Tetrahydrofuran → HCID 58800312, compound

Participants

Reaction Steps

A solution of (R)-4-oxo-2-(4-dimethylamino-2-methoxyphenyl)-butyric acid methyl ester (288 mg, 1.30 mmol, 1.00 equiv) in CH2Cl2 (0.5 mL) was added to a stirring solution of sodium borohydride (48.3 mg, 1.30 mmol, 1.00 equiv) in ethanol (3.0 mL) at 0° C. After 5 min, the reaction was diluted with saturated aqueous NaHCO3 (15 mL) and CH2Cl2 (15 mL). The organic layer was separated and washed with saturated solutions of NaHCO3 and NaCl. The resulting solution was then dried over Na2SO4 and concentrated in vacuo. The residual oil was exposed to tert-butyldimethylsilyl chloride (392 mg, 2.60 mmol, 2.00 equiv), triethylamine (0.40 mL, 2.9 mmol, 2.2 equiv), and DMAP (10 mg) in CH2Cl2 (2.6 mL). After one hour, the reaction mixture was subjected directly to silica gel chromatography. Elution with 10–50% Et2O in hexanes followed by concentration in vacuo afforded 453 mg of a colorless oil (1.19 mmol, 91% yield from aldehyde). This compound was dissolved in Et2O (5.0 mL) and added to a suspension of lithium aluminum hydride (100 mg, 2.63 mmol, 2.21 equiv) in Et2O (10 mL) at 0° C. After 5 min, this mixture was diluted with saturated aqueous sodium potassium tartrate (50 mL) and Et2O (50 mL) and allowed to stir for an additional 8 h. The organic layer was separated, washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (20–100% EtOAc in hexanes) and concentrated in vacuo to afford 201 mg (0.568 mmol, 48% yield) of a pale yellow oil assigned as S5; [α]D=−20.1 (c=1.00, CHCl3). This substance was treated with methanesulfonyl chloride (0.057 mL, 0.74 mmol, 1.30 equiv), triethylamine (0.12 mL, 0.85 mmol, 1.5 equiv), and DMAP (10 mg) in THF (8 mL). After 2 h, the resulting suspension was carefully added to a stirring suspension of lithium aluminum hydride (108 mg, 2.84 mmol, 5.0 equiv) in THF (10 mL). After 6 h, this mixture was diluted with saturated aqueous sodium potassium tartrate (50 mL) and Et2O (50 mL) and allowed to stir for an additional 3 h. The organic layer was separated, washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (25% EtOAc in hexanes) to afford 99.9 mg of S1 that was spectroscopically identical in all respects to S1 generated above from (R)-3-(4-dimethylamino-2- methoxy-phenyl)-butyraldehyde. [α]D (reference)=−13.3 (c=1.12, CHCl3); [α]D (observed)=−11.6 (c=0.999, CHCl3).

Provenance & Evidence