(5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-2-one

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

Procedure: To a solution of (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (48.5 g, 0.21 mol) in THF (100 mL) was added t-BuOK (30.8 g, 0.27 mol) at 0° C. The mixture was stirred at 0° C. for 30 min followed by addition of Cbz-Cl (40.4 mL, 0.27 mol) dropwise at 0° C. The resulting mixture was stirred at RT overnight, quenched with saturated NH4Cl, concentrated to a small amount, and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-benzyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (70 g, 91%). LRMS (M+H-44) m/z 320.2. The resulting mixture was stirred at RT overnight quenched with saturated NH4Cl concentrated to a small amount diluted with EtOAc The organic layer was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (30.0 g, 261 mmol) and imidazole (23.1 g, 340 mmol) in DCM (900 mL) was added TBS-Cl (42.9 g, 288 mmol). The reaction mixture was stirred at RT for 30 min and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (50 g, 83.7%). LRMS (M+H+) m/z 230.2. filtered The filtrate was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (48.5 g, 0.21 mol) in THF (100 mL) was added t-BuOK (30.8 g, 0.27 mol) at 0° C. The mixture was stirred at 0° C. for 30 min followed by addition of Cbz-Cl (40.4 mL, 0.27 mol) dropwise at 0° C. The resulting mixture was stirred at RT overnight, quenched with saturated NH4Cl, concentrated to a small amount, and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-benzyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (70 g, 91%). LRMS (M+H−44) m/z 320.2. The resulting mixture was stirred at RT overnight quenched with saturated NH4Cl concentrated to a small amount diluted with EtOAc The organic layer was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (30.0 g, 261 mmol) and imidazole (23.1 g, 340 mmol) in DCM (900 mL) was added TBS-Cl (42.9 g, 288 mmol). The reaction mixture was stirred at RT for 30 min and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (50 g, 83.7%). LRMS (M+H+) m/z 230.2. filtered The filtrate was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (48.5 g, 0.21 mol) in THF (100 mL) was added t-BuOK (30.8 g, 0.27 mol) at 0° C. The mixture was stirred at 0° C. for 30 min followed by addition of Cbz-Cl (40.4 mL, 0.27 mol) dropwise at 0° C. The resulting mixture was stirred at RT overnight, quenched with saturated NH4Cl, concentrated to a small amount, and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-benzyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (70 g, 91%). LRMS (M+H−44) m/z 320.2. The resulting mixture was stirred at RT overnight quenched with saturated NH4Cl concentrated to a small amount diluted with EtOAc The organic layer was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (30.0 g, 261 mmol) and imidazole (23.1 g, 340 mmol) in DCM (900 mL) was added TBS-Cl (42.9 g, 288 mmol). The reaction mixture was stirred at RT for 30 min and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (50 g, 83.7%). LRMS (M+H+) m/z 230.2. filtered The filtrate was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: A THF (10 ml) solution of the (5S)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (3.71 g, 16.2 mmols) was added dropwise to a THF (70 ml) suspension of NaH (60% oil disp. 778 mg, 19.4 mmols), with the system being cooled with ice, whereafter the mixture was stirred for 30 minutes at room temperature. To the mixture, MeI (5.0 ml, 81 mmols) was added during cooling with ice, and the mixture was stirred for 15 hours at room temperature. During cooling with ice, a saturated aqueous solution (50 ml) of NH4Cl was added, and the solvent was distilled off under reduced pressure. The residue was diluted with water, whereafter the dilution was extracted with AcOEt (50 ml×3), and the organic layer was dried over MgSO4. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 150 g, MeOH—CHCl3 3:97 v/v) to obtain (5S)-5-[(tert-butyldimethylsilyloxy)methyl]-1-methylpyrrolidin-2-one (3.86 g, 97.9%): [α]D29+3.46 (c 1.13, CHCl3). IR νmax (film) cm−1: 1682. 1H-NMR (CDCl3)δ: 3.73 (1H, dd, J=10.2, 3.3 Hz), 3.60 (1H, dd, J=10.2, 4.1 Hz), 3.55 (1H, quint, J=4.1 Hz), 2.85 (3H, s), 2.50-2.37 (1H, m), 2.35−2.23 (1H, m), 2.15-2.01 (1H, m), 1.89-1.77 (1H, m), 0.89 (9H, s), 0.06 (3H, s), 0.05 (3H, s). MS m/z: 228 (M+−15), 186, 98 (100%). HRMS: Calculated for C11H22NO2Si: 228.1420 (M+−15). Found: 228.1441 (M+−15). being cooled with ice, whereafter the mixture during cooling with ice the mixture was stirred for 15 hours at room temperature During cooling with ice the solvent was distilled off under reduced pressure The residue was diluted with water, whereafter the dilution was extracted with AcOEt (50 ml×3) the organic layer was dried over MgSO4 The solvent was distilled off under reduced pressure

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

Procedure: Imidazole (4.09 g, 60 mmols) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) were added to a CH2Cl2 (85 ml) solution of (5S)-5-(hydroxymethyl)-2-pyrrolidinone (3.14 g, 27.3 mmols). Then, with the mixture being cooled with ice, a CH2Cl2 (15 ml) solution of tert-butyldimethylsilyl chloride (4.53 g, 30 mmols) was added, and the mixture was stirred for 15 hours at room temperature. The solvent was distilled off under reduced pressure, and then the residue was subjected to silica gel column chromatography (SiO2 300 g, MeOH—CHCl3 5:95 v/v) to obtain (5S)-5-[(tert-butyldimethylsilyloxy)methyl]pyrrolidin-2-one (6.22 g, 99.5%): [α]D27+42.32 (c 1.136, CHCl3). IR νmax (film) cm−1: 3242, 1697. 1H-NMR (CDCl3)δ: 5.79 (1H, br), 3.80-3.71 (1H, m), 3.63 (1H, dd, J=9.9, 3.8 Hz), 3.44 (1H, dd, J=9.9, 7.7 Hz), 2.44-2.26 (2H, m), 2.24-2.11 (1H, m), 1.80-1.67 (1H, m), 0.89 (9H, s), 0.06 (6H, s). MS m/z: 230 (M++1), 214 (M+−15), 172 (100%). HRMS: Calculated for C10H20NO2Si: 214.1263 (M+−15). Found: 214.1240 (M+−15). Then, with the mixture being cooled with ice The solvent was distilled off under reduced pressure

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

Procedure: To a solution of (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (48.5 g, 0.21 mol) in THF (100 mL) was added t-BuOK (30.8 g, 0.27 mol) at 0° C. The mixture was stirred at 0° C. for 30 min followed by addition of Cbz-Cl (40.4 mL, 0.27 mol) dropwise at 0° C. The resulting mixture was stirred at RT overnight, quenched with saturated NH4Cl, concentrated to a small amount, and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-benzyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (70 g, 91%). LRMS (M+H-44) m/z 320.2. The resulting mixture was stirred at RT overnight quenched with saturated NH4Cl concentrated to a small amount diluted with EtOAc The organic layer was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (30.0 g, 261 mmol) and imidazole (23.1 g, 340 mmol) in DCM (900 mL) was added TBS-Cl (42.9 g, 288 mmol). The reaction mixture was stirred at RT for 30 min and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (50 g, 83.7%). LRMS (M+H+) m/z 230.2. filtered The filtrate was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (48.5 g, 0.21 mol) in THF (100 mL) was added t-BuOK (30.8 g, 0.27 mol) at 0° C. The mixture was stirred at 0° C. for 30 min followed by addition of Cbz-Cl (40.4 mL, 0.27 mol) dropwise at 0° C. The resulting mixture was stirred at RT overnight, quenched with saturated NH4Cl, concentrated to a small amount, and diluted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-benzyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidine-1-carboxylate (70 g, 91%). LRMS (M+H−44) m/z 320.2. The resulting mixture was stirred at RT overnight quenched with saturated NH4Cl concentrated to a small amount diluted with EtOAc The organic layer was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes

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

Procedure: To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (30.0 g, 261 mmol) and imidazole (23.1 g, 340 mmol) in DCM (900 mL) was added TBS-Cl (42.9 g, 288 mmol). The reaction mixture was stirred at RT for 30 min and filtered. The filtrate was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one (50 g, 83.7%). LRMS (M+H+) m/z 230.2. filtered The filtrate was washed with water and brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified on silica gel column a mixture of EtOAc and hexanes