20℃; for 70h; | 3-O-Benzoyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (15) To a cooled (0 °C) and stirred solution of compound 8 (3.00 g, 11.52 mmol) in anhydrous Py (3.5 mL) and CH2Cl2 (10 mL) was added BzCl (2.3 mL, 19.81 mmol) and the solution was left at room temperature for 70 h. The mixture was then acidified with cold 6 M aq HCl (pH ≈ 1-2) and the resulting emulsion was extracted with CH2Cl2 (4 × 20 mL). Extracts were combined, washed with water (1 × 25 mL), saturated solution of NaHCO3 (1 × 20 mL) and again with water (1 × 25 mL), dried and evaporated, to give crude product 15, which was purified by preparative TLC (110 plates, 9:1 toluene/EtOAc, eluting with 1:1 EtOAc/CH2Cl2). Pure 15 (4.158 g, 99%), was obtained as a colourless syrup, [α]D = -40.0 (c 0.2, CHCl3), lit.2 [α]D = -53.5, lit.3 [α]D = -3.5 (c 4.2, CHCl3), Rf = 0.33 (19:1 toluene/EtOAc). |
99% | With pyridine In dichloromethane at 0 - 20℃; for 70h; | 3-O-Benzoyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (15) To a cooled (0 °C) and stirred solution of compound 8 (3.00 g, 11.52 mmol) in anhydrous Py (3.5 mL) and CH2Cl2 (10 mL) was added BzCl (2.3 mL, 19.81 mmol) and the solution was left at room temperature for 70 h. The mixture was then acidified with cold 6 M aq HCl (pH ≈ 1-2) and the resulting emulsion was extracted with CH2Cl2 (4 × 20 mL). Extracts were combined, washed with water (1 × 25 mL), saturated solution of NaHCO3 (1 × 20 mL) and again with water (1 × 25 mL), dried and evaporated, to give crude product 15, which was purified by preparative TLC (110 plates, 9:1 toluene/EtOAc, eluting with 1:1 EtOAc/CH2Cl2). Pure 15 (4.158 g, 99%), was obtained as a colourless syrup, [α]D = -40.0 (c 0.2, CHCl3), lit.2 [α]D = -53.5, lit.3 [α]D = -3.5 (c 4.2, CHCl3), Rf = 0.33 (19:1 toluene/EtOAc). |
98% | With aluminum oxide In acetonitrile at 20℃; for 0.75h; |
92% | With pyridine at 20℃; for 48h; | |
89% | With N-(methylpolystyrene)-4-(methylamino)pyridine In acetonitrile at 170℃; for 0.25h; microwave irradiation; | |
In pyridine | ||
Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: benzoyl chloride With pyridine In N,N-dimethyl-formamide at 20℃; for 2h; Further stages.; | ||
With triethylamine In dichloromethane at 0℃; for 24h; | ||
With pyridine In dichloromethane at 0 - 20℃; for 3h; | 1.a a. Dissolve compound 2 (260g, 1.0mol) in anhydrous dichloromethane (1.5L) and add anhydrous pyridine Py (2mol),The solution was cooled to 0 with ice water, and then benzoyl chloride BzCl (126mL, 1.1mol) was added dropwise,After the addition is complete, react for 3h at room temperature,After the reaction is completed, the reaction solution is slowly poured into a saturated sodium bicarbonate solution at 0°C,The liquid was separated and extracted with dichloromethane. The extract was concentrated, and the obtained oily matter was poured into water at 0°C to form a solid.After the solid was washed three times with water, it was directly reacted in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1H-imidazole In acetonitrile at 20℃; for 1h; | |
93% | With tris(pentafluorophenyl)borate In neat (no solvent) at 20℃; for 0.05h; Green chemistry; | Typical experimental procedure: General procedure: B(C6F5)3 (0.5 mol %) was added to a mixture of alcohol/phenol/thiophenol/amine (1 mmol) and acetic anhydride (1.2 mmol), and the reaction mixture was stirred at room temperature until the complete conversion of starting material (monitored by TLC). After completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 15 mL). The organic layer was washed with cold saturated sodium bicarbonate solution (2 20 mL) followed by brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure and products were purified over silica gel column chromatography in ethylacetate/hexane. All compounds were characterized and confirmed by comparison of their spectral data and physical properties with reported literature. |
90% | With iodine for 0.0833333h; ice-bath temperature; |
90% | With pyridine at 20℃; for 5h; | |
89% | With dmap; triethylamine In dichloromethane at 20℃; for 3h; | |
83% | With dmap; triethylamine In dichloromethane at 20℃; for 3h; | |
72% | With triethylamine In acetonitrile for 0.00277778h; microwave irradiation; | |
30% | With aluminum oxide In acetonitrile at 20℃; for 0.8h; | |
In ethyl acetate at 60℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With pyridine In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; stereoselective reaction; | |
With diisopropylamine In toluene at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane at 25℃; for 12h; | |
75% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 20℃; for 12h; | |
75% | With sodium hydroxide; tetrabutylammomium bromide In dichloromethane; water at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrogen In methanol at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With diphenylphosphinopolystyrene; iodine at 20℃; for 0.5h; | |
90% | With sulfuric acid; copper(II) sulfate at 20℃; for 18h; | |
81.3% | With sulfuric acid at 5 - 25℃; for 8h; | 3.1 Preparation of 1,2: 3,4-di-O-isopropylidene-alpha-D-fructopyranose (II) In a 1000 mL three-necked flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, a dry450mL acetone, ice bath cooling to the solution temperature dropped to about 5 ° C, 12mL concentrated sulfuric acid slowly added to the acetone, the dropping process to maintain the temperature below 10 ° C. 18 g of D-glucose was added to the solution, and the temperature of the ice-water bath was raised, and the D-glucose was completely dissolved by stirring. The reaction was then stirred at 25 ° C for 8 hours.After the reaction solution was cooled to below 5 ° C by cooling in an ice-water bath, the pH value of the reaction solution was adjusted to 7.5 by adding dropwise a 33.3% aqueous solution of sodium hydroxide. Subsequently, the reaction solution was concentrated under reduced pressure to a volume of about 50 mL to remove unreacted acetone. The organic phase was then washed with water (50 mL x 3 times), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then extracted with a mixture of petroleum ether and ethyl acetate (100 mL, V petroleum ether: V ethyl acetate = 2: 1) and recrystallized to give 21. 14 g of white needle-like crystals,The melting point of the product was i9-iirc (uncalibrated thermometer), and the yield was 81.3%. |
With sulfuric acid at 0℃; | ||
With sulfuric acid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.7% | With sulfuric acid; for 6h;Cooling with ice; | Using a 1 L round bottomflask, 30 g (0.17 mol) of anhydrous alpha-D-glucose was addedin 0.6 L of acetone. The mixture was stirred vigorously in an ice-water bath. Concentrated H2SO4 (30mL) was added dropwise for 6 hours. After all the acid was added, the solution was cooled to 0C and neutralized by 50% aqueous potassium hydroxide solution to maintain the pH of the solution near 7. After stirring overnight, thesolution was filtered, and the solvent was removed under reduced pressure. Thesolid was dissolved in 100 mL of dichloromethane and the solution was washed with100 mL of water. The aqueous phase was then extracted three times with 100 mL ofdichloromethane. The organic layers were combined and then concentrated underreduced pressure. Recrystallization from petroleumether gave 28 g of white crystals(64.7% yield).1H NMR (500 MHz, Chloroform-d) delta: 5.94 (d, J = 3.6 Hz, 1 H), 4.53 (d, J = 3.7 Hz, 1 H), 4.39-4.29 (m, 2H), 4.16 (dd, J = 8.7, 6.2 Hz, 1 H), 4.06 (dd,J = 7.6, 2.8 Hz, 1 H), 3.98 (dd, J = 8.6, 5.4 Hz, 1 H), 2.65 (d, J = 3.7 Hz, 1 H), 1.49 (s,3H), 1.44 (s, 3H), 1.36 (s, 3H), 1.31 (s, 3H). 13C NMR (126 MHz, Chloroform-d) delta:111.96, 109.79, 105.42, 85.22, 81.27, 75.34, 73.61, 67.80, 26.99, 26.90, 26.32, 25.28. |
55% | With sulfuric acid; copper(II) sulfate; at 0 - 20℃; for 30.16h; | D-Glucose (30 g, 166.5 mmol) was added to dry acetone (600 mL) at room temperature and wasfollowed by anhydrous CuSO4 (30 g, 610.60 mmol). The reaction mixture was cooled to 0 C,and conc. H2SO4 (22 mL, 0.66 molar in acetone) was added drop-wise over a period of 10 min.The reaction mixture was stirred at room temperature for 30 h. After completion, (TLC) reaction mixture was neutralized with a saturated solution of K2CO3. The solution was filtered and thefiltrate was evaporated under reduced pressure. The residue thus obtained was extracted withchloroform and dried over anhydrous Na2SO4, concentrated under reduced pressure to afford ayellowish solid, which was recrystallized from chloroform: hexane (1:9) to to afford the productglucose-di-acetone (GDA) S9 (24 g, 55%) as white crystals. |
42% | With zinc(II) chloride;iodine; at 20℃; for 21h;Heating / reflux; | To 305 g (1.69 mol) of powdered D-glucose in 2.5 L of acetone (99.9%) is added 500 g (3.67 mol) of anhydrous ZnCl2 and 12 g (0.047 mol) of iodine. The mixture is stirred for 16 hrs at RT and then 5 hrs at reflux. It is then neutralised with 50% NaOH solution (336 g in 330 mL) and addition of sodium thiosulphate solution (23 g). The precipitated salts are filtered off through celite and the precipitate washed with acetone three times. The acetone is evaporated and the residue redissolved in dichloromethane and washed with water two times. After drying with MgSO4 and evaporation of the organic phase the desired product is crystallised from boiling hexane. This yields 185.3 g (42%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; | 1 [Reference Example 1] 1,2:5,6-Di-O-isopropylidene-3-O-[(R)-3-methoxydecyl]-α-D-glucofuranose (Step Aa1) 1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose (14.80 g, 56.857 mmol) and (R)-3-methoxydecyl p-toluenesulfonate (16.50 g, 48.175 mmol) were dissolved in dimethylformamide (DMF, 60 mL), and sodium hydride (55% dispersion in oil, 3.72 g, 85.286 mmol) was added to the solution under ice cooling. After stirring at 0°C for 15 minutes, the mixture was stirred at room temperature overnight. After completion of the reaction, methanol was added to the reaction solution under ice cooling to decompose sodium hydride, and the solution was diluted with ethyl acetate. The solution was washed with water and saturated brine, dried over magnesium sulfate, filtrated and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluent: cyclohexane /ethyl acetate=15/1, then 2/1) to give the title compound as an oil (15.20 g, yield 98%). IR νmax(film) 2987, 2932, 2960 cm-1. 400 MHz 1H NMR (CDCl3) δ 0.88 (3H, t, J=6.6 Hz), 1.28 (10H, bs), 1.37 (3H, s), 1.35 (3H, s), 1.43-1.52 (8H, m, containing two 3H, s, at 1.43 and 1.50 ppm), 1.68-1.74 (2H, m), 3.30 (1H, m), 3.32 (3H, s), 3.57 (1H, m), 3.73 (1H, m), 3.86 (1H, d, J=2.9 Hz), 3.99 (1H, m), 4.08 (1H, m), 4.12 (1H, dd, J=2.9, 7.3 Hz), 4.30 (1H, dd, J=5.9, 13.9 Hz), 4.55 (1H, d, J=3.7 Hz), 5.87 (1H, d, J=3.7 Hz). FABMS (positive-ion) m/z; 431 [M+H]+. HRFABMS; Calcd. for C23H43O7: 431.3009. Found: 431.3018. |
82% | With sodium hydride In N,N-dimethyl-formamide at 20 - 50℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In acetonitrile at 20℃; for 2h; | |
90% | With dimethylbromosulphonium bromide In acetonitrile at 20℃; for 4h; | |
90% | With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)] In acetonitrile at 40℃; for 0.75h; 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. |
7 g | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 20℃; | 1 Preparation of 1,2,5,6-O-diisopropylidene-D-glucose (2) D-glucose (5.0 g, 32.7 mmol) was dissolved in DMF (30 mL), and p-toluenesulfonic acid (0.5 g, 2.90 mmol) was added to the solution at room temperature, followed by dropwise addition of 2,2- Dimethoxypropane (8 ml, 65 mmol). After stirring at room temperature for 4-10 hours, the reaction was poured into cold water (300 mL)The combined organic layer solution was washed with saturated brine and dried over anhydrous sodium sulfate.Concentrated to a colorless oil mixture 1 (7.0 g), directlyTake the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 92 percent / aq. H2SO4 / methanol / 12 h 2: NaIO4; aq. NaHCO3 / CH2Cl2 / 2 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 80percent AcOH / H2O 2: NaIO4 / H2O; methanol | ||
With periodic acid In ethyl acetate at 20℃; for 2h; |
With periodic acid In ethyl acetate at 20℃; for 4h; | ||
Multi-step reaction with 2 steps 1: sulfuric acid; water / 12 h / 20 °C 2: sodium periodate / methanol; water / 0.5 h | ||
With periodic acid In ethyl acetate at 20℃; for 2.5h; | ||
With periodic acid In ethyl acetate at 20℃; for 3.5h; | I.GENERAL PROCEDURE FOR THE PREPARATION OF 7 AND 8 General procedure: I.GENERAL PROCEDURE FOR THE PREPARATION OF 7 AND 8 To a solution of diacetonides S1a or S1b (1 equiv) in dry EtOAc (0.03-0.04 mmol) was added H5IO6 (1 equiv). The mixture was stirred at room temperature until the starting materials were consumed (TLC, 3.5 h for S1a, 6 h for S1b). The mixtures were filtered and evaporated and the remaining crude aldehydes S2a or S2b were dried in a vacuum dessicator for 2 h. To a stirred and cooled (0 °C) solution of S2 in dry ether (0.03-0.04 mmol) was added a 3 M etheral solution of PhMgBr (10 equiv for S2a, 3 equiv for S2b). The mixture was stirred for 5 h at 0 °C, in an atmosphere of nitrogen, then allowed to worm up to room temperature, then poured into 10% aq NH4Cl and extracted first with ether, then with EtOAc. The combined extracts were washed with 10% aq NaCl, organic phase was dried and evaporated and the residue purified by flash column chromatography. | |
Multi-step reaction with 2 steps 1: acetic acid / water / 21 h / 25 - 30 °C 2: sodium periodate / water; methanol / 1 h / 0 °C | ||
With periodic acid In ethyl acetate at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-methyl-1H-imidazole; iodine In tetrahydrofuran at 20℃; for 0.25h; | |
91% | With 1-methyl-1H-imidazole; iodine In tetrahydrofuran at 20℃; for 14h; | |
With 1H-imidazole In N,N-dimethyl-formamide at 50℃; for 80h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1.16667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydroxide; In water; dimethyl sulfoxide; at 20℃; for 20h; | General procedure: The selectively protected saccharide (1 equiv) was dissolved in DMSO and for each hydroxyl group 1.3 equiv 50% sodium hydroxide solution and 1.5 equiv <strong>[6940-78-9]1-bromo-4-chlorobutane</strong> were added. The mixture was stirred at room temperature for 20 h. Distilled water was added, and the solution was extracted three times with diethyl ether. The combined organic fractions were washed with saturated sodium chloride solution and dried with Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography to give the product. |
60% | NaH (0.31 g, 7.7 mmol, 2.0 eq.,60% in mineral oil) was washed three times with 5 mL of n-hexane. The suspension was decanted after each wash and n-hexane traces were removed under reduced pressure. Anhydrous DMF (15 mL) was then added and the suspension was stirred for 5 min. A solution of 1,2,5,6-Di-O-isopropylidene-alpha-D-glucofuranose (4, 1.00 g, 3.8 mmol, 1.0 eq.) in anhydrous DMF (15 mL) was then added dropwise. After stirring for 30 min under nitrogen flow, a solution of <strong>[6940-78-9]1-bromo-4-chlorobutane</strong> (2.63 g, 15.4 mmol,4.0 eq.) in anhydrous DMF (5 mL) was added dropwise and the mixture was vigorously stirred for 24 hours at 40 C. The reaction mixture was then diluted in CH2Cl2 (150 mL) and washed with 0.3 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 column chromatography (CH2Cl2:EtOAc 9:1) to give 5 (0.81 g, 60% yield) as a pale yellow oil. 1H-NMR (CDCl3) delta (ppm) = 5.87 (d, J = 3.7 Hz, 1H, -CH-),4.53 (d, J = 3.8 Hz, 1H, -CH-), 4.32-4.24 (m, 1H, -CH-), 4.12-4.06 (m, 2H, -CH2-), 4.00-3.95 (m, 1H,-CH-), 3.86-3.44 (m, 5H, -CH-, -O-CH2-, -CH2-Cl), 1.84-1.60 (m, 4H, -CH2-CH2-), 1.49, 1.41, 1.34,1.31 (4 s, 12H, 4 × -CH3); 13C-NMR (CDCl3) delta (ppm) = 111.76, 108.98, 105.25, 83.05, 82.12, 81.21,72.34, 69.54, 67.39, 44.76, 29.26, 26.99, 26.80, 26.77, 26.21, 25.34; ESI-MS (ion trap): m/z 351 [M+H]+. Anal. calcd. for C16H27ClO6: C, 54.78; H, 7.76 Found: C, 54.69; H, 7.71. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 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) General procedure: 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%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 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 |
---|---|---|
93% | 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) General procedure: 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%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran; paraffin oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluorononyl)benzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; paraffin oil at 0 - 20℃; for 16h; Inert atmosphere; | 4.2.5. 3-O-[4-(4,4,5,5,6,6,7,7,8,8,9,9,9-Tridecafluorononyl)benzyl]-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose (7a) To a solution of 1,2:5,6-di-O-isopropyridene-α-d-glucofuranose (6) (664 mg, 2.55 mmol) in dry THF (10 mL) was added sodium hydride (55% dispersion in paraffin liquid, 223 mg, 5.11 mmol) at 0 °C under argon. After stirring for 30 min at the same temperature, tetrabutyl ammonium iodide (79 mg, 0.213 mmol) was added, and then a solution of benzyl bromide 5a (1.13 g, 2.13 mmol) in THF (20 mL) was added dropwise to the solution. After stirring for 16 h at room temperature, the reaction mixture was poured into saturated aq NH4Cl solution (30 mL), and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layer was successively washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc=6:1 v/v) to give 7a (1.34 g, 88% yield) as colorless amorphous solids: Rf=0.59 (hexane/EtOAc=2:1 v/v); -11.9 (c 0.202, CHCl3); IR (KBr, disk): ν 2989 cm-1, 2938 cm-1, 2879 cm-1 (CH3); 1H NMR (250 MHz, CDCl3): δ 7.29, 7.16 (4H, each d, J=8.0 Hz, -C6H4-), 5.89 (1H, d, J1,2=3.7 Hz, H-1), 4.67, 4.61 (2H, each d, JAB=11.8 Hz, C6H4CH2), 4.58 (1H, d, J2,1=3.7 Hz, H-2), 4.37 (1H, ddd, J5,4=7.8 Hz, J5,6=6.1 Hz, J5,6'=5.9 Hz, H-5), 4.15 (1H, dd, J4,5=7.8 Hz, J4,3=3.1 Hz, H-4), 4.11 (1H, dd, J6,5=6.1 Hz, J6,6'=8.6 Hz, H-6), 4.02 (1H, d, J3,2=3.1 Hz, H-3), 4.00 (1H, dd, J6',5=5.9 Hz, J6',6=8.6 Hz, H-6'), 2.71 (2H, t, J=7.5 Hz, CH2CH2CH2C6F13), 2.19-1.88 (4H, m, CH2CH2CH2C6F13), 1.49, 1.43, 1.37, 1.31 (12H, each s, CH3×4); 13C NMR (63 MHz, CDCl3): δ 140.3, 135.7, 128.4, 128.0, 111.8, 109.0, 105.3, 82.7, 81.7, 81.3, 72.5, 72.2, 67.4, 34.7, 30.3 (t, JCF=22.3 Hz), 26.8, 26.7, 26.2, 25.4, 21.8; ESI-HRMS calcd for C28H31F13O6Na m/z [M+Na]+: 733.1811. Found: 733.1784. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran; paraffin oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)benzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; paraffin oil at 0 - 20℃; for 16h; Inert atmosphere; | 4.2.6. 3-O-[4-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoroundecyl)benzyl]-1,2:5,6-di-O-isopropylidene-α-d-glucofuranose (7b) To a solution of 1,2:5,6-di-O-isopropyridene-α-d-glucofuranose (6) (549 mg, 2.11 mmol) in dry THF (10 mL) was added sodium hydride (55% dispersion in paraffin liquid, 184 mg, 4.22 mmol) at 0 °C under argon. After stirring for 30 min at the same temperature, tetrabutyl ammonium iodide (65 mg, 0.176 mmol) was added, and then a solution of benzyl bromide 5b (1.11 g, 1.76 mmol) in THF (20 mL) was added dropwise to the solution. After stirring for 16 h at room temperature, the reaction mixture was poured into saturated aq NH4Cl solution (30 mL), and the aqueous layer was extracted with EtOAc (30 mL×3). The combined organic layer was successively washed with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc=6:1) to give 7b (1.26 g, 88% yield) as colorless needles: mp 67.5-69.9 °C (MeOH); Rf=0.59 (hexane/EtOAc=2:1 v/v); -12.04 (c 1.03, CHCl3); IR (KBr, disk): ν 2988, 2937, 2878 cm-1 (CH3); 1H NMR (250 MHz, CDCl3): δ 7.29, 7.16 (4H, each d, J=8.0 Hz, -C6H4-), 5.90 (1H, d, J1,2=3.7 Hz, H-1), 4.67, 4.61 (2H, each d, JAB=11.8 Hz, C6H4CH2), 4.58 (1H, d, J2,1=3.7 Hz, H-2), 4.37 (1H, ddd, J5,4=7.7 Hz, J5,6=6.0 Hz, J5,6'=5.9 Hz, H-5), 4.15 (1H, dd, J4,5=7.7 Hz, J4,3=3.2 Hz, H-4), 4.12 (1H, dd, J6,5=6.0 Hz, J6,6'=8.5 Hz, H-6), 4.02 (1H, d, J3,2=3.2 Hz, H-3), 4.01 (1H, dd, J6',5=5.9 Hz, J6',6=8.5 Hz, H-6'), 2.71 (2H, t, J=7.5 Hz, CH2CH2CH2C8F17), 2.19-1.88 (4H, m, CH2CH2CH2C8F17), 1.49, 1.43, 1.38, 1.31 (12H, each s, CH3×4); 13C NMR (63 MHz, CDCl3): δ 140.3, 135.7, 128.4, 128.0, 111.8, 109.0, 105.3, 82.7, 81.7, 81.3, 72.5, 72.2, 67.4, 34.7, 30.3 (t, JCF=22.3 Hz), 26.8, 26.7, 26.2, 25.4, 21.8; ESI-HRMS calcd for C30H31F17O6Na m/z [M+Na]+: 833.1747. Found: 833.1720. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In acetonitrile; mineral oil at 0℃; for 0.5h; Stage #2: 2-[4-(bromomethyl)phenyl]-6-fluoro-1,3-benzothiazole In acetonitrile; mineral oil at 0 - 20℃; | 4.1.44. 2-(4-(((3aR,5S,6aS)-5-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyl-dihydro-5H-furo[3,2-d][1,3]dioxol-6-yloxy)methyl)phenyl)-6-fluorobenzo[d]thiazole (23) To a solution of d-glucose diacetonide (0.26 g, 1.0 mmol) in dry CH3CN (10 mL) was added NaH 60% w/w (0.060 g, 1.5 mmol) in portions at 0 °C. After stirring for 30 min compound 22 (0.321 g, 1.0 mmol) was added and stirring was continued for further 2-4 h at room temperature till TLC showed complete disappearance of the starting materials. The reaction mixture was then diluted with EtOAc (30 mL) and washed with H2O (2 × 5 mL) and brine (1 × 10 mL). The organic layer was dried over Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was passed through a thin layer of silica gel chromatography using EtOAc: petroleum ether (1:3) as eluent to afford a colorless gummy material 23 (0.446 g, 89% yield). [α]D 32.4° (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ 1.24-1.53 (m, 12H, CH3), 3.94-4.14 (m, 4H, CH2, CH), 4.29-4.40 (m, 1H, CH), 4.54-4.57 (d, 1H, J = 3.78 Hz, CH), 4.71-4.74 (d, 2H, J = 3.02 Hz, Ar-CH2), 5.84-5.86 (d, 1H, J = 3.78 Hz, CH), 7.17-7.25 (m, 1H, Ar-H), 7.42-7.49 (d, 2H, J = 8.31 Hz, Ar-H), 7.54-7.59 (dd, 1H, J1 = 7.55, J2 = 2.26 Hz, Ar-H), 7.95-8.06 (m, 3H, Ar-H); 13C NMR (75 MHz, CDCl3): δ 25.4, 26.2, 26.8, 67.5, 71.8, 72.4, 81.3, 82.0, 105.3, 107.6, 108.0, 109.1, 111.9, 114.8, 115.1, 124.0, 127.5, 128.0, 132.8, 140.9, 150.7, 162.1, 167.3; MS (ESI): m/z (%) = 502 (M + H, 100), 242 (20); Anal. Calcd for C26H28FNO6S: C, 62.26; H, 5.63; N, 2.79. Found: C, 62.14; H, 5.34; N, 2.99. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In dichloromethane; water at -10 - 0℃; for 0.583333h; Alkaline conditions; Large scale; Stage #2: nitromethane With sodium hydroxide In methanol at 0 - 20℃; for 2.5h; Large scale; Stage #3: With acetic anhydride In dimethyl sulfoxide at 20℃; for 68h; Large scale; | 1,2:5,6-Di-O-isopropylidene-α-D-ribo-3-hexofuranose-3-ulose (6) In an open-mouth beaker equipped with mechanical stirrer, a solution of NaBr (4.20g, 0.04 mol, 0.1 equiv) in water (20 mL) was added to a solution of diacetone-α-D-glucose(5) (104 g, 0.4 mol, 1.0 equiv) in CH2Cl2 (400 mL), followed by TEMPO(0.300 g, 1.9 mmol, 0.5 mol-%). The resulting mixture was cooled to -5 - -10°C(internal temperature) and vigorously stirred, and aqueous solution of NaClO (~1.6 mol/L, pH 9.5, 360 mL, 0.58 mol, 1.45 equiv) 3 was added dropwise in 30 minutes while keeping the internal temperature in the range of -10 - 0°C. After addition of the bleach solution, the resulting reaction mixture was stirred for 5 minutes.4 The organic layer was separated and washed successively with solution of KI (1.60 g, 0.01 mol, 2.5 mol-%) in 0.5 M aqueous hydrochloric acid (100 mL), 10% aqueous solution of Na2S2O3 (100 mL), saturated aqueous solution of NaHCO3 (100 mL), and brine (100 mL). After drying (Na2SO4), filtration and evaporation under reduced pressure, the crude product (93.0 g, ~90%) contained a mixture of ketone hydrate 7 and ketone 6 in various proportions with the latter being the major component.If required,5 product can be purified by vacuum distillation: Nitromethane (135 mL, 2.5 mol, 5 equiv) was added to a solutionof NaOH (40.0 g, 1.00 mol, 2 equiv) in MeOH (500 mL) at0 C and stirred for 30 min. The resulting mixture was added to asolution of ketone/ketone hydrate 6/7 (130 g, 0.5 mol, 1 equiv) inMeOH (250 mL) at temperature range 0 to 10 C and vigorouslystirred. The reaction mixture was stirred at ambient temperaturefor 2 h and then it was poured into saturated aqueous solution of(NH4)2SO4 (1 L). The resulting white precipitate was filtered,washed with water (1 L) and dissolved in ethyl acetate (600 mL).The phases were separated and the organic layer was washed withbrine (200 mL), dried over anhydr. Na2SO4, filtered and evaporatedunder reduced pressure to afford the title compound 8 (77 g, 48%,de >99%) as a white solid. NMR data and other physicochemicaldata of the product 8 are consistent with those reported earlier(see electronic supporting information).14,27aThe first filtrate was extracted with CH2Cl2 and the combinedorganic layer was washed with brine (100 mL), dried over anhydr.Na2SO4, filtered and evaporated under reduced pressure to afforddark yellow thick oil (60 g) which consists of epimers 8 (35 g)and 9 (22 g) and a trace amount of unreacted starting materials(6/7). The total yield of major isomer 8 is 112 g, 70% and minor isomer9-22.0 g, 14%. The mixture of 8 and 9 is used in the next stepwithout additional purification. Acetic anhydride (12.7 mL, 0.134 mol, 3 equiv) was added to astirred solution of a diastereomeric mixture of nitro sugars 8 and9 (14.3 g, 44.8 mmol, 1 equiv) in dry DMSO (45.45 mL, 0.639 mol,14 equiv) at ambient temperature. The resulting reaction mixturewas stirred at ambient temperature for 68 h and poured under vigorousstirring into a cold acetate buffer solution (24.6 g AcONa in200 mL H2O adjusted to pH 7 with AcOH) at 0 C. The temperatureof the mixture during the entire neutralization/workup procedure(5 min) was kept at 0 to 10 C. The resulting mixture was further neutralized with saturated aqueous (200 mL) solution of NaHCO3and solid NaHCO3 (3 g) to pH 6 followed by extraction with 15%EtOAc/Hex (3 150 mL). The combined organic layer was washedwith brine (6 150 mL), dried over anhydr. Na2SO4, and evaporated.The purification of the crude product (12.6 g) by columnchromatography on silica gel (60 g) (cyclohexane (0.5 L) followedby 10% of EtOAc in cyclohexane) provided 11.3 g (84%). NMR andother physicochemical data of the product 10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With bismuth(lll) trifluoromethanesulfonate In toluene at 20℃; for 0.5h; Molecular sieve; Inert atmosphere; regioselective reaction; | The optimized procedure for the p-methoxybenzylation is as follows General procedure: To a stirred mixture of 1a (1.3 eq.), alcohol (1 eq.), and 4 Å MS (0.6 w/w (alcohol)) in toluene( mol.L-1) under N2 atmosphere, Bi(OTf)3 (0.03 eq.) was added. The reactionmixture was stirred at rt until the TLC show completion, then quenched with Et3N (3 drops).Purification of the residue was accomplished directly by flash chromatography on silica gel |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With silver trifluoromethanesulfonate; dimethylbromosulphonium bromide In dichloromethane at -35℃; Molecular sieve; Inert atmosphere; | Typical procedure for glycosylations of glycosyl allenoates General procedure: A solution of 3a (70 mg, 0.087 mmol) and 4a (19 mg,0.073 mmol) in dry CH2Cl2 (2 mL) was stirred for 30 min in thepresence of freshly activated AW-300 MS (300 mg) under argonatmosphere. At this point, the mixture was cooled to 35 C followedby the addition of AgOTf (60 mg, 0.23 mmol) and BDMS(23 mg, 0.10 mmol). After the resulting mixture was stirred for another1.5 h, 1.0 mL saturated aqueous NaHCO3 and 1.0 mL saturatedaqueous Na2S2O3 were added to quench the reaction. Thesolid was filtered off, and the filtrate was sequentially washed withsaturated NaHCO3 and brine. The collected organic phases weredried over Na2SO4, filtered off the solid and concentrated. Theresultant residue was purified by silica gel chromatography (petroleumether/ethyl acetate = 5:1) to afford 5aa (51 mg, 0.061 mmol,84%) and bromolacotone 6 (19 mg, 0.064 mmol, 88%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With (1S)-10-camphorsulfonic acid In tetrahydrofuran at 20℃; for 7.5h; Reflux; | 1,2:5,6-Di-O-isopropylidene-3-O-(p-methoxybenzyl)-α-D-glucofuranose (2j) To a solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (104.1 mg, 0.400 mmol) and TriBOT-PM (117.5 mg, 0.240 mmol) in THF (1.33 mL), CSA (13.9 mg, 0.0598 mmol) was added at r.t. The mixture was heated to reflux and additional TriBOT-PM was added after 3.5 h (78.3 mg, 0.160 mmol) and 6.5 h (19.6 mg, 0.0400mmol), respectively. The mixture was stirred for an additional 1 h, the mixture was cooled to r.t., diluted with Et2O (25 mL), and washed with H2O (40 mL), 10% K2CO3 (2 × 27 mL), and brine (27mL). The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane-EtOAc, 19:1 to 14:1 to 9:1) to afford 2j(137.4 mg, 90%) as a clear colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 1,4-bis(bromomethyl)benzene In tetrahydrofuran at 20℃; for 18h; | 1,4-Di-(1,2;5,6-di-O-isopropylidene-3-O-methyl-α-D-glucofuranos-3-yl)benzene 1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose(1.5 g, 5.8 mmol, 2.2 equiv.) was dissolved in anhydrous THF (20 ml) andtemperature was maintained at 0 oC. Subsequently, NaH (0.32 g, 13.3mmol, 5.0 equiv.) was added to it and reaction was kept for stirring. After half an hour α,α’-dibromo-p-xylene (0.7 g, 2.65 mmol, 1.0 equiv.)was added and reaction was allowed to stir at room temperature for overnight.After 18 h, ethyl acetate was added to the reaction mixture then washed withwater and finally dried over anhydrous NaSO4. Organic solvent wasvacumm evaporated to get crude product which upon column chromatography (SiO2)using hexane: ethyl acetate as eluent afforded the desired compound 2a as colourless oil (1.38 g,84%). Rf= 0.54 (Hexane:Ethyl acetate, 2:0.5); 1H NMR (CDCl3, 300 MHz): δ = 7.32 (s, 4 H, Ar-H), 5.89 (d, 2 H, J = 3.9Hz, H-1), 4.70-4.58 (m, 6 H, -OCH2Ph,H-2), 4.37-4.32 (m, 2 H, H-4), 4.16-4.09 (m, 4 H, H-5, H-6b),4.02-3.98 (m, 4 H, H-6a, H-3), 1.49, 1.43, 1.38, 1.31 (each s, 24 H,4 x >C (CH3)2);13C NMR(CDCl3, 75 MHz): 137.3, 127.7, 111.8, 109.0, 105.3, 82.7, 81.7,81.3, 72.5, 72.1, 67.4, 26.8, 26.3, 25.5 ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 1,3-bis-(bromomethyl)benzene In tetrahydrofuran at 20℃; for 18h; | 1,3-Di-(1,2;5,6-di-O-isopropylidene-3-O-methyl-α-D-glucofuranos-3-yl)benzene 1,2:5,6-Di-O-isopropylidene-α-D-glucofuranose(1.5 g, 5.8 mmol, 2.2 equiv.), NaH (0.31 g, 13.3 mmol, 5.0 equiv.) and α,α’-dibromo-m-xylene(0.7 g, 2.65 mmol, 1.0 equiv.) were subjected to reaction similarly as has beendescribed for 2a. After purification2b was isolated as colourless oil (1.42 g,86%). Rf = 0.52 (Hexane: Ethyl acetate, 2:0.5); 1H NMR (CDCl3, 300 MHz): δ = 7.30-7.28 (m, 4 H, Ar-H),5.89 (d, 2 H, J = 3.9 Hz, H-1),4.70-4.58 (m, 6 H, -OCH2Ph,H-2), 4.39-4.33 (m, 2 H, H-4), 4.15-4.09 (m, 4 H, H-5, H-6b),4.02-3.98 (m, 4 H, H-6a, H-3), 1.49, 1.43, 1.37, 1.31 (each s, 24 H,, 4 x >C (CH3)2)ppm; 13C NMR (CDCl3, 75 MHz): δ = 137.9, 128.6, 127.1, 126.6,111.8, 109.0, 105.3, 82.6, 81.8, 81.3, 72.5, 72.2, 67.4, 26.8, 26.2, 25.5 ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine In toluene at -78℃; for 2h; Inert atmosphere; | 5 General method of diastereoselective synthesis of DAG sulphinates of S configuration with respect to sulphur General procedure: The corresponding sulphinyl chloride (3.5 equiv.) is added to a solution of 1,2:5,6-di-O-isopropylidene- -D-glucofuranose (DAG) (1 equiv.) and diisopropyl ethylamine (DIPEA) (3.6 equiv.) in anhydrous toluene, at -78°C, under an argon atmosphere. After stirring for 2h at this same temperature, 1M HCl is added to the reaction mixture and it is extracted with CH2Cl2. the organic extracts are washed successively with saturated NaHCO3 solution and saturated NaCl solution and are dried over anhydrous Na2SO4. The solvent is evaporated under vacuum and the residue obtained is purified by column chromatography using 2-propanol/hexane (1:10) as eluent, obtaining the sulphinate of S configuration with respect to sulphur as the predominant diasteroisomer. 1,2:5,6-di-O-isopropylidene- -D-glucofuranosyl (S)-5-azido-3-oxapentanesulphinate (13-Ss) It is synthesized according to the general method from (DAG) (0.5 g, 1.92 mmol) and DIPEA (1.20 mL) and 5-azido-3-oxapentanesulphinyl chloride 11 (6.72 mmol). The sulphinic esters are thus obtained at 97% yield. Analysis of the crude reaction product in deuterated chloroform shows that the two diasteroisomers formed are in the ratio 91:9. After purification by column chromatography, 13-Ss is obtained (0.7 g, 87%) as the predominant diasteroisomer in the form of brown oil. [0127] 1H NMR (500 MHz, CDCl3): 5.89 (d, J = 3.7 Hz, 1H), 4.75 (d, J = 2.8 Hz, 1H), 4.62 (d, J = 3.7 Hz, 1H), 4.30-4.23 (m, 2H, H4 and H5), 4.08 (dd, J = 5.9 and 6.1 Hz, 1H), 3.99 (dd, J = 3.5 and 5.2 Hz, 1H), 3.90-3.82 (m, 2H), 3.68-3.60 (m, 2H), 3.42-3.34 (m, 2H), 3.15-3.10 (m, 1H), 2.30-2.94 (m, 1H), 1.50 (s, 3H), 1.41 (s, 3H), 1.33 (s, 3H), 1.30 (s, 3H) [0128] 13C NMR (125 MHz, CDCl3): 112.6, 109.4, 105.2, 83.8, 80.5, 79.8, 72.5, 70.4, 67.0, 64.5, 58.2, 50.7, 26.9, 26.8, 26.4, 25.4. [0129] HRMS: calculated for C16H27N3O8NaS: [M+Na]+ 444.1417, found 444.1404 (-2.8 ppm). [ ]25D: -15.3 (approx. 1.0, chloroform). |
87% | With N-ethyl-N,N-diisopropylamine In toluene at -78℃; for 2h; Inert atmosphere; Overall yield = 97 %; | 5 1,2:5,6-di-O-isopropylidene-α-D-glucofuranosyl(S)-5-azido-3-oxapentanesulphinate (13-Ss) General procedure: General Method of Diastereoselective Synthesis of DAG Sulphinates of S Configuration with Respect to Sulphur [0132] The corresponding sulphinyl chloride (3.5 equiv.) is added to a solution of 1,2:5,6-di-0-isopropylidene-α-D-glucofuranose (DAG) (1 equiv.) and diisopropyl ethylamine (DIPEA) (3.6 equiv.) in anhydrous toluene, at -78° C., under an argon atmosphere. After stirring for 2 h at this same temperature, 1M HCl is added to the reaction mixture and it is extracted with CH2Cl2, the organic extracts are washed successively with saturated NaHCO3 solution and saturated NaCl solution and are dried over anhydrous Na2SO4. The solvent is evaporated under vacuum and the residue obtained is purified by column chromatography using 2-propanol/hexane (1:10) as eluent, obtaining the sulphinate of S configuration with respect to sulphur as the predominant diasteroisomer. RRN 68,701,2:5,6-di-O-isopropylidene-α-D-glucofuranosyl(S)-5-azido-3-oxapentanesulphinate (13-Ss) [0133] DAG) (0.5 g, 1.92 mmol) and DIPEA (1.20 mL) and 5-azido-3-oxapentanesulphinyl chloride 11 (6.72 mmol). The sulphinic esters are thus obtained at 97% yield. Analysis of the crude reaction product in deuterated chloroform shows that the two diasteroisomers formed are in the ratio 91:9. After purification by column chromatography, 13-Ss is obtained (0.7 g, 87%) as the predominant diasteroisomer in the form of brown oil. [0135] 1H NMR (500 MHz, CDCl3): δ 5.89 (d, J=3.7 Hz, 1H), 4.75 (d, J=2.8 Hz, 1H), 4.62 (d, J=3.7 Hz, 1H), 4.30-4.23 (m, 2H, H4 and H5), 4.08 (dd, J=5.9 and 6.1 Hz, 1H), 3.99 (dd, J=3.5 and 5.2 Hz, 1H), 3.90-3.82 (m, 2H), 3.68-3.60 (m, 2H), 3.42-3.34 (m, 2H), 3.15-3.10 (m, 1H), 2.30-2.94 (m, 1H), 1.50 (s, 3H), 1.41 (s, 3H), 1.33 (s, 3H), 1.30 (s, 3H) [0136] 13C NMR (125 MHz, CDCl3): δ 112.6, 109.4, 105.2, 83.8, 80.5, 79.8, 72.5, 70.4, 67.0, 64.5, 58.2, 50.7, 26.9, 26.8, 26.4, 25.4. [0137] HRMS: calculated for C16H27N3O8NaS: [M+Na]+ 444.1417. found 444.1404 (-2.8 ppm) [0138] [α]25D: -15.3 (approx. 1.0, chloroform |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Stage #1: 2,3,4,6-tetra-O-benzoyl-D-glucopyranosyl trichloroacetimidate; 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose In dichloromethane at 20℃; for 0.5h; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 0.75h; Molecular sieve; | 7 To a solution of 5 (20 g, 27.5 mmol) and 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose (7.9 g, 30.3 mmol) in DCM (100 mL)was added molecular sieves 4 Å (10 g). After the solution wasstirred for 30 min, TMSOTf (250 mL, 1.4 mmol) was added and thereaction mixture was stirred for 45 min at room temperature. Afterneutralization with Et3N, the solution was concentrated underreduced pressure and the crude mass was recrystallized fromEtOAc/hexane to afford 6 (20.2 g, 89%) as a crystalline white solid:mp 197e199 C; Rf 0.42 (EtOAc/hexane 1:2); [a]D 3.6 (c 1.0,CHCl3); 1H NMR (500 MHz, CDCl3) d 1H NMR (700 MHz, CDCl3)d 8.06e7.99 (m, 6H, AreH), 1.26e1.23 (m, 3H), 7.64e7.57 (m, 2H,AreH), 7.54 (ddt, 1H, J8.8, 7.4, 1.3 Hz, AreH), 7.51e7.47 (m, 2H,AreH), 7.46e7.42 (m, 2H, AreH), 7.41e7.37 (m, 2H, AreH),7.08e7.04 (m, 1H, AreH), 7.01 (d, 4H, J5.0 Hz, AreH), 5.60 (dd, 1H,J9.9, 9.0 Hz, C-40), 5.46 (d, 1H, J3.7 Hz, H-1), 5.38 (dd, 1H, J9.1,7.7 Hz, H-20), 4.81 (d,1H, J7.7 Hz, H-10), 4.61 (dd, 1H, J12.0, 3.4 Hz,H-60a), 4.59 (d, 2H, J1.0 Hz, AreCH2), 4.45 (dd, 1H, J12.0, 5.3 Hz,H-60b), 4.36 (dt, 1H, J6.5, 5.6 Hz, H-5), 4.31 (d, 1H, J3.7 Hz, H-2),4.28 (d, 1H, J3.2 Hz, H-3), 4.23 (dd, 1H, J5.4, 3.1 Hz, H-4), 4.08 (t,1H, J9.1 Hz, H-30), 4.04e3.99 (m, 2H, H-50, H-6a), 3.96 (dd, 1H,J8.7, 5.8 Hz, H-6b), 1.42 (s, 3H, CH3), 1.37 (s, 3H, CH3), 1.24 (s, 3H,CH3)1.12 (s, 3H, CH3); 13C NMR (126 MHz, CDCl3) d 166.2, 165.0,164.6, 137.1, 133.5, 133.5, 133.01, 129.9, 129.7, 129.7, 129.6, 129.4,129.2, 128.6, 128.5, 128.4, 128.2, 128.0, 127.7, 111.8, 108.6, 104.9, 99.8,82.7, 81.1, 80.4, 79.1, 77.2, 77.0, 76.8, 73.8, 73.33, 73.02, 72.48, 70.92,66.11, 63.20, 26.67, 26.57, 25.97, 25.07. HRMS (ESI) calcd (MNa)C39H42O14Na: 757.2467. Found: 757.2457. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium hexamethylsilazane In N,N-dimethyl-formamide; toluene at 0 - 20℃; for 16h; Inert atmosphere; Schlenk technique; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | 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 |
---|---|---|
81% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride; potassium iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.416667h; Cooling with ice; Stage #2: methanesulfonic acid 2-propenyloxyethyl ester In N,N-dimethyl-formamide; mineral oil at 60℃; for 48h; | 5 3 -(2-(allyloxy)ethyloxy) 1,2: 5,6-di-O-isopropylidene-3 -deoxy-ct-D-glucofuranoside, 1 6b 1,2:5,6-di-O-isopropylidene-ct-D-glucofuranose (0.75 g, 2.9 mmol) and KI (0.46 g, 2.9 mmol) were dried under high vacuum for Ca. 15 mi DMF (40 mL) was transferred by cannula into the reaction flask, and the mixture was cooled on an ice bath. 60% NaH (0.17g, 4.3 mmol) was added in one portion. After 5 mm, the ice bath was removed and the mixture was allowed to stir 20mm at room temperature. 2-allyloxyethyl methanesulfonate (1.2 mL, 5.7 mmol) was added and the mixture was stirred 48 h on a 60° C oil bath. The reaction mixture was concentrated under high vacuum overnight. The residue was directly purified by flash chromatography (7.5% Acetone/Hexanes). Alkene 16b (0.80 g, 81% yield) was recovered as a thick colorless oil. RF 0.24; 10% Acetone/Hexanes. ‘H NIVIR (400 IVIFIz, CDC13, 25 °C): 5.89 (m, 2 H), 5.29 (dm, J17.3Hz, 1H),5.19(dm,J=10.9Hz, 1H),4.59(d,J=4.lHz, 1H),4.32(q,J=6.12, 1H),4.12(dd, J 7.5, 3.0 Hz, 1 H), 4.08 (dd, J 8.5, 6.1 Hz, 1 H), 4.00 (m, 3 H), 3.93 (d, J= 2.7 Hz, 1 H),3.75 (m, 2 H), 3.56 (t, J= 4.8 Hz, 2 H), 1.49 (s, 3 H), 1.42 (s, 3 H), 1.34 (s, 3 H), 1.30 (s, 3 H). ‘3CNIVIR (100 IVIFIz, CDC13, 25°C): 134.6, 116.8, 111.6, 108.8, 105.2, 82.7, 82.6, 81.1, 72.5, 72.1,70.2, 69.3, 67.1, 26.8, 26.7, 26.1, 25.3. ESI-MS m/z = 367.18 [lvi + Na] (calcd 367.17 forC,7H28O7Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With tetra-(n-butyl)ammonium iodide; sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.5h; Inert atmosphere; Cooling with ice; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In N,N-dimethyl-formamide; mineral oil at 20℃; for 24h; Inert atmosphere; | |
84.2% | Stage #1: 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose With sodium hydride In tetrahydrofuran for 1.16667h; Inert atmosphere; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In tetrahydrofuran at 5 - 15℃; for 3h; | 3.2 Preparation of t-butyl 3-0-carboxymethyl-1,2: 5,6-di-O-isopropylidene-alpha-D-glucofuranose (III) Into a 500 mL three-necked flask were placed 13 g (0.05 mol) of the product (II) and 200 mL of purified THF,Pass N2 protection, magnetic stirring so completely dissolved. 6 g of 60% NaH was weighed into a three-necked flask and stirred for 70 min. Then cooled to 5 ° C in an ice-water bath, and 20 mL of tert-butyl bromoacetate was slowly added dropwise. After the dropwise addition of tert-butyl bromoacetate, the temperature was raised to 15 ° C. The reaction was carried out for 3 h. The reaction mixture was poured into a separatory funnel containing 200 mL of saturated saline. The separatory funnel was shaken until no bubbles were formed. The mixture was extracted with dichloromethane 100 mL x 3 times. The organic phase was combined and washed with ice water 100 mL x 3 times to neutral. Water sodium sulfateDrying, filtration, anhydrous ethanol crystallization, recrystallization obtained 15. 75g white needle-like crystals, the product range of 90-92 ° C (thermometer not corrected), yield 84. 2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 4h; Inert atmosphere; | 3.1.1. 3-O-Allyl-1,2:5,6-di-O-isopropylidene-α-D-glucofuranose(6) To a solution of 1,2:5,6-O-diisopropyliden-α-D-glucofuranose DAG (2 g, 7.68 mmol) in 430 mL of dry THF at 0°C was treated with sodium hydride (610 mg, 15.4 mmol,60% in dispersion oil) and allyl iodide (1.05 mL, 11.5 mmol). The reaction mixture was warmed to room temperature and allowed to react for 4 h. The reaction was treated with 5 mL of water, extracted with EtOAc (3 x 50 mL), driedand evaporated under reduced pressure. The reaction crude was purified by the flash column chromatography on silica gel (eluent hexane/EtOAc: 15/1) to give 2.18 g of 6 (95%) as a yellow pale oil. [α]D20 = - 25.3 (c 1.0, CHCl3). 1H NMR (400 MHz, CDCl3) δ 1.32 (s, 3H), 1.35 (s, 3H), 1.43 (s, 3H),1.50 (s, 3H), 3.94 (d, J = 2.8 Hz, 1H), 4.00 (dd, J = 8.4, 5.6Hz, 1H), 4.07-4.14 (m, 4H), 4.31 (dt, J = 7.6, 6.0 Hz, 1H),4.55 (d, J = 3.6 Hz, 1H), 5.20 (dq, J = 10.4, 1.6 Hz, 1H),5.31 (dq, J = 17.0, 1.5 Hz, 1H), 5.84-5.94 (m, 1H), 5.89 (d,J = 3.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 25.4, 26.2,26.8 (2C), 67.3, 71.3, 72.5, 81.1, 81.3, 82.7, 105.2, 108.9,111.7, 117.3, 134.1. HRMS (DART) m/z calcd for C15H25O6[M + H]+ 301.1651; found 301.1660. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: ethyl 3-O-acetyl-4-O-benzoyl-2-O-benzyl-1-thio-L-fucopyranoside; 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose In diethyl ether at 20℃; for 0.5h; Inert atmosphere; Molecular sieve; Stage #2: With N-iodo-succinimide; trimethylsilyl trifluoromethanesulfonate In diethyl ether at 0℃; for 0.5h; Inert atmosphere; Molecular sieve; | General Procedure for Fucosylation of 4 with Acceptors General procedure: To a solution of compound 4 (10 mg, 0.0225 mmol, 1 equiv)and acceptor (0.0248-0.225 mmol, 1.1-10 equiv) in 500 Lanhyd Et2O with argon protection was added 4 Å MS. Themixture was stirred at room temperature for 0.5 h and thencooled to 0 °C, then NIS (10.1 mg, 0.045 mmol, 2 equiv) andTMSOTf (0.4 L, 0.00225 mmol, 0.1 equiv) were added. Themixture was stirred for 0.5 h after which TLC indicated full conversionand quenched with Et3N. The mixture was filtered,evaporated, and purified by column chromatography to afford product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With 2-methyl-1,2-epoxypropane; bathophenanthroline In tert-butyl methyl ether at 50℃; for 48h; Schlenk technique; Sealed tube; Inert atmosphere; stereoselective reaction; | |
63% | With 2-isopropyloxirane; bathophenanthroline In tert-butyl methyl ether at 50℃; for 48h; Schlenk technique; | 3 General procedure: Phenanthroline-catalyzed glycosylation reactions. General Procedure. FIG. 40 shows a phenanthroline-catalyzed glycosylation reaction carried out using various reacting conditions. Under standard conditions A, a 10 ml Schlenk flask was charged with glycosyl bromide (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), catalyst4 (see FIG. 22, A) (0.03 mmol, 15 mol %), IBO (0.4 mmol, 2.0 equiv.) and MTBE (0.4 ml). The resulting solution was stirred at 50° C. for 24 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 5/143/1) to give the desired product. With standard conditions B, a 10 ml Schlenk flask was charged with glycosyl bromide (0.4 mmol, 2.0 equiv.), alcohol (0.2 mmol, 1.0 equiv.), catalyst 4 (0.06 mmol, 30 mol %), IBO (0.4 mmol, 2.0 equiv.) and MTBE (0.2 ml). The resulting solution was stirred at 50° C. for 48 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 5/1→3/1) to give the desired product. In standard conditions B′, a 10 ml Schlenk flask was charged with glycosyl bromide (0.4 mmol, 2.0 equiv.), alcohol (0.2 mmol, 1.0 equiv.), catalyst 4 (0.06 mmol, 30 mol %), IBO (0.4 mmol, 2.0 equiv.) and MTBE (0.4 ml). The resulting solution was stirred at 50° C. for 24 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 9/1→4/1) to give the desired product. Using standard condition C, a 10 ml Schlenk flask was charged with glycosyl bromide (0.6 mmol, 3.0 equiv.), alcohol (0.2 mmol, 1.0 equiv.), catalyst 4 (0.1 mmol, 50 mol %), IBO (0.6 mmol, 3.0 equiv.) and MTBE (0.2 ml). The resulting solution was stirred at 50° C. for 48 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 5/1→3/1) to give the desired product. In standard condition D, a 10 ml Schlenk flask was charged with glycosyl bromide (0.2 mmol, 2.0 equiv.), alcohol (0.1 mmol, 1.0 equiv.), catalyst4 (0.02 mmol, 20 mol %), IBO (0.2 mmol, 2.0 equiv.) and MTBE (0.2 ml). The resulting solution was stirred at 25° C. for 24 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 9/1→4/1) to give the desired product. In standard conditions D′, a 10 ml Schlenk flask was charged with glycosyl bromide (0.2 mmol, 2.0 equiv.), alcohol (0.1 mmol, 1.0 equiv.), catalyst 4 (0.02 mmol, 20 mol %), IBO (0.2 mmol, 2.0 equiv.) and MTBE (0.2 ml). The resulting solution was stirred at 25° C. for 48 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 9/1→4/1) to give the desired product. In standard condition E, a 10 ml Schlenk flask was charged with glycosyl bromide (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), catalyst 4 (0.04 mmol, 20 mol %), IBO (0.4 mmol, 2.0 equiv.) and MTBE (0.4 ml). The resulting solution was stirred at 25° C. for 24 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 9/1→4/1) to give the desired product. In standard conditions F, a 10 ml Schlenk flask was charged with glycosyl bromide (0.2 mmol, 1.0 equiv.), alcohol (0.6 mmol, 3.0 equiv.), catalyst 4 (0.04 mmol, 20 mol %), IBO (0.4 mmol, 2.0 equiv.) and MTBE (0.4 ml). The resulting solution was stirred at 50° C. for 24 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 9/1→4/1) to give the desired product. In standard conditions G, a 10 ml Schlenk flask was charged with glycosyl bromide (0.22 mmol, 1.1 equiv.), alcohol (0.2 mmol, 1.0 equiv.), catalyst 4 (0.03 mmol, 15 mol %), IBO (0.4 mmol, 2.0 equiv.) and MTBE (0.4 ml). The resulting solution was stirred at 50° C. for 24 h, diluted with toluene, and purified by silica gel flash chromatography (toluene/ethyl acetate: 33/1→9/1) to give the desired product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With diammonium hydrogen orthophosphate; Triphenylphosphine oxide In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; Sealed tube; diastereoselective reaction; | Methods To an 8 ml screw-capped vial that contained a magnetic stir bar was sequentially added an allyl glycosyl sulfone (0.3 mmol, 1.5 equiv.), a nucleophile (0.2 mmol,1.0 equiv.), Ph3PO (0.06 mmol, 0.3 equiv.), (NH4)2HPO4 (1.0 mmol, 5.0 equiv.), C4F9I (1.0 mmol, 5.0 equiv.) and MTBE (1 ml) under a N2 atmosphere. The vial was tightly sealed with a Teflon-lined cap and allowed to stir for 24 h at room temperature, with irradiation from a 10 W, 455 nm LED bulb placed ~3 cm below it. The reaction mixture was then diluted with ethyl acetate (10 ml) and filtered through a pad of cotton. The combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product. |
Tags: 582-52-5 synthesis path| 582-52-5 SDS| 582-52-5 COA| 582-52-5 purity| 582-52-5 application| 582-52-5 NMR| 582-52-5 COA| 582-52-5 structure
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