Synthesis of chiral nonracemic 4- trans-substituted pipecolic acid derivatives

Abstract

The syntheses and resolutions of enantiomerically enriched 4-phenyl, 4- tert-butyl, and 4-isopropyl pipecolic acids are described. Optically active diastereomers were prepared by diastereomeric salt formation with the chiral base, l-tyrosine hydrazide, to provide Cbz or Boc protected 4- cis- d-pipecolic acid derivatives in >98% ee. Subsequent esterification followed by sodium methoxide catalyzed epimerization provided the isomeric 4- trans- l-pipecolic esters. In addition, an efficient synthesis of 4-phenyl- cis-pipecolic acid is described.