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Horner-Wadsworth-Emmons (HWE) Reaction - 01

 

 

Trimethyl phosphonoacetate (78.6 mL, 485 mmol) was added to a 0 ℃ solution of 4-(4-hydroxyphenyl)cyclohexanone A-1 (76.9 g, 404 mmol) in tetrahydrofuran (3.0 L) in a flame-dried 5.0 L 3-neck round bottom flask equipped with mechanical stirrer and placed under an atmosphere of nitrogen. Sodium hydride (60% in mineral oil, 37.2 g) was added portionwise so that the internal temperature was maintained below 10 ℃. The reaction mixture was stirred at 0 ℃ for 20 minutes and slowly warmed to R.T. and stirred for additional 2.5 h. After disappearance of starting material on TLC (EtOAc:Hexanes 3:7), the reaction mixture was quenched with water (200 ml), then concentrated under reduced pressure to a volume of ca. 1.5 L and diluted with water (500 ml). The aqueous layer was extracted with ethyl acetate (3 x 800 mL). The combined extracts were dried with anhydrous sodium sulfate and magnesium sulfate, filtered, and concentrated to give methyl 2-(4-(4-hydroxyphenyl)cyclohexylidene) acetate A-2. White solid, yield 110.0 g, 100%.

 

10.1021/ml400527n

 

 

To an ice-cooled solution of ethyl diethylphosphonoacetate (9.45 g, 42.1 mmol) in tetrahydrofuran (50 mL) was added sodium hydride (60% oil suspension, 1.54 g, 38.5 mmol) and the mixturewas stirred for 15 min. A solution of 2-fluoro-4-methoxybenzaldehyde (5.00 g, 32.4 mmol) in tetrahydrofuran (30 mL) was added dropwise. The mixture was stirred at room temperature for 2 hrs. and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (7.07 g, yield 97%) as a colorless oil. Reference Example 38. tert-butyl (2E)-3-[4-(benzyloxy)phenyl]acrylate. The title compound was obtained as colorless crystals from 4-(benzyloxy)benzaldehyde and tert-butyl diethylphosphonoacetate according to a method similar to the method of Reference Example12 (yield 94%).

 

WO2005063729A1

 

 

A stirred ice-cold suspension of NaH (1.19 g, 24.8 mmol) in 50 mL of dry THF, maintained under a nitrogen atmosphere, was treated with diethyl (cyanomethyl)-phosphonate (4.39 g, 24.8 mmol, Aldrich). When the evolution of hydrogen was over (ca. 20 min), a solution of benzylated vanillin 13 (5.00 g, 20.7 mmol) in 15 mL of dry THF was added dropwise, and the resulting mixture was stirred at 0 ℃ for 1.5 h. The reaction mixture was then filtered through a pad of TLC-grade silica gel and washed several times with Et2O. Evaporation of the solvents afforded 14 as a white solid, which was used without any further purification (5.47 g, quantitative yield).

 

10.1021/jo020010d

 

 

A solution of aldehyde 95 (4.02 g, 7.9 mmol) in THF (20 mL) was added at 0 ℃ to a stirred mixture of NaH (417 mg, 10.3 mmol) and phosphonate 96 (2.20 mL, 10.3 mmol) in THF (80 mL). The mixture was stirred for 1.5 h at rt, before sat. aq. NH4Cl and Et2O (each 100 mL) were added. The layers were separated, the aq. layer was extracted with Et2O (3 x 80 mL), the combined organic solutions were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography (hexanes - EtOAc, 2 : 1) to yield amide 97 (4.32 g, 92%) as a colorless oil. 

(2E,7E,5S,6S)-5-(tert-Butyldiphenylsilanyloxy)-6-(methoxymethoxy)-8-[(2S)-4-methyl-3,6-dihydro-2H-pyran-2-yl]-octa-2,7-dienoic N-methoxy-N-methyl-amide (97), yield (4.32 g, 92%) .

 

10.1021/jo026743f

 

■ Z選択的な条件

 

通常の HWE 反応は、E選択的に反応が進行する。

一方で、特殊なホスホン酸ジエステルを用いると、

Z選択的に反応が進行するようになる。

 

・Still-Gennari法10.1016/S0040-4039(00)85909-2

 

 

To a solution of (CF3CH2O)2P(O)CH2CO2Me (4.09 mL, 19.3 mmol) and 18-crown-6 (17.0 g, 64.3 mmol) in anhydrous THF (100 mL) at -78 ℃ was added KHMDS (0.5 M in toluene, 38.5 mL, 19.3 mmol) dropwise. After stirring for 20 min at the same temperature, a solution of aldehyde 15 (3.83 g, 12.8 mmol) in anhydrous THF (140 mL) was added dropwise via cannula. Thereaction was allowed to warm to 0 ℃ over 3 hrs and quenched with sat. NH4Cl (250 mL). The resulting solution was extracted with EtOAc (350 mL) and the organic layer was washed with H2O, brine, dried (Na2SO4) and concentrated. Purification by silica-gel chromatography (hexane/EtOAc, 1/1) provided Z-enolate 7 (4.32 g, 95%) as a yellow oil.

 

10.1021/ol061267r

 

・安藤法 (10.1021/jo970057c)

 

 

(PhO)2P(O)CH2CO2Et (260 mg, 0.810 mmol) was added to a suspension of NaH (60% in oil) (35.1 mg, 0.878 mmol) in THF (5 mL) with stirring at 0 ℃ and the stirring was continued at this temperature for 15 min. Then, a solution of the (E)-aldehyde (150 mg, 0.675 mmol) in THF (1 mL) was added to the mixture and the whole was stirred at rt for 1 h. The reaction was quenched with saturated NH4Cl and the mixture was extracted with EtOAc. The extract was washed with brine prior to drying and solvent evaporation. The residue was chromatographed on silica gel with hexane.EtOAc (1:1) to give 1b (159 mg, 80%) and (2E)-isomer of 1b (20.9 mg, 10%) each as a yellow oil. Ethyl (2Z,6E)-7-[(R)-(p-Tolylsulfinyl)]-2,6-heptadienoate (1b), yield (159 mg, 80%).

 

10.1021/jo0492923

 

■ ルイス酸による活性化

 

ルイス酸を系中に共存させると、

ルイス酸がホスホン酸ジエステルの酸素原子に配位し、

活性プロトンがさらに活性化される。

その結果、比較的弱い塩基でも、脱プロトン化が生じるようになる。

 

・Roush-正宗法

 

 

A solution of aldehyde 5 (0.25g, 0.65 mmol), LiCl (0.03 g, 1.21 mmol), trimethylphosphonoacetate (0.11 mL, 0.71 mmol) and DBU (0.19 mL, 1.21 mmol) in CH3CN (10 mL) was stirred under a N2 atmosphere at RT for 2 h. The reaction mixture was partitioned between 2 M HCl (15 mL) and EtOAc (20 mL). The organic layer was separated, washed with sat. NaHCO3 (15 mL), brine (15 mL), dried (Na2SO4) and the volatiles were removed in vacuo to give a crude ester 6. Yield 0.31g, 99%.

 

WO2012003414

 

・亜鉛による活性化

 

 

Phosphonate (0.10 g, 0.52 mmol, 1 equiv) was added along with anhyd THF (1.5 mL) to a flask containing Zn(OTf)2 (2.2 equiv, 0.42 g, 1.2 mmol). TMEDA (0.09 mL, 0.63 mmol) was added. DBU (0.31 mL, 4 equiv, 6.3 mmol) was added followed by aldehyde (1.1 equiv, 0.58 mmol). The reaction mixture was stirred at 25 ℃ for 12 h under argon. The reaction was quenched with 1 N HCl (5 mL) and extracted with CH2Cl2 (4 × 15 mL). The organic phases were combined and dried over Na2SO4. Solvent was removed in vacuo to yield crude carboxylic acid. A known quantity of mesitylene was added to the crude material. Crude yields were quantified by 1H NMR via comparison of the most upfield olefinic proton signal vs. the aromatic mesitylene signal.

 

10.1055/s-2006-950292

 

ホーナー・ワズワース・エモンス反応 Horner-Wadsworth-Emmons (HWE) Reaction

 

・「ホスフィンオキシドの除去問題」を回避できる。

 そういう意味で、Wittig 反応より後処理や精製が楽。

 

・様々なホスホン酸ジエステルが市販されているが、

 自前で作る必要がある場合は、Michaelis-Arbuzov 反応により合成する。

 

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