1-O-tert-butyl 2-O-methyl (2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate

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

Procedure: To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (0.63 g, 2.56 mmol) in CH2Cl2 (12 mL) at rt was added imidazole (0.35 g, 5.14 mmol), and then tert-butydimethylsilyl chloride (0.43 g, 2.83 mmol). After stirring for 3 h, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, NaHCO3 and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield the title compound (0.91 g). LC/MS m/z 360 [M+H]+. the reaction mixture was partitioned between H2O and CH2Cl2 The CH2Cl2 layer was washed with 1 M H3PO4, NaHCO3 and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane

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

Procedure: To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (0.63 g, 2.56 mmol) in CH2Cl2 (12 mL) at rt was added imidazole (0.35 g, 5.14 mmol), and then tert-butydimethylsilyl chloride (0.43 g, 2.83 mmol). After stirring for 3 h, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, NaHCO3 and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield the title compound (0.91 g). LC/MS m/z 360 [M+H]+. the reaction mixture was partitioned between H2O and CH2Cl2 The CH2Cl2 layer was washed with 1 M H3PO4, NaHCO3 and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane

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

Procedure: To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (1.13 g, 4.61 mmol) in THF (73 mL) at −78° C. was slowly added a 1.8 M solution of LDA (7.70 mL, 13.86 mmol). After stirring for 1 h, iodomethane (2.87 mL, 46.10 mmol) was added, and the reaction was stirred for 1 h at −78° C., before warming gradually to −20° C. for 3 h, and then was stored at −40° C. overnight. After quenching with saturated aqueous NH4Cl, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified using preparative HPLC (Luna C-18, 21.2×250 mm, eluting with 50-90% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide a mixture of the starting material and its epimer as a yellow oil (490 mg) and the title compound as a yellow oil (362 mg); LC/MS m/z 260 [M+H]+. the reaction was stirred for 1 h at −78° C. was stored at −40° C. overnight After quenching with saturated aqueous NH4Cl, water and EtOAc were added the layers were separated The organic layer was washed with brine the aqueous layer was extracted with EtOAc The combined organics were dried (MgSO4) filtered concentrated under reduced pressure The residue was purified eluting with 50-90% solvent B (A=90% H2O—10% MeOH and B=10% H2O—90% MeOH) over 30 min UV detection at 220 nm) to provide

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

Procedure: To a solution of compound 1C (88.44 g, 0.253 mol) in anhydrous MeOH (700 mL) cooled to 0° C. was slowly added a freshly prepared 1N solution of KOH in anhydrous MeOH (367 mL, 0.367 mol) over 25 min through an addition funnel. After the addition, the light yellow solution was stirred at 0° C. for 2 h, and then the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel. The resulting white suspension was concentrated under reduced pressure to remove most of the solvent, and the remaining mixture was partitioned between water and EtOAc. The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine, and then dried (Na2SO4). The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane, then 5% MeOH in 30% EtOAc/hexane to furnish compound 1D (44.6 g) as a pale yellow oil. After the addition the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel The resulting white suspension was concentrated under reduced pressure to remove most of the solvent the remaining mixture was partitioned between water and EtOAc The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine dried (Na2SO4) The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane

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

Procedure: To a solution of compound 1C (88.44 g, 0.253 mol) in anhydrous MeOH (700 mL) cooled to 0° C. was slowly added a freshly prepared 1N solution of KOH in anhydrous MeOH (367 mL, 0.367 mol) over 25 min through an addition funnel. After the addition, the light yellow solution was stirred at 0° C. for 2 h, and then the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel. The resulting white suspension was concentrated under reduced pressure to remove most of the solvent, and the remaining mixture was partitioned between water and EtOAc. The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine, and then dried (Na2SO4). The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane, then 5% MeOH in 30% EtOAc/hexane to furnish compound 1D (44.6 g) as a pale yellow oil. After the addition the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel The resulting white suspension was concentrated under reduced pressure to remove most of the solvent the remaining mixture was partitioned between water and EtOAc The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine dried (Na2SO4) The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane

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

Procedure: To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (0.63 g, 2.56 mmol) in CH2Cl2 (12 mL) at rt was added imidazole (0.35 g, 5.14 mmol), and then tert-butydimethylsilyl chloride (0.43 g, 2.83 mmol). After stirring for 3 h, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, NaHCO3 and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane to yield the title compound (0.91 g). LC/MS m/z 360 [M+H]+. the reaction mixture was partitioned between H2O and CH2Cl2 The CH2Cl2 layer was washed with 1 M H3PO4, NaHCO3 and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was chromatographed (silica gel) eluting with 30% EtOAc/hexane

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

Procedure: To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (1.13 g, 4.61 mmol) in THF (73 mL) at −78° C. was slowly added a 1.8 M solution of LDA (7.70 mL, 13.86 mmol). After stirring for 1 h, iodomethane (2.87 mL, 46.10 mmol) was added, and the reaction was stirred for 1 h at −78° C., before warming gradually to −20° C. for 3 h, and then was stored at −40° C. overnight. After quenching with saturated aqueous NH4Cl, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified using preparative HPLC (Luna C-18, 21.2×250 mm, eluting with 50-90% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide a mixture of the starting material and its epimer as a yellow oil (490 mg) and the title compound as a yellow oil (362 mg); LC/MS m/z 260 [M+H]+. the reaction was stirred for 1 h at −78° C. was stored at −40° C. overnight After quenching with saturated aqueous NH4Cl, water and EtOAc were added the layers were separated The organic layer was washed with brine the aqueous layer was extracted with EtOAc The combined organics were dried (MgSO4) filtered concentrated under reduced pressure The residue was purified eluting with 50-90% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 30 min UV detection at 220 nm) to provide

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

Procedure: To a solution of (2S,3R)—N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1D) (1.13 g, 4.61 mmol) in THF (73 mL) at −78° C. was slowly added a 1.8 M solution of LDA (7.70 mL, 13.86 mmol). After stirring for 1 h, iodomethane (2.87 mL, 46.10 mmol) was added, and the reaction was stirred for 1 h at −78° C., before warming gradually to −20° C. for 3 h, and then was stored at −40° C. overnight. After quenching with saturated aqueous NH4Cl, water and EtOAc were added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified using preparative HPLC (Luna C-18, 21.2×250 mm, eluting with 50-90% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 30 min; Flow rate at 10 mL/min. UV detection at 220 nm) to provide a mixture of the starting material and its epimer as a yellow oil (490 mg) and the title compound as a yellow oil (362 mg); LC/MS m/z 260 [M+H]+. the reaction was stirred for 1 h at −78° C. was stored at −40° C. overnight After quenching with saturated aqueous NH4Cl, water and EtOAc were added the layers were separated The organic layer was washed with brine the aqueous layer was extracted with EtOAc The combined organics were dried (MgSO4) filtered concentrated under reduced pressure The residue was purified eluting with 50-90% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 30 min UV detection at 220 nm) to provide

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

Procedure: To a solution of compound 1C (88.44 g, 0.253 mol) in anhydrous MeOH (700 mL) cooled to 0° C. was slowly added a freshly prepared 1N solution of KOH in anhydrous MeOH (367 mL, 0.367 mol) over 25 min through an addition funnel. After the addition, the light yellow solution was stirred at 0° C. for 2 h, and then the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel. The resulting white suspension was concentrated under reduced pressure to remove most of the solvent, and the remaining mixture was partitioned between water and EtOAc. The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine, and then dried (Na2SO4). The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane, then 5% MeOH in 30% EtOAc/hexane to furnish compound 1D (44.6 g) as a pale yellow oil. After the addition the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel The resulting white suspension was concentrated under reduced pressure to remove most of the solvent the remaining mixture was partitioned between water and EtOAc The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine dried (Na2SO4) The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane

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

Procedure: To a solution of compound 1C (88.44 g, 0.253 mol) in anhydrous MeOH (700 mL) cooled to 0° C. was slowly added a freshly prepared 1N solution of KOH in anhydrous MeOH (367 mL, 0.367 mol) over 25 min through an addition funnel. After the addition, the light yellow solution was stirred at 0° C. for 2 h, and then the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel. The resulting white suspension was concentrated under reduced pressure to remove most of the solvent, and the remaining mixture was partitioned between water and EtOAc. The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine, and then dried (Na2SO4). The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane, then 5% MeOH in 30% EtOAc/hexane to furnish compound 1D (44.6 g) as a pale yellow oil. After the addition the reaction was quenched by slow addition (over 25 min) of a solution of 1N HCl in dioxane/EtOAc (380 mL) through an addition funnel The resulting white suspension was concentrated under reduced pressure to remove most of the solvent the remaining mixture was partitioned between water and EtOAc The separated organic phase was washed with water (2×), saturated aqueous NaHCO3 (2×), water, brine dried (Na2SO4) The filtrate was concentrated under reduced pressure to give a light yellow oily residue, which was chromatographed (silica gel) eluting first with 25-30% EtOAc/hexane

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

Procedure: To a solution of 500 mg (2.05 mmol) of N-BOC-3(R)-hydroxy-(L)-proline, methyl ester and 1.7 g (12.2 mmol) of MeI in 10 mL of DMF was added 473 mg (2.05 mmol) of Ag2O. The mixture was stirred for 18 h and was then filtered through a pad of celite and concentrated. The crude residue was dissolved in EtOAc and washed with 1M HCl (2×10 mL), saturated NaHCO3 (2×10 mL), brine (1×10 mL), dried anhydrous MgSO4, and concentrated to give 500 mg of N-BOC-3(R)-methoxy-(L)-proline, methyl ester as a light yellow oil which was used without further purification. was then filtered through a pad of celite concentrated The crude residue was dissolved in EtOAc washed with 1M HCl (2×10 mL), saturated NaHCO3 (2×10 mL), brine (1×10 mL), dried anhydrous MgSO4 concentrated

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

Procedure: To a solution of 7B (18 g, 51.5 mmol) in anhydrous MeOH (360 mL) at RT was slowly added a freshly prepared 1N solution of KOH in anhydrous MeOH (77 mL, 77 mmol) in portions. The mixture was stirred at RT until the reaction was completed (about 1 hour). The reaction was cooled at 0° C., then quenched by slow addition of 1N aqueous HCl (77 mL). The mixture was concentrated under reduced pressure to remove most of the MeOH solvent, and the remaining mixture partitioned between water and EtOAc. The separated EtOAc phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed eluting with 30% EtOAc/hexane to give 12.4 g of the title compound as a colorless oil. (about 1 hour) The reaction was cooled at 0° C. quenched by slow addition of 1N aqueous HCl (77 mL) The mixture was concentrated under reduced pressure to remove most of the MeOH solvent the remaining mixture partitioned between water and EtOAc The separated EtOAc phase was washed with saturated aqueous NaHCO3 and brine dried over Na2SO4 filtered The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed eluting with 30% EtOAc/hexane