A short and convenient synthesis of enantiopure cis- and trans-4-hydroxypipecolic acid

The synthesis of (2S,4R)- and (2R,4R)-4-hydroxypipecolic acid has been realized from commercial ethyl (R)-4-cyano-3-hydroxybutanoate through palladium-catalyzed methoxycarbonylation of a 4-hydroxy-substituted lactam-derived vinyl phosphate followed by the stereocontrolled reduction of the enamine double bond. The stereoselective hydrogenation of the suitably 4-hydroxy-protected enantiomer afforded the cis-(2S,4R)-4-hydroxypipecolic acid product, obtained in 66% overall yield over seven steps. The trans-product (42% overall yield over 8 steps) was instead obtained by hydride conjugate addition to the same alpha,beta-unsaturated ester.