4.2.4 Synthesis of methyl (S)-2,3-dihydroxypropionate (14): concentrated sulfuric acid (4.1 mL, 7.5 g) was slowly added to a solution of L-serine (12 g, 110 mmol) in water (150 mL) at 0°C. Subsequently, a solution of NaNO2 (6.8 g, 99 mmol) in water (75 mL) was added dropwise over 24 hours. The reaction system was again cooled to 0°C, a pre-cooled solution of concentrated sulfuric acid (3.3 mL, 6.0 g) in water (20 mL) was added, and a solution of NaNO2 (6.8 g, 99 mmol) in water (75 mL) was again added dropwise over the next 24 hours. The reaction mixture was continued to be stirred at room temperature for 24 hours. After the reaction solution was concentrated under vacuum to about 1/3 of the original volume, aqueous NaOH (3.8 g, 95 mmol) was added. Next, methanol (100 mL) and acetone (30 mL) were added and the insoluble material was removed by filtration. After evaporation of the filtrate, the residue was dissolved in methanol (100 mL). To this solution was added trimethyl orthoformate (75 mL) and p-toluenesulfonic acid (1.9 g, 10 mmol) and the mixture was heated to reflux for 16 hours. Upon completion of the reaction, the reaction was quenched by the addition of saturated aqueous NaHCO3 and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried with anhydrous Na2SO4, filtered and the solvent was removed in vacuum. The residue was purified by fast column chromatography (column diameter 8 cm, height 15 cm, eluent volume 65 mL, cyclohexane/ethyl acetate = 1:2, Rf = 0.17) to afford the colorless oily product 14 (3.0 g, 25 mmol, 23% yield). The product was characterized as follows:[α]D20 = -2.5 (c=1.1, methanol); 1H NMR (CDCl3): δ=3.84 (s, 3H, CO2CH3), 3.85 (dd, J=11.7/3.9 Hz, 1H, HOCHCH2OH), 3.91 (dd, J=11.7/3.3 Hz, 1H HOCHCH2OH), 4.28 (t, J=3.6 Hz, 1H, HOCHCH2OH); 13C NMR (CDCl3): δ=53.1 (CO2CH3), 64.1 (HOCHCH2OH), 71.6 (HOCHCH2OH), 173.6 (CO2CH3); IR (pure): ν=3402. 2955, 1732, 1439, 1215, 1115, 1061, 1007, 972, 648 cm-1; HRMS (m/z): [M+H]+ calculated value C4H9O4, 121.0495; measured value, 121.0517.
