Synthesis of Cyclic a-Hydrazino and a-N-Hydroxyamino Acids for Incorporation into Peptides

In the realm of peptide chemistry, the identification of novel peptide natural products and their diverse amino acid components has significantly impacted the field. These unique residues present valuable opportunities for the development of novel chemical frameworks and for investigating their role in peptide mimicry. A particularly intriguing example is the N-aminated backbone motif found in piperazic acid (Piz), a six-membered cyclic hydrazino acid residue present in various non-ribosomal peptide (NRP) natural products. These compounds exhibit a diverse range of biological activities, including antibacterial, antifungal, and antiproliferative effects. Additionally, the N-amino modification of the peptide backbone plays a crucial role in influencing amide bond conformation, isomerization kinetics, and resistance to proteolytic degradation. This work presents the first successful total synthesis of pargamicin A, a complex antibacterial compound featuring Piz, five consecutive backbone-modified residues, and multiple side-chain oxidations. Pargamicin A exhibits potent growth-inhibitory activity against methicillin-resistant staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), highlighting its potential for treating drug-resistant infections. Intrigued by Piz’s strong trans amide propensity, we expanded our synthetic approach to develop the d-heteroatom-substituted proline analogues dehydro-d-azaproline (?aPro) and d-oxaproline (oPro) for studying peptide secondary structures. We found that ?aPro stabilizes avian pancreatic polypeptide as an unpuckered proline surrogate, while introduction of oPro into a collagen mimetic peptide resulted in a faster-folding mimetic with equivalent thermal stability. Additionally, we explored leveraging N-hydroxy peptides as substrates for synthesizing the ribosomally synthesized and post-translationally modified peptide natural products threoglucins A and B.