1-O-tert-butyl 2-O-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate

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

Procedure: To 193 g of (2S,4R)-1-(t-butoxycarbonyl)-2-ethoxycarbonyl -4-hydroxypyrrolidine dissolved in 500 ml of pyridine and cooled on an ice bath was added 213 g of p-toluenesulfonyl chloride, followed by 20 hours of stirring at room temperature. The reaction mixture was concentrated, and the resulting residue was dissolved in ethyl acetate, washed with water, 10% citric acid aqueous solution, 5% sodium bicarbonate aqueous solution and water in that order, followed by evaporation of the solvent under a reduced pressure to yield 289 g of (2S,4R)-1-(t-butoxycarbonyl)-2-ethoxycarbonyl-4-(p-toluenesulfonyloxy)pyrrolidine. cooled on an ice bath The reaction mixture was concentrated the resulting residue was dissolved in ethyl acetate washed with water, 10% citric acid aqueous solution, 5% sodium bicarbonate aqueous solution and water in that order followed by evaporation of the solvent under a reduced pressure

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

Procedure: To a solution of 1-tert-butyl 2-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (100 g, 0.38 mol) in dry dichloromethane (1.51) at 25° C. was added DMAP (47 g, 0.38 mol), followed by triethylamine (39 g, 0.38 mol). To the above reaction mixture was added TBDMSCl (64 g, 0.42 mol) dissolved in dry dichloromethane (200 ml) drop-wise over a period of 45 min. After stirring at RT for 20 h, the reaction mixture was diluted with water and separated the organic layer. The organic layer was washed with 5% aq. citric acid, brine and dried over Na2SO4. The solvent was removed under vacuum to give 1-tert-butyl 2-ethyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (140 g) as a colorless liquid. Yield: 97% separated the organic layer The organic layer was washed with 5% aq. citric acid, brine dried over Na2SO4 The solvent was removed under vacuum

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

Procedure: To a solution of 1-tert-butyl 2-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (100 g, 0.38 mol) in dry dichloromethane (1.51) at 25° C. was added DMAP (47 g, 0.38 mol), followed by triethylamine (39 g, 0.38 mol). To the above reaction mixture was added TBDMSCl (64 g, 0.42 mol) dissolved in dry dichloromethane (200 ml) drop-wise over a period of 45 min. After stirring at RT for 20 h, the reaction mixture was diluted with water and separated the organic layer. The organic layer was washed with 5% aq. citric acid, brine and dried over Na2SO4. The solvent was removed under vacuum to give 1-tert-butyl 2-ethyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (140 g) as a colorless liquid. Yield: 97% separated the organic layer The organic layer was washed with 5% aq. citric acid, brine dried over Na2SO4 The solvent was removed under vacuum

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Freshly prepared silver oxide (5.32 g, 3 eq.) and allyl iodide (15 mL, 4 eq.) were added to a solution of N-(tert-butoxycarbonyl)-trans-4-hydroxy-L-proline ethyl ester (2.2 g, 7.71 mmol) in dimethylformamide (15 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 25° C. for 12 hours, then at 55° C. for 5 hours. The reaction mixture was filtered, poured into ethyl acetate, washed twice with water, once with brine, dried (Na2SO4), concentrated and purifed by flash chromatography (20% ethyl acetate/hexane) to give the title compound (2.18 g, 94%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.38 (m, 3H), 1.48, 1.54 (2s, 9H), 2.17 (m, 1H), 2.23 (m, 1H), 3.58 (bd, J=12.4 Hz, 0.5H), 3.70 (m, 1.5H), 4.05 (m, 2H), 4.22 (m, 3H), 4.43 (m, 1H), 5.29 (dd, J=10.1; 0.7 Hz, 1H), 5.39 (dd, J=17.6; 0.6 Hz, 1H) and 5.99 (m, 1H). at 55° C. for 5 hours The reaction mixture was filtered poured into ethyl acetate washed twice with water, once with brine dried (Na2SO4) concentrated

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

Procedure: To the solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester-2-ethyl ester (27) (1.8 g, 7 mmol) in dry pyridine (40 ml) was added p-toluenesulfonyl chloride (4.0 g, 21 mmol) under nitrogen at 0° C. The reaction mixture was kept refrigerated at 0° C. for 2 days. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (150 ml). The organic was washed with water (30 ml, 2×), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using pet ether: EtOAc (1:1) to give 2.6 g of desired product. The reaction was then concentrated under reduced pressure The residue was dissolved in ethyl acetate: water (10:1) (150 ml) The organic was washed with water (30 ml, 2×) dried over MgSO4 evaporated to dryness The resulting residue was purified by column chromatography

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

Procedure: To a solution of (4R)-(tert-Butoxycarbonyl)-4-hydroxy-L-proline (26) (0.92 g, 4.0 mmol) in dry CH2Cl2 (30 ml) was added ethanol (1 ml, 21 mmol). To the reaction was added DCC (1.64 g, 8.0 mmol) and DMAP (cat) and the reaction mixture was, stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (30 ml, 2×) and 10% NaOH (10 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using CH2Cl2:CH3OH (10:1)to give 1.8 g oil as desired product. The reaction was then concentrated under reduced pressure The residue was dissolved in ethyl acetate: water (10:1) (100 ml) The organic was washed with water (30 ml, 2×) and 10% NaOH (10 ml) dried over MgSO4 evaporated to dryness The resulting residue was purified by column chromatography

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

Procedure: To 193 g of (2S,4R)-1-(t-butoxycarbonyl)-2-ethoxycarbonyl -4-hydroxypyrrolidine dissolved in 500 ml of pyridine and cooled on an ice bath was added 213 g of p-toluenesulfonyl chloride, followed by 20 hours of stirring at room temperature. The reaction mixture was concentrated, and the resulting residue was dissolved in ethyl acetate, washed with water, 10% citric acid aqueous solution, 5% sodium bicarbonate aqueous solution and water in that order, followed by evaporation of the solvent under a reduced pressure to yield 289 g of (2S,4R)-1-(t-butoxycarbonyl)-2-ethoxycarbonyl-4-(p-toluenesulfonyloxy)pyrrolidine. cooled on an ice bath The reaction mixture was concentrated the resulting residue was dissolved in ethyl acetate washed with water, 10% citric acid aqueous solution, 5% sodium bicarbonate aqueous solution and water in that order followed by evaporation of the solvent under a reduced pressure

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

Procedure: To a solution of 1-tert-butyl 2-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (100 g, 0.38 mol) in dry dichloromethane (1.51) at 25° C. was added DMAP (47 g, 0.38 mol), followed by triethylamine (39 g, 0.38 mol). To the above reaction mixture was added TBDMSCl (64 g, 0.42 mol) dissolved in dry dichloromethane (200 ml) drop-wise over a period of 45 min. After stirring at RT for 20 h, the reaction mixture was diluted with water and separated the organic layer. The organic layer was washed with 5% aq. citric acid, brine and dried over Na2SO4. The solvent was removed under vacuum to give 1-tert-butyl 2-ethyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (140 g) as a colorless liquid. Yield: 97% separated the organic layer The organic layer was washed with 5% aq. citric acid, brine dried over Na2SO4 The solvent was removed under vacuum