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

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

Procedure: To a stirred solution of compound 1B (69.1 g, 0.282 mol), Ph3P (88.7 g, 0.338 mol) and benzoic acid (41.32 g, 0.338 mol) in anhydrous THF (1.35 L) cooled to 0° C. was added a solution of DEAD (62 mL, 0.33 mol) in anhydrous THF (50 mL) dropwise over 1 h through an addition funnel. After the addition, the resulting light yellow solution was stirred at rt until the reaction was complete (˜8 h). The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to yield a crude product as a semi-solid. The crude product was suspended in 25% EtOAc/hexane and stirred vigorously for 3 h. The resulting suspension was filtered and the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×). The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane as described above to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane to furnish pure compound 1C (88.4 g) as a light yellow viscous oil. After the addition (˜8 h) The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3 The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine dried (Na2SO4) concentrated under reduced pressure to yield a crude product as a semi-solid stirred vigorously for 3 h The resulting suspension was filtered the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×) The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane

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

Procedure: To a stirred solution of compound 1B (69.1 g, 0.282 mol), Ph3P (88.7 g, 0.338 mol) and benzoic acid (41.32 g, 0.338 mol) in anhydrous THF (1.35 L) cooled to 0° C. was added a solution of DEAD (62 mL, 0.33 mol) in anhydrous THF (50 mL) dropwise over 1 h through an addition funnel. After the addition, the resulting light yellow solution was stirred at rt until the reaction was complete (˜8 h). The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to yield a crude product as a semi-solid. The crude product was suspended in 25% EtOAc/hexane and stirred vigorously for 3 h. The resulting suspension was filtered and the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×). The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane as described above to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane to furnish pure compound 1C (88.4 g) as a light yellow viscous oil. After the addition (˜8 h) The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3 The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine dried (Na2SO4) concentrated under reduced pressure to yield a crude product as a semi-solid stirred vigorously for 3 h The resulting suspension was filtered the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×) The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane

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

Procedure: To a solution of 7A (13.5 g, 55 mmol) in anhydrous THF (500 mL) was added triphenylphosphine (26 g, 99 mmol), followed by benzoic acid (10.1 g, 82.7 mmol) and DEAD (9.5 mL, 60 mmol). The reaction mixture was stirred at RT for 2 hours, then partitioned between water and CH2Cl2. The organic 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 (silica gel) eluting with 15% EtOAc/hexane to give 18.1 g of the title compound as a colorless oil. partitioned between water and CH2Cl2 The organic 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 (silica gel) eluting with 15% EtOAc/hexane

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

Procedure: To a solution of (2S,3S)-N-tert-butyloxycarbonyl-3-hydroxy-2 pyrrolidinecarboxylic acid methyl ester (1B) (4.90 g, 20.0 mmol) in DMF (20 mL) at rt was added imidazole (3.41 g, 50.1 mmol), and then tert-butydimethylsilyl chloride (3.91 g, 25.9 mmol). After stirring at rt overnight, the reaction mixture was partitioned between H2O and CH2Cl2. The CH2Cl2 layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine, dried (MgSO4), then filtered and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 0-20% EtOAc/hexane to yield (2S,3S)-3-(tert-butyldimethylsilanyloxy)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (6.86 g). the reaction mixture was partitioned between H2O and CH2Cl2 The CH2Cl2 layer was washed with 1 M H3PO4, saturated aqueous NaHCO3 and brine dried (MgSO4) filtered concentrated under reduced pressure The residue was chromatographed (silica gel) eluting with 0-20% EtOAc/hexane

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

Procedure: To diisopropylamine (4.88 mL, 34.8 mmol) in THF (33 mL) at −78° C. was added a 1.37 M solution of n-butyllithium in hexane (24.6 mL, 33.7 mmol). After stirring at the same temperature for 40 min, the LDA solution was transferred via cannula over 30 min to a solution of compound 1B (2.75 g, 11.2 mmol) in THF (112 mL) at −78° C. The reaction was stirred for 1.5 h when iodomethane (10.5 mL, 168 mmol) was added and the reaction was stirred at −78° C. for 2 h then was stored at −40° C. overnight. After warming to rt and stirring overnight, the reaction was quenched with saturated aqueous ammonium chloride. Ethyl acetate was added and the layers were separated. The organic layer was washed with brine, and the aqueous layer was back-extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified using preparative HPLC (Luna C-18, 30×250 mm, eluting with 40-100% 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 compound 3A as a yellow oil (591 mg). was added the reaction was stirred at −78° C. for 2 h then was stored at −40° C. overnight stirring overnight the reaction was quenched with saturated aqueous ammonium chloride Ethyl acetate was added the layers were separated The organic layer was washed with brine the aqueous layer was back-extracted with EtOAc The combined organic layers were dried (MgSO4) filtered concentrated under reduced pressure The resulting residue was purified eluting with 40-100% solvent B (A=90% H2O-10% MeOH and B=10% H2O- 90% MeOH) over 30 min

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

Procedure: To a stirred solution of compound 1B (69.1 g, 0.282 mol), triphenylphosphine (88.7 g, 0.338 mol) and benzoic acid (41.3 g, 0.338 mol) in anhydrous THF (1.35 L) cooled to 0° C. was added a solution of DEAD (62.0 mL, 0.330 mol) in anhydrous THF (50 mL) dropwise over 1 h through an addition funnel. After the addition, the resulting light yellow solution was stirred at rt until the reaction was complete (˜8 h). The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to yield a crude product as a semi-solid. The crude product was suspended in 25% EtOAc/hexane and stirred vigorously for 3 h. The resulting suspension was filtered and the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×). The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane as described above to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified via flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane to furnish pure compound 1C (88.4 g) as a light yellow viscous oil. After the addition (˜8 h) The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3 The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine dried (Na2SO4) concentrated under reduced pressure to yield a crude product as a semi-solid stirred vigorously for 3 h The resulting suspension was filtered the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×) The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified via flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane

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

Procedure: To a solution of 7A (13.5 g, 55 mmol) in anhydrous THF (500 mL) was added triphenylphosphine (26 g, 99 mmol), followed by benzoic acid (10.1 g, 82.7 mmol) and DEAD (9.5 mL, 60 mmol). The reaction mixture was stirred at RT for 2 hours, then partitioned between water and CH2Cl2. The organic 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 (silica gel) eluting with 15% EtOAc/hexane to give 18.1 g of the title compound as a colorless oil. partitioned between water and CH2Cl2 The organic 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 (silica gel) eluting with 15% EtOAc/hexane

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

Procedure: To a stirred solution of compound 1B (69.1 g, 0.282 mol), Ph3P (88.7 g, 0.338 mol) and benzoic acid (41.32 g, 0.338 mol) in anhydrous THF (1.35 L) cooled to 0° C. was added a solution of DEAD (62 mL, 0.33 mol) in anhydrous THF (50 mL) dropwise over 1 h through an addition funnel. After the addition, the resulting light yellow solution was stirred at rt until the reaction was complete (˜8 h). The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to yield a crude product as a semi-solid. The crude product was suspended in 25% EtOAc/hexane and stirred vigorously for 3 h. The resulting suspension was filtered and the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×). The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane as described above to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane to furnish pure compound 1C (88.4 g) as a light yellow viscous oil. After the addition (˜8 h) The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3 The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine dried (Na2SO4) concentrated under reduced pressure to yield a crude product as a semi-solid stirred vigorously for 3 h The resulting suspension was filtered the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×) The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane

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

Procedure: To a stirred solution of compound 1B (69.1 g, 0.282 mol), Ph3P (88.7 g, 0.338 mol) and benzoic acid (41.32 g, 0.338 mol) in anhydrous THF (1.35 L) cooled to 0° C. was added a solution of DEAD (62 mL, 0.33 mol) in anhydrous THF (50 mL) dropwise over 1 h through an addition funnel. After the addition, the resulting light yellow solution was stirred at rt until the reaction was complete (˜8 h). The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3. The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine, dried (Na2SO4) and concentrated under reduced pressure to yield a crude product as a semi-solid. The crude product was suspended in 25% EtOAc/hexane and stirred vigorously for 3 h. The resulting suspension was filtered and the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×). The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane as described above to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane to furnish pure compound 1C (88.4 g) as a light yellow viscous oil. After the addition (˜8 h) The reaction mixture was then partitioned between EtOAc and aqueous NaHCO3 The organic layer was washed with saturated aqueous NaHCO3, water (2×), brine dried (Na2SO4) concentrated under reduced pressure to yield a crude product as a semi-solid stirred vigorously for 3 h The resulting suspension was filtered the collected white solid (triphenylphosphine oxide) rinsed with 20% EtOAc/hexane (2×) The combined filtrate was concentrated under reduced pressure to yield an oily residue, which was triturated twice with 20% EtOAc/hexane to yield approximately 150 g of the partially purified product as a yellow oil, which was further purified by flash chromatography (silica gel) eluting with 10-20% EtOAc/hexane

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

Procedure: To a solution of 7A (13.5 g, 55 mmol) in anhydrous THF (500 mL) was added triphenylphosphine (26 g, 99 mmol), followed by benzoic acid (10.1 g, 82.7 mmol) and DEAD (9.5 mL, 60 mmol). The reaction mixture was stirred at RT for 2 hours, then partitioned between water and CH2Cl2. The organic 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 (silica gel) eluting with 15% EtOAc/hexane to give 18.1 g of the title compound as a colorless oil. partitioned between water and CH2Cl2 The organic 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 (silica gel) eluting with 15% EtOAc/hexane