Synthesis of Enantiomerically Pure 5-Substituted-Piperazine-2-Acetic Acid Esters as Intermediates for Library Production

The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using a bifurcated six-step synthesis, chiral amino acids were transformed, with high diastereoselectivity, into either cis or trans 5-substituted-piperazine-2-acetic acid esters that could be chromatographically rendered diastereomerically homogenous. From six amino acids (both antipodes), through their derived amino alcohols, a complete matrix of 24 protected chiral 2,5-disubstituted piperazines was obtained, each as a single absolute stereoisomer, mostly in multi-gram quantities. These diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis or intermediates for the production of novel piperazine compounds.