Step 3: Preparation of (R)-1-benzyloxycarbonyl-pyrrolidine-3-carboxylic acid (X): (R)-(1-benzyloxycarbonyl-pyrrolidin-3-yl)-methanol (IX, 80 g) was dissolved in acetone (800 ml), and Jones' reagent (200 ml, prepared by dissolving 53.4 g of CrO3 in 46 ml of H2SO4 and 140 ml of water under stirring) was added dropwise. solution, the final volume was adjusted to 200 mL). The reaction was carried out at 20 °C until the solution took on a deep red color and green solids precipitated. The suspension was continued to be stirred for 30 min. After confirming that the reaction was complete by thin layer chromatography (TLC, the unfolding agent was a chloroform solution of 10% methanol), isopropanol (100 ml) was added drop by drop to quench the reaction and the green color lasted for 10 minutes. The reaction mixture was filtered through a bed of diatomaceous earth and the solid was washed with fresh acetone (100 mL, twice). The filtrate was concentrated under vacuum and the residue was adjusted to pH 8 by addition of saturated aqueous sodium bicarbonate (600 ml).The resulting mixture was extracted with ethyl acetate (400 ml) to separate the organic and aqueous layers. The aqueous layer was adjusted to pH 2 with aqueous 6N hydrochloric acid (125 ml) and then extracted with ethyl acetate (500 ml x 2). The organic layers were combined, dried with sodium sulfate, and the solvent evaporated to give 67 g of (R)-1-benzyloxycarbonyl-pyrrolidine-3-carboxylic acid (X) as an oily syrup in 79% yield. The product was analyzed by nuclear magnetic resonance (NMR, CDCl3) and mass spectrometry (MS) to confirm: NMR (CDCl3): δ 9.25 (br s, 1H), 7.25-7.35 (m, 5H), 5.13 (s, 2H), 3.62-3.71 (m, 2H), 3.52-3.54 (m, 1H), 3.43-3.49 (m, 1H). 3.07-3.10 (m, 1H), 2.09-2.18 (m, 2H). Mass spectrum (M-1): 248.1 for C14H15NO4.
