dimethyl (2S)-2-hydroxybutanedioate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl (S)-(−) malate (0.27 mL, 2 mmol) is dissolved in anhydrous N,N-dimethylforamide (8 mL), and powdered cesium carbonate (1.95 g, 6 mmol, 3 eq) is added. The suspension is then stirred at room temperature while passing carbon dioxide gas for 1 hour before benzyl chloride (0.69 mL, 6 mmol, 3 eq) is added to the solution. Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed. The reaction is quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc) to yield 384 mg of the desired dimethyl malate benzyl carbonate (65%): IR (thin film) 3034, 2957, 1746, 1439, 1383, 1216, 1042, 909, 756, 699 cm−1; 1H NMR (360 MHz, CDCl3) d 2.93 (d, 2H, J=6.26 Hz), 3.71 (s, 3H), 3.78 (s, 3H), 5.22 (s, 2H, J=6.08 Hz), 7.34-7.38 (m, 5H); 13C NMR (90 MHz, CDCl3) d 35.60, 51.97, 52.55, 70.00, 71.13, 128.17, 128.43, 153.94, 168.80, 169.10. for 1 hour is added to the solution Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed The reaction is quenched with water (20 mL) extracted with EtOAc (3×20 mL) The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL) dried over anhydrous sodium sulfate Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl (S)-(−) malate (0.27 mL, 2 mmol) is dissolved in anhydrous N,N-dimethylforamide (8 mL), and powdered cesium carbonate (1.95 g, 6 mmol, 3 eq) is added. The suspension is then stirred at room temperature while passing carbon dioxide gas for 1 hour before benzyl chloride (0.69 mL, 6 mmol, 3 eq) is added to the solution. Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed. The reaction is quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc) to yield 384 mg of the desired dimethyl malate benzyl carbonate (65%): IR (thin film) 3034, 2957, 1746, 1439, 1383, 1216, 1042, 909, 756, 699 cm−1; 1H NMR (360 MHz, CDCl3) d 2.93 (d, 2H, J=6.26 Hz), 3.71 (s, 3H), 3.78 (s, 3H), 5.22 (s, 2H, J=6.08 Hz), 7.34-7.38 (m, 5H); 13C NMR (90 MHz, CDCl3) d 35.60, 51.97, 52.55, 70.00, 71.13, 128.17, 128.43, 153.94, 168.80, 169.10. for 1 hour is added to the solution Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed The reaction is quenched with water (20 mL) extracted with EtOAc (3×20 mL) The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL) dried over anhydrous sodium sulfate Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −78° C. solution of 9.09 mL (65 mmol) of diisopropylamine in 100 mL of tetrahydrofuran was added dropwise 40.5 mL (65 mmol) of 1.6 M n-butyl lithium in hexanes. The solution was allowed to warm to 0° C. briefly before being cooled to −78° C. To the solution was added 4.09 mL (30.9 mmol) of dimethyl (S)-(−)-malate dropwise and the resulting solution was allowed to warm to room temperature. After 30 min at room temperature, it was cooled to −78° C. before 2.3 mL (37.1 mmol) of methyl iodide was added dropwise. The solution was allowed to warm to room temperature, and was stirred for 18 h. It was then poured onto a mixture of ether, ice water, and 9.27 mL of acetic acid. The resulting mixture was extracted with ether, and the extracts were combined, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to afford 1.04 g (5.9 mmol) of dimethyl (2S,3S)-2-hydroxy-3-methylbutanedioate. before being cooled to −78° C to warm to room temperature was added dropwise to warm to room temperature The resulting mixture was extracted with ether washed with saturated sodium bicarbonate and brine dried over magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate

Conditions: temp:79.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethylazodicarboxylate (0.254 mL, 1.61 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (0.600 g, 1.10 mmol), dimethyl (S)-(-)-malate (0.213 mL, 1.61 mmol) and triphenylphosphine (0.421 g, 1.61 mmol) in benzene (7.5 mL) under a dry nitrogen atmosphere. The solution was heated in an 79° C. oil bath for 23 h. Additional Dimethyl (S)-(-)-malate (0.043 mL, 0.321 mmol) and triphenylphosphine (0.084 g, 0.321 mmol) and diethylazodicarboxylate (0.050 mL, 0.321 mmol) were added and the reaction mixture was heated for an additional 10 hours. The reaction mixture was cooled to room temperature, diluted with methylene chloride combined with silica gel (20 mL) and concentrated. The silica adsorbate was flash chromatographed (92:8 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.389 g, 51%): mp 118-121° C.: NMR (CDCl3); δ8.36 (dd, J=8, 0.5 Hz, 1 H), 7.83 (dd, J=8, 0.5 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.61 - 7.59 (m, 3 H), 7.55 -7.43 (m, 2 H), 7.26 - 7.21 (m, 1 H), 6.79 (d, J=8 Hz, 1 H), 5.46 (t, J=6 Hz, 1 H), 3.90 (s, 3 H), 3.77 (s, 3 H), 3.32 - 3.30 (m, 1 H); MS (EI): [M+], 3 bromine isotope pattern, 704 (5%), 706 (15%), 708 (15%), 710 (4%); Anal. Calc. for C28H19Br3O5S: C, 47.55, H, 2.71, N, 0.00. Found: C, 47.93, H, 2.65, N, 0.14. the reaction mixture was heated for an additional 10 hours The reaction mixture was cooled to room temperature concentrated chromatographed (92:8 petroleum ether:ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl (S)-(−) malate (0.27 mL, 2 mmol) is dissolved in anhydrous N,N-dimethylforamide (8 mL), and powdered cesium carbonate (1.95 g, 6 mmol, 3 eq) is added. The suspension is then stirred at room temperature while passing carbon dioxide gas for 1 hour before benzyl chloride (0.69 mL, 6 mmol, 3 eq) is added to the solution. Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed. The reaction is quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL), and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc) to yield 384 mg of the desired dimethyl malate benzyl carbonate (65%): IR (thin film) 3034, 2957, 1746, 1439, 1383, 1216, 1042, 909, 756, 699 cm−1; 1H NMR (360 MHz, CDCl3) d 2.93 (d, 2H, J=6.26 Hz), 3.71 (s, 3H), 3.78 (s, 3H), 5.22 (s, 2H, J=6.08 Hz), 7.34-7.38 (m, 5H); 13C NMR (90 MHz, CDCl3) d 35.60, 51.97, 52.55, 70.00, 71.13, 128.17, 128.43, 153.94, 168.80, 169.10. for 1 hour is added to the solution Carbon dioxide gas is continuously bubbled through the solution for another 2˜3 hours until the starting material is consumed The reaction is quenched with water (20 mL) extracted with EtOAc (3×20 mL) The resulting organic layer is washed consecutively with water (3×20 mL), brine (20 mL) dried over anhydrous sodium sulfate Filtration and concentration in vacuo provides an oil, which is purified by column chromatography (9:1 Hexanes-EtOAc)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −78° C. solution of 9.09 mL (65 mmol) of diisopropylamine in 100 mL of tetrahydrofuran was added dropwise 40.5 mL (65 mmol) of 1.6 M n-butyl lithium in hexanes. The solution was allowed to warm to 0° C. briefly before being cooled to −78° C. To the solution was added 4.09 mL (30.9 mmol) of dimethyl (S)-(−)-malate dropwise and the resulting solution was allowed to warm to room temperature. After 30 min at room temperature, it was cooled to −78° C. before 2.3 mL (37.1 mmol) of methyl iodide was added dropwise. The solution was allowed to warm to room temperature, and was stirred for 18 h. It was then poured onto a mixture of ether, ice water, and 9.27 mL of acetic acid. The resulting mixture was extracted with ether, and the extracts were combined, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to afford 1.04 g (5.9 mmol) of dimethyl (2S,3S)-2-hydroxy-3-methylbutanedioate. before being cooled to −78° C to warm to room temperature was added dropwise to warm to room temperature The resulting mixture was extracted with ether washed with saturated sodium bicarbonate and brine dried over magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate