Exploring Nitrone Chemistry: Towards the Enantiodivergent Synthesis of 6‐Substituted 4‐Hydroxypipecolic Acid Derivatives

A methodology for the stereoselective preparation of all‐ cis 6‐substituted 4‐hydroxypipecolic acid derivatives using nitrone chemistry, involving both nucleophilic additions and cycloadditions, is presented. The N ‐benzyl nitrone derived from 1,2‐di‐ O ‐isopropylidene‐ D ‐glyceraldehyde was shown to undergo stereocontrolled allylation reactions to provide enantiomerically pure homoallyl hydroxylamines. Further transformation of these substrates into N ‐alkenyl nitrones was achieved in high yields and regioselectivities by oxidation with manganese(IV) oxide. The oxidation reaction is thermodynamically controlled and directed by a phenyl group which became the 6‐substituent. A transoximation reaction of the intermediate N ‐alkenyl‐ C ‐phenyl nitrone was needed to add versatility to the methodology by varying the substituent at the 6‐position. The resulting N ‐alkenyl nitrones underwent stereoselective intramolecular 1,3‐dipolar cycloaddition reactions to provide the immediate precursors of the target compounds. The selectivity observed in the intramolecular cycloaddition was dictated by both the steric preference and the electronic nature of the substrate, which promoted a hitherto unknown aza‐Cope rearrangement of the N ‐alkenyl nitrone. The chiral induction exerted by the dioxolane moiety as well as its synthetic equivalence with the carboxy group provided the basis for the enantiodivergency achieved in the synthesis of 6‐substituted (2 R ,4 S ,6 R )‐4‐hydroxypipecolic acids and their enantiomers. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)