dimethyl (2R,3R)-2,3-dihydroxybutanedioate

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

Procedure: A suspension of 1.78 g of dimethyl L-tartrate and 4.85 g of tris-hydroxymethyl-methylamine in 50 ml of methanol was heated under reflux for 6 days and then concentrated. The residue was purified by chromatography over silica gel with ethyl acetate/methanol/water as the eluent and gave N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-L-tartaramide, [a]+101.00 (c 0.4; dimethyl sulfoxide), MS: m/z 357.3 ([M+H]+). was heated under reflux for 6 days concentrated The residue was purified by chromatography over silica gel with ethyl acetate/methanol/water as the eluent

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

Procedure: A suspension of 1.78 g of dimethyl L-tartrate and 4.85 g of tris-hydroxymethyl-methylamine in 50 ml of methanol was heated under reflux for 6 days and then concentrated. The residue was purified by chromatography over silica gel with ethyl acetate/methanol/water as the eluent and gave N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-L-tartaramide, [a]+101.00 (c 0.4; dimethyl sulfoxide), MS: m/z 357.3 ([M+H]+). was heated under reflux for 6 days concentrated The residue was purified by chromatography over silica gel with ethyl acetate/methanol/water as the eluent

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

Procedure: A suspension of 1.78 g of dimethyl L-tartrate and 4.85 g of tris-hydroxymethyl-methylamine in 50 ml of methanol was heated under reflux for 6 days and then concentrated. The residue was purified by chromatography over silica gel with ethyl acetate/methanol/water as the eluent and gave N,N'-bis-(2-hydroxy-1,1-bis-hydroxymethyl-ethyl)-L-tartaramide, [a]+101.00 (c 0.4; dimethyl sulfoxide), MS: m/z 357.3 ([M+H]+). was heated under reflux for 6 days concentrated The residue was purified by chromatography over silica gel with ethyl acetate/methanol/water as the eluent

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

Procedure: A solution of 0.8 g of (S)-2-(4-formylphenyl)-4-isopropyl-2-oxazoline and 1 g of dimethyl L(+)-tartrate in 50 ml of toluene is treated with 0.1 g of toluene-4-sulphonic acid. The mixture is heated to boiling for 2.5 hours and the water formed is distilled off simultaneously. Then, 4 drops of triethylamine are added to the reaction mixture. After cooling the mixture is washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 1:1) and recrystallization from ethanol gives pure dimethyl (4R,5R)-2-(4-[(S)-4-isopropyl-2-oxazolinyl]phenyl)-1,3-dioxolane-4,5-dicarboxylate The mixture is heated is distilled off simultaneously Then, 4 drops of triethylamine are added to the reaction mixture After cooling the mixture is washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time dried over sodium sulphate concentrated Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 1:1) and recrystallization from ethanol

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

Procedure: A solution of 0.8 g of (S)-2-(4-formylphenyl)-4-isopropyl-2-oxazoline and 1 g of dimethyl L(+)-tartrate in 50 ml of toluene is treated with 0.1 g of toluene-4-sulphonic acid. The mixture is heated to boiling for 2.5 hours and the water formed is distilled off simultaneously. Then, 4 drops of triethylamine are added to the reaction mixture. After cooling the mixture is washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 1:1) and recrystallization from ethanol gives pure dimethyl (4R,5R)-2-(4-[(S)-4-isopropyl-2-oxazolinyl]phenyl)-1,3-dioxolane-4,5-dicarboxylate The mixture is heated is distilled off simultaneously Then, 4 drops of triethylamine are added to the reaction mixture After cooling the mixture is washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time dried over sodium sulphate concentrated Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 1:1) and recrystallization from ethanol

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−10° C.) suspension of NaH (60% dispersion in mineral oil, 6.73 g, 168 mmol) in DMF (240 mL) was added dropwise a solution of (+)-dimethyl L-tartrate (15.0 g, 84.0 mmol) in DMF (40 mL) over a period of 30 min. After the addition was complete, the mixture was stirred for another 30 min at −10° C., and then 3-bromo-2-methylpropene (25.5 mL, 253 mmol) was added while maintaining the reaction temperature below 0° C. The mixture was stirred for 1.5 h at −10° C., quenched with H2O and saturated aqueous sodium chloride (NaCl, brine), and extracted with EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated to yield a yellow oil. Purification by flash chromatography (SiO2, hexanes/EtOAc gradient) yielded the title compound as a colorless oil (17.05 g, 71%): IR (neat) 2953, 1758, 1435, 1270, 1203, 1106 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.92-4.86 (m, 4H), 4.37 (s, 2H), 4.19 (d, J=12.3 Hz, 2H), 3.82 (d, J=12.3 Hz, 2H), 3.77 (s, 6H), 1.68 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 169.84, 141.04, 114.10, 78.60, 75.66, 52.22, 19.52; HRMS-ESI (m/z) [M]+ calcd for C14H22O6, 286.1416; found, 286.1417. To a cooled After the addition while maintaining the reaction temperature below 0° C The mixture was stirred for 1.5 h at −10° C. quenched with H2O and saturated aqueous sodium chloride (NaCl, brine) extracted with EtOAc The phases were separated the aqueous phase was further extracted with EtOAc The combined organic phases were washed with brine dried over magnesium sulfate (MgSO4) filtered concentrated to yield a yellow oil Purification by flash chromatography (SiO2, hexanes/EtOAc gradient)

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−10° C.) suspension of NaH (60% dispersion in mineral oil, 6.73 g, 168 mmol) in DMF (240 mL) was added dropwise a solution of (+)-dimethyl L-tartrate (15.0 g, 84.0 mmol) in DMF (40 mL) over a period of 30 min. After the addition was complete, the mixture was stirred for another 30 min at −10° C., and then 3-bromo-2-methylpropene (25.5 mL, 253 mmol) was added while maintaining the reaction temperature below 0° C. The mixture was stirred for 1.5 h at −10° C., quenched with H2O and saturated aqueous sodium chloride (NaCl, brine), and extracted with EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated to yield a yellow oil. Purification by flash chromatography (SiO2, hexanes/EtOAc gradient) yielded the title compound as a colorless oil (17.05 g, 71%): IR (neat) 2953, 1758, 1435, 1270, 1203, 1106 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.92-4.86 (m, 4H), 4.37 (s, 2H), 4.19 (d, J=12.3 Hz, 2H), 3.82 (d, J=12.3 Hz, 2H), 3.77 (s, 6H), 1.68 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 169.84, 141.04, 114.10, 78.60, 75.66, 52.22, 19.52; HRMS-ESI (m/z) [M]+ calcd for C14H22O6, 286.1416; found, 286.1417. To a cooled After the addition while maintaining the reaction temperature below 0° C The mixture was stirred for 1.5 h at −10° C. quenched with H2O and saturated aqueous sodium chloride (NaCl, brine) extracted with EtOAc The phases were separated the aqueous phase was further extracted with EtOAc The combined organic phases were washed with brine dried over magnesium sulfate (MgSO4) filtered concentrated to yield a yellow oil Purification by flash chromatography (SiO2, hexanes/EtOAc gradient)

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

Procedure: 3.0 g of 3-chloro-2-(4-chloro-3-dimethoxymethylphenyl)-5-trifluoromethyl-pyridine, 5.4 g of dimethyl L(+)-tartrate and 100 mg of p-toluenesulfonic acid in 180 ml of anhydrous toluene were refluxed for 10 hours. The solution was cooled and then washed with 50 ml of 10% by weight sodium bicarbonate solution and three times with 50 ml of water each time, dried over sodium sulfate and concentrated. Chromatography on silica gel resulted in 3.0 g (77%) of colorless crystals; melting point: 48°-53° C. The solution was cooled washed with 50 ml of 10% by weight sodium bicarbonate solution and three times with 50 ml of water each time dried over sodium sulfate concentrated

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

Procedure: In a fashion similar to that described in Example 4, α-hexylcinnamaldehyde dimethyl acetal and dimethyl L-tartrate were condensed to provide a mixture of (E)-and (Z)-(4R,5R)-2-(1-hexyl-2-phenyl-1-ethenyl)-4,5-dicarbomethoxy-1,3-dioxolane in an approximate ratio of 90:10 Crystallization provided the pure E-isomer, mp 49°-50° C., [α]D25 -2.2 (c, 0.2, methanol). 1H-NMR (CDCl3) δ7.35-7.26 (5H,m), 6.74 (1H,s), 5.84 (1H,s) 4.86 (1H, d, J=4.4 Hz), 4.70 (1H, d, J=4.4 Hz), 3.85 (3H,s), 3.80 (3H,s), 2.34-2.27 (2H,m), 1.58-1.55 (2H,m), 1.37-1.26 (6H,m), 0.93-0.87 (3H,m), IR (KBr) 2900, 2840, 1730, 1430, 1340, 1200, 1100, 1060, 1030, 980, 950, 915, 870, 790, 750, 730, 690 cm-1. MS m/e (% abundance) 305 (4), 292 (17), 291 (100), 145 (18), 142 (25), 131 (73), 129 (76), 128 (26), 117 (74), 116 (17), 115 (51), 104 (29), 91 (57), 59 (31), 41 (25). condensed to provide in an approximate ratio of 90:10 Crystallization provided the pure E-isomer, mp 49°-50° C., [α]D25 -2.2 (c, 0.2, methanol)

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

Procedure: In a fashion similar to that described for Example 3, vanillin and dimethyl L-tartrate were condensed to provide (4R,5R)-2-(3-methoxy-4-hydroxy-phenyl)-4,5-dicarbomethoxy-1,3-dioxolane, mp 88°-90° C., [α]D25 -35.1° (c, 0.1, methanol). 1H-NMR (CDCl3) δ7.20 (1H, d, J=1.8 Hz), 7.06 (1H, dd, J=1.8 Hz and 8.2 Hz), 6.19 (1H, d, J=8.2 Hz), 6.08 (1H,s), 5.82 (1H, s), 4.96 (1H, d, J=3.8 Hz), 4.85 (1H, d, J=3.8 Hz), 3.91 (3H,s), 3.87 (3H,s), 3.84 (3H,s). IR (film) 3450, 1750, 1600, 1510, 1460, 1430 cm-1. Ms m/e (% abundance) 313(2), 312(12), 253(40), 168(84), 151(100), 124(22), 109(14), 59(18). condensed

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−10° C.) suspension of NaH (60% dispersion in mineral oil, 6.73 g, 168 mmol) in DMF (240 mL) was added dropwise a solution of (+)-dimethyl L-tartrate (15.0 g, 84.0 mmol) in DMF (40 mL) over a period of 30 min. After the addition was complete, the mixture was stirred for another 30 min at −10° C., and then 3-bromo-2-methylpropene (25.5 mL, 253 mmol) was added while maintaining the reaction temperature below 0° C. The mixture was stirred for 1.5 h at −10° C., quenched with H2O and saturated aqueous sodium chloride (NaCl, brine), and extracted with EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated to yield a yellow oil. Purification by flash chromatography (SiO2, hexanes/EtOAc gradient) yielded the title compound as a colorless oil (17.05 g, 71%): IR (neat) 2953, 1758, 1435, 1270, 1203, 1106 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.92-4.86 (m, 4H), 4.37 (s, 2H), 4.19 (d, J=12.3 Hz, 2H), 3.82 (d, J=12.3 Hz, 2H), 3.77 (s, 6H), 1.68 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 169.84, 141.04, 114.10, 78.60, 75.66, 52.22, 19.52; HRMS-ESI (m/z) [M]+ calcd for C14H22O6, 286.1416; found, 286.1417. To a cooled After the addition while maintaining the reaction temperature below 0° C The mixture was stirred for 1.5 h at −10° C. quenched with H2O and saturated aqueous sodium chloride (NaCl, brine) extracted with EtOAc The phases were separated the aqueous phase was further extracted with EtOAc The combined organic phases were washed with brine dried over magnesium sulfate (MgSO4) filtered concentrated to yield a yellow oil Purification by flash chromatography (SiO2, hexanes/EtOAc gradient)

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

Procedure: In a fashion similar to that described in Example 4, α-hexylcinnamaldehyde dimethyl acetal and dimethyl L-tartrate were condensed to provide a mixture of (E)-and (Z)-(4R,5R)-2-(1-hexyl-2-phenyl-1-ethenyl)-4,5-dicarbomethoxy-1,3-dioxolane in an approximate ratio of 90:10 Crystallization provided the pure E-isomer, mp 49°-50° C., [α]D25 -2.2 (c,0.2, methanol). 1H-NMR (CDCl3)δ7.35-7.26 (5H,m), 6.74 (1H,s), 5.84 (1H,s), 4.86 (1H,d,J=4.4 Hz), 4.70 (1H,d,J=4.4 Hz), 3.85 (3H,s), 3.80 (3H,s), 2.34-2.27 (2H,m), 1.58-1.55 (2H,m), 1.37-1.26 (6H,m), 0.93-0.87 (3H,m). IR (KBr)2900, 2840, 1730, 1430, 1340, 1200, 1100, 1060, 1030, 980, 950, 915, 870, 790, 750, 730, 690 cm-1. MS m/e (% abundance) 305 (4), 292 (17), 291 (100), 145 (18), 142 (25), 131 (73), 129 (76), 128 (26), 117 (74), 116 (17), 115 (51), 104 (29), 91 (57), 59 (31), 41 (25). condensed to provide in an approximate ratio of 90:10 Crystallization provided the pure E-isomer, mp 49°-50° C., [α]D25 -2.2 (c,0.2, methanol)