The Synthesis of 4‐Hydroxypipecolic Acids by 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 (2 R ,4 R )‐ and (2 S ,4 S )‐4‐hydroxypipecolic 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 (2 R ,4 S )‐4‐hydroxypipecolic acid, albeit in low yield. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)