methyl (2R)-2-(benzylamino)propanoate

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

Procedure: Methylphenyl-phosphinic chloride (361 mg, 2.07 mmol) is dissolved in dichloromethane (2.5 mL) and then cooled to 0° C. To this is added a solution of N-benzyl D-alanine methyl ester (400 mg, 2.07 mmol) and N-methyl morpholine (0.51 mL, 4.6 mmol) in dichloromethane (2.5 mL). A catalytic amount of 4-dimethylaminopyridine is then added to the stirring mixture. The reaction is stirred for 16 hours at room temperature, washed with water and brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel flash chromatography (100% ethyl acetate) to give N-((R)-methylphenylphosphinyl)-N-benzyl-D-leucine methyl ester as an oil. washed with water and brine dried over sodium sulfate concentrated The crude product is purified by silica gel flash chromatography (100% ethyl acetate)

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

Procedure: D-Alanine methyl ester (4 g, 28.66 mmol) is taken up in methanol (100 mL). To this is added sodium acetate (5.88 g, 71.65 mmol) and benzaldehyde (2.9 mL, 28.66 mmol). The mixture is stirred for 15 minutes and then a solution of sodium cyanoborohydride (1.08 g, 17.2 mmol) in methanol (5 mL) is added dropwise to the mixture. After stirring for 2 hours methanol is evaporated under reduced pressure and the product is extracted into ether and washed with water (2×). The crude product is purified by silica gel flash chromatography (8:2 hexane:ethyl acetate) to give 3.3 g of N-benzyl D-alanine methyl ester as an oil. is evaporated under reduced pressure the product is extracted into ether washed with water (2×) The crude product is purified by silica gel flash chromatography (8:2 hexane:ethyl acetate)

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

Procedure: To a solution of N-benzyl-D-alanine methyl ester (~2 g) in methylene chloride (40 mL) containing triethylamine (2.47 mL, 17.7 mmol) is added 4-methoxybenzenesulfonyl chloride (2.44 g, 11.8 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is acidified with 1N HCl and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (10%→20% ethyl acetate/hexanes) to provide methyl 2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]propionate. extracted with methylene chloride The combined organic extracts are washed with brine dried (Na2SO4) the solvent is evaporated The crude product is purified by silica gel chromatography (10%→20% ethyl acetate/hexanes)

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

Procedure: To a solution of N-benzyl-D-alanine methyl ester (~2 g) in methylene chloride (40 mL) containing triethylamine (2.47 mL, 17.7 mmol) is added 4-methoxybenzenesulfonyl chloride (2.44 g, 11.8 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is acidified with 1N HCl and extracted with methylene chloride. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is purified by silica gel chromatography (10%→20% ethyl acetate/hexanes) to provide methyl 2(R)-[[4-methoxybenzenesulfonyl]-(benzyl)amino]propionate. extracted with methylene chloride The combined organic extracts are washed with brine dried (Na2SO4) the solvent is evaporated The crude product is purified by silica gel chromatography (10%→20% ethyl acetate/hexanes)

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

Procedure: To a solution of D-alanine methyl ester hydrochloride (3.0 g, 21.5 mmol) in methanol (10 mL) is added benzaldehyde (2.3 mL, 22.6 mmol). The reaction mixture is stirred at room temperature for 3 hours. The solvent is then evaporated. To the resultant residue is added acetic acid (15 mL) and methanol (1 mL) followed by portionwise addition of sodium cyanoborohydride (1.35 g, 21.5 mmol) at room temperature. The mixture is stirred overnight, and then the solvent is evaporated. The remaining residue is diluted with water (75 mL) and basified with Na2CO3. The mixture is extracted with ethyl acetate (3×75 mL). The combined organic extracts are washed with brine (50 mL), dried (Na2SO4), and the solvent is evaporated to give N-benzyl-D-alanine methyl ester. The solvent is then evaporated To the resultant residue is added acetic acid (15 mL) and methanol (1 mL) The mixture is stirred overnight the solvent is evaporated The remaining residue is diluted with water (75 mL) The mixture is extracted with ethyl acetate (3×75 mL) The combined organic extracts are washed with brine (50 mL) dried (Na2SO4) the solvent is evaporated

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

Procedure: To a solution of D-alanine methyl ester hydrochloride (3.0 g, 21.5 mmol) in methanol (10 mL) is added benzaldehyde (2.3 mL, 22.6 mmol). The reaction mixture is stirred at room temperature for 3 hours. The solvent is then evaporated. To the resultant residue is added acetic acid (15 mL) and methanol (1 mL) followed by portionwise addition of sodium cyanoborohydride (1.35 g, 21.5 mmol) at room temperature. The mixture is stirred overnight, and then the solvent is evaporated. The remaining residue is diluted with water (75 mL) and basified with Na2CO3. The mixture is extracted with ethyl acetate (3×75 mL). The combined organic extracts are washed with brine (50 mL), dried (Na2SO4), and the solvent is evaporated to give N-benzyl-D-alanine methyl ester. The solvent is then evaporated To the resultant residue is added acetic acid (15 mL) and methanol (1 mL) The mixture is stirred overnight the solvent is evaporated The remaining residue is diluted with water (75 mL) The mixture is extracted with ethyl acetate (3×75 mL) The combined organic extracts are washed with brine (50 mL) dried (Na2SO4) the solvent is evaporated

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH2Cl2 (300 mL). The solution was stirred at 22° C. for 19 h. The reaction mixture was cooled with an ice-water bath and solid sodium triacetoxyborohydride (46 g, 0.22 mol) was added in portions over ˜15 min. The cooling bath was removed and the milky white solution was stirred at 22° C. for 7 h. The solvent was removed by rotary evaporation under reduced pressure and the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). The aqueous layer was adjusted to pH ˜10 with 1 N NaOH (450 mL) and the milky aqueous layer was extracted immediately with EtOAc (3×250 mL). The combined organic layers were washed with brine (˜250 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford N-benzyl-D-alanine methyl ester (28 g, 80%) as a colorless semi-solid. The reaction mixture was cooled with an ice-water bath The cooling bath was removed the milky white solution was stirred at 22° C. for 7 h The solvent was removed by rotary evaporation under reduced pressure the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL) The aqueous layer was extracted with EtOAc (˜50 mL) the milky aqueous layer was extracted immediately with EtOAc (3×250 mL) The combined organic layers were washed with brine (˜250 mL) dried over anhydrous MgSO4 filtered concentrated under reduced pressure

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH2Cl2 (300 mL). The solution was stirred at 22° C. for 19 h. The reaction mixture was cooled with an ice-water bath and solid sodium triacetoxyborohydride (46 g, 0.22 mol) was added in portions over ˜15 min. The cooling bath was removed and the milky white solution was stirred at 22° C. for 7 h. The solvent was removed by rotary evaporation under reduced pressure and the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). The aqueous layer was adjusted to pH ˜10 with 1 N NaOH (450 mL) and the milky aqueous layer was extracted immediately with EtOAc (3×250 mL). The combined organic layers were washed with brine (˜250 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford N-benzyl-D-alanine methyl ester (28 g, 80%) as a colorless semi-solid. The reaction mixture was cooled with an ice-water bath The cooling bath was removed the milky white solution was stirred at 22° C. for 7 h The solvent was removed by rotary evaporation under reduced pressure the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL) The aqueous layer was extracted with EtOAc (˜50 mL) the milky aqueous layer was extracted immediately with EtOAc (3×250 mL) The combined organic layers were washed with brine (˜250 mL) dried over anhydrous MgSO4 filtered concentrated under reduced pressure

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH2Cl2 (300 mL). The solution was stirred at 22° C. for 19 h. The reaction mixture was cooled with an ice-water bath and solid sodium triacetoxyborohydride (46 g, 0.22 mol) was added in portions over ˜15 min. The cooling bath was removed and the milky white solution was stirred at 22° C. for 7 h. The solvent was removed by rotary evaporation under reduced pressure and the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). The aqueous layer was adjusted to pH ˜10 with 1 N NaOH (450 mL) and the milky aqueous layer was extracted immediately with EtOAc (3×250 mL). The combined organic layers were washed with brine (˜250 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford N-benzyl-D-alanine methyl ester (28 g, 80%) as a colorless semi-solid. The reaction mixture was cooled with an ice-water bath The cooling bath was removed the milky white solution was stirred at 22° C. for 7 h The solvent was removed by rotary evaporation under reduced pressure the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL) The aqueous layer was extracted with EtOAc (˜50 mL) the milky aqueous layer was extracted immediately with EtOAc (3×250 mL) The combined organic layers were washed with brine (˜250 mL) dried over anhydrous MgSO4 filtered concentrated under reduced pressure

Conditions: temp:22.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH2Cl2 (300 mL). The solution was stirred at 22° C. for 19 h. The reaction mixture was cooled with an ice-water bath and solid sodium triacetoxyborohydride (46 g, 0.22 mol) was added in portions over ˜15 min. The cooling bath was removed and the milky white solution was stirred at 22° C. for 7 h. The solvent was removed by rotary evaporation under reduced pressure and the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). The aqueous layer was adjusted to pH ˜10 with 1 N NaOH (450 mL) and the milky aqueous layer was extracted immediately with EtOAc (3×250 mL). The combined organic layers were washed with brine (˜250 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford N-benzyl-D-alanine methyl ester (28 g, 80%) as a colorless semi-solid. The reaction mixture was cooled with an ice-water bath The cooling bath was removed the milky white solution was stirred at 22° C. for 7 h The solvent was removed by rotary evaporation under reduced pressure the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL) The aqueous layer was extracted with EtOAc (˜50 mL) the milky aqueous layer was extracted immediately with EtOAc (3×250 mL) The combined organic layers were washed with brine (˜250 mL) dried over anhydrous MgSO4 filtered concentrated under reduced pressure

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

Procedure: The title compound was prepared according to the procedure outlined in Example 255 substituting L-aspartic acid for D-aspartic acid and (R)-methyl 2-(benzylamino)propanoate for N-benzylglycine ethyl ester. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.84-7.01 (m, 3H), 6.73-6.85 (m, 1H), 4.35-4.51 (m, 1H), 3.99-4.14 (m, 1H), 2.80-3.28 (m, 6H), 1.95-2.14 (m, 1H), 1.66-1.85 (m, 1H), 1.20 (d, J=6.44 Hz, 3H); MS (DCI) m/z 219 (M+H)+. The title compound was prepared Purification via flash chromatography (0-30% methanol/dichloromethane)

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

Procedure: The title compound was prepared according to the procedure outlined in Example 255 substituting L-aspartic acid for D-aspartic acid and (R)-methyl 2-(benzylamino)propanoate for N-benzylglycine ethyl ester. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.84-7.01 (m, 3H), 6.73-6.85 (m, 1H), 4.35-4.51 (m, 1H), 3.99-4.14 (m, 1H), 2.80-3.28 (m, 6H), 1.95-2.14 (m, 1H), 1.66-1.85 (m, 1H), 1.20 (d, J=6.44 Hz, 3H); MS (DCI) m/z 219 (M+H)+. The title compound was prepared Purification via flash chromatography (0-30% methanol/dichloromethane)