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

The piperazine heterocycle
is housed within a large number of FDA-approved
drugs and biological probe compounds. Structurally, however, these
compounds are mostly confined to substitutions on the two ring nitrogen
atoms, rationalizing the expansion of piperazine chemical diversity
through carbon substitutions. On the basis of the concept of systematic
chemical diversity, a divergent six-step synthesis was developed in
which 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 homogeneous. Starting from six commercially
available amino acids or their respective amino alcohols (both antipodes),
we obtained a complete set of 24 protected chiral 2,5-disubstituted
piperazines, as single stereoisomers in multigram quantities. These
diverse and versatile piperazines can be functionalized on either
nitrogen atom, allowing them to be used as starting materials for
parallel library synthesis and as intermediates for the targeted production
of more complex C-substituted piperazine compounds.