Benzyl chloroformate → tert-butyl (3R,4R)-3-(benzyloxycarbonylamino)-4-fluoro-pyrrolidine-1-carboxylate

Participants

Reaction Steps

A solution of (2S)-2-phenylbutanedioic acid-tert-butyl (3R,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (1:1) (500 mg, 1.2 mmol) in DCM (20 mL) was cooled in an ice/water bath. DIPEA (0.69 mL, 4 mmol, 3.3 mol eq) was added, followed by CBZ-Cl (185 μL, 1.26 mmol, 1.05 mol eq). The resulting reaction solution was capped, stirred in the cold bath and allowed to warm to rt and stirred for 2 hr. The reaction was diluted with DCM (30 mL) and washed with sat. aq. NaHCO3 (10 mL). The organic layer was separated, dried over Na2SO4, and evaporated to give a colorless residue that was purified via flash chromatography (eluting with a gradient of 100% heptane to 50 ethyl acetate-50% heptane) to give the title compound as a colorless oil (388 mg, 96 yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.30-7.42 (m, 5 H) 5.12 (br. s., 2 H) 4.74-5.04 (m, 1 H) 4.28 (br. s., 1 H) 3.28-3.80 (m, 4 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −180.76-−178.52 (m, 1 F). m/z (APCI+) for C17H23FN2O4 239.2 (M+H)+. Chiral purity was determined as below (using the racemic material to compare):

Provenance & Evidence