* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With C39H33N3O2*2ClH In methanol; water at 20℃; for 72 h;
General procedure: To a 5 mL vial equipped with a magnetic stirrer bar were added 3-cyclohexyl-2-oxopropanoic acid (1j) (0.0510 g, 0.30 mmol), 2,2-diphenylglycine (2) (0.0681 g, 0.30 mmol), chiral pyridoxamine 6g (0.0195 g, 0.030 mmol), and MeOH-H2O (8:2) (3.0 mL). The mixture was stirred at 20 °C for 3 days. The reaction mixture was transferred to a 25 mL round-bottom flask and MeOH was added until all the solid was dissolved. Then silica gel (0.50 g) was added. After removal of the solvent in vacuo at 20 °C, the resulting residue was submitted to column chromatography on silica gel (EtOH/ethyl acetate/25-28percent ammonia solution =100:58:16) to give compound 3j (0.0401 g, 78percent yield, 52percent ee) as a white solid. The enantiomeric excesses of 3b-k were deteremined by HPLC analysis after being converted to N-benzoyl methyl esters by treatment with thionyl chloride in methanol and subsequent reaction benzoyl chloride.7 The enantiomeric excess of 3a was deteremined by HPLC analysis after being converted to its methyl ester by treatment with CH2N2 in methanol.
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 40, p. 12977 - 12983
3
[ 7345-79-1 ]
[ 267225-27-4 ]
[ 42538-40-9 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 40, p. 12977 - 12983
4
[ 120240-65-5 ]
[ 3060-50-2 ]
[ 119-61-9 ]
[ 267225-27-4 ]
[ 42538-40-9 ]
Yield
Reaction Conditions
Operation in experiment
46 % ee
With C39H33N3O2*2ClH In methanol; water at 20℃; for 72 h;
General procedure: To a 5 mL vial equipped with a magnetic stirrer bar were added 3-cyclohexyl-2-oxopropanoic acid (1j) (0.0510 g, 0.30 mmol), 2,2-diphenylglycine (2) (0.0681 g, 0.30 mmol), chiral pyridoxamine 6g (0.0195 g, 0.030 mmol), and MeOH-H2O (8:2) (3.0 mL). The mixture was stirred at 20 °C for 3 days. The reaction mixture was transferred to a 25 mL round-bottom flask and MeOH was added until all the solid was dissolved. Then silica gel (0.50 g) was added. After removal of the solvent in vacuo at 20 °C, the resulting residue was submitted to column chromatography on silica gel (EtOH/ethyl acetate/25-28percent ammonia solution =100:58:16) to give compound 3j (0.0401 g, 78percent yield, 52percent ee) as a white solid. The enantiomeric excesses of 3b-k were deteremined by HPLC analysis after being converted to N-benzoyl methyl esters by treatment with thionyl chloride in methanol and subsequent reaction benzoyl chloride.7 The enantiomeric excess of 3a was deteremined by HPLC analysis after being converted to its methyl ester by treatment with CH2N2 in methanol.
methyl 2-bromo-D-phenylalaninate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
> 99%
With acetyl chloride; at 20℃; for 36h;
Dissolve <strong>[267225-27-4]2-bromo-D-phenylalanine</strong> (22.4 g, 91.8 mmol) in MeOH (459 mL). Add acetyl chloride (65.3 mL, 917.7 mmol) at room temperature and stir for 36 hr. Concentrate under reduced pressure to give the title compound (27.2 g, >99% yield). MS: m/z 258/260 [M-Cl, 79Br/81Br].
27.2 g
With acetyl chloride; at 20℃; for 36h;
Preparation 1 Synthesis of methyl 2-bromo-D-phenylalaninate hydrochloride Dissolve <strong>[267225-27-4]2-bromo-D-phenylalanine</strong> (22.4 g, 91.8 mmol) in methanol (459 mL). Add acetyl chloride (65.3 mL, 917.7 mmol) at room temperature. Stir for 36 hours. Concentrate under reduced pressure to give the title compound (27.2 g, 92.3 mmol). MS (m/z): 258 (M+1).
589 g
Alternative synthesis of methyl 2-bromo-D-phenylalaninate hydrochloride. Add acetyl chloride (562.79 g, 7.17 mol) to methanol (10.00 L) at 0 C in an appropriate vessel. Heat the mixture to 17.5 C and stir. After 30 minutes add 2-bromo- D-phenylalanine (500.00 g, 2.05 moles) and heat to reflux. After 4 hours, cool to 20 C and remove the solvent under reduced pressure to give the title compound (589 g, 1.96 mol) as an off-white solid. MS (m z): 258(M-C1 (79Br)), 260(M-C1 (81Br)).
With C39H33N3O2*2ClH; In methanol; water; at 20℃; for 72h;
General procedure: To a 5 mL vial equipped with a magnetic stirrer bar were added 3-cyclohexyl-2-oxopropanoic acid (1j) (0.0510 g, 0.30 mmol), 2,2-diphenylglycine (2) (0.0681 g, 0.30 mmol), chiral pyridoxamine 6g (0.0195 g, 0.030 mmol), and MeOH-H2O (8:2) (3.0 mL). The mixture was stirred at 20 °C for 3 days. The reaction mixture was transferred to a 25 mL round-bottom flask and MeOH was added until all the solid was dissolved. Then silica gel (0.50 g) was added. After removal of the solvent in vacuo at 20 °C, the resulting residue was submitted to column chromatography on silica gel (EtOH/ethyl acetate/25-28percent ammonia solution =100:58:16) to give compound 3j (0.0401 g, 78percent yield, 52percent ee) as a white solid. The enantiomeric excesses of 3b-k were deteremined by HPLC analysis after being converted to N-benzoyl methyl esters by treatment with thionyl chloride in methanol and subsequent reaction benzoyl chloride.7 The enantiomeric excess of 3a was deteremined by HPLC analysis after being converted to its methyl ester by treatment with CH2N2 in methanol.
With C39H33N3O2*2ClH; water; 2,2-diphenylglycine; In methanol; at 20℃; for 72h;
General procedure: Take 5mL of the reaction bottle. Was weighed into the flask the keto acid 2a (0.046 g, 0.20 mmol), the chiral pyridoxamine catalyst 1a (0.013 g, 0.020 mmol), and 2,2-diphenylglycine 14 (0.045 g, 0.20 mmol). To the flask was added MeOH (1.6 mL) and water (0.4 mL). Adding a magnet, plug a good stopper, placed in 20°C constant temperature reaction tank reaction for 3d. The reaction was stopped. The contents of the flask were transferred to a 25 mL eggplant flask. 10 mL of methanol was added to dissolve all the solids in the flask. Silica gel (0.2 g) was added. The solvent was removed at room temperature. Dry on the column. Silica gel column chromatography gave the product amino acid 3a (0.023 g, 50percent). The ee value of 3a was obtained by HPLC analysis of its carboxymethylated derivative with an ee value of 34percent.
16
[ 267225-27-4 ]
methyl 3-(3-bromophenyl)-2-((methoxycarbonyl)amino)propanoate[ No CAS ]
methyl 2-amino-3-(3-bromophenyl)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With thionyl chloride; at 0℃;Reflux;
2-Bromo-D-phenylalanine (2g, 8.19 mmol) was dissolved in methanol (5OmL) and cooled to 0C. Thionyl chloride (1.5mL, 20 mmol) was added drop-wise to the stirred reaction mixture. The reaction was allowed to warm up to the ambient temperatureand heated for 14h under reflux. Crude reaction mixture was concentrated under reduced pressure, extracted with saturated bicarbonate and brine, dried and concentrated to obtain the title compound (2.37g, 98% yield).?H NMR (400 MI-Tz, DMSO-d6) 3 ppm 3.12 (m, J=1.00 Hz, 2 H) 3.69 (s, 3 H) 4.34 (t, J=6.72 Hz, 1 H) 7.22 - 7.34 (m, 2 H) 7.45 - 7.53 (m, 2 H) 8.54 (br. s., 2 H). MS (m/z): 258.0, 260.0 (M+H) for two bromine isomers.
1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one[ No CAS ]
1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one[ No CAS ]
1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one[ No CAS ]
benzyl (1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate[ No CAS ]
1-((1S,3R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1-methyl-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-2-(2,6-dichlorophenyl)ethan-1-one[ No CAS ]
2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one hydrochloride[ No CAS ]
2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one hydrobromide[ No CAS ]
2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one hydroiodide[ No CAS ]
With phenylalanine ammonia-lyase from Pseudozyma antarctica yeast; In aq. buffer; at 30℃; for 17h;pH 8.5;Resolution of racemate;
General procedure: The ammonia elimination reaction mixtures containing 5mM of theracemic phenylalanines (rac-1a-s) in 100mM TRIS buffer (pH 8.5) andpurified PzaPAL or PcPAL (50 Xg, either) in 1 mL reaction volume wereincubated at 30 C. Samples (50 XL) taken at different time points (17,40, 64, and 168 h) from the reaction mixtures were analyzed by HPLCfor conversion and ee values, using previously developed methods [44].The ammonia addition and elimination reactions were followed byHPLC measurements. Conversions were determined on Agilent 1200HPLC instrument using Phenomenex Gemini NX-C-18 column and amixture of NH4OH buffer (0.1 M, pH 8.5) and MeOH at a flow rate of1 mL min-1. Conversions were calculated from peak area integrationswith use of appropriate response factor (Table S2). Enantiomer separationswere carried out on Agilent 1100 HPLC instrument usingCrownpak CR-I (+) column and a mixture of aqueous HClO4, pH 1.5and acetonitrile as eluent at a flow rate of 0.4 mL min-1. (Table S3).
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