Nature has long served as a source of scientific inspiration, leading to groundbreaking designs and discoveries. The field of peptide chemistry has benefited greatly from the discovery of new peptide natural products and the unique amino acid residues encountered within them. These residues represent an exciting opportunity for developing novel synthetic strategies towards unusual chemical scaffolds and for exploring the utility of these scaffolds in peptide mimicry. One such scaffold is the backbone N-aminated motif found in piperazic acid (Piz), a six-membered cyclic hydrazino acid residue found in several non-ribosomal peptide (NRP) natural products. These molecules exhibit a wide array of biological function such as antibacterial, antifungal and antiproliferative activity. The N-amino backbone modification also has a profound effect on amide bond conformation, isomerization kinetics, and proteolytic stability.
We describe the total synthesis of two Piz-containing NRP natural products via an electrophilic amination/late stage cyclization strategy. L-156,373 is an oxytocin receptor antagonist that harbors a di-Piz motif as well as a rare N-hydroxyisoleucine residue. We show that our submonomer approach is effective in installing this unusual motif when compared to other strategies that incorporate pre-formed Piz residues. We also employ this approach towards the first total synthesis of pargamicin A, a complex Piz-containing antibacterial agent that harbors five contiguous backbone-modified residues and various side chain oxidations. Pargamicin A exhibits potent activity against Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococci (VRE) and thus serves as a promising candidate for treating bacterial infections that are refractory to current treatments.
We also evaluate the impact of backbone N-amination on the conformation of peptides and peptidomimetics. Intrigued by the unique trans amide propensity of Piz, we investigated the conformational properties of its lower homologue, δ-azaproline, and two oxidized variants. Here, cis-trans conformational equilibria and amide isomerization barriers of residue model systems are examined in comparison to proline. We show with NMR, DFT calculations, and NBO analyses that N-heteroatom backbone modification can modulate peptidyl prolyl amide conformations and result in faster amide isomerization. Our work demonstrates that δ-azaprolines can be useful conformational probes of prolyl peptide structure and folding.