ethyl (3S)-3-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoate

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

Procedure: Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. 1H-NMR (300 MHz, d6 -DMSO) δ1.03 (t, J=7 Hz, 3H), 3.02 (dd, J=10 Hz, J=15 Hz, 1H), 3.25 (dd, J=6 Hz, J=15 Hz, 1H), 3.96 (m, 2H), 4.55 (m, 1H), 7.3-7.6 (m, 5H), 8.93 (s, 3H). the solvent was removed under reduced pressure

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

Procedure: To a stirred solution of N-BOC-D-phenylglycine (5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in EtOAc (100 mL) at 0° C. was added isobutyl chloroformate (2.73 g, 20 mmol). After 15 minutes the reaction mixture was filtered to remove the amine salts then an ethereal solution of diazomethane (60 mL, 30 mmol) was added. The cooling bath was removed and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane. The reaction mixture was diluted with EtOAc, washed with 1N HCl , saturated NaHCO3, and dried (MgSO4). Evaporation of the solvent afforded the crude diazoketone which was dissolved in EtOH (100 mL) and then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and triethylamine (6.06 g, 60 mmol). After 20 hours the reaction mixture was concentrated and chromatographed (silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of product as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ1.17 (t, J=7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07 (q, J=7 Hz, 2H), 5.10 (m, 1H), 5.48 (m, 1H), 7.22-7.39 (m, 5H). After 15 minutes the reaction mixture was filtered to remove the amine salts The cooling bath was removed The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane The reaction mixture was diluted with EtOAc washed with 1N HCl , saturated NaHCO3 dried (MgSO4) Evaporation of the solvent afforded the crude diazoketone which After 20 hours the reaction mixture was concentrated chromatographed (silica gel, 15% EtOAc/hexanes)

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

Procedure: Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. 1H-NMR (300 MHz, d6 -DMSO) δ1.03 (t, J=7 Hz, 3H), 3.02 (dd, J=10 Hz, J=15 Hz, 1H), 3.25 (dd, J=6 Hz, J=15 Hz, 1H), 3.96 (m, 2H), 4.55 (m, 1H), 7.3-7.6 (m, 5H), 8.93 (s, 3H). the solvent was removed under reduced pressure

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

Procedure: To a stirred solution of N-BOC-D-phenylglycine (5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in EtOAc (100 mL) at 0° C. was added isobutyl chloroformate (2.73 g, 20 mmol). After 15 minutes the reaction mixture was filtered to remove the amine salts then an ethereal solution of diazomethane (60 mL, 30 mmol) was added. The cooling bath was removed and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane. The reaction mixture was diluted with EtOAc, washed with 1N HCl, saturated NaHCO3, and dried (MgSO4). Evaporation of the solvent afforded the crude diazoketone which was dissolved in EtOH (100 mL) and then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and triethylamine (6.06 g, 60 mmol). After 20 hours the reaction mixture was concentrated and chromatographed (silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of product as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ1.17 (t, J=7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07 (q, J=7 Hz, 2H), 5.10 (m, 1H), 5.48 (m, 1H), 7.22-7.39 (m, 5H). After 15 minutes the reaction mixture was filtered to remove the amine salts The cooling bath was removed The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane The reaction mixture was diluted with EtOAc washed with 1N HCl, saturated NaHCO3 dried (MgSO4) Evaporation of the solvent afforded the crude diazoketone which After 20 hours the reaction mixture was concentrated chromatographed (silica gel, 15% EtOAc/hexanes)

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

Procedure: To a stirred solution of N-BOC-D-phenylglycine (5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in EtOAc (100 mL) at 0° C. was added isobutyl chloroformate (2.73 g, 20 mmol). After 15 minutes the reaction mixture was filtered to remove the amine salts then an ethereal solution of diazomethane (60 mL, 30 mmol) was added. The cooling bath was removed and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane. The reaction mixture was diluted with EtOAc, washed with 1N HCl, saturated NaHCO3, and dried (MgSO4). Evaporation of the solvent afforded the crude diazoketone which was dissolved in EtOH (100 mL) and then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and triethylamine (6.06 g, 60 mmol). After 20 hours the reaction mixture was concentrated and chromatographed (silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of product as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ1.17 (t, J=7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07 (q, J=7 Hz, 2H), 5.10 (m, 1H), 5.48 (m, 1H), 7.22-7.39 (m, 5H). After 15 minutes the reaction mixture was filtered to remove the amine salts The cooling bath was removed The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane The reaction mixture was diluted with EtOAc washed with 1N HCl, saturated NaHCO3 dried (MgSO4) Evaporation of the solvent afforded the crude diazoketone which After 20 hours the reaction mixture was concentrated chromatographed (silica gel, 15% EtOAc/hexanes)

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

Procedure: Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. 1H-NMR (300 MHz, d6 -DMSO) δ1.03 (t, J=7 Hz, 3H), 3.02 (dd, J=10 Hz, J=15 Hz, 1H), 3.25 (dd, J=6 Hz, J=15 Hz, 1H), 3.96 (m, 2H), 4.55 (m, 1H), 7.3-7.6 (m, 5H), 8.93 (s, 3H). the solvent was removed under reduced pressure

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

Procedure: Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. 1H-NMR (300 MHz, d6 -DMSO) δ1.03 (t, J=7 Hz, 3H), 3.02 (dd, J=10 Hz, J=15 Hz, 1H), 3.25 (dd, J=6 Hz, J=15 Hz, 1H), 3.96 (m, 2H), 4.55 (m, 1H), 7.3-7.6 (m, 5H), 8.93 (s, 3H). the solvent was removed under reduced pressure

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

Procedure: To a stirred solution of N-BOC-D-phenylglycine (5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in EtOAc (100 mL) at 0° C. was added isobutyl chloroformate (2.73 g, 20 mmol). After 15 minutes the reaction mixture was filtered to remove the amine salts then an ethereal solution of diazomethane (60 mL, 30 mmol) was added. The cooling bath was removed and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane. The reaction mixture was diluted with EtOAc, washed with 1N HCl , saturated NaHCO3, and dried (MgSO4). Evaporation of the solvent afforded the crude diazoketone which was dissolved in EtOH (100 mL) and then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and triethylamine (6.06 g, 60 mmol). After 20 hours the reaction mixture was concentrated and chromatographed (silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of product as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ1.17 (t, J=7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07 (q, J=7 Hz, 2H), 5.10 (m, 1H), 5.48 (m, 1H), 7.22-7.39 (m, 5H). After 15 minutes the reaction mixture was filtered to remove the amine salts The cooling bath was removed The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane The reaction mixture was diluted with EtOAc washed with 1N HCl , saturated NaHCO3 dried (MgSO4) Evaporation of the solvent afforded the crude diazoketone which After 20 hours the reaction mixture was concentrated chromatographed (silica gel, 15% EtOAc/hexanes)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a dry, cooled (−78° C.) solution of ethyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate from Step A (1.00 g, 3.41 mmol) was added a solution of DiBAl-H (6.82 mL, 6.82 mmol, 1 M in CH2Cl2) slowly over 30 min. After an additional 30 min of stirring at −78° C., the reaction was quenched by the rapid addition of saturated aqueous Rochelle's salt (32 mL). The cooling bath was then removed and the reaction was allowed to rapidly stir until a noticeable decrease in the amount of emulsion was observed. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×30 mL). Combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of EtOAc:hexanes 5:95 to 40:60, to give the title compound. MS: m/z=150 (M−CO2C4H7). the reaction was quenched by the rapid addition of saturated aqueous Rochelle's salt (32 mL) The cooling bath was then removed to rapidly stir until a noticeable decrease in the amount of emulsion The layers were separated the aqueous layer was extracted with CH2Cl2 (2×30 mL) Combined organics were dried over sodium sulfate filtered concentrated in vacuo to give an oil This oil was purified by silica gel chromatography eluting with a gradient of EtOAc:hexanes 5:95 to 40:60

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

Procedure: Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. 1H-NMR (300 MHz, d6 -DMSO) δ 1.03 (t, J=7Hz, 3H), 3.02 (dd, J=10Hz, J=15Hz, 1H), 3.25 (dd, J=6Hz, J=15Hz, 1H), 3.96 (m, 2H), 4.55 (m, 1H), 7.3-7.6 (m, 5H), 8.93 (s, 3H). the solvent was removed under reduced pressure

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

Procedure: Dry HCl gas was bubbled through a solution of the product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL) at ambient temperature for 15 minutes. After stirring for an additional 30 minutes, the solvent was removed under reduced pressure affording 2.30 g (98%) of product as a yellow oil. 1H-NMR (300 MHz, d6 -DMSO) δ 1.03 (t, J=7Hz, 3H), 3.02 (dd, J=10Hz, J=15Hz, 1H), 3.25 (dd, J=6Hz, J=15Hz, 1H), 3.96 (m, 2H), 4.55 (m, 1H), 7.3-7.6 (m, 5H), 8.93 (s, 3H). the solvent was removed under reduced pressure

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

Procedure: To a stirred solution of N-BOC-D-phenylglycine (5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in EtOAc (100 mL) at 0° C. was added isobutyl chloroformate (2.73 g, 20 mmol). After 15 minutes the reaction mixture was filtered to remove the amine salts then an ethereal solution of diazomethane (60 mL, 30 mmol) was added. The cooling bath was removed and the reaction mixture stirred at ambient temperature for 2 hours. The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane. The reaction mixture was diluted with EtOAc, washed with 1N HCl, saturated NaHCO3, and dried (MgSO4). Evaporation of the solvent afforded the crude diazoketone which was dissolved in EtOH (100 mL) and then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and triethylamine (6.06 g, 60 mmol). After 20 hours the reaction mixture was concentrated and chromatographed (silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of product as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 1.17 (t, J=7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07 (q, J=7 Hz, 2H), 5.10 (m, 1H), 5.48 (m, 1H), 7.22-7.39 (m, 5H). After 15 minutes the reaction mixture was filtered to remove the amine salts The cooling bath was removed The reaction mixture was purged with nitrogen for 15 minutes to remove the excess diazomethane The reaction mixture was diluted with EtOAc washed with 1N HCl, saturated NaHCO3 dried (MgSO4) Evaporation of the solvent afforded the crude diazoketone which After 20 hours the reaction mixture was concentrated chromatographed (silica gel, 15% EtOAc/hexanes)