Carbon tetrabromide → (4S)-1-Boc-4-bromo-D-proline methyl ester

Participants

Reaction Steps

To a solution of (2R,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (320 g, 1.30 mol) and carbon tetrabromide (540 g, 1.94 mol) in dichloromethane (3.2 L) at 0-5° C. (dry ice/dichloromethane bath) add triphenylphosphine (1.95 mol, 514 g) in portions over 30 min and stir at room temperature for 4 h. Add ethanol (3.2 L) and stir for an additional 2 h. Transfer the reaction to an 18 L carboy and add ether (8 L) until precipitation occurs. Stir the mixture overnight. Filter off the solids and concentrate the ether layer. Dissolve the oily residue in dichloromethane and filter through a silica plug eluting with dichloromethane until no more product can be detected by TLC. Concentrate the dichloromethane layer and treat with 5% ethyl acetate in hexanes (4 L) causing a white solid to form. Pass the mixture through a silica plug eluting with 5% ethyl acetate in hexanes and collect only the fractions that contain the desired product. Concentrate the solution, dissolve in 5% ethyl acetate in hexanes (2 L) and purify through a 1 kg silica gel pad eluting with 5% ethyl acetate in hexanes to obtain the title compound as a yellowish oil (372.4 g, 93%). [α]D20+53.6 (c=1.0 in methanol). 1H NMR (400 MHz, DMSO-d6) δ 1.33 and 1.39 (two s, 9H), 2.40 (m, 1H), 2.53 (m, 1H), 3.35 (m, 1H), 3.66 (s, 3H), 3.80 (m, 1H), 4.35 (q, 1H), 4.73 (m, 1H).

Provenance & Evidence