Chemoenzymatic Synthesis of cis‐4‐Hydroxy‐D‐proline

Candida antarctica lipase fraction B (CALB) catalyzed the hydrolysis of the (S)-enantiomer of racemic 4-oxo-1,2-pyrrolidinedicarboxylic acid dimethyl ester with high enantioselectivity (> 99.5% ee at 51% conversion). Regioselective hydrogenation of the isolated (R)-4-oxo-1,2-pyrrolidinedicarboxylic acid dimethyl ester produced (2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylic acid dimethyl ester in 98% yield, and subsequent hydrolysis of the ester and N-(alkoxycarbonyl) groups produced cis-4-hydroxy-D-proline in 98% yield and 96% de. Diastereomeric mixtures of 4-hydroxy-1,2-pyrrolidinedicarboxylic acid dimethyl esters were also resolved using CALB to produce cis-4-hydroxy-D-proline or trans-4-hydroxy-L-proline in 93 to > 99.5% diastereomeric excess.