ditert-butyl (2S)-4-oxopyrrolidine-1,2-dicarboxylate

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

Procedure: To an oven-dried 2-necked round-bottomed flask was added sodium hydride (80% oil dispersion) (497 mg, 16.56 mmol) followed by dry tetrahydrofuran (42 mL) and methyltriphenyl-phosphonium bromide (5.92 g, 16.56 mmol). The suspension was stirred for 4 hours at 50° C., at which time a solution of 1-(tert-butyloxycarbonyl)-4-oxo-L-proline tert-butyl ester (1.18 g, 4.14 mmol) in THF (10 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was stirred for 2 hours at 50° C., cooled, filtered, and evaporated. The residue was taken up in ethyl acetate (100 mL), washed with N hydrochloric acid (2×), water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product was subjected to flash silica gel chromatography eluting with 15% diethyl ether/hexane. The title compound was obtained as a colorless oil; yield 519 mg (43%). 400 MHz 1HNMR (CDCl3): δ1.42-1.47 (3s, 18H); 2.54 (m, 1H); 2.92 (m, 1H); 4.03 (m, 2H); 4.23-4.38 (m, 1H); 4.98 (m, 2H). was added dropwise The reaction mixture was stirred for 2 hours at 50° C. cooled filtered evaporated washed with N hydrochloric acid (2×), water (2×), saturated brine solution dried (Na2SO4) evaporated eluting with 15% diethyl ether/hexane

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

Procedure: To an oven-dried 2-necked round-bottomed flask was added sodium hydride (80% oil dispersion) (497 mg, 16.56 mmol) followed by dry tetrahydrofuran (42 mL) and methyltriphenyl-phosphonium bromide (5.92 g, 16.56 mmol). The suspension was stirred for 4 hours at 50° C., at which time a solution of 1-(tert-butyloxycarbonyl)-4-oxo-L-proline tert-butyl ester (1.18 g, 4.14 mmol) in THF (10 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was stirred for 2 hours at 50° C., cooled, filtered, and evaporated. The residue was taken up in ethyl acetate (100 mL), washed with N hydrochloric acid (2×), water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product was subjected to flash silica gel chromatography eluting with 15% diethyl ether/hexane. The title compound was obtained as a colorless oil; yield 519 mg (43%). 400 MHz 1HNMR (CDCl3): δ1.42-1.47 (3s, 18H); 2.54 (m, 1H); 2.92 (m, 1H); 4.03 (m, 2H); 4.23-4.38 (m, 1H); 4.98 (m, 2H). was added dropwise The reaction mixture was stirred for 2 hours at 50° C. cooled filtered evaporated washed with N hydrochloric acid (2×), water (2×), saturated brine solution dried (Na2SO4) evaporated eluting with 15% diethyl ether/hexane

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

Procedure: To an oven-dried 2-necked round-bottomed flask was added sodium hydride (80% oil dispersion) (497 mg, 16.56 mmol) followed by dry tetrahydrofuran (42 mL) and methyltriphenyl-phosphonium bromide (5.92 g, 16.56 mmol). The suspension was stirred for 4 hours at 50° C., at which time a solution of 1-(tert-butyloxycarbonyl)-4-oxo-L-proline tert-butyl ester (1.18 g, 4.14 mmol) in THF (10 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was stirred for 2 hours at 50° C., cooled, filtered, and evaporated. The residue was taken up in ethyl acetate (100 mL), washed with N hydrochloric acid (2×), water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product was subjected to flash silica gel chromatography eluting with 15% diethyl ether/hexane. The title compound was obtained as a colorless oil; yield 519 mg (43%). 400 MHz 1HNMR (CDCl3): δ1.42-1.47 (3s, 18H); 2.54 (m, 1H); 2.92 (m, 1H); 4.03 (m, 2H); 4.23-4.38 (m, 1H); 4.98 (m, 2H). was added dropwise The reaction mixture was stirred for 2 hours at 50° C. cooled filtered evaporated washed with N hydrochloric acid (2×), water (2×), saturated brine solution dried (Na2SO4) evaporated eluting with 15% diethyl ether/hexane

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

Procedure: Zinc dust (1.05 g, 16 mmol, 1.6 eq.) in a flask was heated with a heat gun two times. Dry THF (10 mL) and chlorotrimethylsilane (0.405 mL, 3.2 mmol, 0.32 eq.) were added to this flask. The suspension was stirred for 15 min at room temp., heated to reflux, and then removed from the heat. (S)-di-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylate (2.85 g, 10 mmol, 1 eq.) and ethyl 2-bromoacetate (1.77 mL, 16 mmol, 1.6 eq.) were combined with dry THF (10 mL), and added slowly to the Zinc suspension at a rate that at which a gentle reflux was observed. The reaction was refluxed for 2 hrs and monitored by TLC. Upon completion, the reaction was concentrated. Chromatography using hexanes and ethyl acetate gave 2.64 g (7.3 mmol) of (2S)-di-tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypyrrolidine-1,2-dicarboxylate (A1) as a 4:1 (2S,4S:2S,4R) mixture of the diastereomers. 1H NMR (300 MHz, DMSO) 4.97 (m, 1H), 4.14-4.01 (m, 3H), 3.48-3.33 (m, 2H), 2.56 (m, 2H), 2.35-2.19 (m, 1H), 2.03 (dd, 1H), 1.40-1.35 (m, 18H), 1.18 (t, 3H). heated to reflux removed from the heat a gentle reflux The reaction was refluxed for 2 hrs Upon completion, the reaction was concentrated

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

Procedure: To an oven-dried 2-necked round-bottomed flask was added sodium hydride (80% oil dispersion) (497 mg, 16.56 mmol) followed by dry tetrahydrofuran (42 mL) and methyltriphenyl-phosphonium bromide (5.92 g, 16.56 mmol). The suspension was stirred for 4 hours at 50° C., at which time a solution of 1-(tert-butyloxycarbonyl)-4-oxo-L-proline tert-butyl ester (1.18 g, 4.14 mmol) in THF (10 mL) was added dropwise with stirring over 30 minutes. The reaction mixture was stirred for 2 hours at 50° C., cooled, filtered, and evaporated. The residue was taken up in ethyl acetate (100 mL), washed with N hydrochloric acid (2×), water (2×), saturated brine solution, dried (Na2SO4), and evaporated. The crude product was subjected to flash silica gel chromatography eluting with 15% diethyl ether/hexane. The title compound was obtained as a colorless oil; yield 519 mg (43%). 400 MHz 1HNMR (CDCl3): δ1.42-1.47 (3s, 18H); 2.54 (m, 1H); 2.92 (m, 1H); 4.03 (m, 2H); 4.23-4.38 (m, 1H); 4.98 (m, 2H). was added dropwise The reaction mixture was stirred for 2 hours at 50° C. cooled filtered evaporated washed with N hydrochloric acid (2×), water (2×), saturated brine solution dried (Na2SO4) evaporated eluting with 15% diethyl ether/hexane