Efficient one-pot synthesis of enantiomerically pure N-protected-α-substituted piperazines from readily available α-amino acids

A new pathway towards enantiomerically pure 3-substituted piperazines, bearing a benzyl protecting group, has been developed in good overall yields (83-92%), starting from commercially available N-protected amino acids. The methodology represents an efficient and simple one-pot procedure, employing a synthetic sequence consisting of an Ugi-4 component reaction, a Boc-deprotection, an intramolecular cyclisation reaction and a final reduction (UDCR). From the benzyl protected precursors, the 2-substituted piperazines bearing a Boc-protecting group could consequently also be obtained via a simple protection and deprotection step of the corresponding piperazines. The practical utility of this methodology was demonstrated for chiral drug synthesis.