Ammonia → (R)-4-oxo-2-(4-pyrrolidin-1-yl-phenyl)-butyric acid methyl ester

Participants

Reaction Steps

A solution of (R)-4-oxo-2-(4-pyrrolidin-1-yl-phenyl)-butyric acid methyl ester (2.23 g, 8.53 mmol, 1.00 equiv) in THF (15 mL) was added carefully to a stirring suspension of lithium aluminum hydride (1.27 g, 33.5 mmol, 4.0 equiv) in Et2O (45 mL). After 5 min, this mixture was diluted with saturated aqueous sodium potassium tartrate (100 mL) and Et2O (100 mL) and allowed to stir for an additional 8 h. The organic layer was separated and the aqueous was extracted three times with CH2Cl2. The combined organics were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (100% EtOAc) to afford 1.97 g (8.37 mmol, 98% yield) of a white solid assigned as S17; [α]D=−19.1 (c=1.03, CHCl3). This compound was then exposed to tert-butyldimethylsilyl chloride (2.83 g, 18.8 mmol, 2.20 equiv), triethylamine (2.63 mL, 18.8 mmol, 2.2 equiv), and CH2Cl2 (20 mL). After 7.5 h, the reaction mixture was subjected directly to silica gel chromatography. Gradient elution with 10–20% EtOAc in hexanes followed by concentration in vacuo afforded 3.41 g (7.37 mmol, 86% yield) of a faint-yellow oil. A portion of this substance (1.17 g, 2.53 mmol, 1.00 equiv) was dissolved in CH3I (0.47 mL, 7.6 mmol, 3.0 equiv) and stirred for 48 h and subsequently diluted with Et2O and filtered to provide 1.484 g of a yellow solid. A portion of the ammonium salt (128 mg, 0.200 mmol, 1.00 equiv) was suspended in THF (20 mL) and added to a stirring solution of dissolved sodium (18.4 mg, 0.800 mmol, 4.00 equiv) in freshly condensed liquid ammonia (25 ml) at −78° C. After 30 min, the reaction mixture was quenched with excess methanol, diluted with ether (20 mL) and allowed to warm to ambient temperature. The ethereal solution was washed with aqueous HCl (1N) and saturated NaCl and subsequently dried over Na2SO4. This residue was purified by silica gel chromatography to afford 52.0 mg of S11 (0.132 mmol, 61% yield) that was spectroscopically identical in all respects to the S11 generated above from (R)-4-oxo-2-(4- dimethylamino-phenyl)-butyric acid methyl ester. [α]D (reference)=−22.0 (c=1.08, CHCl3); [α]D (observed)=−22.8 (c=0.92, CHCl3).

Provenance & Evidence