Syntheses of 4-hydroxypipecolic acids through stereoselective cycloaddition of configurationally stable nitrones

The diastereoselective synthesis of trans- and cis-4-hydroxypipecolic acids has been achieved with geometry-controlled nitrone cycloaddition chemistry. The cycloaddition of 3-butenol to enantiopure C-aminocarbonyl and C-alkoxycarbonyl nitrones having a definite (Z) and (E) configuration, respectively, occurs with complete regio- and exo selectivity. The acyclic (Z)-nitrone 12 affords two cycloadducts in a 1:1 ratio, which can be separated and converted into (2R,4R)- and (2S,4S)-4-hydroxypiperolic acids, respectively, in four steps, The cyclic (E)-nitrone 17 reacts with complete diastereofacial selectivity and the elaboration of its sole adduct gives the methyl ester of (2R,4S)-4- hydroxypip e colic acid, albeit in low yield