tert-butyl N-[(2R)-1-hydroxy-3-phenylmethoxypropan-2-yl]carbamate

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

Procedure: (R)-tert-butyl 1-(2-amino-3-carbamoyl-9H-pyrido[2,3-b]indol-9-yl)-3-(benzyloxy)propan-2-ylcarbamate (xvi-d) was prepared following the procedure detailed in the preparation of 63, substituting (S)-tert-butyl 1-(benzyloxy)-3-iodopropan-2-ylcarbamate (prepared as detailed in the synthesis of xxvii from commercial N-Boc-L-Ser(Bzl)-ol) for tert-butyl[1-(iodomethyl)cyclopropyl]carbamate. NH4OAc QC conditions. M+H=490. prepared

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

Procedure: tert-Butyl N-[(1R)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]carbamate (1.2 g, 4.3 mmole) was dissolved in CH2Cl2 (40 mL). Dess-Martin periodinane (2.4 g, 5.5 mmole) was added. The solution was stirred for 2 h at room temperature and then quenched with Na2S2O3 and saturated bicarbonate solution. After extracting with CH2Cl2, the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.4) afforded (S)-tert-butyl 1-(benzyloxy)-3-oxopropan-2-ylcarbamate as a white solid (1.1 g, 96%). quenched with Na2S2O3 and saturated bicarbonate solution After extracting with CH2Cl2 the organic layer was dried over MgSO4 filtered concentrated by rotary evaporation Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.4)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoic acid (7.2 g, 24.4 mmole) was dissolved in ethylene glycol dimethyl ether (50 mL). N-Methylmorpholine (2.7 ml, 24.4 mmole) was added, and the resulting clear solution was cooled to −20° C. Isobutyl chloroformate (3.19 ml, 24.4 mmole) was added dropwise to cause N-methylmorpholine HCl salt precipitation. Stirring was continued for 15 min and the supernatant was then transferred via a filter-tipped funnel into a rapidly stirred solution of NaBH4 (2.93 g, 73.2 mmole) in ice water and washed with dry DME. After the mixture was stirred for 30 min, it was extracted with EtOAc and washed with H2O. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.2) afforded tert-butyl N-[(1R)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]carbamate as a white solid (6.3 g, 92%). N-methylmorpholine HCl salt precipitation washed with dry DME After the mixture was stirred for 30 min it was extracted with EtOAc washed with H2O dried over Na2SO4 concentrated in vacuo Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.2)

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

Procedure: Under an atmosphere of argon, to a solution of 2,5-dioxopyrrolidin-1-yl O-benzyl-N-t-butoxycarbonyl-L-serinate (4.41 g) in tetrahydrofuran (30 mL) was added sodium borohydride (644 mg) in ice bath and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (3.30 g) having the following physical data. was extracted with ethyl acetate The organic layer was washed with an aqueous saturated ammonium chloride solution and brine dried over anhydrous magnesium sulfate concentrated

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

Procedure: Under an atmosphere of argon, to a solution of 2,5-dioxopyrrolidin-1-yl O-benzyl-N-t-butoxycarbonyl-L-serinate (4.41 g) in tetrahydrofuran(30 mL) was added sodium borohydride (644 mg) in ice bath and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and concentrated to give the title compound (3.30 g) having the following physical data. was extracted with ethyl acetate The organic layer was washed with an aqueous saturated ammonium chloride solution and brine dried over anhydrous magnesium sulfate concentrated

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

Procedure: (R)-tert-butyl 1-(2-amino-3-carbamoyl-9H-pyrido[2,3-b]indol-9-yl)-3-(benzyloxy)propan-2-ylcarbamate (xvi-d) was prepared following the procedure detailed in the preparation of 63, substituting (S)-tert-butyl 1-(benzyloxy)-3-iodopropan-2-ylcarbamate (prepared as detailed in the synthesis of xxvii from commercial N-Boc-L-Ser(Bzl)-ol) for tert-butyl[1-(iodomethyl)cyclopropyl]carbamate. NH4OAc QC conditions. M+H=490. prepared

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

Procedure: tert-Butyl N-[(1R)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]carbamate (1.2 g, 4.3 mmole) was dissolved in CH2Cl2 (40 mL). Dess-Martin periodinane (2.4 g, 5.5 mmole) was added. The solution was stirred for 2 h at room temperature and then quenched with Na2S2O3 and saturated bicarbonate solution. After extracting with CH2Cl2, the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.4) afforded (S)-tert-butyl 1-(benzyloxy)-3-oxopropan-2-ylcarbamate as a white solid (1.1 g, 96%). quenched with Na2S2O3 and saturated bicarbonate solution After extracting with CH2Cl2 the organic layer was dried over MgSO4 filtered concentrated by rotary evaporation Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.4)

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoic acid (7.2 g, 24.4 mmole) was dissolved in ethylene glycol dimethyl ether (50 mL). N-Methylmorpholine (2.7 ml, 24.4 mmole) was added, and the resulting clear solution was cooled to −20° C. Isobutyl chloroformate (3.19 ml, 24.4 mmole) was added dropwise to cause N-methylmorpholine HCl salt precipitation. Stirring was continued for 15 min and the supernatant was then transferred via a filter-tipped funnel into a rapidly stirred solution of NaBH4 (2.93 g, 73.2 mmole) in ice water and washed with dry DME. After the mixture was stirred for 30 min, it was extracted with EtOAc and washed with H2O. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.2) afforded tert-butyl N-[(1R)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]carbamate as a white solid (6.3 g, 92%). N-methylmorpholine HCl salt precipitation washed with dry DME After the mixture was stirred for 30 min it was extracted with EtOAc washed with H2O dried over Na2SO4 concentrated in vacuo Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.2)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Add N-iodosuccinimide (14.19 g, 74.63 mmol) to ((R)-2-benzyloxy-1-hydroxymethylethyl)-carbamic acid tert-butyl ester (15.00 g, 53.30 mmol) and 2,2-dimethyl-1-vinyloxypropane (9.13 g, 79.96 mmol) in acetonitrile (267 mL) at room temperature. Heat to 60° C. under nitrogen for 2 hours. Cool to room temperature and dilute with ethyl acetate. Wash with water and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes) to give the desired compound as an oil (23.4 g 84.2%). Cool to room temperature Wash with water and saturated aqueous sodium chloride Dry (magnesium sulfate) filter concentrate purify (silica gel chromatography, eluting with 0:100 to 10:90 ethyl acetate:hexanes)

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

Procedure: Dissolve ((R)-2-benzyloxy-1-hydroxymethylethyl)-carbamic acid tert-butyl ester (1.0 g, 3.55 mmol) and 1,1-diphenylethylene (0.534 g, 2.96 mmol) in acetonitrile (20 mL). Add N-iodosuccinimide (0.800 g, 3.55 mmol) and stir at room temperature 72 hours. Pour into ethyl acetate and wash with saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate. Purify on silica gel, eluting with 0:100 to 30:70 ethyl acetate:hexanes to give the desired compound. wash with saturated aqueous sodium chloride Dry (magnesium sulfate) filter concentrate Purify on silica gel eluting with 0:100 to 30:70 ethyl acetate

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

Procedure: To t-butyl (1R)-2-(benzyloxy)-1-(hydroxymethyl)ethylcarbamate (3.23 g) obtained in Step 1 were added dichloromethane (40 ml), methanesulfonyl chloride (1.07 ml) and triethylamine (3.20 ml), and the mixture was stirred at 0° C. for 3 hrs. The reaction mixture was diluted with dichloromethane and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated to give a crude product. To this crude product were added dimethylformamide (30 ml) and lithium chloride (2.4 g), and the mixture was stirred overnight at 40° C. The solvent was evaporated, and the residue was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give a crude product. To this crude product were added dimethylformamide (20 ml), potassium carbonate (2.4 g) and m-cresol (1.47 ml), and the mixture was stirred overnight at 90° C. The mixture was diluted with ethyl acetate and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give t-butyl (1S)-2-(benzyloxy)-1-[(3-methylphenoxy)methyl]ethylcarbamate (1.5 g). after washing with water the organic layer was dried over anhydrous sodium sulfate The solvent was evaporated to give a crude product the mixture was stirred overnight at 40° C The solvent was evaporated the residue was diluted with ethyl acetate washed with water The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated to give a crude product the mixture was stirred overnight at 90° C after washing with water the organic layer was dried over anhydrous sodium sulfate The solvent was evaporated the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane)

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

Procedure: O-benzyl-N-(t-butoxycarbonyl)-L-serine (2 g) was dissolved in tetrahydrofuran (20 ml), triethylamine (1.22 ml) was added, and ethyl chloroformate (713 μl) was further added dropwise at 0° C. After stirring the reaction mixture at room temperature for 30 min, the reaction mixture was filtered, and one piece of ice was added to the filtrate. Sodium borohydride (515 mg) was further added, and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was diluted with ethyl acetate and, after washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane) to give t-butyl (1R)-2-(benzyloxy)-1-(hydroxymethyl)ethylcarbamate (1.7 g) the reaction mixture was filtered one piece of ice was added to the filtrate Sodium borohydride (515 mg) was further added the mixture was stirred at room temperature for 6 hrs The reaction mixture was diluted with ethyl acetate after washing with water the organic layer was dried over anhydrous sodium sulfate The solvent was evaporated the obtained crude product was purified by silica gel chromatography (ethyl acetate-hexane)