Synthesis of Enantiomerically Pure 3‑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 an efficient six-step synthesis,
chiral amino acids were transformed into 3-substituted piperazine-2-acetic
acid esters as diastereomeric mixtures whose cis and trans products (dr 0.56 → 2.2:1, respectively) could
be chromatographically separated. From five amino acids (both antipodes)
was obtained a complete matrix of 20 monoprotected chiral 2,3-disubstituted
piperazines, each as a single absolute stereoisomer, all but one in
multigram quantities. In keeping with our overall purpose of constructing
more Csp3-enriched compound libraries for drug discovery,
these diverse and versatile piperazines can be functionalized on either
nitrogen atom, allowing them to be used as scaffolds for parallel
library synthesis and as intermediates for the production of novel
piperazine compounds.