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

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

Procedure: In 59 ml of methylene chloride are dissolved 11.8 g of 1-benzyl 2-ethyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate, 11 ml of 3,4-dihydropyrane and 2.0 g of pyridinium p-toluenesulfonate. The solution is heated under reflux for one hour. The reaction mixture is added to 50 ml of saturated aqueous solution of sodium bicarbonate, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to obtain 12.9 g of 1-benzyl 2-ethyl (2S,4R)-4-(tetrahydro-2H-pyran-2-yloxy)-1,2-pyrrolidinedicarboxylate as a colorless oily product. The solution is heated under reflux for one hour the organic layer is separated The organic layer is washed with water and saturated aqueous solution of sodium chloride successively dried over anhydrous magnesium sulfate the solvent is distilled off under reduced pressure The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1)

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

Procedure: In 59 ml of methylene chloride are dissolved 11.8 g of 1-benzyl 2-ethyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate, 11 ml of 3,4-dihydropyrane and 2.0 g of pyridinium p-toluenesulfonate. The solution is heated under reflux for one hour. The reaction mixture is added to 50 ml of saturated aqueous solution of sodium bicarbonate, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1) to obtain 12.9 g of 1-benzyl 2-ethyl (2S,4R)-4-(tetrahydro-2H-pyran-2-yloxy)-1,2-pyrrolidinedicarboxylate as a colorless oily product. The solution is heated under reflux for one hour the organic layer is separated The organic layer is washed with water and saturated aqueous solution of sodium chloride successively dried over anhydrous magnesium sulfate the solvent is distilled off under reduced pressure The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=2:1)

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

Procedure: To a solution of N-CBZ-trans-4-hydroxy-L-proline ethyl ester (5.6 g, 19 mmol) and anhydrous pyridine (4.6 mL, 4.5 g, 57 mmol) in CHCl3 (30 mL) was added p-toluenesulfonyl chloride (7.2 g, 38 mmol) in one portion. After stirring at room temperature for 72 h, the reaction was diluted with CH2Cl2 (70 mL) and pyridine removed by repeated extraction with 10% HCl (4×10 mL). The organic layer was dried (MgSO4) and concentrated to a golden oil which was purified by silica gel flash chromatography (gradient elution, using 1:1, 2:1 ethyl ether-petroleum ether) to yield 8.2 g (98%) of pure 2 as a colorless oil: TLC Rf 0.27 (3:3:1 ethyl ether-petroleum ether-CH2CL2); [α]24D -29° (c 1.5, CHCl3); 1H NMR (250 MHz, CDCl3 δ 7.79-7.74 (m, 2 H), 7.37-7.26 (m, 7 H), 5.18-5.00 (m, 3H, phCH2 and H-4), 4.44 (app q, J=7.5 Hz, 1 H, H-2), 4.19-3.99 (q, J=7.1 Hz, 2H, CO2CH2CH3, two rotamers), 3.76-3.60 (m, 2 H, H-5), 2.62-2.38 (m, 1 H, H-3), 2.45+2.43 (s, 3 H, PhCH3), 2.23-2.08 (m, 1 H, H-3), 1.25+1.08 (t, J=7.1 Hz, 3 H, CO2CH2CH3); 13C NMR (75.5 MHz, CDCl3) δ 171.59, 171.39, 154.12, 153.64, 145.10, 135.96, 135.81, 133.14, 133.08, 129.88, 129.86, 128.25, 128.17, 127.85, 127.60, 127.48, 78.66, 78.00, 67.14, 67.11, 61.25, 61.17, 57.39, 57.07, 52.25, 51.87, 36.99, 35.86, 21.41, 13.84, 13.69; IR (CHCl3) 1740, 1705, 1420, 1355, 1175 cm-1 ; LRMS (EI, 70 eV) m/e 447 (M+, 0.23), 374 (2), 202 (2), 158 (24), 91 (100); HRMS (EI, 40 eV) m/e 447.1337 (447.1351 calcd for C22H25NO7S). removed extraction with 10% HCl (4×10 mL) The organic layer was dried (MgSO4) concentrated to a golden oil which was purified by silica gel flash chromatography (gradient elution, using 1:1, 2:1 ethyl ether-petroleum ether)