A versatile route towards 6-arylpipecolic acids.

Abstract

Pipecolic acid is known as a non-proteinogenic amino acid with a secondary amine. It contains a six-membered ring and is, like its five-membered correlate, known for its secondary structure inducing properties, which are particularly useful in the design of peptide conformations. We present a new and improved way to generate enantiomerically pure pipecolic acid derivatives with aryl modifications in C⁶ position by utilising the chiral pool of a non-proteinogenic amino acid in combination with transition metal-catalysed cross-coupling reactions. Moreover, we present an in-depth NMR analysis of the key intermediate steps, which illustrates the conformational constraints in accordance with coupling constants and resulting dihedral angles.