Piperazic acid (Piz) is found in a number of structurally complex non-ribosomal peptide natural products that exhibit diverse biological activity. Despite the known impact of the Piz residue on amide bond rotamer equilibrium, this residue has not been generally employed in peptidomimetic chemistry, primarily due synthetic challenges. In natural product syntheses, most approaches introduce pre-formed orthogonally protected Piz residues, prepared in many steps, onto a growing peptide chain. L-156,373, a cyclic hexapeptide and oxytocin antagonist isolated from <i>Streptomyces silvensis, </i>features two consecutive enantiomeric forms of the Piz residue. Here, we present the first total synthesis of L-156,373 and its analogues via a sub-monomer-based electrophilic amination approach. Our strategy relies on a tandem S<sub>N</sub>2 cyclization to afford both Piz residues in one step and employs l- and d- glutamic acid residues as chiral synthons. This approach provides a means to efficiently introduce Piz and δ-oxo piperazic acid (oxoPiz) residues into host peptides using readily available amino acid building blocks. Application of this approach towards the synthesis and structural confirmation of the pargamicin antibiotics will also be discussed.

Submonomer-based approach towards Piperazic acid (Piz) natural products: The total synthesis of L-156,373

2019 Spring National Meeting

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