General procedure for the synthesis of (4R)-N-CBZ-4-hydroxy-D-proline methyl ester from cis-4-hydroxy-D-proline: to a stirred 4R-hydroxypyrrolidine-2R-carboxylic acid (5.02 g, 38.3 mmol, 1 eq.) and sodium bicarbonate (8.05 g, 95.8 mmol, 2.5 eq.) in water (85 mL) at 23°C was A solution of benzyl chloroformate (6.28 mL, 44.0 mmol, 1.15 eq.) in toluene (20 mL) was added slowly over 15 minutes. After 24 hours of reaction, the organic and aqueous layers were separated, the aqueous layer was extracted with ether (2 x 100 mL), and the organic layers were combined and discarded. Subsequently, the aqueous layer was acidified to pH 2 with concentrated hydrochloric acid and the product was extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuum to give (4R)-N-benzyloxycarbonyl-4-hydroxy-D-proline methyl ester (9.97 g, 100% yield).
