Qiu et al. 10.1073/pnas.0704461104. |
SI Text
3-Acetoxy-3-phenyl-2-methylenepropanoic acid methyl ester (3a).
Acetic anhydride (49.00 g, 480 mmol) was added dropwise into a mixture of 3-hydroxy-3-phenyl-2-methylenepropanoic acid methyl ester (4a) (76.88 g, 400 mmol) and DMAP (4.89 g, 40 mmol) in toluene (400 ml) in ≈30 min at 0-5°C. The resulting solution was allowed to warm to room temperature in 1 h. After stirring for 1 h at room temperature, the reaction mixture was cooled to 0-5°C, and 1 N hydrochloric acid (100 ml) was added in ≈20 min. The organic layer was separated and washed sequentially with water (100 ml), saturated aqueous sodium bicarbonate (2 ´ 100 ml) and water (100 ml). The organic layer was concentrated under reduced pressure (20 mbar) until no further solvent distilled to afford 3a (86.8 g, 92.6%) as a colorless liquid. The crude product was used in the next step without further purification, and its spectroscopic data were in agreement with published data (51-52).3-Acetoxy-2-methylenehexanoic acid methyl ester (3b).
Acetic anhydride (42.88 g, 420 mmol) was added dropwise into a mixture of 3-hydroxy-2-methylenehexanoic acid methyl ester (4b) (55.37 g, 350 mmol) and DMAP (4.28 g, 35 mmol) in toluene (400 ml) in ≈30 min at 0-5°C. The resulting solution was allowed to warm to room temperature in 1 h. After stirring for 3 h at room temperature, the reaction mixture was cooled to 0-5°C, and 1 N hydrochloric acid (80 ml) was added in ≈20 min. The organic layer was separated and washed sequentially with water (80 ml), saturated aqueous sodium bicarbonate (2 ´ 80 ml) and water (80 ml). The organic layer was concentrated under reduced pressure (20 mbar) until no further solvent distilled to afford 3b (68.3 g, 97.5%) as a colorless liquid. The crude product was used in the next step without further purification, and its spectroscopic data were in agreement with the published data (51-52).
(E/Z)-2-[(Benzyloxyformylamino)methyl]-3-phenylacrylic acid methyl ester (6a).
Formic acid (5.53 g, 120 mmol) was added to acetic anhydride (3.06 g, 30 mmol) in ≈15 min at 0-5°C. The resulting solution was warmed to room temperature and stirred for 30 min. The mixed anhydride solution was added to a solution of ≈80:20 mixture of (E) and (Z)-2-[(benzyloxyamino)methyl]-3-phenylacrylic acid methyl ester (2a) (4.46 g, 15 mmol) in ethyl acetate (15 ml) in ≈15 min at -10 to -20°C. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was cooled to 0-5°C, and ethyl acetate (15 ml) and saturated aqueous potassium carbonate (25 ml) were added sequentially. The ethyl acetate layer was separated and washed sequentially with saturated aqueous sodium bicarbonate (20 ml) and water (20 ml). The organic layer was concentrated under reduced pressure (20 mbar) until no further solvent distilled to afford an ≈80:20 mixture of (E) and (Z)- 6a (4.85 g, 99%) as a colorless liquid: 1H NMR (300 MHz, CDCl3) (≈80:20 mixture of E/Z isomers and rotamers) d 3.65 (s, 0.2 ´ 3H), 3.82 (s, 0.8 ´ 3H), 4.3-5.0 (m, 4 H), 6.91 (s, 0.2 ´ 1H), 7.97 (s, 0.8 ´ 1H), 7.1-7.5 (m, 10H), 8.05-8.3 (m, 1H); MS(ESI) 326.2 (MH+).
(E/Z)-2-[(Benzyloxyformylamino)methyl]-2-hexenoic acid methyl ester (6b).
Formic acid (9.21 g, 200 mmol) was added to acetic anhydride (5.11 g, 50 mmol) in ≈15 min at 0-5°C. The resulting solution was warmed to room temperature and stirred for 30 min. The mixed anhydride solution was added into a solution of ≈1:1 mixture of (E) and (Z)-2-[(benzyloxyamino)methyl]-2-hexenoic acid methyl ester (2b) (5.00 g, 19 mmol) in ethyl acetate (20 ml)) in ≈15 min at -10 to -20°C. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure (20 mbar) until no further solvent distilled. To the residue was added ethyl acetate (30 ml) and saturated aqueous sodium bicarbonate (30 ml). The ethyl acetate layer was separated and washed sequentially with saturated aqueous sodium bicarbonate (30 ml) and water (30 ml). The organic layer was concentrated under reduced pressure (20 mbar) until no further solvent distilled to afford an ≈1:1 mixture of (E) and (Z)-6b (5.50 g, 99%) as a colorless liquid: 1H NMR (300 MHz, CDCl3) (≈1:1 mixture of E/Z isomers and rotamers) d 0.85-0.95 (m, 3H), 1.4-1.6 (m, 2H), 2.26 (m, 0.5 ´ 2H), 2.52 (m, 0.5 ´ 2H), 3.75 (s, 3H), 4.0-4.7 (m, 2H), 4.8-5.1 (m, 2H), 6.18 (t, 0.5 ´ 1H, J = 7.35 Hz), 7.05 (t, 0.5 ´ 1H, J = 7.35 Hz), 7.2-7.5 (m, 5H), 8.0-8.2 (m, 1H); 13C NMR (75 MHz, CDCl3) d 13.82, 21.79, 22.28, 30.85, 31.61, 47.40, 51.58, 52.04, 77.96, 128.62, 129.01, 129.47, 129.61, 149.23; MS(ESI) 292.1 (MH+).
(E/Z)-2-[(Benzylformylamino)methyl]-2-hexenoic acid methyl ester (6c).
Formic acid (6.26 g, 136 mmol) was added to acetic anhydride (3.47 g, 34 mmol) in ≈15 min at 0-5°C. The resulting solution was warmed to room temperature and stirred for 30 min. The mixed anhydride solution was added to a solution of ≈65:35 mixture of (E) and (Z)-2-[(benzylamino)methyl]-2-hexenoic acid methyl ester (2c) (4.20 g, 17 mmol) in ethyl acetate (15 ml)) in ≈15 min at -10 to -20°C. The resulting solution was allowed to warm to room temperature and stirred for 1 h. To the reaction mixture was added ethyl acetate (15 ml) and saturated aqueous sodium bicarbonate (30 ml). The ethyl acetate layer was separated and washed sequentially with saturated aqueous sodium bicarbonate (30 ml) and water (30 ml). The organic layer was concentrated under reduced pressure (20 mbar) until no further solvent distilled to afford an ≈65:35 mixture of (E) and (Z)-6c (4.55 g, yield: 97%) as a colorless liquid: 1H NMR (300 MHz, CDCl3) (≈65:35 mixture of E/Z isomers and rotamers) d 0.8-1.0 (m, 3H), 1.35-1.55 (m, 2H), 1.95-2.05 (m, 1H), 2.1-2.55 (m, 1H), 3.67-3.77 (m, 3H), 3.9-4.2 (m, 2H), 4.37-4.48 (m, 2H), 5.95-6.05 (m, 0.35 ´1H), 6.9-7.0 (m, 0.65 ´ 1H), 7.15-7.45 (m, 5H), 8.25-8.45 (m, 1H); 13C NMR (75 MHz, CDCl3) d 13.74, 13.77, 13.85, 21.86, 21.97, 22.35, 30.50, 30.57, 31.51, 37.39, 42.34, 44.25, 44.31, 44.45, 50.34, 50.75, 50.84, 51.45, 51.60, 51.86, 52.01, 125.74, 126.24, 126.41, 126.60, 127.27, 127.49, 127.57, 127.66, 127.89, 128.06, 128.23, 128.59, 128.68, 128.74, 128.86, 135.96, 136.23, 136.46, 147.06, 148.18, 148.41, 149.26, 162.85, 163.55, 164.01, 166.29, 166.82, 167.60; MS(ESI) 276.21 (MH+).
2-[(Benzyloxyformylamino)methyl]-3-phenylpropionic acid methyl ester (7a).
Asymmetric hydrogenation of an ≈80:20 mixture of (E) and (Z)-2-[(benzyloxyformylamino)methyl]-3-phenylpropionic acid methyl ester (6a) was carried out with bis(norbornadiene)rhodium(I) tetrafluoroborate (5.0 mol%) and (1S,1'S,2R,2'R)-Tangphos (5.5 mol%) at 50 psig H2 for 72 h at room temperature. Only 35% conversion was observed by HPLC analysis.
2-[(Benzyloxyformylamino)methyl]hexanoic acid methyl ester (7b).
Asymmetric hydrogenation of an ≈1:1 mixture of (E) and (Z)-2-[(benzyloxyformylamino)methyl]-2-hexenoic acid methyl ester (6b) was carried out with bis(norbornadiene)rhodium(I) tetrafluoroborate (3.0 mol%) and (1S,1'S,2R,2'R)-Tangphos (3.3 mol%) at 50 psig H2 for 72 h at room temperature to afford 7b (98%): oil; 1H NMR (300 MHz, CDCl3) d 0.87 (t, 3H, J = 6.9 Hz), 1.2-1.35 (m, 4H), 1.4-1.7 (m, 2H), 2.6-2.9 (m, 1H), 3.61 (s, 3H), 3.7-3.9 (m, 2H), 4.6-5.0 (m, 2H), 7.36 (m, 5H), 8.16 (bs, 1H); MS(ESI) 294.0 (MH+). Chiral analysis was performed after N-deformylating it to 2-[(benzyloxyamino)methyl]hexanoic acid methyl ester (1b) with 2 N HCl. N-Deformylation procedure: To 7b (25 mg) was added 2 N HCl (0.5 ml) and THF (1.0 ml). The reaction was allowed to continue at room temperature for 6 h. The resulting solution was basified with saturated aqueous sodium bicarbonate (2.0 ml) and extracted with isopropyl acetate (3.0 ml). The organic layer was concentrated under reduced pressure (20 mbar) until no further solvent distilled. The residue was dissolved in a mixture of hexane/2-propanol (95/5) for chiral HPLC analysis (ee = 7% (R)).
2-[(Benzylformylamino)methyl]hexanoic acid methyl ester (7c).
Asymmetric hydrogenation of an ≈65:35 mixture of (E) and (Z)-2-[(benzylformylamino)methyl]-2-hexenoic acid methyl ester (6c) was carried out with (2R,5R)-[(COD)Rh(Me-Duphos)]+CF3SO3- (15 mol%) at 50 psig H2 for 120 h at room temperature to afford 7c in 75% conversion. Chiral analysis was performed after N-deformylating it to 2-[(benzylamino)methyl]hexanoic acid methyl ester (1c) with HCl in methanol. The residue was dissolved in a mixture of hexane/2-propanol (95/5) for chiral HPLC analysis (ee = 19% (S)).