Stereoconvergent approach for synthesizing enantiopure 5, 6-dialkylpipecolic acids

Investigating a general route for synthesizing pipecolic acid ) piperidine-2-carboxylic acid ( derivatives with substituents at the 3-, 4-, 5- and 6-position, we discovered a stereoconvergent process that provides an effective means for making 5, 6-dialkyl-epsilonpipecolate (Scheme 1, PhF = 9-phenylfluoren-9-yl). Hydrogenation of diastereomeric mixtures of gamma-oxo gamma-hydroxy and gamma-acetoxy alpha-N-(PhF)amino tert-butyl esters causes the eventual loss of the gamma-substituent to furnish an azadiene intermediate that can reduce diastereoselectively to 5, 6-dialkylpipecolate having the all cis relative stereoconfiguration. Five enantiopure (>94% ee) 5,6-dialkylpipecolic acids were synthesized, employing aspartic acid as an inexpensive chiral educt in this process.