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CAS No. : | 89238-99-3 | MDL No. : | MFCD00134547 |
Formula : | C10H10Cl3NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | TYHGKLBJBHACOI-UHFFFAOYSA-N |
M.W : | 282.55 | Pubchem ID : | 11087263 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With camphor-10-sulfonic acid In dichloromethane for 16h; Inert atmosphere; | |
99% | With camphor-10-sulfonic acid In dichloromethane for 16h; Inert atmosphere; Schlenk technique; | |
99% | With (1S)-10-camphorsulfonic acid In dichloromethane for 16h; Inert atmosphere; |
98% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 18h; Inert atmosphere; Schlenk technique; | |
96% | With camphor-10-sulfonic acid In dichloromethane at 20℃; | |
95% | With camphor-10-sulfonic acid In dichloromethane for 18h; Ambient temperature; | |
94% | ||
93% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 15h; | |
92% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 19h; | |
92% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 17h; | |
92% | With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane Inert atmosphere; | |
91% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 16h; | |
88% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 12h; | |
88% | With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane at 20℃; for 40h; | |
86% | With pyridinium p-toluenesulfonate In hexane; dichloromethane at 20℃; for 18h; | |
86% | With 10-camphorsufonic acid In dichloromethane for 15h; | |
86% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 19h; | |
80% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 16h; Inert atmosphere; | |
80% | With trifluorormethanesulfonic acid In diethyl ether at 0 - 20℃; for 16h; Inert atmosphere; | 4.2.1. Methyl(S)-3-((4-methoxybenzyl)oxy)-2-methylpropanoate (12) To a stirred solution of 11 (3.4 g, 12.1 mmol) in Et2O (51 mL) at 0 °C, were added 10 (1.0 g, 8.47 mmol) and TfOH (34 mL, 0.33 mmol). After being stirred under room temperature for 16 h, saturated NaHCO3 was added. The mixture was extracted with Et2O, washed with brine, dried, concentrated and chromatographed (SiO2 50 g, hexane: AcOEt = 10:1) to give 12 (1.61 g, 6.8 mmol, 80%) as a colorless oil. [α]D17 +9.34 (c 1.13, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.45 (s, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 3.62 (dd, J = 7.2, 8.8 Hz, 1H), 3.45 (dd, J = 6.0, 8.8 Hz, 1H), 2.81-2.72 (m, 1H), 1.16, (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.2, 159.2, 130.1, 129.1, 113.6, 72.6, 71.5, 55.1, 51.6, 40.1, 13.9; FT-IR (KBr) 2950, 2862, 1738, 1613, 1514, 1248, 1091 cm-1; HRMS (EI) calcd for C13H18O4 (M+), 238.1205, found 238.1205. |
75% | Stage #1: 3-hydroxy-(2S)-methylpropionate; O-(4-methoxybenzyl)-trichloroacetimidate In dichloromethane; pentane at 0℃; for 0.5h; Stage #2: With boron trifluoride diethyl etherate In dichloromethane; pentane at 0 - 20℃; | |
70% | With trifluorormethanesulfonic acid In diethyl ether at 20 - 25℃; | |
67% | With camphor-10-sulfonic acid In dichloromethane at 25℃; for 18h; | |
67% | With pyridinium p-toluenesulfonate In dichloromethane for 22h; Ambient temperature; | |
58% | With trifluorormethanesulfonic acid In diethyl ether at 0℃; for 2h; | |
With camphor-10-sulfonic acid | ||
With pyridinium p-toluenesulfonate In dichloromethane | ||
With camphor-10-sulfonic acid In dichloromethane | ||
With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane at 20℃; for 14h; | ||
With trifluorormethanesulfonic acid In diethyl ether at 20℃; for 0.75h; | ||
With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane at 0 - 20℃; for 43h; | ||
With trifluorormethanesulfonic acid In diethyl ether at 20℃; for 1h; | ||
With trifluorormethanesulfonic acid In diethyl ether at 20℃; for 2h; | ||
With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane at 0 - 20℃; Inert atmosphere; | ||
With camphor-10-sulfonic acid In dichloromethane at 25℃; for 12h; Inert atmosphere; | ||
With pyridinium p-toluenesulfonate In dichloromethane; benzene Inert atmosphere; | ||
67.16 kg | With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane at 0 - 24℃; for 21h; Large scale; | |
In dichloromethane at 20℃; for 12h; | ||
11.2 g | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 14h; | |
With 10-camphorsulfonic acid In dichloromethane at 20℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With (1S)-10-camphorsulfonic acid In dichloromethane for 25h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In hexane at 0℃; for 0.25h; | Synthesis of PMB-TCAI (2) at a 500 mg scale To a suspension of PMBOH (500 mg, 3.62 mmol) and Cl3CCN (575 mg, 3.98 mmol) in hexane (9 mL) was addedDBU (55.1 mg, 362 μmol) at 0 °C. After the suspension changed to be a solution (actual reaction time =15 min), hexane(10 mL) and saturated aq NH4Cl (10 mL) were added to the reaction mixture. The separated hexane layer was washed withsaturated aq NH4Cl (20 mL). The general drying procedure gave PMB-TCAI (2) (1.08 g, 100%) as a colorless oil. TheNMR spectra of 2 were in good agreement with the literature data.2 |
98% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.25h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 0℃; | |
96% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; Further stages.; |
96% | With tetra(n-butyl)ammonium hydrogensulfate; potassium hydroxide In dichloromethane; water at 0 - 20℃; for 24h; | |
95% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; Stage #3: With methanol In pentane for 0.5h; Further stages.; | |
94% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 20℃; for 4h; Further stages.; | |
93% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20 - 25℃; for 0.75h; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 25℃; for 5h; | (S)-2-((4-Methoxybenzyl)oxy)propanal (5)1 A solution of PMBOH (109 mmol) in Et2O (44 mL) was added to a solution of NaH (60% in oil, 32.6 mmol, 0.3 equiv) in Et2O(65 mL). The solution was stirred at room temperature for 45 min. After cooling to 0 °C, Cl3CCN (109 mmol, 1 equiv) was addedand the solution was stirred at 0 °C for 1 h, then at room temperature for 4 h. The solution was filtered through a pad of celite anda saturated aqueous solution of NaHCO3 (40 mL) was added. The product was extracted with Et2O (3 30 mL). The combinedorganic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the desired imidate (28.5 g, 93%)as an orange oil which was used without further purification. |
91% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere; | |
89% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.333333h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 0℃; for 1h; Inert atmosphere; | |
87% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0℃; for 0.75h; Inert atmosphere; | |
87% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 0℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0℃; for 0.75h; | |
70.2% | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 20℃; for 2h; Inert atmosphere; | 1 Example 1 Synthesis of PMB ester Under nitrogen protection,A solution of p-methoxybenzyl alcohol (5.565 g) in ether (13 ml) was added at 0 ° C (403 mg, 60%) in NaH, stirred at room temperature for 30 min, and then cooled to 0 ° C. Trichloroacetonitrile (4.04 ml), which was then allowed to warm to room temperature and stirred at room temperature for 2 h. After completion of the reaction, the reaction was first concentrated by rotary evaporator and n-hexane(100 ml) and rinsed the precipitate and then filtered with a small amount of celite. The filtrate was concentrated to give an orange oil, PMB ester (8 g, 70.2%). |
41% | With sodium hydride In diethyl ether 1) 0 deg C, 50 min, 2) 0 to 20 deg C in 2h, 3) 20 deg C, 1h; | |
With sodium hydride 1.) Et2O, 0 deg C, 10 min, 2.) 1 h; Multistep reaction; | ||
With sodium hydride | ||
With sodium hydride 1.) ether, RT, 30 min, 2.) from 0 deg to RT, 4 h; Multistep reaction; | ||
With sodium hydride 1.) ether, 3.5 h, 2.) 25 deg C, 1 h; Multistep reaction; | ||
With sodium hydride 1.) Et2O, room temperature, 1 h, 2.) 0 deg C, 5 min; room temperature, 20 min; Multistep reaction; | ||
With sodium hydride 1.) Et2O, room temperature, 30 min, 2.) 0 deg C to room temperature, 4 h; Multistep reaction; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 4h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 1h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 0.416667h; | ||
With sodium hydride In diethyl ether | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 20℃; for 1.5h; | ||
With sodium hydride In tetrahydrofuran at 20℃; for 2h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 23℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; | ||
With sodium hydride In diethyl ether at 0 - 20℃; | ||
37 g | With sodium hydride In diethyl ether at 0℃; for 1.5h; | |
With sodium hydride In diethyl ether at 0 - 20℃; for 4h; | ||
With sodium hydride In diethyl ether; hexane at 0 - 20℃; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 0℃; for 0.25h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 1.5h; Further stages.; | ||
With sodium hydride In diethyl ether at 0 - 20℃; for 4h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 2h; Stage #2: trichloroacetonitrile In diethyl ether for 2.83333h; Further stages.; | ||
With sodium hydride In diethyl ether; hexane at 0 - 20℃; | ||
With sodium hydride In diethyl ether at 20℃; for 2h; | ||
With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine | ||
With sodium hydride In diethyl ether at 20℃; for 2h; | ||
Stage #1: trichloroacetonitrile; 4-Methoxybenzyl alcohol With potassium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane; water at -10℃; for 0.5h; Alkaline aqueous solution; Stage #2: In dichloromethane; water at 20℃; for 0.5h; | 2, 2, 2-Trichloro-acetimidic acid 4-methoxy-benzyl ester adapted from Tetrahedron Letters, 1996,37, 1461 To a solution of 4-methoxy benzyl alcohol (17g, 123mmol) in dichloromethane (170ML) was added 50% aqueous potassium hydroxyde solution (170ML) and tetrabutylammonium hydrogen- sulfate (NBu4HS04) (0.257 g). After cooling TO-10C, tri- chloroacetonitrile (14.9mL, 148MMOL) was added dropwise. The mixture was then stirred 30 minutes at the same temperature and then 30 minutes at room temperature. The two phases were separated and the aqueous layer was extracted twice with dichloromethane (2 x 170ML). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was then removed under reduced pressure. The resulting oil was used in the next step without further purification. | |
With NaH In methanol | 18 Ethyl O-(4-methoxybenzyl)-(S)-lactate EXAMPLE 18 Ethyl O-(4-methoxybenzyl)-(S)-lactate p-Methoxybenzyl alcohol (200 g) is added to a suspension of NaH (5.82 g of a 60% dispersion in oil) in 450 mL of anhydrous ether over 1 hour at ambient temperature. After an additional 1 hour, the mix is cooled on ice and treated with trichloroacetonitrile (158 mL) over 80 minutes. After an additional 1.5 hour the solution is concentrated at low temperature. The residue is treated with a mix of pentane (1500 mL) and methanol (5.6 mL), stirred for 30 minutes, then filtered through a short plug of Celite and concentrated to give 4-methoxybenzyl trichloroacetimidate. | |
With sodium hydride In diethyl ether at 20℃; for 1h; | ||
With sodium hydride In diethyl ether at 0 - 20℃; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; Stage #2: trichloroacetonitrile In diethyl ether at 0℃; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 0 - 23℃; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 23℃; for 1.5h; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 24℃; for 0.333333h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 24℃; for 4h; Inert atmosphere; Stage #3: With methanol In diethyl ether; pentane Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 1.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0℃; for 1.66667h; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 30℃; Inert atmosphere; Cooling with ice; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 30℃; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 6h; Stage #3: With methanol In hexane | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; for 4h; Inert atmosphere; Stage #3: With methanol In mineral oil; Petroleum ether | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 23℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 0.75h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 6h; | ||
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 20℃; for 2h; Inert atmosphere; | ||
With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 4h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether; acetonitrile at 0 - 20℃; for 6h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; Inert atmosphere; | 1-But-3-ynyloxymethyl-4-methoxy-benzene A solution of p-methoxybenzylalcohol (3.32 g, 24 mmol) in 24 mL anhydrous Et2O was added into a suspension of NaH (58 mg, 2.4 mmol, washed with anhydrous hexane) at r.t under N2 protection. After 30 min., the mixture was cooled down to 0°C and added trichloroacetonitrile (3.46 g, 24 mmol). The resulting mixture was allowed to warm up to room temperature, and stirred for 4 h. After concentrated to remove Et2O, the residue was dissolved in 28 mL anhydrous hexane and 0.12 mL anhydrous MeOH. The suspension was filtered through celite. The filtrate was concentrated to give 6.8 g light yellow oil. The crude intermediate was dissolved in 40 mL anhydrous hexane and 20 mL anhydrous CH2Cl2. Then 3-butyn-1-ol (1.12 g, 16 mmol) was added dropwise. The resulting solution was cooled to 0°C and treated with catalytic amount of 10-camphorsulfonic acid. The mixture was then allowed to warm up slowly to room temperature and stirred overnight, while white precipitate was formed. The resulted mixture was filtered through celite. The filtrate was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated. The residue was purified with chromatography on silica gel with a Hexane/EtOAc (20:1) solvent system as eluent to give 2.4 g colorless oil in 80% yield. | |
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 4h; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In mineral oil at 0 - 20℃; for 5h; Inert atmosphere; | ||
97.2 kg | Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In tert-butyl methyl ether; mineral oil at 20 - 22℃; for 1.5h; Large scale; Stage #2: trichloroacetonitrile In tert-butyl methyl ether; mineral oil at 0 - 4℃; for 1.5h; Large scale; | |
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 20℃; for 6h; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 4h; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: trichloroacetonitrile In tetrahydrofuran for 0.5h; | ||
Stage #1: trichloroacetonitrile; 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; for 4h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; | 4.3 1-(((10-Bromodecyl)oxy)methyl)-4-methoxybenzene (16a) To a suspension of NaH (60% dispersion in oil, 80 mg, 2.41mmol) in ether (30mL) was added 4-methoxybenzyl alcohol (3mL, 24.16mmol) drop wise at 0°C. After being stirred at 0°C for 5 min, trichloroacetonitrile (2.5mL, 25.37mmol) was added and then the reaction mixture was warmed to rt. The reaction mixture was again cooled to 0 °C and stirred for another 15 min and concentrated under reduced pressure. The resulting residue was diluted with hexane and filtered through Celite bed. The filtrate was concentrated under reduced pressure to give crude p-methoxybenzyltrichloroacetimidate (6.5g), which was immediately used for the reaction. | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 0℃; for 0.25h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 6h; Inert atmosphere; | tert-Butyl[(S)-4-(4-methoxybenzyloxy)hex-5-en-1-yl]oxy}dimethylsilane To a stirred solution of 4-methoxybenzyl alcohol (3.5 g, 25.3 mmol) in Et2O (20 mL) was added a suspension of NaH (0.2 g, 60%, 5 mmol) dissolved in Et2O (20 mL) at r.t. The resulting mixture was stirred for 30 min and cooled to 0 °C, to this was added trichloroacetonitrile (1.93mL, 1.2 mmol) slowly and stirring was continued at r.t. for 6 h. The solvent was evaporated to give an orange syrup, which was dissolved in anhyd hexane (50 mL) containing a few drops of MeOH. This suspension was shaken vigorously and filtered on Celite bed; filtrate was concentrated to afford the imidate. | |
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 1h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; for 0.5h; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 0.2℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; for 6h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; for 6h; | 6 4.10.6 (R)-2-((4-Methoxybenzyloxy)methyl)-2-methylpent-4-enyl benzoate 6 A solution of 4-methoxybenzyl alcohol (2.2 g, 16.0 mmol) in 30 mL of ether was added to a suspension of 60% NaH (0.08 g, 2.0 mmol) in 10 mL of ether at room temperature. The resulting mixture was stirred at room temperature for 30 min and cooled to 0 °C. Trichloroacetonitrile (TCA;1.6 mL, 16.0 mmol) was then added and the reaction mixture was allowed to warm slowly to room temperature over 6 h. The solution was concentrated to an orange syrup, which was dissolved in anhydrous hexane (15 mL) containing a few drops of MeOH. This suspension was shaken vigorously and filtered through Celite, and the filtrate was concentrated to afford the crude imidate. The crude imidate was taken in cyclohexane (50 mL) and a solution of alcohol 5 (3.74 g, 16 mmol) in 30 mL of DCM was added. The resulting solution was cooled to 0 °C and CSA (0.37 g, 1.6 mmol) was added to it. The reaction mixture was stirred overnight at room temperature, and a white precipitate of trichloroacetamide slowly developed. The solution was filtered off, and washed with DCM. The filtrate was washed with saturated aqueous NaHCO3 solution, water and brine. Purification by means of silica gel chromatography (EtOAc/hexane, 1:5) yielded compound 6 (5.0 g) in 88% yield. Rf = 0.4 (EtOAc/hexane, 1:5). | |
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether at 0 - 20℃; for 2h; | 1 In 0 °C conditions and under the protection of nitrogen, to the the p-methoxybenzylalcohol (2 ml, 8mmol) of ethyl ether (6 ml) solution is slowly added sodium hydride powder (161.6 mg, 2mmol), then heating to room temperature, and the reaction stirred at room temperature 30 minutes. And then again the reaction mixture system cooling to 0 °C, at the same time adding trichloro acetonitrile (1.6 ml, 8mmol), and then the mixed system of reaction temperature to room temperature, after 2 hours of stirring the reaction is quenched by adding saturated sodium bicarbonate solution. The obtained mixing system by dichloromethane (3×20 ml) extraction liquid, combined with the phase, saturated salt water for washing and drying treatment of anhydrous sodium sulfate, then concentrated under reduced pressure to remove organic solvent to obtain reddish orange oily liquid type 4 compound (4.36g, 96%). The crude product thus obtained does not need to be purified, can be directly placed in the next step reaction. | |
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 0.5h; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; for 4h; | ||
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 0℃; for 4h; | (R/S)-Methyl 3,4-bis(4-methoxybenzyloxy)-2-methylenebutanoate (rac-27) [ref. S7 with some modifications] General procedure: 4-Methoxybenzyl alcohol (MPMOH; 1.42 g, 10.3 mmol) was dissolved in an anhydrous CH2Cl2 (10 mL) and treated with 1,8-diazabicyclo [5.4.0]-7-undecene (DBU; 154 mL, 1.03 mmol) and Cl3CCN (2.60 mL, 25.8 mmol) at 0°C and stirred for 4 h. After adding 0.5 M HCl (10 mL) to the mixture, the product was extracted by CH2Cl2 (x 3) and the combined organic layers were successively washed with H2O, sat. NaHCO3 solution, brine, and dried (Na2SO4). 4-Methoxybenzyl trichloroacetoimidate thus obtained by evaporation was mixed with rac-15 (1.37 g, 5.15 mmol) and (+)-10-camphorsulfonic acid (CSA; 119 mg, 0.515 mmol) in a mixed solvent of anhydrous CH2Cl2/cyclohexane (1/2, 30 mL) and stirred for 24 h at room temperature. The reaction was stopped by adding sat. NaHCO3 solution (20 mL) and extracted with Et2O (x 3). The combined organic layers were washed with H2O and brine, and dried (Na2SO4). Evaporation and purification by column chromatography (silica, hexane/ethyl acetate = 4/1) afforded rac-27 as a colorless oil (1.41 g, 70.9%) | |
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 1h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; for 1.33h; Inert atmosphere; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil at 20℃; for 1h; Inert atmosphere; Stage #2: trichloroacetonitrile In diethyl ether; mineral oil at 0 - 20℃; for 1.08333h; | (2S,4R,5R)-5-((4-Methoxybenzyl)oxy)-4-methyl-3-oxohexan-2-yl benzoate (16) To a mixture with p-methoxybenzyl alcohol (1.5 equiv.,36.0 mmol, 4.9740 g, 4.4 mL) in diethyl ether (19 mL) atroom temperature under an inert atmosphere, it was addedsodium hydride in mineral oil (0.15 equiv., 3.6 mmol,0.1440 g of NaH). The suspension was stirred for 1 h.The mixture was cooled to 0 °C followed by addition oftrichloroacetonitrile (1.5 equiv., 36.0 mmol, 5.1980 g,3.6 mL) over 15 min. The mixture was maintained at 0 °Cfor 5 min and at room temperature for a further 1 h. Thereaction was washed with saturated NaHCO3 (20 mL).The organic phase was dried with MgSO4. After filtration,the solvent was evaporated under reduced pressure.To the residue, it was added the alcohol 15 (1 equiv.,24.0 mmol, 6.00 g), CSA (0.2 equiv., 4.8 mmol, 1.12 g)and CH2Cl2 (40 mL). The reaction mixture was stirred atroom temperature for 18 h. Subsequently, the reaction waswashed with saturated aqueous NaHCO3 solution (200 mL),which was extracted with Et2O (4 × 100 mL). The organicphase was dried with MgSO4. The product was purifiedby fash column chromatography on hexane/ethyl acetate(9:1) as eluent, providing a colorless oil (16) in 7.4683 g,84% yield (20.2 mmol). Rf: 0.12, PMA (Hex:EtOAc, 9:1); ]D20 -26.6 (c 2.0, CHCl3); IR (ATR) / cm-1 3064, 3034,2975, 2937, 2909, 2879, 2837, 1716, 1613, 1513, 1451,1246, 1114, 1028, 823, 712; 1H NMR (500 MHz, CDCl3)d 8.08 (d, J 7.2 Hz, 2H), 7.57 (t, J 7.4 Hz, 1H), 7.44 (t,J 7.7 Hz, 2H), 7.16 (d, J 8.6 Hz, 2H), 6.83 (d, J 8.6 Hz,2H), 5.37 (q, J 7.0 Hz, 1H), 4.42 (d, J 10.8 Hz, 1H), 4.27(d, J 10.8 Hz, 1H), 3.78 (s, 3H), 2.94 (dq, J 14.2, 7.1 Hz,1H), 1.47 (d, J 7.0 Hz, 3H), 1.18 (d, J 6.2 Hz, 3H), 1.14 (d,J 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 209.9, 165.8,159.0, 133.1, 130.5, 129.8, 129.3, 128.3, 113.6, 76.8, 75.1,71.1, 55.2, 49.0, 16.7, 15.2, 13.6. | |
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 0℃; Inert atmosphere; | ||
With 1,8-diazabicyclo[5.4.0]undec-7-ene In dichloromethane at 5 - 20℃; for 0.5h; | ||
Stage #1: 4-Methoxybenzyl alcohol With sodium hydride In diethyl ether; mineral oil for 0.5h; Inert atmosphere; Stage #2: trichloroacetonitrile In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; | Dimethyl {4-[(4-Methoxybenzyl)oxy]-2-oxobutyl}phosphonate (9b). Methyl 3-[(4-Methoxybenzyl)oxy]propanoate (S3) Following the procedure of Iversen et al.[21] 4-methoxybenzyl alcohol (14.9 mL, 120 mmol, 1.2 equiv) was added to a suspension of NaH (60% in mineral oil, 600 mg, 15 mmol, 0.15 equiv) in anhyd Et2O (200 mL). After stirring for 30 min, the solution was cooled to 0 °C and trichloroacetonitrile (13.5 mL, 135 mmol, 1.35 equiv) was added dropwise over 20 min. The mixture was stirred for 1 h at 0 °C and the solvent was removed under vacuum. The crude was diluted with cyclohexane (150 mL) and MeOH (250 L), stirred for 30 min, and filtered on Celite. The acetimidate was evaporated under vacuum and diluted with MeCN (500 mL). The alcohol S1 (10.2 g, 100 mmol, 1 equiv) and Lewis acid La(OTf)3 (1.17 g, 20 mmol, 0.2 equiv) were added. The resulting mixture was stirred until the acetimidate had disappeared. The solvent was removed. THF (250 mL) and a solution of LiOH (1 M, 250 mL) were added. The solution was stirred for 1 h and extracted with EtOAc (3 × 250 mL). The combined organic phases were washed with aq 1 M NaOH (3 × 100 mL). All aqueous phases were acidified with a solution of 10% H2SO4 (10%) until pH 1, and extracted with EtOAc (4 × 250 mL). The combined organic phases were washed with brine (3 × 100 mL), dried (MgSO4), and the solvent was removed under vacuum. The resulting acid was esterified with TMSCHN2 (2 M in heptane, 75 mL,150 mmol, 1.5 equiv) in Et2O/MeOH (4:1, v/v; 200 mL) at rt. When the yellow coloration persists, the excess of TMSCHN2 was neutralized with AcOH and the solvents were removed under vacuum. The crude was purified by column chromatography on silica gel (500 mL) with pentane/Et2O (90:10 to 80:20) as eluent to give the protected alcohol S3 as a colorless oil; yield: 12.79 g (57.0 mmol, 57 %); Rf = 0.30 (cyclohexane/EtOAc 75:25). 1H NMR (300 MHz, CDCl3): δ = 7.33-7.22 (m, 2 H), 6.95-6.86 (m, 2 H), 4.49 (s, 2 H), 3.82 (s, 3 H), 3.74 (t, 3JH, H = 6.4 Hz, 2 H), 3.72 (s, 3 H), 2.63 (t, 3JH, H = 6.4 Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 172.2, 159.3, 130.2, 129.4 (2 C), 113.9 (2C), 72.9, 65.3, 55.4, 51.8, 35.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; | |
98% | With camphor-10-sulfonic acid In dichloromethane for 16h; | |
96% | With camphor-10-sulfonic acid In hexane; dichloromethane at 20℃; for 12h; Inert atmosphere; | (R)-Methyl 3-((4-methoxybenzyl)oxy)-2-methylpropanoate (S1) To a solution of R-(-)-Roche ester (2.0 g, 16.9 mmol, 1.0 eq) in DCM (10 mL) were added a solution of p-methoxybenzyl trichloroacetimidate (1.1 M in hexanes, 23 mL, 23.35 mmol, 1.5 eq) and camphorsulfonic acid (314 mg, 1.35 mmol, 0.08 eq) successively. The reaction mixture was stirred for 12 hours at room temperature until TLC-control showed total consumption of the starting material. The reaction was quenched by the addition of saturated NaHCO3 solution (15 mL), the layers were separated and the aqueous phase was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. After flash column chromatography (hexane/EtOAc 19:1) S1 (3.86 g) was isolated in 96% yield as a light yellow oil. |
91% | With trifluorormethanesulfonic acid In dichloromethane at 20℃; for 1h; Inert atmosphere; | Methyl (R)-3-(PMB-oxy)-2-methylpropanoate (S6) To a solution of Roche ester (+)-21 (1.15 g, 9.70 mmol) in CH2Cl2 (18 mL) were added PMB-imidate (2.82 mL, 13.58 mmol) and TfOH (5.9 mL, 0.06 mmol) at room temperature under N2 atmosphere. After stirring for 1 h at room temperature, the reaction mixture was cooled to 0 °C and quenched with sat. NaHCO3 aq. (100 mL). The aqueous layer was extracted with CHCl3 (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (hexane/EtOAc = 20/1) to provide the title compound S6 (2.11 g, 91%) as a pale yellow oil. |
90% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 18h; | 1 Example 1 : Preparation of Compound (2A1):- To a solution of 4-Methoxybenzyl-2,2,2-trichloroacetimidate (18 g, 76 mmol, 1.5 eq) in dichloromethane (50 ml) at room temperature, was added (S)-methyl 3- hydroxy-2-methylpropanoate (5 g, 42 mmol, 1.5 eq) followed by camphor sulfonic acid (CSA) (176 mg, 0.76 mmol, 0.018 eq). The reaction mixture was stirred at ambient temperature for 18 hr, and then diluted with Dichloromethane (20 ml). The reaction mixture was washed with sat. aqueous NaHC03 (40 mL), followed by brine (40 mL), dried over sodium sulphate and evaporated under reduced pressure. The product was purified by column chromatography by using SiCh and eluted with Ethyl acetate/ hexane. The collected fractions were evaporated to give a compound 2A1 (9 g, 90%) [alpha 25 D] = +7.5 deg (c = 1.0 in CHC13). |
89% | With camphor-10-sulfonic acid In dichloromethane; cyclohexane at 0 - 20℃; | |
85% | With pyridinium p-toluenesulfonate In dichloromethane for 17h; Inert atmosphere; | |
84% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 30h; | |
83% | With (+)-10-camphorsulfonic acid In dichloromethane at 20℃; for 29h; | |
83% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 21.5h; Inert atmosphere; | |
75% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 24h; | |
74% | With trifluorormethanesulfonic acid In diethyl ether at 20℃; for 1h; | |
With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane | ||
With camphor-10-sulfonic acid In dichloromethane | ||
In hexane; dichloromethane at 0℃; | ||
5.7 g | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 22h; | |
9.6 g | With trifluorormethanesulfonic acid In dichloromethane; Petroleum ether at 20℃; for 0.5h; | |
With camphor-10-sulfonic acid In dichloromethane | ||
Stage #1: methyl (R)-3-hydroxy-2-methylpropionate; O-(4-methoxybenzyl)-trichloroacetimidate In dichloromethane; pentane at 0℃; for 0.5h; Stage #2: With boron trifluoride diethyl etherate In dichloromethane; pentane at 0 - 20℃; | ||
With pyridinium p-toluenesulfonate In dichloromethane at 10 - 30℃; for 21h; Inert atmosphere; | ||
In dichloromethane at 20℃; for 12h; | ||
6.29 g | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 22h; Inert atmosphere; | |
With 10-camphorsulfonic acid In dichloromethane at 20℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 36h; | |
94% | With camphorsulfonic acid In dichloromethane at 20℃; Inert atmosphere; | (R)-methyl 3-((4-methoxybenzyl)oxy)butanoate 9 To a solution of (R)-methyl 3-hydroxybutanoate 7 (1.44 mL, 12.86 mmol) dissolved in dichloromethane (30 mL) at 0 °C was added a solution of 4-methoxyphenyl trichloroacetimidate 8 (4.36 g, 15.43 mmol) in dichloromethane (20 mL) and catalytic CSA (296 mg, 1.29 mmol). The mixture was then warmed up to room temperature. After stirring at rt over night, the reaction was quenched with a saturated solution of NaHCO3 (50 mL). The resulting mixture was extracted with dichloromethane (3 × 50 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (Hexane: EtOAc =10:1) offered the desired compound 9 (2.88 g, 94% yield) as a yellow oil. [α]25D = -23.6 (c=0.85, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.26 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 4.52 (d, J = 11.2 Hz, 1H), 4.44 (d, J = 11.2 Hz, 1H), 4.02-3.98 (m, 1H), 3.81 (s, 3H), 3.69 (s, 3H), 2.65 (dd, J = 15.1, 7.3 Hz, 1H), 2.43 (dd, J = 15.1, 5.6 Hz, 1H), 1.26 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 171.9, 159.1, 130.5, 129.2, 113.7, 71.5, 70.5, 55.2, 51.5, 41.8, 19.8. HRMS (ESI): m/z calcd. for C13H18O4Na [M+Na]+ 261.1097, found 261.1099. |
93.7% | With camphor-10-sulfonic acid In dichloromethane at 20℃; Inert atmosphere; | 2 Example 2 Synthesis of Compound Formula 2 Under the protection of nitrogen, hydroxybutyric acid methyl ester was first added(2.6 ml) was dissolved in dichloromethane (DCM, 56 ml) and the PMB ester was addedWas dissolved in 56 ml DCM. The diluted PMB ester solution was added dropwise to the solution under nitrogen and then 535 mg of camphorsulfonic acid (CSA) was added and stirred at room temperature for 15 h. The reaction was quenched with 10 ml of saturated NaHC03 solution and extracted with DCM (115 ml X). The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by column chromatography. Ethyl acetate: petroleum ether = 1: 15), and finally the eluate was concentrated to give the compound of the formula 2 as an orange oil (5.15 g, 93.7%) |
74% | With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane for 24h; Ambient temperature; | |
72% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; Inert atmosphere; | (R)-Methyl 3-(4-methoxybenzyloxy)butanoate (17). To a stirred solution of alcohol 16 (1.0 g, 8.4 7 mmol) in dry CH2Cl2 (15 mL) at 0 °C, p-methoxybenzyl trichloro acetimidate (4.78 g, 16.9 mmol) and PTSA (0.16 g, 0.84 mmol) were added under nitrogen atmosphere and allowed to warm to room temperature and stir for 2 h. The reaction mixture was quenched with NaHCO3 solution (3 mL) and the aq. layer was separated. The organic layers were washed with brine (2 x 20 mL), dried (Na2SO4) and evaporated. The residue was purified by column chromatography (60-120 mesh Silica gel, 7% EtOAc in pet. ether) to afford 17 (1.45 g, 72%) as a light brown syrup. [α]D25 = -52.7 (c 0.75, CHCl3). IR (neat): 3024, 2964, 2857, 1712, 1081. 1H NMR (300 MHz, CDCl3): δ 7.22 (d, 2H, J = 9.0 Hz, Ar-H), 6.87 (d, 2H, J = 8.6 Hz, Ar-H), 4.52-4.40 (m, 2H, -OCH2Ar), 4.03-3.93 (m, 1H, -OCH), 3.79 (s, 3H, -OCH3), 3.67 (s, 3H, -OCH3), 2.67-2.60 (m, 1H, -CH-CO), 2.45-2.35 (m, 1H, -CH-CO), 1.23 (d, 3H, J = 6.4 Hz, -CH3). 13C NMR (75 MHz, CDCl3): δ 171.9, 159.0, 129.3, 129.2, 113.7, 71.5, 70.4, 60.2, 55.2, 51.5, 41.8, 19.8. HRMS m/z: [M+Na]+ calcd for C13H18O4Na, 275.1259; found 275.2960. |
With camphor-10-sulfonic acid In dichloromethane | ||
1.11 g | With camphorsulfonic acid In dichloromethane at 23℃; for 12h; Inert atmosphere; | |
2.88g | With camphor-10-sulfonic acid In dichloromethane at 0 - 20℃; Inert atmosphere; | 1 Example 1, synthesis of compound 5 In 0 °C conditions (ice water mixture) and under the protection of nitrogen, to the (R) - 3 hydroxy-butyric acid methyl ester 3 (1.44 ml, 12 . 86mmol) in dichloromethane (30 ml) slowly in solution instillment type 4 compound (4.36g, 15 . 43mmol) of dichloromethane (20 ml) solution, after dropping, then adding camphor sulfonic acid (CSA) powder (296 mg, 1 . 29mmol), then the elevated temperature of the reaction system to the room temperature, and stirred overnight. After the reaction is ended, is added to the reaction in the mixed system saturated sodium bicarbonate solution (50 ml) quenching the reaction, the obtained mixing system by dichloromethane (3×50 ml) extraction, the organic phase is the merger of saturated salt water and for washing, the thus obtained water-free, the organic phase of the drying process after the sodium sulfate, concentrated under reduced pressure to remove organic solvent, the crude product obtained after dodges the type column chromatography (ethyl acetate: petroleum ether = 1:10) separating and purifying get colorless oily liquid type 5 compound (2.88g, 94%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 16h; | |
91% | In dichloromethane at 25℃; for 2h; | |
88% | With camphor-10-sulfonic acid In dichloromethane at 0 - 20℃; |
88% | With camphor-10-sulfonic acid In dichloromethane 0 deg C to r.t.; | |
88% | With camphor-10-sulfonic acid In dichloromethane at 0 - 20℃; | |
86% | With (1S)-10-camphorsulfonic acid In dichloromethane at 25℃; for 16h; | |
86% | With trifluorormethanesulfonic acid In dichloromethane; cyclohexane at 0 - 20℃; | |
With toluene-4-sulfonic acid | ||
With pyridinium p-toluenesulfonate In dichloromethane; cyclohexane; ethyl acetate | 18 Ethyl O-(4-methoxybenzyl)-(S)-lactate A mixture of ethyl (S)-lactate (128 g) and 4-methoxybenzyl trichloroacetimidate (371 g) in 1:2 CH2Cl2/cyclohexane (1500 mL) is cooled on ice and treated with pyridinium p-toluenesulfonate (13.7 g). After 3 hours, the mixture is warmed to ambient temperature and kept 40 hours, then concentrated. The residue is filtered through a plug of silica gel using 20% ethyl acetate in hexanes and concentrated to yield the product. | |
With camphor-10-sulfonic acid In dichloromethane; cyclohexane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With CSA In dichloromethane at 20℃; Cooling with ice; | 4.2 1-[(But-3-yn-1-yloxy)methyl]-4-methoxybenzene (10) To an ice-cold solution of PMBOC(NH)CCl3 (11.85 g, 41.9 mmol) in CH2Cl2 (100mL) was added but-3-yn-1-ol (1.47 g, 20.97 mmol) and CSA (731 mg, 3.15 mmol). The solution was stirred at rt overnight and diluted with hexane (200 mL). The resulting mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was diluted with hexane (100mL) and filtered again. The filtrate was concentrated to give a residue, which was purified by chromatography on silica gel (hexane/EtOAc) to afford alcohol 10 (3.23 g, 81%): liquid; Rf 0.62 (hexane/EtOAc 2:1); 1H NMR (400MHz, CDCl3) δ 1.99 (t, J=2.4Hz, 1H), 2.49 (dt, J=2.8, 7.2Hz, 2H), 3.57 (t, J=7.2Hz, 2H), 3.81 (s, 3H), 4.49 (s, 2H), 6.88 (d, J=8.8Hz, 2H), 7.27 (d, J=8.8Hz, 2H); 13C NMR (100MHz, CDCl3) δ 19.9 (-), 55.3 (+), 67.8 (-), 69.4 (-), 72.6 (-), 81.4 (-), 113.8 (+), 129.3 (+), 130.1 (-), 159.3 (-). The 1H and 13C NMR spectra were consistent with those in the literature |
With trifluorormethanesulfonic acid In diethyl ether at 0℃; | ||
With trifluorormethanesulfonic acid In diethyl ether at 20℃; |
With trifluorormethanesulfonic acid In diethyl ether at 0℃; for 0.5h; | ||
2.4 g | With camphor-10-sulfonic acid In hexane; dichloromethane at 0 - 20℃; | 1-But-3-ynyloxymethyl-4-methoxy-benzene General procedure: A solution of p-methoxybenzylalcohol (3.32 g, 24 mmol) in 24 mL anhydrous Et2O was added into a suspension of NaH (58 mg, 2.4 mmol, washed with anhydrous hexane) at r.t under N2 protection. After 30 min., the mixture was cooled down to 0°C and added trichloroacetonitrile (3.46 g, 24 mmol). The resulting mixture was allowed to warm up to room temperature, and stirred for 4 h. After concentrated to remove Et2O, the residue was dissolved in 28 mL anhydrous hexane and 0.12 mL anhydrous MeOH. The suspension was filtered through celite. The filtrate was concentrated to give 6.8 g light yellow oil. The crude intermediate was dissolved in 40 mL anhydrous hexane and 20 mL anhydrous CH2Cl2. Then 3-butyn-1-ol (1.12 g, 16 mmol) was added dropwise. The resulting solution was cooled to 0°C and treated with catalytic amount of 10-camphorsulfonic acid. The mixture was then allowed to warm up slowly to room temperature and stirred overnight, while white precipitate was formed. The resulted mixture was filtered through celite. The filtrate was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated. The residue was purified with chromatography on silica gel with a Hexane/EtOAc (20:1) solvent system as eluent to give 2.4 g colorless oil in 80% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With trifluorormethanesulfonic acid; In dichloromethane; cyclohexane; at 0 - 25℃; for 21.25h; | A solution of PMBOH (109 mmol) in Et2O (44 mL) was added to a solution of NaH (60% in oil, 32.6 mmol, 0.3 equiv) in Et2O(65 mL). The solution was stirred at room temperature for 45 min. After cooling to 0 C, Cl3CCN (109 mmol, 1 equiv) was addedand the solution was stirred at 0 C for 1 h, then at room temperature for 4 h. The solution was filtered through a pad of celite anda saturated aqueous solution of NaHCO3 (40 mL) was added. The product was extracted with Et2O (3 30 mL). The combinedorganic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give the desired imidate (28.5 g, 93%)as an orange oil which was used without further purification.TfOH (0.202 mmol, 0.003 equiv) was added dropwise to a solution of imidate (101 mmol, 1.5 equiv) and methyl (L)-lactate (67.2mmol) in a mixture CH2Cl2/cyclohexane (6:4, 152 mL) cooled at 0 C. The solution was stirred at 0 C for 15 min, then at roomtemperature for 21 h. The solution was filtered through a pad of celite and concentrated under reduced pressure. A saturatedaqueous solution of NaHCO3 (30 mL) was added and the product was extracted with CH2Cl2 (3 30 mL). The combined organiclayer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flashchromatography (EtOAc/cyclohexane, 5:95 to 10:90) to afford ester (14.7 g, 92%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With trifluorormethanesulfonic acid In diethyl ether at 20℃; for 0.75h; Inert atmosphere; | |
90% | With trifluorormethanesulfonic acid In diethyl ether | |
90% | With trifluorormethanesulfonic acid In diethyl ether at 20℃; for 0.5h; |
90% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; for 8h; | 11 4.1.11 (S)-tert-Butyl((2-((4-methoxybenzyl)oxy)hex-5-en-1-yl)oxy)dimethylsilane 19 To a cooled (0 °C) solution of alcohol 18 (6.0 g, 26.08 mmol) in dry CH2Cl2 (80 mL) was added PMB imidate (14.70 g, 52.16 mmol) followed by PTSA (catalytic amount) after which the reaction was stirred at room temperature for 8 h. After completion of the reaction, it was quenched with triethylamine, diluted with water (50 mL), and extracted into CH2Cl2 (3 * 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was then purified by column chromatography on silica gel using petroleum ether/ethyl acetate (9:1) as eluent to give compound 19 (8.19 g). Yield: 90%; colorless liquid; [α]D25 = -21.8 (c 1.0, CHCl3); IR (CHCl3, cm-1) 1242, 1512, 1588, 1615; 1H NMR (200 MHz, CDCl3): δ 0.06 (s, 6H), 0.90 (s, 9H), 1.52-1.65 (m, 2H), 2.10-2.14 (m, 2H), 3.40-3.74 (m, 3H), 3.80 (s, 3H), 4.45 (d, J = 11.0 Hz, 1H), 4.60 (d, J = 11.0 Hz, 1H), 4.91-5.05 (m, 2H), 5.70-5.91 (m, 1H), 6.80-6.90 (m, 2H), 7.24-7.33 (m, 2H); 13C NMR (50 MHz, CDCl3): δ -5.4, -5.3, 18.2, 25.9, 30.9, 55.2, 65.6, 71.9, 78.8, 113.6, 114.5, 129.7, 131.1, 132.8, 133.6, 138.7, 159.0; HRMS (m/z): calculated [M+Na]+ for C20H34NaO3Si: 373.2175 found: 373.2173. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In toluene at 20℃; for 0.0833333h; | |
82% | With trityl tetrafluoroborate In tetrahydrofuran at 0 - 20℃; for 1h; | 4.9. 4-((4-Methoxybenzyl)Oxy)Butan-2-One (16) To a stirred solution of 4-hydroxy-2-butanone (1.1 mL ,12.8 mmol) in dry THF (20 mL)at 0 °C, 4-methoxybenzyl 2,2,2-trichloroacetimidate (2 mL, 10.7 mmol) and triphenylcarbeniumtetrafluoroborate (cat.) were added sequentially. The reaction was continued further for 1 h atroom temperature prior to quenching with the saturated NH4Cl solution (50 mL) and extracted withDCM (2 100 mL). The combined organic layers were washed with brine, dried over Na2SO4,and concentrated in vacuum. Purification by column chromatography (PE/EA = 6:1) affordedcompound 16 (1.8 g, 82%) as a colorless oil [14].1H NMR (400 MHz, CDCl3)δ 7.33-7.18 (m, 2H), 6.94-6.81 (m, 2H), 4.45 (s, 2H), 3.81 (s, 3H), 3.72(t, J = 6.3 Hz, 2H), 2.71 (t, J = 6.3 Hz, 2H), 2.18 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 207.51, 159.27,130.16, 129.42, 113.84, 72.91, 64.96, 55.31, 43.81, 30.48. HRMS (ESI+): calcd. for C12H16O3 [M + H]+,209.1172, found 209.1170. |
77% | With camphor-10-sulfonic acid In dichloromethane at 0℃; |
77% | With camphor-10-sulfonic acid In dichloromethane at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 10-camphorsulfonic acid In dichloromethane at 20℃; for 7h; | |
70% | With D,L-camphorsulfonic acid In dichloromethane at 20℃; for 12h; Inert atmosphere; | |
With camphor-10-sulfonic acid In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With trifluorormethanesulfonic acid In dichloromethane at -10℃; for 2h; | |
82% | With trifluorormethanesulfonic acid In dichloromethane at -30 - -10℃; for 2h; | 6 PMB Ether (-) -7. To a solution of alcohol 6 (0.102 g, 0.182 mmol) in methylene chloride (2. 0mL) at-30 was added PMB-trichloroacetimidate (0.050 g, 0.182 mmol) followed by trifluoromethanesulfonic acid as a 0.5M solution in CH2CI2 (0.050 mL, 0.025 mmol). The solution slowly warmed to-10 °C and stirred 1 h, after which additional PMB-trichloroacetimidate (0.050 g, 0.182 mmol) was added. The reaction mixture stirred for an additional 1 h at-10 °C and quenched with NH4CI (1 mL) and extracted with methylene chloride (3 x 10 mL). The combined organic layers were washed 2 x 5 mL H2O, 1 x 5 mL brine, and dried (Na2SO4), and concentrated in vacuo. Flash chromatography (ethyl acetate/hexane, 2%) gave 0.100 g (82% yield) of (-)-7. [oc] 2D-6. 1° (c = 1, CHCl3) ; IR (NaCl) 3059,2956, 2928,2882, 2855,1613, 1513, 1490,1462, 1448, 1248, 1172,1061, 1036,912, 836,767, 702,743, 632; 1H NMR (500 MHz, CDCl3) No. 7.45-7-40 (m, 6H), 7.27-7. 24 (m, 6H), 7.22-7. 17 (m, 5H), 6.85-6. 79 (m, 2H), 5.87 (ddd, J= 17.5, 10.4, 8.2 Hz, 1H), 5.01-4. 94 (m, 2H), 4.50 (d, J= 10.8 Hz, 1H), 4.39 (d, J= 10.8 Hz, 1H), 3.79 (s, 3H), 3.62 (dd, J= 5.6, 3.0 Hz, 1H), 3.18 (dd, J= 5.2, 5.2 Hz, 1H), 3.08 (dd, J= 8.9, 5.6 Hz, 1H), 2.91 (dd, J= 8.6, 8.6 Hz, 1H), 2.50-2. 43 (m, 1 H), 2.07-1. 98 (m, 1 H), 1.76 (ddddd, J = 7. 1,7. 1,6. 0,6. 0,6. 0 Hz, 1 H), 1.05 (d, J = 6. 7 Hz, 3H), 0.94 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 7.1 Hz, 3H), 0.79 (s, 9H), -0. 03 (s, 3H), -0. 23 (s, 3H); 13C NMR (125 MHz, CDCI3) 8 158.9, 144.4, 141.1, 131.2, 128.9, 128.7, 127.6, 126.8, 114.6, 113.6, 86.5, 84.1, 74.4, 73.7, 67.1, 55.2, 41.4, 39.9, 38.7, 26.1, 18.4, 17.6, 12. 2, 10.9,-3. 6, -4.0 ; high resolution mass spectrum (ES+) m/z 701.3982, [(M) +, calcd for C44Hs804SiNa : 701. 4002]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With boron trifluoride diethyl etherate In dichloromethane | |
39% | In diethyl ether at 0 - 20℃; for 2h; | 2 Method 2B. Synthesis of ω-p-methoxybenzyloxy-ω-phenylcarbamoyl alkanoic acid methyl esters. In a typical procedure, to a solution of the suitable alcohol in anhydrous Et2O (1.5 mL/mmol) under an argon atmosphere a freshly prepared solution of /^-methoxybenzyl-trichloroacetimidate (0.5 M, 2.0 eq) (Audia, J. E., Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738-3740) was added. After cooling at 0 0C catalytic BF3-Et2O (0.01 eq) was added, and the solution was allowed to reach room temperature during 2 h under stirring while developing a white precipitate. The mixture was filtered through Celite, and the solid was washed with n-hexane. The filtrate was washed with a saturated aqueous solution OfNaHCO3, dried over MgSO4, and concentrated in vacuo. After purification by flash chromatography (gradient 9:1 to 7:3 hexanes/EtOAc), pure /?-methoxybenzyl ether intermediates (see examples 8d, 8m, (S)-Sd, and (i?)-8d)were recovered in 35-39% yield.; (+/-)-7-(4-Methoxybenzyloxy)-7-phenylcarbamoyl heptanoic acid methyl ester (8d). Ether 8d was prepared according to the general procedure (Method 2B) starting from 250 mg of alcohol 8a' (0.90 mmol) in 1.3 mL OfEt2O in the presence of catalytic BF3-Et2O (1 μL, 9 x 10~3 mmol). After purification by flash chromatography (gradient 9:1 to 7:3 hexanes/EtOAc) pure /?-methoxybenzyl ether 8d (140 mg) was recovered in 39% yield as a pale yellow oil: 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, IH), 7.55 (d, J= 7.6 Hz, 2H), 7.35 (t, J= 7.6 Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 7.14 (t, J = 7.4 Hz, IH), 6.93 (d, J = 9.0 Hz, 2H), 4.57 (s, 2H), 3.97 (dd, J = 7.1, 4.4 Hz, IH), 3.84 (s, 3H), 3.68 (s, 3H), 2.31 (t, J = 7.4 Hz, 2H), 1.83 (m, 2H), 1.63 (m, 2H), 1.45 (m, 2H), 1.32 (m, 2H). 13C-NMR (CDCl3, 100 MHz) δ 173.8, 170.7, 159.3, 136.9, 129.5 (2C), 128.7 (2C), 128.6, 124.0, 119.2 (2C), 113.6 (2C), 79.7, 72.4, 55.0, 51.1, 33.6, 32.3, 28.5, 24.4, 24.3. MS (ESI) m/z: 400.1 (M+l). |
With boron trifluoride diethyl etherate In diethyl ether; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With trifluorormethanesulfonic acid In diethyl ether at 20℃; for 4h; | |
84% | With CSA In dichloromethane at 20℃; for 18h; | (2S,4R,5R)-5-((4-Methoxybenzyl)oxy)-4-methyl-3-oxohexan-2-yl benzoate (16) To a mixture with p-methoxybenzyl alcohol (1.5 equiv.,36.0 mmol, 4.9740 g, 4.4 mL) in diethyl ether (19 mL) atroom temperature under an inert atmosphere, it was addedsodium hydride in mineral oil (0.15 equiv., 3.6 mmol,0.1440 g of NaH). The suspension was stirred for 1 h.The mixture was cooled to 0 °C followed by addition oftrichloroacetonitrile (1.5 equiv., 36.0 mmol, 5.1980 g,3.6 mL) over 15 min. The mixture was maintained at 0 °Cfor 5 min and at room temperature for a further 1 h. Thereaction was washed with saturated NaHCO3 (20 mL).The organic phase was dried with MgSO4. After filtration,the solvent was evaporated under reduced pressure.To the residue, it was added the alcohol 15 (1 equiv.,24.0 mmol, 6.00 g), CSA (0.2 equiv., 4.8 mmol, 1.12 g)and CH2Cl2 (40 mL). The reaction mixture was stirred atroom temperature for 18 h. Subsequently, the reaction waswashed with saturated aqueous NaHCO3 solution (200 mL),which was extracted with Et2O (4 × 100 mL). The organicphase was dried with MgSO4. The product was purifiedby fash column chromatography on hexane/ethyl acetate(9:1) as eluent, providing a colorless oil (16) in 7.4683 g,84% yield (20.2 mmol). Rf: 0.12, PMA (Hex:EtOAc, 9:1); ]D20 -26.6 (c 2.0, CHCl3); IR (ATR) / cm-1 3064, 3034,2975, 2937, 2909, 2879, 2837, 1716, 1613, 1513, 1451,1246, 1114, 1028, 823, 712; 1H NMR (500 MHz, CDCl3)d 8.08 (d, J 7.2 Hz, 2H), 7.57 (t, J 7.4 Hz, 1H), 7.44 (t,J 7.7 Hz, 2H), 7.16 (d, J 8.6 Hz, 2H), 6.83 (d, J 8.6 Hz,2H), 5.37 (q, J 7.0 Hz, 1H), 4.42 (d, J 10.8 Hz, 1H), 4.27(d, J 10.8 Hz, 1H), 3.78 (s, 3H), 2.94 (dq, J 14.2, 7.1 Hz,1H), 1.47 (d, J 7.0 Hz, 3H), 1.18 (d, J 6.2 Hz, 3H), 1.14 (d,J 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 209.9, 165.8,159.0, 133.1, 130.5, 129.8, 129.3, 128.3, 113.6, 76.8, 75.1,71.1, 55.2, 49.0, 16.7, 15.2, 13.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.7% | With trifluorormethanesulfonic acid; sodium hydrogencarbonate; In dichloromethane; | EXAMPLE 27 Preparation of (1R,4R,5R,8R)-4,8-dimethyl-8-(p-methoxybenzyloxy)-4-phenylsulfonylmethyl-2,3-dioxabicyclo[3.3.1]nonane (34a) (Scheme 11). To a suspension of hydroxysulfone 21a (280 mg, 0.858 mmol) in ether (3 mL) at 0 C. was added a solution of O-(p-methoxybenzyl) trichloroacetimidate 44 (1.287 g of ca. 93%, 4.19 mmol) in CH2 Cl2 (1.5 mL), the mixture was stirred for 10 min until homogeneous solution was formed. Then at 0 C. a solution of TfOH in ether (0.43 mL of 0.1M TfOH solution in abs. ether, 0.043 mmol) was added and the green-yellow mixture was stirred for 1.5 h at 0 C. and for 10 h at rt A second portion of TfOH solution (0.25 mL, 0.025 mmol) was added and the mixture was stirred for 12 h and then additional portions of imidate 44 (772 mg, 2.51 mmol) and TfOH solution (0.25 mL, 0.025 mmol) were added and the mixture was stirred for additional 8 h until consumption of 21a (TLC monitoring). The mixture was diluted with ether (15 mL) and hexane (15 mL), NaHCO3 (0.6 g) and Na2 SO4 (2 g) were added. After being stirred overnight the mixture was filtered, evaporated, fractionated by flash chromatography (hexane-EtOAc 75:25) and purified by a number of MPLC (hexane-EtOAc 78:22) to afford 34a (175 mg, 45.7%) as a pale yellowish oil, Rf 0.40 (hexane-EtOAc 75:25). 1 H NMR (400 MHz, CDCl3, delta): 1.38 (s, 3H, Me10), 1.53 (br.s, 3H, Me11), 1.81 (dddd, 1H, 2 J=3 J6a7a 14.0 Hz, 3 J6a5e =6.4 Hz, 3 J6a7e =3.3 Hz, Ha6), 1.85 (m, 1H, He6), 1.94 (br.dd, 1H, 2 J=14.6 Hz, 3 J7e6e =5.0 Hz, He7), 2.11 (ddd, 1H, 2 J=3 J7a6a =14.0 Hz, 3 J7a6e =6.4 Hz, Ha7), 2.17 (m, 2H, He9 +Ha9), 2.27 (br.dddd, 1H, 3 J5e6e ~3 J5e6a =6.4 Hz, 3 J5e9e ~3 J5e9a =3.2 Hz, He5), 3.29 (d, 1H, 2 J=14.3 Hz, H12), 3.81 (s, 3H, MeO), 3.825 (br.dd, 1H, 3 J1e9e =3 J1e9a =3.0 Hz, He1), 4.24 (br.d, 1H, 2 J=14.3 Hz, H'12), 4.29 and 4.41 (ABq, 2H, 2 J=10.7 Hz, CH17 H17 'O), 6.88 (ddd, 2H, 3 J=8.7 Hz, 4 J1 =4 J2 =2.0 Hz, 2Hm-benz.), 7.24 (br.d, 3 J=8.7 Hz, 2Ho-benz.), 7.58 (dddd, 2H, 3 J15,14 =3 J15,16 =7.3 Hz, 4 J1514' =4 J15'14 =1.4 Hz, H15,15'), 7.66 (dddd, 1H, 3 J16,15 =3 J16,15' =7.3 Hz, 4 J1614 =4 J1614' =1.4 Hz, H16), 7.95 (br.d, 2H, 3 J14,15 =7.3 Hz, H14,14'); 13 C NMR (100 MHz, CDCl3, delta): 22.16 (Me10), 22.92 (Me11), 23.53 (C6 H2), 24.57 (C9 H2), 19.86 (C5 H), 30.76 (C7 H2), 61.10 (C12 H2), 62.91 (C17 H2 O), 75.94 (C8), 80.84 (C1 H), 82.71 (C4), 113.78 (2Cm-benz. H), 127.55 (2C14 H), 128.72 (2Co-benz. H), 129.33 (2C15 H), 131.26 (C1-benz.), 133.68 (C16 H), 141.17 (C13), 158.92 (Cp-benz.). DCI HRMS: obsd 447.18690, calcd for C24 H31 O6 S (M+1) 447.18414. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With camphor-10-sulfonic acid In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With toluene-4-sulfonic acid In dichloromethane at 20℃; | |
63% | With toluene-4-sulfonic acid In dichloromethane at 20℃; for 16h; | 3.2.11 Methyl (5Z,8S)-8-hydroxy-9-(p-methoxybenzyloxy)non-5-enoate (21) .2.11 Methyl (5Z,8S)-8-hydroxy-9-(p-methoxybenzyloxy)non-5-enoate (21) (0024) RRN 78,80(a) (S)-21: To a stirred solution of diol (S)- 20 (841mg, 4.16mmol) in CH2Cl2 (40ml) was added PMBOC(NH)CCl3 (1.23g, 4.36mmol) and p-TsOH (40.0mg, 0.21mmol). After stirring at room temperature for 16h, the resulting mixture was neutralized with saturated NaHCO3 solution and extracted with CH2Cl2. The combined organic layer was dried with MgSO4, and then evaporated. Purification of the residue on silica gel (2:1 hexanes/EtOAc) gave ether (S)- 21 as a yellow oil (790mg, 2.62mmol, 63%). n20DnD20=1.5162. [α]23D[α]D23=+2.0 (c 0.2, CHCl3). IR (film): ν=3460, 2950, 1732, 1248, 1035cm-1. 1H NMR (300MHz, CDCl3): δ (ppm)=1.57 (1H, br), 1.69 (2H, qui, J=7.2Hz), 2.08 (2H, q, J=7.2Hz), 2.20-2.25 (2H, m), 2.31 (2H, t, J=7.2Hz), 3.33 (1H, dd, J=9.3, 7.2Hz), 3.48 (1H, dd, J=9.3, 3.3Hz), 3.66 (3H, s), 3.81 (3H, s), 3.85 (1H, m), 4.48 (2H, s), 5.42-5.53 (2H, m), 6.89 (2H, d, J=8.7Hz), 7.25 (2H, d, J=8.7Hz). 13C NMR (125MHz, CDCl3): δ (ppm)=24.9, 26.8, 31.5, 33.6, 51.7, 55.4, 70.4, 73.2, 73.8, 114.0, 126.0, 129.6, 130.2, 131.5, 159.5, 174.2. ESI-HRMS m/z calcd for C18H26NaO5 [M+Na]+ 345.1672, found 345.1700. (0025) (b) (R)-21: In the same manner as the synthesis of (S)- 21 described above, (R)-20 (1.21g, 5.97mmol) was converted into (R)-21 (986mg, 3.06mmol, 51%, yellow oil). n20DnD20=1.5162. [α]21D[α]D21=-2.7 (c 0.32, CHCl3). Its IR and NMR spectra were identical with those of (S)-21. ESI-HRMS m/z calcd for C18H26NaO5 [M+Na]+ 345.1672, found 345.1709. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 12h; Inert atmosphere; | (3S,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((4-methoxybenzyl)oxy)methyl)-3-methyldihydrofuran-2(3H)-one (5) To a solution of the corresponding primary alcohol (2.0 g; 9.58 mmol) in 48 mL of anhydrous CH2Cl2 and under nitrogen atmosphere, 4-methoxy benzyl 2,2,2-trichloroacetimidate (3.25 g; 11.55 mmol) and camphorsulfonic acid (62.0 mg; 0.27 mmol) were added. The mixture was stirred at room temperature for 12 h. Then, the crude reaction mixture was washed with 20 mL of saturated aqueous solution of NaHCO3, 15 mL of saturated aqueous solution of NaCl and 15 mL of water. The organic phases were combined, dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography (20% ethyl acetate/hexanes) gave 2.5 g of ether of PMB 5 as a yellow oil in 85% yield. Rf 0.50 (20% ethyl acetate/hexanes). 1H NMR (CDCl3, 250 MHz): d (ppm) 0.01 (s, 3H), 0.06 (s, 3H), 0.85 (s, 9H), 1.25 (d, J = 7.3 Hz, 3H), 2.59-2.47 (m, 1H), 3.75-3.50 (m, 5H), 4.16-4.00 (m, 2H), 4.46-4.38 (m, 2H), 6.83 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H). RMN 13C (CDCl3, 62.5 MHz): d (ppm) -4.8, -4.3, 12.8, 17.7, 25.5, 44.2, 55.2, 67.1, 73.2, 83.4, 129.4, 130.4, 159.1, 176.7. [α]D20 +27 (c 2.5, CH2Cl2). IR (filme, cm-1): 3001, 2933, 2852, 1784, 1612, 1514, 1457, 1302, 1248, 1171, 1075, 1036. HRMS calculated for C20H32O5Si [M+]: 381.2097, found 381.2208. |
83% | With 10-camphorsufonic acid In dichloromethane at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With CSA In dichloromethane at 0 - 20℃; Inert atmosphere; | 4.1.9. 2-((4-Methoxybenzyloxy)methyl)cyclopentenone, 23 To a solution of 35 (1.0 g, 8.92 mmol) and 4-methoxybenzyl 2,2,2-trichloroacetimidate 36 (6.85 g, 24.4 mmol) in CH2Cl2 (30 mL) was added dropwise a solution of CSA (207 mg, 0.892 mmol) in CH2Cl2 (6 mL) at 0 °C. After stirring for 10 min, the resulting mixture was warmed to rt and stirred for 3 h. Saturated aqueous NaHCO3 (10 mL) was added to quench the reaction. The separated water layer was extracted with AcOEt, and the combined organic layers were washed with brine and dried over Na2SO4. After volatile material was removed under reduced pressure, the resulting residue was purified by column chromatography (SiO2, hexane/AcOEt=3/1) to give 23 (1.55 g, yield 75%) as a colorless oil: 1H NMR (400 MHz, CDCl3): δ 2.43 (ddd, J=2.4, 2.4, 4.8 Hz, 2H), 2.62 (ddt, J=2.4, 2.4, 4.8 Hz, 2H), 3.80 (s, 3H), 4.17 (dd, J=2.4, 8.0 Hz, 2H), 4.51 (s, 2H), 6.89-90 (m, 2H), 7.26-7.31 (m, 2H), 7.61 (tt, J=1.6, 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 26.7, 34.7, 55.1, 63.6, 72.6, 113.6, 128.3, 129.2, 143.2, 159.1, 159.6, 208.3; IR (ATR): ν 2931, 2857, 2836, 1690, 1612 cm-1; LRMS (EI) m/z 232 (M); HRMS (EI) m/z calcd for C14H16O3 (M) 232.1099, found 232.1095. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With trifluorormethanesulfonic acid In diethyl ether at 0 - 20℃; | Preparation of 3-[2-(4-Hydroxy-3-[(4-methoxybenzyl)oxy]methyl}-1-butynyl)phenyl]-propanoic acid (5) 318 mg 4 (1.21 mmol, 1 eq) in 400 mL dry diethyl ether were cooled to 0 °C and 6 mg trifluoromethanesulfonic acid (0.01 mmol, 1 mol%) dissolved in 50 mL dry diethyl ether were added. Via an addition funnel 342 mg 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.35 mmol, 1.1 eq) were added during 4.5 h at 0 °C. The mixture was allowed to come to rt and was stirred for further 16 h. After the addtition of ice water the phases were separated and the aqueous phase was extracted thrice with DCM. The combined organic phases were washed once with water and once with sat. sodium chloride solution, dried over MgSO4 and the solvent was removed in vacuo. Purification of the crude product byFC (DCM/methanol = 100/3) yielded 364 mg of methyl 3-[2-(4-hydroxy-3-[(4-methoxybenzyl)oxy]methyl}-1-butynyl)phenyl]propanoate (0.95 mmol, 79 %) as a slightly yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 3h; Inert atmosphere; | 1 3.1.1 8-(4-Methoxybenzyloxy)-oct-1-en-4-yn-3-ol (9) To a solution of 4-pentyn-1-ol (1.00 g, 11.8 mmol) in dry dichloromethane (10 mL) 20 °C under an atmosphere of nitrogen, was added a solution of freshly prepared p-methoxybenzyl trichloroacetimidate (6.71 g, 23.7 mmol) in dichloromethane (3 mL) in a slow stream. After 5 min, pyridinium p-toluenesulfonate (1.49 g, 5.94 mmol) was added in one portion. The mixture was stirred at room temperature for 3 h and then quenched with solid sodium hydrogen carbonate followed by saturated aqueous sodium hydrogen carbonate (10 mL). The resulting mixture was diluted with dichloromethane (5 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. Chromatography of the residue on silica gel (1:15 ethyl acetate/petroleum ether) gave 9 (2.40 g, 98%) as a colourless oil; IR νmax (cm-1) 3292, 2935, 2857, 2117, 1611; 1H NMR (300 MHz, CDCl3) δ 7.27 (2H, d, J=8.6 Hz), 6.88 (2H, d, J=8.6 Hz), 4.44 (2H, s), 3.80 (3H, s), 3.55 (2H, t, J=6.2 Hz), 2.31 (2H, td, J=7.1, 2.7 Hz), 1.95 (1H, t, J=2.7 Hz), 1.86-1.78 (2H, m); 13C NMR (75 MHz, CDCl3) δ 159.2, 130.6, 129.2, 113.8, 84.0, 72.7, 68.5, 68.4, 55.3, 28.7, 15.3; LRMS m/z (+CI, %) 204 (18), 203 (49), 121 (100); HRMS+CI calcd for C13H16O2 204.1145, found: 204.1145. |
80% | With lanthanum(lll) triflate In toluene at 80℃; for 0.0333333h; | General procedure for the preparation of the PMB ethers (General Method A) General procedure: To a solution of the alcohol (3.0 mmol) in dry toluene (30 mL) was added 4-methoxybenzyl trichloroacetimidate (S3) (1.27 g, 4.5 mmol) and La(OTf)3 (88 mg, 0.15 mmol). The reaction mixture was heated for 2 min at 80 °C. After cooling to 21 °C the solvent was removed under reduced pressure and the residue was treated with a mixture of hexanes-ethyl acetate (5:1, V:V).The resulting precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash-chromatography to yield the corresponding PMB ether. |
With camphor-10-sulfonic acid In hexane; dichloromethane at 0 - 20℃; | 1-But-3-ynyloxymethyl-4-methoxy-benzene General procedure: A solution of p-methoxybenzylalcohol (3.32 g, 24 mmol) in 24 mL anhydrous Et2O was added into a suspension of NaH (58 mg, 2.4 mmol, washed with anhydrous hexane) at r.t under N2 protection. After 30 min., the mixture was cooled down to 0°C and added trichloroacetonitrile (3.46 g, 24 mmol). The resulting mixture was allowed to warm up to room temperature, and stirred for 4 h. After concentrated to remove Et2O, the residue was dissolved in 28 mL anhydrous hexane and 0.12 mL anhydrous MeOH. The suspension was filtered through celite. The filtrate was concentrated to give 6.8 g light yellow oil. The crude intermediate was dissolved in 40 mL anhydrous hexane and 20 mL anhydrous CH2Cl2. Then 3-butyn-1-ol (1.12 g, 16 mmol) was added dropwise. The resulting solution was cooled to 0°C and treated with catalytic amount of 10-camphorsulfonic acid. The mixture was then allowed to warm up slowly to room temperature and stirred overnight, while white precipitate was formed. The resulted mixture was filtered through celite. The filtrate was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered, and concentrated. The residue was purified with chromatography on silica gel with a Hexane/EtOAc (20:1) solvent system as eluent to give 2.4 g colorless oil in 80% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With trityl tetrafluoroborate In diethyl ether at 23℃; for 4h; | 1 [00462] (45.6S)-6-(fgrf-Butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)cvclohex-2- enone. Triphenylmethyl tetrafluoroborate ( 16 mg, 50 μϖιο, 0.050 equiv) was added to a solution of 4-methoxybenzyl-2,2,2-trichloroacetimidate (445 μΙ_, 2.5 mmol, 2.5 equiv) and alcohol (242 mg, 1 .0 mmol, 1 equiv) in ether ( 10 mL) at 23 °C. After 4 h, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate solution ( 15 mL) and ethyl acetate (50 mL). The layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL). The organic layers were combined. The combined solution was washed with water (2 x 20 mL) and the washed solution was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (5% ethyl acetate-hexanes initially, grading to 10% ethyl acetate-hexanes) to provide 297 mg of the product, (4S,6S)-6-(im-butyldimethylsilyloxy)-4-(4- methoxybenzyloxy)cyclohex-2-enone, as a colorless oil (82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With lanthanum(lll) triflate In toluene at 80℃; for 0.0333333h; | General procedure for the preparation of the PMB ethers (General Method A) General procedure: To a solution of the alcohol (3.0 mmol) in dry toluene (30 mL) was added 4-methoxybenzyl trichloroacetimidate (S3) (1.27 g, 4.5 mmol) and La(OTf)3 (88 mg, 0.15 mmol). The reaction mixture was heated for 2 min at 80 °C. After cooling to 21 °C the solvent was removed under reduced pressure and the residue was treated with a mixture of hexanes-ethyl acetate (5:1, V:V).The resulting precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash-chromatography to yield the corresponding PMB ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With lanthanum(lll) triflate In toluene at 80℃; for 0.0333333h; | General procedure for the preparation of the PMB ethers (General Method A) General procedure: To a solution of the alcohol (3.0 mmol) in dry toluene (30 mL) was added 4-methoxybenzyl trichloroacetimidate (S3) (1.27 g, 4.5 mmol) and La(OTf)3 (88 mg, 0.15 mmol). The reaction mixture was heated for 2 min at 80 °C. After cooling to 21 °C the solvent was removed under reduced pressure and the residue was treated with a mixture of hexanes-ethyl acetate (5:1, V:V).The resulting precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash-chromatography to yield the corresponding PMB ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With lanthanum(lll) triflate In toluene at 80℃; for 0.0333333h; | General procedure for the preparation of the PMB ethers (General Method A) General procedure: To a solution of the alcohol (3.0 mmol) in dry toluene (30 mL) was added 4-methoxybenzyl trichloroacetimidate (S3) (1.27 g, 4.5 mmol) and La(OTf)3 (88 mg, 0.15 mmol). The reaction mixture was heated for 2 min at 80 °C. After cooling to 21 °C the solvent was removed under reduced pressure and the residue was treated with a mixture of hexanes-ethyl acetate (5:1, V:V).The resulting precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash-chromatography to yield the corresponding PMB ether. |
85% | With lanthanum(lll) triflate In toluene at 80℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With lanthanum(lll) triflate In toluene at 80℃; for 1h; | |
80% | With lanthanum(lll) triflate In toluene at 80℃; for 0.0333333h; | General procedure for the preparation of the PMB ethers (General Method A) General procedure: To a solution of the alcohol (3.0 mmol) in dry toluene (30 mL) was added 4-methoxybenzyl trichloroacetimidate (S3) (1.27 g, 4.5 mmol) and La(OTf)3 (88 mg, 0.15 mmol). The reaction mixture was heated for 2 min at 80 °C. After cooling to 21 °C the solvent was removed under reduced pressure and the residue was treated with a mixture of hexanes-ethyl acetate (5:1, V:V).The resulting precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash-chromatography to yield the corresponding PMB ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With lanthanum(lll) triflate In toluene at 80℃; for 0.0333333h; | General procedure for the preparation of the PMB ethers (General Method A) General procedure: To a solution of the alcohol (3.0 mmol) in dry toluene (30 mL) was added 4-methoxybenzyl trichloroacetimidate (S3) (1.27 g, 4.5 mmol) and La(OTf)3 (88 mg, 0.15 mmol). The reaction mixture was heated for 2 min at 80 °C. After cooling to 21 °C the solvent was removed under reduced pressure and the residue was treated with a mixture of hexanes-ethyl acetate (5:1, V:V).The resulting precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash-chromatography to yield the corresponding PMB ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With lanthanum(lll) triflate In toluene at 80℃; for 0.0333333h; | General procedure for the preparation of the PMB ethers (General Method A) General procedure: To a solution of the alcohol (3.0 mmol) in dry toluene (30 mL) was added 4-methoxybenzyl trichloroacetimidate (S3) (1.27 g, 4.5 mmol) and La(OTf)3 (88 mg, 0.15 mmol). The reaction mixture was heated for 2 min at 80 °C. After cooling to 21 °C the solvent was removed under reduced pressure and the residue was treated with a mixture of hexanes-ethyl acetate (5:1, V:V).The resulting precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash-chromatography to yield the corresponding PMB ether. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With lanthanum(lll) triflate In toluene at 80℃; for 2h; | |
56% | With lanthanum(lll) triflate In toluene at 80℃; for 0.0333333h; | Cholesteryl (4-methoxybenzyl) ether (5). To a solution of cholesterol (6) (1.16 g, 3.0 mmol) in dry toluene (30 mL) was added 4-methoxybenzyl trichloroacetimidate (S3) (1.27 g, 4.5 mmol) and La(OTf)3 (88 mg, 0.15 mmol). The reaction mixture was heated for 2 min at 80 °C. After cooling to 21 °C the solvent was removed under reduced pressure and the residue was treated with acetone (20 mL) to precipitate the PMB ether 5 from the reaction mixture. The precipitate was filtered off, washed with acetone and dried. Yield: 0.86 g (56%), colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.28-7.26 (m, 2H), 6.67 (d, J = 8.6 Hz, 2H), 5.35-5.33 (m, 1H), 4.49 (s,2H), 3.80 (s, 3H), 2.43-2.37 (m, 1H), 2.29-2.23 (m, 1H), 2.02-1.78 (m, 5H), 1.61-0.97 (m, 25H),0.91 (d, J = 6.5 Hz, 3H), 0.87, 0.86 (2d, J = 6.6 Hz, 6H), 0.68 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.0, 141.0, 131.1, 129.2 (2C), 121.5, 113.8 (2C), 78.3, 69.6, 56.8, 56.2, 55.3, 50.2,42.3, 39.8, 39.5, 39.2, 37.3, 36.9, 36.2, 35.8, 32.0, 31.9, 28.5, 28.3, 28.0, 24.3, 23.8, 22.8, 22.6,21.1, 19.4, 18.7, 11.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; for 8h; | 4.5. Ethyl (4R,7R,E)-7-(tert-butyldimethylsilyloxy)-4-(4-methoxybenzyloxy)oct-2-enoate 10 To a cooled (0 °C) solution of alcohol 9 (0.8 g, 2.52 mmol) in dry DCM (30 mL) was added PMB imidate (0.858 g, 3.03 mmol) followed by PTSA (catalytic amount) and the reaction was stirred at room temperature for 8 h. After completion of the reaction, it was quenched with triethylamine, diluted with water (30 mL), and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane /ethyl acetate, 95: 5) to give compound 10 (0.902 g, 82%) as a brown liquid. (c 1.1, CHCl3); IR (neat, cm-1): νmax 2955, 2930, 2856, 1721, 1655, 1513, 1464, 1250, 1172, 1039, 832, 773; 1H NMR (300 MHz, CDCl3): δ 7.20 (d, J = 8.3 Hz, 2H), 6.86-6.75 (m, 3H), 5.95 (d, J = 15.6 Hz, 1H), 4.50 (d, J = 11.3 Hz, 1H), 4.27 (d, J = 11.3 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.93-370 (m, 5H), 1.72-1.42 (m, 4H), 1.33 (t, J = 7.1 Hz, 3H), 1.11 (d, J = 6 Hz, 3H), 0.88 (s, 9H), 0.02 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 166.2, 159.1, 148.3, 130.1, 129.2, 121.9, 113.7, 77.7, 70.5, 68.3, 60.3, 55.1, 34.9, 31.0, 25.8, 23.8, 18.0, 14.1, -4.4, -4.7. ESI/MS (m/z): 459 (M+Na+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With trifluorormethanesulfonic acid In dichloromethane at 20℃; | The procedure to prepare 9d: To a solution of 7(0.348 g, 2 mmol) and 12 (1.13 g, 4 mmol) in DCM (20 mL) was added TfOH (46.4 mg, 10 mol%) at room temperature. The solution was stirred for 36 hours and concentrated. The residue was suspended on hexanes and filtered through filter paper. The filtrate was concentrated and purified by silica gel chromatography with hexanes/ethyl acetate (v/v = 9:1) as eluent to give 9d as colorless oil (0.47 g, 80%).1H NMR (400 MHz, CDCl3) 7.25 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.51 (d, J = 10.9 Hz, 1H), 4.43 (d, J = 10.9 Hz, 1H), 4.18-4.10 (m, 2H), 3.95-3.89 (m, 1H), 3.79 (s, 3H), 2.60 (dd, J = 6.8, 15.0 Hz, 1H), 2.44 (dd, J = 5.8, 14.9 Hz, 1H), 1.81-1.71 (m, 1H), 1.61-1.54 (m, 1H), 1.33-1.22 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H). IR (thin film, cm-1) 2956, 1732, 1614, 1514, 1368, 1302, 1174, 1083, 822. Rf = 0.25, hexanes/ethyl acetate = 90:10 PMA. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; for 3h; | E)-Ethyl 4-(4-methoxybenzyloxy)-3-methylbut-2-enoate (9): To a stirred solution of compound 8 (1.10 g, 7.6 mmol) in dry CH2Cl2 (5 mL), PMB imidate (2.59 g, 9.10 mmol) was added at 0 oC to this catalytic amount of PTSA was added at the same temperature and allowed it to stirr at room temperature for 3 h. Later, reaction mixture was extracted with CH2Cl2 (2 x 100 mL), the combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2SO4) and concentrated in vaccuo and the residue was purified by column chromatography (Silica gel, 60-120 mesh, EtOAc:n-hexane, 1:99) to give 9 (1.81 g, 90%) as a colorless liquid. 1H NMR (500 MHz, CDCl3): δ 7.23 (d, 2H, J = 8.4 Hz), 6.84 (d, 2H, J = 8.4 Hz), 5.95 (s, 1H), 4.45 (s, 2H), 4.16 (q, 2H, J = 14.3, 6.9 Hz), 3.93 (s, 2H), 3.81 (s, 3H), 2.11 (s, 3H), 1.31(t, 3H, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3): δ 166.6, 159.2, 154.5, 131.9, 129.8, 129.2, 115.2, 114.2, 113.8, 73.7, 72.1, 59.6, 55.2, 15.7, 14.2; HRMS m/z: calcd for C15H20O4Na [M+Na]+: 287.1253; found: 287.1262. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With bismuth(lll) trifluoromethanesulfonate In toluene at 20℃; Molecular sieve; Inert atmosphere; | 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 |
---|---|---|
90% | With bismuth(lll) trifluoromethanesulfonate In toluene at 20℃; Molecular sieve; Inert atmosphere; | 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 |
---|---|---|
86% | In dichloromethane at 20℃; for 24h; Inert atmosphere; | |
82% | In dichloromethane at 20℃; for 48h; Inert atmosphere; | The carboxylic acid (1.50 mmol) was dissolved in anhydrous CH2Cl2 (6 mL, to provide a 0.25M solution). 4-Methoxybenzyl-2,2,2-trichloroacetimidate (430 mg, 3.00 mmol, 2.0 equiv) was then added. After 24 hTLC indicated that all of the starting material had been consumed. The reaction mixture was taken up inethyl acetate and washed with sodium bicarbonate (sat. aq., 3x). The organic layer was dried (Na2SO4),filtered and concentrated. The residue was adsorbed on silica gel and purified by silica gelchromatography to provide the corresponding PMB ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In dichloromethane; at 0 - 20℃; for 16h; | Following a protocol by Shah et al.,10 3-butenoic acid 16 (1.013 g, 11.77 mmol) was dissolved in CH2Cl2 (50 mL) and the solution cooled to 0 C. 4-Methoxybenzyl-2,2,2-trichloroacetimidate (4.980 g, 17.65 mmol) was added and the mixture was stirred for 16 hrs, being allowed to come to rt. The reaction was filtered. The filtrate was condensed by rotary evaporation. The crude residue was dissolved in EtOAc (50 mL) and washed with sat. aqueous NaHCO3 (3x25 mL) and brine (1x25 mL). The EtOAc was evaporated under vaccum. The product was purified by silica gel chromatography, 9:1 hexanes:EtOAc, isocratic. The product was isolated as a clear, colorless liquid (2.407 g, 99%). Rf 0.46 in 9:1 hexanes:EtOAc. 1H NMR (500 MHz, CDCl3) delta 7.31 (d, J=8.5 Hz, 2H); 6.90 (d, J=8.5 Hz, 2H); 5.89-6.01 (m, 1H); 5.18-5.21 (m, 1H); 5.15-5.18 (m, 1H); 5.08 (s, 2H); 3.82 (s, 3H); 3.13 (dt, J=7.0, 1.3 Hz, 2H). 13C NMR (125 MHz, CDCl3) delta 171.3 C; 159.6 C; 130.1 CH; 130.0 CH; 127.9 C; 118.5 CH2; 113.9 CH; 66.2 CH2; 55.2 CH3; 39.1 CH2. |
83% | In dichloromethane; at 20℃; for 24h;Inert atmosphere; | The carboxylic acid (1.50 mmol) was dissolved in anhydrous CH2Cl2 (6 mL, to provide a 0.25M solution). 4-Methoxybenzyl-2,2,2-trichloroacetimidate (430 mg, 3.00 mmol, 2.0 equiv) was then added. After 24 hTLC indicated that all of the starting material had been consumed. The reaction mixture was taken up inethyl acetate and washed with sodium bicarbonate (sat. aq., 3x). The organic layer was dried (Na2SO4),filtered and concentrated. The residue was adsorbed on silica gel and purified by silica gelchromatography to provide the corresponding PMB ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In dichloromethane; at 20℃; for 24h;Inert atmosphere; | The carboxylic acid (1.50 mmol) was dissolved in anhydrous CH2Cl2 (6 mL, to provide a 0.25M solution). 4-Methoxybenzyl-2,2,2-trichloroacetimidate (430 mg, 3.00 mmol, 2.0 equiv) was then added. After 24 hTLC indicated that all of the starting material had been consumed. The reaction mixture was taken up inethyl acetate and washed with sodium bicarbonate (sat. aq., 3x). The organic layer was dried (Na2SO4),filtered and concentrated. The residue was adsorbed on silica gel and purified by silica gelchromatography to provide the corresponding PMB ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In dichloromethane; at 20℃; for 24h;Inert atmosphere; | The carboxylic acid (1.50 mmol) was dissolved in anhydrous CH2Cl2 (6 mL, to provide a 0.25M solution). 4-Methoxybenzyl-2,2,2-trichloroacetimidate (430 mg, 3.00 mmol, 2.0 equiv) was then added. After 24 hTLC indicated that all of the starting material had been consumed. The reaction mixture was taken up inethyl acetate and washed with sodium bicarbonate (sat. aq., 3x). The organic layer was dried (Na2SO4),filtered and concentrated. The residue was adsorbed on silica gel and purified by silica gelchromatography to provide the corresponding PMB ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With lanthanum(lll) triflate In toluene at 20℃; for 0.5h; | 61 (2S,3S)-Methyl-2-(tert-butoxycarbonylamino)-3-(4-methoxybenzyloxy)-3- phenylpropanoate 64 A solution of A/-fe/f-butoxycarbonyl-(2S,3R)-p-hydroxyphenylalanine methyl ester (563 mg, 1 .91 mmol) and 4-methoxybenzyl 2,2,2-trichloroacetimidate (801 mg, 2.86 mmol) in toluene (40 mL) was treated with lanthanum triflate (56 mg, 0.095 mmol) and the mixture was stirred for at room temperature for 30 minutes. Saturated aqueous NaHC03 solution was added and the mixture was extracted with diethyl ether. The organic layer was dried, filtered and concentrated to give a residue which was purified by column silica gel column chromatography (hexane:diethyl ether, 85:15) affording (2S,3S)-methyl 2-(fe/f-butoxycarbonylamino)-3-(4-methoxybenzyloxy)-3-phenylpropanoate (719 mg, 91 % yield). 1H NMR (400 MHz, CDCI3) δ 1 .32 (s, 9H), 3.65 (s, 3H), 3.77 (s, 3H), 4.17 (d, J= 1 1 .4 Hz, 1 H), 4.50 (d, J= 1 1 .6 Hz, 2H), 4.94 (d, J= 2.8 Hz, 1 H), 5.42 (d, J= 9.6 Hz, 1 H), 6.87 (d, J= 8.6 Hz, 2H), 7.14 (d, J= 8.6 Hz, 2H), 7.37 (d, J= 4.0 Hz, 5H); 13C NMR (101 MHz, CDCI3) δ 27.9, 51 .9, 54.9, 59.1 , 70.2, 79.2, 79.3, 1 13.5, 126.7, 126.7, 127.8, 128.2, 128.2, 129.2, 129.3, 129.3, 137.1 , 155.1 , 159.1 , 170.6; HRMS (ESI)+: m/z calcd for C23H29NNa06 [M+Na]+: 438.1887, found 438.1879; IR (v, cm"1): 3448, 1753, 1716, 1513, 121 1 ; [a]22D = -44.5 (c = 1 .41 , MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With scandium tris(trifluoromethanesulfonate) In toluene at 0℃; for 9h; Inert atmosphere; | Amide 7-1 To a stirred solution of known amide1(502.3 mg, 1.79 mmol) in toluene (17.9 ml) were added PMBOCNHCCl3(0.67 ml, 3.21 mmol) and Sc(OTf)3 (131.8 mg, 0.268 mmol) at 0°C. After the reaction mixture was stirred at same temperature for 6 h, additional PMBOCNHCCl3 (1.85 ml, 8.90 mmol) was added at 0°C. After 3 h, hexane (20 ml) was added at ambient temperature and then the resulting mixturew as cooled to 0°C. After filtered through Hirsch funnel, the reaction was quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane/ethyl acetate = 4/1 to 1/1) afforded amide 7-1 (608.4 mg, 1.52 mmol, 85%). Amide7-1: orange oil; Rf = 0.40 (silica gel,hexane/ethyl acetate = 1/1); [a]D24+24.8 (c 0.42, CHCl3); 1H NMR (CDCl3, 500MHz): d 7.35-7.27 (5H, m), 7.23-7.20 (2H, m), 6.86-6.83(2H, m), 4.50 (1H, d, J = 10.5 Hz), 4.49(1H, d, J = 12.0 Hz), 4.44 (1H, d, J = 12.0 Hz), 4.43 (1H, d, J = 10.5 Hz), 3.79 (3H, s), 3.83-3.75(2H, m), 3.61 (3H, s), 3.59-3.56 (2H, m), 3.16 (3H, s), 1.96-1.89 (1H, m), 1.83-1.77(1H, m), 1.23 (3H, d, J = 7.0 Hz); 13C NMR (CDCl3,100 MHz): d 176.2, 159.3, 138.6, 130.8, 129.8, 128.4,127.9, 127.6, 113.9, 78.0, 73.0, 73.0, 67.0, 61.5, 55.4, 40.5, 33.5, 32.3, 14.4;IR (neat) 2937, 2864, 1657, 1612, 1514, 1455, 1420, 1384, 1369, 1302, 1248,1175, 1100, 1076, 1034, 994, 822, 738, 700 cm-1; HRMS (ESIMS): m/z calcd for C23H31NO5Na[M+Na]+ 424.2097, found 424.2101. |
70% | With scandium tris(trifluoromethanesulfonate) In toluene at 20℃; | |
70% | With scandium trifluoromethanesulfonate In toluene at 0 - 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With camphor-10-sulfonic acid In dichloromethane at 20 - 50℃; for 15h; Inert atmosphere; | ((4R,5R)-5-(((4-Methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)(pyrrolidin-1-yl)methanone (S12) To a solution of alcohol 55 (15.7 g, 68.5 mmol, 1.0 eq) in DCM (115 mL) were added p-methoxybenzyl trichloroacetimidate (29.7 g, 105 mmol, 1.53 eq), dissolved in DCM (30 mL), and camphorsulfonic acid (1.27 g, 5.48 mmol, 0.08 eq) at room temperature. The reaction mixture was stirred for 12 hours at room temperature and 3 hours at 50 °C when TLC-control showed total conversion of the starting material. The reaction was quenched by the addition of saturated NaHCO3 solution, the layers were separated and the aqueous phase was extracted with DCM (3 x 80 mL). The combined organic extracts were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. After flash column chromatography (hexane/EtOAc 1:1) S12 (20.4 g) was isolated in 85% yield as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; for 8h; | 7 4.1.7. tert-Butyl((S,6Z,8E)-10-(4-methoxybenzyloxy)deca-6,8-dien-5-yloxy)dimethylsilane 13 To a cooled (0°C) solution of alcohol 12 (2.7 g, 9.507 mmol) in dry CH2Cl2 (50 mL) was added PMB imidate (3.4 g, 19.014 mmol) followed by PTSA (catalytic amount) and the reaction was stirred at room temperature for 8 h. After completion of the reaction, it was quenched with triethylamine, diluted with water (50 mL), and extracted into CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (hexane/ethylacetate, 93:7) to give compound 13 (3.45 g, 90%) as a colorless liquid. [α]D25 = -26.4 (c 2.2, CHCl3). IR (neat): 3003, 2955, 2930, 2856, 1612, 1512, 1464, 1358, 1248, 1175, 1040, 835, 775 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.30-7.24 (m, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.48 (dd, J = 14.9, 11.3 Hz, 1H), 5.94 (t, J = 11.1 Hz, 1H), 5.83-5.73 (m, 1H), 5.43-5.34 (m, 1H), 4.56-4.42 (m, 3H), 4.08-4.03 (m, 2H), 3.81 (s, 3H), 1.55-1.20 (m, 6H), 0.93-0.83 (m, 12H), 0.04 (s, 3H) 0.01 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.2, 136.0, 130.7, 129.6, 129.3, 127.6, 126.6, 113.7, 71.6, 70.0, 68.9, 55.2, 38.1, 27.4, 25.8, 22.6, 18.2, 14.1, -4.3, -4.8 ppm. HRMS (ESI): calcd for C24H40O3NaSi [M+Na]+ 427.2638; found 427.2632. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With trifluorormethanesulfonic acid In dichloromethane; cyclohexane at 0℃; for 18h; | 4.2.1 Procedure A-protection of alcohol with benzyl ether or PMB ether General procedure: To a cooled (0 °C) solution of alcohol (1 equiv) in a solvent mixture of dry cyclohexane and CH2Cl2 (2:1, 0.1 M) was added successively 2,2,2-benzyltrichloroacetimidate (Bn, 1.5 equiv) or 4-methoxybenzyl 2,2,2-trichloroacetimidate (PMB, 1.5 equiv) and TfOH (0.1 equiv), followed by stirring overnight at 0 °C. The reaction mixture was treated with Et3N (0.15 equiv), and concentrated in vacuo. The residue was solubilized in hexanes, filtered onto a pad of Celite, washed thoroughly with hexanes and the filtrate concentrated in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With (-)-CSA In hexane; dichloromethane at 0 - 20℃; for 18h; | |
90% | With (1S)-10-camphorsulfonic acid In hexane; dichloromethane at 0 - 20℃; for 18h; Inert atmosphere; | (2E,4E,7R,9S)-7,9-bis(tert-Butyldimethylsilyloxy)-11-(tertbutyldiphenylsilyloxy)-1-(4-methoxybenzyloxy)undeca-2,4-diene (8'''). To a solution of 4-methoxybenzyltrichloroacetimidate (2.62 g, 9.26 mmol, 1.67 equiv) in hexane (46 mL) was added alcohol 8'' (3.79 g, 5.55 mmol, 1 equiv) in CH2Cl2 (23 mL) via a cannula.The mixture was cooled to 0 C and (-)-CSA (128 mg, 554 mmol,10 mol %) was added. After 5 min at 0 C, the mixture was warmed to rt and stirred for 18 h. The white suspension was diluted with CH2Cl2 (50 mL) and filtered through a pad of Celite. The filtrate was washed with a saturated aqueous solution of NaHCO3 (50 mL), H2O (50 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (petroleum ether/EtOAc 98:2) to afford PMB ether 8''' (3.99 g, 4.97 mmol, 90%, dr>98:2) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 24h; Inert atmosphere; | |
81% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 24h; Inert atmosphere; | (S,E)-Methyl-4-((tert-butyldimethylsilyl)oxy)-2-(3-((4-methoxybenzyl)oxy)propyl)pent-2-enoate (55) (±)-Camphorsulfonic acid (3.5 mg, 14.9 mol) was added to a solution of alcohol 54 (45.1 mg, 149 mol), 4-methoxybenzyl-2,2,2-trichloroacetimidate (131 mg, 447 mol) and CH2Cl2 (1.5 mL) at room temperature. Thesolution was stirred at room temperature for 1 d, quenched with Et3N (0.06 M in hexane, 500 L, 30 mol), andconcentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane 1:40) and HPLC(PEGASIL Silica 120-5 250×20 mm, UV 254 nm, EtOAc/hexane 1:5, 10 mL/min, TR= 11 min) to give 50.7mg of MPM ether 55 (81%): a colorless oil; []24D +6.8 (c 1.04, CHCl3); IR (film) 2953, 2930, 2857, 1718,1513, 1250, 1086, 832, 777 cm1; 1H NMR (500 MHz, CDCl3) 7.26 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz,2H), 6.66 (d, J = 8.6 Hz, 1H), 4.63 (dq, J = 8.6, 6.3 Hz, 1H), 4.43 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H), 3.45 (t, J= 6.3 Hz, 2H), 2.35 (t, J = 7.7 Hz, 2H), 1.79-1.61 (m, 2H), 1.23 (d, J = 6.3 Hz, 3H), 0.87 (s, 9H), 0.04 (s, 3H),0.02 (s, 3H); 13C NMR (125 MHz, CDCl3) 168.4 (C), 159.2 (C), 146.5 (CH), 130.8 (C), 129.6 (C), 129.2 (CH),113.9 (CH), 72.5 (CH2), 69.6 (CH2), 65.6 (CH), 55.4 (CH3), 51.9 (CH3), 29.4 (CH2), 25.9 (CH3), 24.3 (CH3),24.1 (CH2), 18.2 (C), 4.4 (CH3), 4.5 (CH3); HRMS (ESI), calcd for C23H38O5NaSi+ (M+Na)+ 445.2386, found445.2398. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With CSA In dichloromethane at 20℃; Inert atmosphere; | 2 Manufacturing Example 2: Manufacturing Example 2: Preparation of Methyl 2-(3,4-dimethoxyphenyl)-3-(4-methoxybenzyloxy)propanoate (33) The compound 32 (500 mg, 2.38 mmol) prepared in Manufacturing Example 1 and paraformaldehyde paraformaldehyde (76 mg, 2.50 mmol) were dissolved in anhydrous DMSO (5.0 mL), which was then treated with sodium methoxide (6.8 mg, 0.12 mmol). The mixture was stirred at room temperature for 24 hours, which was poured into ice water (10 mL), followed by stirring. The mixture was neutralized with 2 N-HCl solution, which was poured into water, followed by extraction with EtOAc (*3). The organic layer was washed with saturated brine once and dried over MgSO4, followed by filtering and concentrating under reduced pressure. Then, the residue was purified by silica gel resolution chromatography (EtOAc:n-hexane=1:1) to give the aldol product as a yellow solid (yield: 58%, 331 mg). 1H NMR (CDCl3, 300 MHz) δ6.74 (m, 3H), 4.05 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.73 (m, 2H), 3.65 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With lanthanum(lll) triflate In toluene at 0 - 20℃; for 1h; Inert atmosphere; | To the solution of 8 (1.10 g, 2.76 mmol) and p-methoxy benzyl trichloroacetimidate (1.58g, 4.14 mmol) in anhydrous toluene (70 mL) at 0 °C, was added La(OTf)3 (80 mg, 0.14mmol). The mixture was stirred at room temperature for 1 h and then concentrated. The residue was purified by flash chromatography (0-15% EtOAc / hexanes) to afford 5a as colorless oil (1.24 g, 87%). The spectroscopic data were identical to that of 5a obtained via alkylation with MPMOCH2Cl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With lanthanum(lll) triflate In toluene at 20℃; for 0.5h; | tert-butyl ((2S,3R,E)-1-((tert-butyldimethylsilyl)oxy)-3-hydroxyoctadec-4-en-2-yl)carbamate tert-butyl ((2S,3R,E)-1-((tert-butyldimethylsilyl)oxy)-3-hydroxyoctadec-4-en-2-yl)carbamate To a solution of S5 (500mg, 0.97 mmol) in toluene (10 mL) was added p-methoxybenzyltrichloroacetimidate (0.24 mL, 1.16 mmol) and lanthanum triflate (87.9 mg, 0.15 mmol) at room temperature. After stirring at the same temperature for 30 min, the reaction mixture was washed with water. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate/hexane = 1:10) to afford S6 (460.8 mg,75%) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With (1S)-10-camphorsulfonic acid In dichloromethane at 20℃; for 19h; | 1-Methoxy-4-((oct-7-yn-1-yloxy)methyl)benzene (14) To a solution of 13 (792 mg, 6.28 mmol) in dichrolomethane (3 mL) was added a solution of 4-methoxybenzyl trichloroacetimidate (1.30 mL, 6.28 mmol) in dichrolomethane (3 mL) at r.t.. Then, a solution of D-camphorsulfonic acid (333 mg, 0.63 mmol) in dichrolomethane (3 mL) was added dropwise. The reaction mixture was stirred at r.t. for 19 h, and quenched with saturated aqueous sodium bicarbonate solution, and the whole was extracted with ethyl acetate. The extract successively washed with water and then dried over Na 2SO 4. The solvent was evaporated, and the residue was purified by means of silica gel column chromatography (hexane/ethyl acetate 10/1 to 4/1) give 14 (520 mg, 34%) as an yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With camphor-10-sulfonic acid In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With (1S)-10-camphorsulfonic acid In dichloromethane at 0 - 20℃; for 17h; | 1.3 Example 1, Step 3: Preparation of 0)}-methyl 2-((5}1-((4-methoxybenzyi)oxy)ethyl)- 5-methylhexanoate Example 1, Step 3: Preparation of 0)}-methyl 2-((5}1-((4-methoxybenzyi)oxy)ethyl)-5-methylhexanoateTo a solution of (S)-methyl2-((S)-1-hydroxyethyl)-5-methylhexanoate (5.00 g, 26.6 nnnol)and ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesul±onic acid (camphorsulfonic acid, CSA; 0.617 g, 2.66 mmol) in DCM (53.1 mL) was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (8.27 mL, 39.8 mmol) at 0 °C. The reactionmixture was removed from the cold bath and stirred at room temperature for 17 h. Hexane (50 mL) "Vas added to the reaction and the precipitate was removed by filtration. The solids were vashed with hexanes (2 x lO mL), Celite (2 scoopulatip-fulls) was addedto the combined filtrate and washes, and the solventwasremoved under reduced pressure.The resulting adsorbedmaterial was directlyloaded onto a colmnn and purified using tlash columnchromatography (80 g Si02 , 0-735% EtOAc/hexanes) to afford thetitle compound (6.3 g, 20.4 mmol, 77)) as a colorlessoil; 1H NMR (400 MHz, CDCh) 8 7.24- 7.16 (m, 21-1), 6.89 ---6.79 (m, 21-1), 4.49 (d, J'" 11.2 Hz, 1H), 4.33 (d, }'" 1 L1 Hz, 1H), 3.75 (s, 3H), 3.74-3.62 (m,4H), 2.49 (ddd,J= 10.7, 8.2, 4.0 Hz, 1H), L62 -1.40 (m, 3H), L23 -1.16 (m, 3H), 1.16- 1.03 (m, 2El:), 0.87 (d, J '" 3.9Hz, 3H), 0.85 (d, J '" 3.9 Hz, 3H); 13C NMR (101 MHz, CDCh)8 175.03,159.10, 130.63, 129.14,113.62, 76.16, 70.71, 55.11, 52.64, 51.25, 36.58, 27.97,26.00, 22.69, 22.17,17.08; ESIMS m/z331([M+Na]'). |
77% | With (1S)-10-camphorsulfonic acid In dichloromethane at 0 - 20℃; for 17h; | 1.3 Example 1, Step 3: Preparation of (S)-methyl 2-((5)-l-((4-methoxybenzyl)oxy)ethyl)- 5 -methylhexanoate Example 1, Step 3: Preparation of (S)-methyl 2-((5)-l-((4-methoxybenzyl)oxy)ethyl)- 5 -methylhexanoateTo a solution of (S)-methyl 2-((S)- 1 -hydroxyethyl)-5-methylhexanoate (5.00 g, 26.6 mmol) and ((15',4i?)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl)methanesulfonic acid(camphorsulfonic acid, CSA; 0.617 g, 2.66 mmol) in DCM (53.1 mL) was added 4-methoxybenzyl 2,2,2 -trichloroacetimidate (8.27 mL, 39.8 mmol) at 0 °C. The reaction mixture was removed from the cold bath and stirred at room temperature for 17 h. Hexane (50 mL) was added to the reaction and the precipitate was removed by filtration. The solids were washed with hexanes (2 x 10 mL), Celite(2 scoopula tip-fulls) was added to the combined filtrate and washes, and the solvent was removed under reduced pressure. The resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (80 g Si02, 0- 35% EtOAc/hexanes) to afford the title compound (6.3 g, 20.4 mmol, 77%) as a colorless oil; 1H NMR (400 MHz, CDC13) δ 7.24 - 7.16 (m, 2H), 6.89 - 6.79 (m, 2H), 4.49 (d, J= 11.2 Hz, 1H), 4.33 (d, J= 11.1 Hz, 1H), 3.75 (s, 3H), 3.74 - 3.62 (m, 4H), 2.49 (ddd, J= 10.7, 8.2, 4.0 Hz, 1H), 1.62 - 1.40 (m, 3H), 1.23 - 1.16 (m, 3H), 1.16 - 1.03 (m, 2H), 0.87 (d, J= 3.9 Hz, 3H), 0.85 (d, J= 3.9 Hz, 3H);13C NMR (101 MHz, CDC13) 5 175.03, 159.10, 130.63, 129.14, 113.62, 76.16, 70.71, 55.11, 52.64, 51.25, 36.58, 27.97, 26.00, 22.69, 22.17, 17.08; ESIMS m/z 331 ([M+Na]+). |
77% | With (1S)-10-camphorsulfonic acid In dichloromethane at 0 - 20℃; for 17h; | 1.3 Preparation of(S)-methyl 2-((S)-1 -((4-methoxyben- zyl)oxy)ethyl)-5-methylhexanoate To a solution of(S)-methyl 2-((S)-1 -hydroxyethyl)5-methylhexanoate (5.00 g, 26.6 mmol) and CSA (0.617 g,2.66 mmol) in DCM (53.1 mE) was added 4-methoxybenzyl2,2,2-trichloroacetimidate (8.27 mE, 39.8 mmol) at 00 C. The reaction mixture was removed from the cold bath and stirred at room temperature for 17 h. Hexane (50 mE) was added to the reaction mixture and the precipitate was removed by filtration. The solids were washed with hexanes (2x 10 mE), and Celite was added to the combined filtrate and washes and the solvent was removed under reduced pressure. The resulting adsorbed material was directly loaded onto a column and purified using flash column chromatography (5i02, 1 -35% EtOAc in hexanes) to afford the title compound (6.3 g, 77%) as a colorless oil: ‘H NMR (400 MHz, CDC13) ö 7.24-7.16 (m, 2H), 6.89-6.79 (m, 2H), 4.49 (d, J=11.2 Hz, 1H), 4.33 (d, J=1 1.1 Hz, 1H), 3.75 (s, 3H), 3.74-3.62 (m, 4H),2.49 (ddd, J=10.7, 8.2, 4.0 Hz, 1H), 1.62-1.40 (m, 3H), 1.23-1.16 (m, 3H), 1.16-1.03 (m, 2H), 0.87 (d, J=3.9 Hz, 3H), 0.85 (d, J=3.9 Hz, 3H); ‘3C NMR (101 MHz, CDC13) ö 175.03, 159.10, 130.63, 129.14, 113.62, 76.16, 70.71, 55.11, 52.64,51.25, 36.58, 27.97, 26.00, 22.69, 22.17, 17.08; ESIMS mlz331 ([M+Na]). |
77% | With (1S)-10-camphorsulfonic acid In dichloromethane at 0 - 20℃; for 17h; | 9.3 Example 9, Step 3: Preparation of (S)-methyl 2-((S)-1-((4-methoxybenzyl)oxy)ethyl)-5-methylhexanoate To a solution of (S)-methyl 2-((S)-l -hydroxy ethyl)-5-methylhexanoate (5.00 g, 26.6 mmol) and ((l,S',4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l-yl)methanesulfonic acid (0.617 g, 2.66 mmol) in CH2CI2 (53 mL) was added 4-methoxybenzyl 2,2,2-trichloroacetimidate (8.27 mL, 39.8 mmol) at 0 °C, and the reaction mixture was removed from the cold bath, warmed to room temperature, and stirred for 17 h. The reaction mixture was diluted with hexanes (50 mL) and the resulting precipitate was removed by filtration and washed with hexanes (2 x 10 mL). To the combined filtrate and washings was added Celite and the solvent was removed under reduced pressure. The resulting adsorbed material was purified by column chromatography (Si02; 0- 35% EtOAc in hexanes) to afford the title compound (6.3 g, 77%) as a colorless oil: 1H NMR (400 MHz, CDCI3) δ 7.24 - 7.16 (m, 2H), 6.89 - 6.79 (m, 2H), 4.49 (d, J= 11.2 Hz, 1H), 4.33 (d, J= 11.1 Hz, 1H), 3.75 (s, 3H), 3.74 - 3.62 (m, 4H), 2.49 (ddd, J= 10.7, 8.2, 4.0 Hz, 1H), 1.62 - 1.40 (m, 3H), 1.23 - 1.16 (m, 3H), 1.16 - 1.03 (m, 2H), 0.87 (d, J= 3.9 Hz, 3H), 0.85 (d, J= 3.9 Hz, 3H); 13C NMR (101 MHz, CDC13) δ 175.03, 159.10, 130.63, 129.14, 113.62, 76.16, 70.71, 55.11, 52.64, 51.25, 36.58, 27.97, 26.00, 22.69, 22.17, 17.08; ESIMS m/z 331 ([M+Na]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With CSA In dichloromethane at 20℃; Inert atmosphere; | 2 Manufacturing Example 2 Preparation of Methyl 2-(3,4-dimethoxyphenyl)-3-(4-methoxybenzyloxy)propanoate (33) p-methoxybenzyl 2,2,2-trichloroacetamidate (84 mg, 0.30 mmol) and CSA (catalytic amount) were added to anhydrous CH2Cl2 solution (1.0 mL) containing the aldol product (36 mg, 0.15 mmol) prepared above at room temperature. The reaction mixture was stirred under argon atmosphere overnight, followed by filtering. The resultant filter cake was washed with CH2Cl2. The filtrate was extracted with saturated NaHCO3 solution and brine. The organic layer was dried over MgSO4, filtered, and then evaporated. Then, the residue was purified by flash column chromatography (EtOAc:n-hexane=1:3) to give the compound 33 of Manufacturing Example 2 as a white solid (yield: 100%, 54 mg). [0167] 1H NMR (CDCl3, 500 MHz) δ7.19 (d, 2H, J=8.5 Hz), 6.84 (d, 2H, J=8.5 Hz), 6.78 (m, 3H), 4.46 (AB quartet, 2H, J=33.4, 11.7 Hz), 3.98 (m, 1H), 3.83 (s, 6H), 3.80 (m, 2H), 3.77 (s, 3H), 3.67 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With lanthanum(lll) triflate In toluene at 20℃; for 3h; | To a solution of 10 (1.02 g, 2.1 mmol, 1.0 eq) in toluene (5 mL) were added p-methoxybenzyltrichloroacetimidate (0.78mL, 3.15 mmol, 1.5 eq) and lanthanum triflate (122 mg, 0.21 mmol, 0.1 eq) at room temperature. After stirring at the same temperature for 3 h, the reaction mixture was diluted with ethyl acetate and washed with saturated aq. NaHCO3. The combined organic layers were washed with brine and dried over Na2SO4. Filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate in n-hexane, 0% to 10%) to afford 11 (1.2 g, 96%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With trifluorormethanesulfonic acid In chloroform; cyclohexane at 0℃; for 3h; | Synthesis of (((4-methoxybenzyl)oxy)methyl)diphenylphosphine oxide (7) 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.56 g, 5.53 mmol, 1.2 equiv.) was added to a stirred suspension of (hydroxymethyl)diphenylphosphine oxide (1.1 g, 4.61 mmol, 1 equiv.) in a mixtureof cyclohexane/ CH2Cl2 (2/1 : 8 mL/4 mL) at room temperature. The clear mixture formed wascooled to 0°C and triflic acid (0.04 mL, 0.46 mmol, 0.1 equiv.) added. A white precipitate formedupon standing. The suspension was stirred at 0°C for 3hbefore beingallowed to warm to roomtemperature. The precipitate was filtered, washed with 4mL of CH2Cl2 and the filtrate washed withsaturated aqueous Na2CO3 (10 mL). The aqueous phase was extracted with CH2Cl2 (2 x 5 mLportions). The combined organic layers were washed with brine (20 mL), dried with anhydrousMgSO4, filtered and concentrated under reduced pressure.The crude product was purified by silica gel chromatography(cyclohexane / EtOAC: 4/1 → 2/1 → 1/4 → EtOAc) to afford(((4-methoxybenzyl)oxy)methyl)diphenylphosphine oxide (1.2g, 85% yield) as a white solid.1H NMR (400 MHz, CDCl3)δ ppm 3.79 (s, 3H, CH3O), 4.18 (d, 2H, J P-H= 6.6 Hz, P-CH2O), 4.53(s, 2H, ArCH2O), 6.82 (d, 2H, J = 8.70 Hz, ArH), 7.11 (d, 2H, J = 8.70 Hz, ArH), 7.43-7.48 (m,4H, Ph), 7.51-7.57 (m, 2H, Ph), 7.75-7.80 (m, 4H, Ph).13C NMR (100 MHz, CDCl3)δ ppm 55.07, 67.52 (d, JP-C = 88.18 Hz), 75.21, 113.89, 128.52,128.63, 129.90, 130.83, 131.56, 131.65, 131.83, 132.18, 159.57.31P NMR (162 MHz, CDCl3) δ ppm 28.57.HRMS (APCI) calcd for C21H22O3P (M+H)+, calc.353.1306, obs. 353.1343 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tetrabutyl ammonium fluoride; triphenylcarbenium tetrafluoroborate In tetrahydrofuran at 25℃; for 5h; Reflux; | 3 The required cyclohexenone 10 was prepared enantioselectively from cyclohexadiene 11, as summarized in Scheme 1. Thus, 11 was subjected to Upjohn dihydroxylation (0s04cat., NMO, 50% yield) and the resulting diol 12 was silylated to afford bis-TBS ether 13 (TBSC1, 92% yield). Epoxidation of the latter (mCPBA, 89% yield) led selectively to epoxide 14, whose regioselective opening with (-)-norephedrine-derived amine 15 in the presence of nBuLi fumished allylic alcohol 16 in 94% yield and 89% ee (Maras et aL, 1998; O’Brien et al., 1998; Coleman et a., 1999; deSousa et a., 2002). Protection of this alcohol with 4- methoxybenzyl-2,2,2-trichloroacetimidate (PMBTCA) followed by TBAF-induced desilylation led to PMB-ether diol 17 in 84% yield. Selective oxidation of the allylic alcohol of the latter (TEMPO, pTSA, 74% yield) (Banwell et a., 1994) furnished hydroxyenone 18,whose silylation (TBSC1, 99% yield) led to the targeted key building block enone 10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 24h; | 2 Compound 2 (82g, 0.286mol) was dissolved in dichloromethane (820 mL), stirred and dissolved, 4-methoxybenzyl-2,2,2-trichloroacetimidate (192g, 80%, 0.544mol ) and CSA (6.64g, 0.0286mol) were added, after the addition was completed, the reaction was stirred well at room temperature, a saturated sodium bicarbonate solution was added after 24h (200mL), stirred well and extracted with dichloromethane until the aqueous layer was checked by TLC, the combined organic layers was washed with saturated brine (400mL), dried over anhydrous sodium sulfate, and concentrated by rotary evaporation and purified by column chromatography to obtain product 3 (100g, 86% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With camphor-10-sulfonic acid In dichloromethane at 20℃; | 31 (R)-methyl 3-(4-methoxybenzyloxy)tetradecanoate To a solution of compound 30 (3.50 g, 12.9 mmol) and 4-methoxybenzyl trichloroacetimidate (4.65 g, 17.3 mmol) in DCM (100 mL) was added camphorsulfonic acid (450 mg, 1.92 mmol). The mixture was stirred overnight at room temperature. The mixture was washed with a saturated solution of NaHCO3(300 mL) and water (300 mL) and dried over Na2SO4. The drying agent was removed by filtration and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (120 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 70 min, 85 mL/min) to give the product 32 (4.01 g, 81%) as a colorless liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With (1S)-10-camphorsulfonic acid In dichloromethane at 20℃; for 12h; Inert atmosphere; | 4.2.2. (3R)-N-Methoxy-3-((4-methoxybenzyl)oxy)-N-methylbutanamide (8) To a solution of freshly prepared 4-methoxybenzyl trichloroacetimidate (35.2 g, 125 mmol) in CH2Cl2 (230 ml), a solution of alcohol 7 (3.67 g, 24.9 mmol) in CH2Cl2 (20 ml) and (+)-10-camphorsulfonic acid (2.89 g, 12.5 mmol) was successively added at 0 °C in an argon atmosphere. After 12 h of stirring at room temperature, the reaction mixture was poured into a saturated aqueous NaHCO3 solution at 0 °C and extracted with ethyl acetate. The combined organic layer was washed with a saturated aqueous NaHCO3 solution, water and brine; dried over anhydrous MgSO4; and concentrated in vacuo. The residue was filtrated through a Celite pad and subjected to chromatography over silica gel. The elution with hexanes-ethyl acetate (3/1) produced 8 (5.83 g, 87%) as a slightly yellow oil: [α]D25 = +3.3 (c 0.1, CHCl3); IR (film): ν = 2969, 2937, 2838, 1661 cm-1; 1H NMR (400 MHz, CDCl3, δ): 1.25 (3H, d, J = 6.0 Hz), 2.45 (1H, dd, J = 15.1, 6.0 Hz), 2.88 (1H, m), 3.19 (3H, s), 3.66 (3H, s), 3.79 (3H, s), 4.08 (1H, ddq, J = 6.0, 6.0, 6.0 Hz), 4.45 (1H, d, J = 11.0 Hz), 4.50 (1H, d, J = 11.0 Hz), 6.82-6.85 (2H, m), 7.22-7.28 (2H, m); 13C NMR (100 MHz, CDCl3, δ): 20.2, 32.0, 39.3, 55.2, 61.3, 70.7, 72.0, 113.7, 129.2, 130.9, 159.1, 172.4; ESI-TOFMS m/z calcd. For C14H21NNaO4+ [M+Na]+ 290.1363, we found 290.1366. |
62% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 22.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With copper(II) bis(trifluoromethanesulfonate) In toluene at 23℃; for 6h; Inert atmosphere; | 6 (8S,1OS)-4-Bromo-2,2-di-tert-butyl-1O-[tert-butyl(dimethyl)silyl]oxy}-7-methoxy-8- [(4-methoxy-benzyl)oxyj-5-methyl-9,1O-dihydroanthra[1,9-dej[1,3,2jdioxasilin-11(8H)-one (13): To a stirred solution of 23 (21.4 mg, 0.0335 mmol, 1.0 equiv) in toluene (0.5 ml) at 23 °C were added a solution of freshly prepared 4-methoxybenzyl-2,2,2-trichloroacetimidate (22 mg, 0.077 mmol, 2.3 equiv) in toluene (0.2 ml) and Cu(OTf)2 (2.0 mg, 0.0055 mmol, 0.2 equiv). The resulting mixture was stirred at this temperature for 6 h before it was directly subject to a flash column chromatography (silica gel, EtOAc:hexanes 1 : 10) to afford the title compound (13, 17.8 mg, 0.0235 mmol, 70%) as a colorless oil together with the recovered starting material (4.8 mg, 0.0075 mmol, 22%). 13: [α]5=+37.5 (c = 0.6, CH2CI2); Enantiomeric ratio of 13 was determined by HPLC (Chiralcel OD-H, 25 °C, flow rate: 1 mL/min, hexanes/isopropanol: 99/1, 254 nm) as 54: 1. Other physical and spectral data are identical with those reported in the previous route. |
22% | With copper(II) bis(trifluoromethanesulfonate) In toluene at 23℃; for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With pyridinium p-toluenesulfonate In dichloromethane at 0 - 20℃; for 2h; | tert-butyl(((2S,3R,E)-5-iodo-1-((4-methoxybenzyl)oxy)-2-methylhex-4-en-3-yl)oxy)dimethylsilane (10) To a stirred solution of 19 (1.40 g, 3.78 mmol) in DCM (12.6 mL) at 0 °C was added PMB imidate (1.57 mL, 7.56 mmol). After 10 min, PPTS (1.90 g, 7.56 mmol) was added to the reaction mixture. After stirred for an hour at °0 C, the reaction mixture was stirred at r.t for 1 h. The reaction mixture was diluted with water (20 mL). The aqueous phase was extracted with DCM (15 mL × 3) and washed with H2O and brine. The combined organic layer was dried with MgSO4 and concentrated in vacuo. The residue was purified via flash column chromatography (EtOAc : Hexane = 1 : 9) to provide 10 (1.75 g, 94 %) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 2.5h; | 38 Example 38 (Production of sugar acceptor 11) Compound (1-20) (123.8 mg, 51.3 μmol) was dissolved in dichloromethane (1.0 ml), 4-methoxybenzyl-2,2,2-trichloroacetimidate (26.1 mg, 92.4 μmol) and CSA (4.3 mg , 18.5 μmol), and the mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, dichloroAfter adding romethane, dilute it, wash with aqueous sodium bicarbonate, extract the aqueous layer with dichloromethane, wash the obtained organic layer with saturated brine, and dry over magnesium sulfate. The organic layer was filtered, the filtrate was concentrated, and the resulting residue was subjected to column purification to obtain a sugar acceptor (3a-11) (110.5 mg, yield 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 3h; | 43 Example 43 (Production of sugar acceptor 12) Compound (1-24) (56.6 mg, 15.6 μmol) was dissolved in dichloromethane (2.7 ml) and 4-methoxybenzyl-2,2,2-trichloroacetimidate (8.6 mg, 31.1 μmol) and CSA (1.8 mg, 7.8 μmol), and the mixture was stirred at room temperature for 1.5 hours. Further, 4-methoxybenzyl-2,2,2-trichloroacetimidate (13.6 mg, 47.9 μmol) and CSA (3.3 mg, 14.3 μmol) were added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 4-methoxybenzyl2,2,2-trichloroacetimidate (13.6 mg, 47.9 μmol) and CSA (5.1 mg, 22.0 μmol), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate, and the aqueous layer was extracted with dichloromethane. The obtained organic layer was washed with saturated brine and then dried over magnesium sulfate. The organic layer was filtered, the filtrate was concentrated, and the resulting residue was subjected to column purification to obtain a sugar acceptor (3a-12) (48.2 mg, yield 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 7.33h; | 7 Example 7 (Production of sugar acceptor 1) Compound (9-1) (91.3 mg, 92.8 μmol) was dissolved in dichloromethane (1 ml)4-Methoxybenzyl-2,2,2-trichloroacetimidate (43.1 mg, 152 μmol) and CSA (4.8 mg, 20.4 μmol) were added, and the mixture was stirred at room temperature for 7 hours. Further, 4-methoxybenzyl- 2,2-Trichloroacetimidate (25.0 mg, 88.5 μmol) was added and the reaction was further carried out for 20 minutes. Thereafter, the reaction mixture was diluted with dichloromethane, washed with an aqueous sodium bicarbonate solution, and the aqueous layer was extracted with dichloromethane. The obtained organic layers were combined, washed with a saturated saline solution, and dried over magnesium sulfate. The organic layer was filtered, the filtrate was concentrated, and the resulting residue was subjected to column purification to obtain a sugar acceptor (3a-1) (92.2 mg, yield 90%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 3h; | 10 Example 10 (Production of sugar acceptor 4) Compound (9-2) (179.7 mg, 143.3 μmol) was dissolved in dichloromethane (1.4 ml), 4-methoxybenzyl-2,2,2-trichloroacetimidate (25.4 mg) and CSA (6.7 mg, 28.66 μmol ) Was added and the mixture was stirred at room temperature for 2 hours, 4-methoxybenzyl-2,2,2-trichloroacetimidate (25.4 mg, 89.9 μmol) was further added and the reaction was carried out for 1 hour. Dilute by adding dichloromethane, wash with aqueous sodium bicarbonate, extract aqueous layer with dichloromethane, obtainThe organic layer was washed with saturated brine and then dried over magnesium sulfate. The organic layer was filtered, the filtrate was concentrated, and the resulting residue was subjected to column purification to obtain a sugar acceptor (3a-4) (166.7 mg, yield 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With trifluorormethanesulfonic acid In dichloromethane; cyclohexane; N,N-dimethyl-formamide at 0 - 20℃; for 16h; | 2.2.34 Example 2.34-Intermediate Compound (4R,5R)-3-bromo-4-hydroxy-5-(((4-methoxybenzyl)oxy)methyl)-3-methyldihydrofuran-2(3H)-one. To a solution of lactones (2.01 g, 8.92 mmol) in DCM/Cyclohexane (1:2, 90 mL, 0.1 M) with DMF (a3 mL) at 0 °C was added 4-methoxybenzyl-2,2,2-trichloroacetimidate (2.04 mL, 9.81 mmol) and TfOH (78.7 PL, 0.892 mmol) dropwise. The mixture was warmed to room temperature, stirred for 16 hours and quenched with Et3N (187 PL, 1.34 mmol) at 0 °C. After 10 minutes, the reaction was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (Hexanes/Et2O, 30:70) to give the products (2.60 g, 84% yield) as a pale yellow solid in a a16:1 ratio. Rf = 0.25 (Hexanes/Et2O, 30:70); Formula: C14H17BrO5; MW: 345.19 g/mol; IR (neat) νmax 3435, 2931, 2866, 1782, 1513 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.26 (d, J = 8.6 Hz, 4Ha,b), 6.90 (d, J = 8.6 Hz, 4Ha,b), 4.71 (d, J = 6.0 Hz, 2Hb), 4.53 (d, J = 2.0 Hz, 2Ha), 4.35 (dt, J = 5.9, 4.9 Hz, 1Hb), 4.25 (ddd, J = 8.3, 4.0, 2.8 Hz, 1Ha), 3.85 (dd, J = 11.5, 2.8 Hz, 2Ha), 3.82 (s, 6Ha,b), 3.80- 3.77 (m, 3Hb), 3.74 (dd, J = 11.5, 4.0 Hz, 1Ha), 1.95 (s, 3Ha), 1.87 (s, 3Hb) ppm (Labile protons were not observed due to exchange with deuterated solvent); 13C NMR (125 MHz, CDCl3) δ 171.5, 159.5, 129.5 (2C), 129.3, 113.9 (2C), 81.5, 74.3, 73.4, 66.1, 61.7, 55.3, 24.0 ppm; HRMS calcd for: C14H17BrNaO5 [M+Na]+: 367.0152; found 367.0151 (-0.21 ppm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With camphor-10-sulfonic acid In dichloromethane at 20℃; for 12h; Inert atmosphere; | (S)-1-((tert-Butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)hex-5-ene (35)36c,37 A solution of alcohol 34 (100 mg, 0.43 mmol) and 4-methoxybenzyl2,2,2-trichloroacetimidate30 (182 mg, 0.645 mmol) in anhydrous CH2- Cl2 (3 mL) was treated with CSA (1 mg, 0.0043 mmol). The reaction mixture was stirred at r.t. for 12 h and then quenched with H2O (2 mL). The layers were separated and the aqueous layer was extracted with Et2O (3 × 2 mL). The combined organic layers were washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated in vacuo. The crude ether was purified by flash chromatography (petroleum ether/Et2O, 2:1) to give pure 35 (98 mg, 64%) as a colorless oil. [α]D 20 +8.5 (c 1.0, CH2Cl2); Rf = 0.81 (petroleum ether/Et2O, 2:1). 1H NMR (400 MHz, CDCl3): δ = 0.00 (s, 6 H, Si(CH3)2), 0.85 (s, 9 H, SiC(CH3)3), 1.60-1.76 (m, 2 H, 2-H), 2.13-2.22 (m, 1 H, 4-H), 2.28 (t, J = 5.9 Hz, 1 H, 4-H), 3.44-3.48 (m, 1 H, 3-H), 3.55-3.69 (m, 2 H, 1-H), 3.73 (s, 3 H, OCH3), 4.38 (d, J = 10.9 Hz, 1 H, OCH2Ar), 4.39 (d, J = 10.9 Hz, 1 H, OCH2Ar), 4.96-5.06 (m, 2 H, 6-H), 5.71-5.85 (m, 1 H, 5-H), 6.81 (dd, J = 6.6, 2.3 Hz, 2 H, Haromat), 7.20 (dd, J = 8.6, 3.3 Hz, 2 H, Haromat). 13C NMR (100 MHz, CDCl3): δ = -5.4 (Si(CH3)2), 18.2 (SiC(CH3)3), 25.9 (SiC(CH3)3), 37.2 (C-2), 38.5 (C-4), 55.1 (OCH3), 59.6 (C-1), 70.8 (OCH2Ar), 75.1 (C-3), 113.7 (Caromat), 116.9 (C-6), 129.2 (Caromat), 130.9 (Caromat), 134.9 (C-5), 159.0 (Caromat). HRMS (ESI-TOF): m/z [M + Na]+ calcd for C20H34O3Si: 373.21694; found: 373.21735. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 18h; | General procedure for C3-monoalkylation of indoles General procedure: In a flame dried flask, the imidate (1.0 equiv) was dissolved in anhydrous DCM (0.3M). The indole (2.0equiv) was then added. To this solution, freshly distilled TMSOTf (0.2 equiv) was added and the resultingmixture was stirred at room temperature for 18 h. The reaction mixture was then quenched with 10 mL1M NaOH. The organic layer was separated and the aqueous layer was extracted with DCM (3 x 5 mL).The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue waspurified by silica gel chromatography using the solvent systems listed for each compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With toluene-4-sulfonic acid In dichloromethane at 40℃; for 12h; Inert atmosphere; | |
91% | With p-toluenesulfonic acid monohydrate In dichloromethane at 40℃; | 10 Example 10 Compound 6 (731 mg, 3.6 mmol, 1.0 equiv.) was dissolved in dichloromethane (20 mL).4-methoxybenzyl-2,2,2-trichloroacetimidate (1.6 mL, 7.3 mmol,) was added to the reaction system at room temperature.2.0equiv.)And TsOH.H2O (62 mg, 0.36 mmol, 0.1 equiv.), and the reaction was heated to 40 ° C and stirring was continued overnight.After the reaction,Triethylamine (0.5 mL) was added to the reaction system to quench the reaction, and the reaction solution was directly concentrated under reduced pressure by a vacuum pump.And separated by flash column chromatography (ethyl acetate / n-hexane = 1:2).Obtaining a colorless viscous oily compound 20(1.1g, 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; for 6h; | p-Methoxybenzyl trichloroacetimidate (61.4 g, 217 mmol)and p-toluenesulfonic acid monohydrate (3.50 g, 18.4mmol) were added to a solution of 2 (12.0 g, 7.07 mmol) indichloromethane (300 mL) at 0 °C. After stirring at room temperature for 6 h, the reaction was quenched with saturatedsodium hydrogen carbonate solution in water anddichloromethane extraction was performed three times. Thecombined organic phases were washed with saturatedaqueous sodium chloride solution once, dried over sodiumsulfate, and filtrated, then the solvent was removed underreduced pressure and the resultant residue was purified byflash column chromatography on neutral silica gel(20-70% ethyl acetate in hexane) to produce the dimethoxybenzylcompound 3 (11.15 g, 81%) as apale yellow amorphous substance. Palladium on carbon(10 wt%, 3.70 g) was added to a solution of 3 (11.1 g, 8.30mmol) in tetrahydrofuran (70 mL) and water (50 mL) underan argon atmosphere. The flask was evacuated and purgedwith hydrogen gas five times on a hydrogen manifold, thenthe mixture was stirred under a hydrogen atmosphere atroom temperature for 4 h. After complete conversion(monitored by thin layer chromatography), the catalyst wasremoved by filtration through celite, which was washedwith tetrahydrofuran and water. The filtrate was used in thenext reaction without further purification. p-Nitrobenzyloxycarbonylchloride (4.21 g, 19.5 mmol) and sodiumcarbonate (2.07 g, 19.5 mmol) were added to the filtrate of4 at 0 °C. After stirring at 0 °C for 0.5 h, the reactionmixture was quenched with aqueous potassium hydrogensulfate solution and ethyl acetate extraction was performedthree times. The combined organic phases were washedwith water three times and with saturated aqueous sodiumchloride solution once, dried over sodium sulfate, and filtrated.The solvent was removed under reduced pressureand the resultant residue was purified by flash columnchromatography on neutral silica gel (0-30% methanol inethyl acetate) to produce the carboxylic acid 5 (7.79 g,80%) as a pale yellow amorphous substance. Potassiumcarbonate (4.63 g, 33.5 mmol) was added to a solution of 5(7.79 g, 6.64 mmol) in methanol (380 mL) at room temperature.After stirring at room temperature for 4 days, thepH of the reaction mixture was adjusted to 4 using Dowex50W (H+ form), then the mixture was filtered. Theremaining Dowex 50W was washed with 5% aqueousammonium solution. The combined filtrate was concentratedin vacuo and the resultant residue was used forthe next step without further purification. Diazodiphenylmethane(3.00 g, 15.4 mmol) and acetic acid (0.5 mL)were added to a solution of the resulting residue of 6 indichloromethane (100 mL) at room temperature. Afterstirring at room temperature for 0.5 h, the solvent wasremoved under reduced pressure and the resultant residuewas purified by flash column chromatography on neutralsilica gel (20-100% ethyl acetate in hexane) to produce thetitle compound (2.93 g, 53%) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridinium p-toluenesulfonate In dichloromethane at 0 - 20℃; Inert atmosphere; | 3.2.7. (Z)-9-(t-Butyldimethylsilyloxy)-3-[2-(4-methoxybenzyloxy)ethyl]-6-methylnon-5-en-1-yne (16) Under Ar atmosphere, to a solution of 15 (500 mg, 1.61 mmol) and PPTS (204 mg, 0.812 mmol) in CH2Cl2 (15 mL) was added a solution of 4-methoxybenzyl 2,2,2-trichloroacetimidate (1.00 g, 3.54 mmol) in CH2Cl2 (10 mL) at 0 °C. The mixture was allowed to slowly warm to room temperature and stirred overnight. After completion of the reaction, the reaction mixture was poured into saturated NaHCO3 solution, and the mixture was extracted with CH2Cl2. Combined organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel. Elution with hexane/ethyl acetate (25:1) gave 16 (680 mg, 1.58 mmol, 98%) as a colorless oil. nD24 1.4928. IR (film): νmax (cm-1) 3308, 2953,1613, 1514, 1463, 1250, 1173, 1099, 837, 776, 633. 1H NMR (400 MHz, CDCl3): δ (ppm) 0.05 (6H, s), 0.90 (9H, s), 1.55-1.70 (3H, m), 1.71 (3H, s), 1.80 (1H, m), 2.03 (1H, d, J = 2.0 Hz), 2.03-2.08 (2H, m), 2.20 (2H, t, J = 7.2 Hz), 2.56 (1H, m), 3.56-3.63 (4H, m), 3.80 (3H, s), 4.44 (2H, s), 5.23 (1H, t, J = 7.2 Hz), 6.88 (2H, d, J = 8.0 Hz), 7.27 (2H, d, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3): δ (ppm) 5.3, 18.3, 23.5, 26.0, 28.3, 28.7, 31.2, 33.1, 34.4, 55.3, 62.9, 67.9, 69.4, 72.7, 87.2, 113.7,122.0, 129.2, 130.7, 137.1, 159.1. HRMS (DART-TOFMS): m/z calcd. for C26H43O3Si [M + H]+ 431.2976, found 431.2974. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With camphor-10-sulfonic acid In dichloromethane at 0 - 20℃; for 20h; | tert-butyl(((3R,4R)-4-((4-methoxybenzyl)oxy)-1-phenylhex-5-en-3-yl)oxy)dimethylsilane (15): p-Methoxybenzyl trichloroacetimidate (0.17 g, 0.6 mmol) and then camphorsulfonic acid (0.014 g, 0.6 mmol) were added to a solution of alcohol 14 (0.10 g, 0.3 mmol) in dichloromethane (5 mL). After 20 h, the reaction mixture was diluted with diethyl ether and then treated with NaHCO3. After extraction withdiethyl ether, organic phases were dried over Na2SO4, filtered and concentrated. Crude product waspurified on silica gel using petroleum ether:diethyl ether (9:1) to furnish the pure product 15 (0.1 g, 75 % ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With zinc trifluoromethanesulfonate In diethyl ether at 20℃; for 24h; | Preparation of 9 To a stirred solution of 3-phenyl-1-propanol (6a) (19.6 mg, 144 μmol), PMB-TCAI (48.9 mg, 173μmol) in Et2O (1 mL) was added Zn(OTf)2 (5.2 mg, 14.4 μmol) at rt. After being stirred for 24 h at rt, thereaction mixture was concentrated. The residue was purified by column chromatography (SiO2 of 2.0 g,hexane/EtOAc = 1/1 to 25/1) to give 9 (31.7 mg, 87%) as a colorless oil. The 1H NMR spectral data of 9was in good agreement with the literature data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With toluene-4-sulfonic acid In dichloromethane at 23℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | 4.1.4 3,6-anhydro-2-deoxy-4,5-O-(1-methylethylidene)-7-O-(p-methoxybenzyl)-d-ribo-heptanoic acid methyl ester 9 To a solution of 4 (100mg, 0.40mmol) in dry dichloromethane (5mL), 225mg of 4-methoxybenzyl 2,2,2-trichloroacetimidate (2eq., 0.80mmol) were added under inert atmosphere. The reaction mixture was cooled at 0°C and 2µL of BF3.OEt2 (0.04eq, 0.016mmol) were added and the mixture was stirred overnight a room temperature. After 16h, the catalyst was filtered off through a Celite pad and the solvent was removed under vacuum. The crude product was purified by flash chromatography on silica gel (eluent: cyclohexane/EtOAc 100/0 to 60/40) to afford compound 9 (110mg). Yield: 75 %; colorless gum; Rf=0.40 (cyclohexane/EtOAc 8/2); [α]D25 -4.6 (c=0.11, CHCl3); IR (film): ν 3370, 2936, 1732, 1670, 1610, 1512, 1458, 1373, 1301, 1246cm-1; 1H NMR (CDCl3, 400MHz): δ 1.31 (s, 3H, CH3), 1.46 (s, 3H, CH3), 2.69 (dd, 2H, J2a,2b=16.5Hz, J2a,3=7.0Hz, H-2a), 2.74 (dd, 2H, J2b,3=6.5Hz, H-2b), 3.46-3.51 (m, 2H, H-7), 3.70 (s, 3H, OCH3), 3.80 (s, 3H, Ar-OCH3), 4.16 (app t, 1H, J6,7a=J6,7b=4.5Hz, H-6), 4.40-4.47 (m, 1H, H-3), 4.42 (d, 1H, J=11.5Hz, CH2Ph), 4.47 (d, 1H, J=11.5Hz, CH2Ph), 4.72-4.76 (m, 2H, H-4, H-5), 6.87 (bd, 2H, J=8.5Hz, H-Ar), 7.22 (bd, 2H, J=8.5Hz, H-Ar); 13C NMR (CDCl3, 100.6MHz): δ 25.1 (CH3), 26.3 (CH3), 34.7 (C-2), 51.9 (OCH3), 55.4 (OCH3), 70.5 (C-7), 73.2 (CH2Ph), 78.1 (C-3), 81.7, 82.8, 83.3 (C-4, C-5, C-6), 112.5 (C(CH3)2), 114.0 (2CAr), 129.3 (2CAr), 130.0 (CqAr), 159.4 (CqAr), 172.0 (C=O). HRMS (ESI): calcd for C19H26NaO7 [M+Na]+: 389.157, found: 389.1590. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridinium p-toluenesulfonate In dichloromethane at 0 - 20℃; for 48h; Inert atmosphere; | N3-[2-(3,5-Dinitrobenzoyloxy)ethyl]-N5-(4-methoxybenzyloxy)methyl-N1-tosyluracil (S11) 2 M HCl (50 μL) was added to a solution of S10 (32.4 mg, 50 μmol) in THF (1.25 mL) at 0 °C, and then the mixture was stirred at rt for 5 h. The mixture was partitioned between EtOAc and H2O. The organic layer was wash with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (n-hexane/EtOAc, 3:1~1:1) to give N3-[2-(3,5-dinitrobenzoyloxy)ethyl]-N5-hydroxymethyl-N1-tosyluracil as a colorless solid (23.4 mg, 88%). p-Methoxybenzyl 2,2,2-trichloroacetimidate (PMB-TCAI) (678 μL, 3.25 mmol) and pyridinium p-toluenesulfonate (PPTS) (186 mg, 740 μmol) were added to a suspension of N3-[2-(3,5-dinitrobenzoyloxy)ethyl]-N5-hydroxymethyl-N1-tosyluracil (793 mg, 1.48 mmol) in CH2Cl2 (34 mL) at 0 °C, and then the mixture was stirred at rt for 48 h. After the reaction mixture was diluted with EtOAc, saturated aqueous NaHCO3 solution was added. The mixture was partitioned between EtOAc and H2O. The organic layer was wash with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CHCl3) to give S11 as a colorless solid (899 mg, 93%). |
Tags: 89238-99-3 synthesis path| 89238-99-3 SDS| 89238-99-3 COA| 89238-99-3 purity| 89238-99-3 application| 89238-99-3 NMR| 89238-99-3 COA| 89238-99-3 structure
[ 81927-55-1 ]
Benzyl 2,2,2-trichloroacetimidate
Similarity: 0.85
[ 81927-55-1 ]
Benzyl 2,2,2-trichloroacetimidate
Similarity: 0.85
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P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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