Enantioselective Synthesis of Substituted Pipecolic Acid Derivatives

Abstract

Enantiomerically pure 4-piperidones, prepared by asymmetric [4 + 2] Diels−Alder cycloadditon of chiral 2-aminodienes with imines, have been used as starting materials for the synthesis of several derivatives of pipecolic acid. The α-amino acid moiety is obtained after the oxidation of a hydroxy group or a furan ring of a conveniently protected 2-aryl-6-(hydroxymethyl)-4-piperidone. Depending on the starting piperidone and the synthetic strategy, it is possible to obtain d- or l-functionalized pipecolic acid derivatives by a short synthetic procedure. Moreover, a stereoselective epimerization of the α-carbon atom of a particular pipecolate allows for the preparation of both cis- and trans- 6-(hydroxymethyl)pipecolic acids, structures related with dipeptide isosteres.