The identification of unnatural residues that stabilize polyproline type 2 (PPII) folds can aid in the design of peptidomimetics targeting PPII-binding domains. Here, we examine the impact of peptide backbone N-amination on PPII helix stability and find N-aminoglycine (aGly) to be an effective PPII promoter. Further derivatization of an aGly-containing peptide affords N′-alkylated analogues with increased helical propensity. Backbone N-amination of glycine represents a convenient approach to stabilize PPII conformation and allows for the diversity-oriented synthesis of optimally constrained folds.

We report the total synthesis and configurational assignment of pargamicin A, a highly oxidized nonribosomal peptide that potently inhibits the growth of drug-resistant bacteria. Our synthetic approach relies on late-stage piperazine ring formation and careful selection of condensation reagents to assemble the densely substituted hexapeptide backbone. This work enables the synthesis of pargamicin congeners for the development of structure−activity relationships and informs strategies for accessing other sterically congested piperazic acid-containing natural products.

We report the total synthesis and configurational assignment of pargamicin A, a highly oxidized non-ribosomal peptide that potently inhibits the growth of drug-resistant bacteria. Our synthetic approach relies on late-stage piperazine ring formation and careful selection of condensation reagents to assemble the densely substituted hexapeptide backbone. This work enables the synthesis of pargamicin congeners for the development of structure-activity relationships and informs strategies to access other sterically congested piperazic acid-containing natural products.

We report an asymmetric synthesis of the (3R,5R)-γ-hydroxypiperazic acid (γ-OHPiz) residue encountered in several bioactive nonribosomal peptides. Our strategy relies on a diastereoselective enolate hydroxylation reaction and electrophilic N-amination to provide the acyclic γ-OHPiz precursor. This orthogonally protected α-hydrazino acid intermediate is amenable to late-stage diazinane ring formation following incorporation into a peptide chain. We determined the N-terminal amide rotamer propensity of the γ-OHPiz residue and showed that the γ-OH substituent enhances trans-amide bias relative to piperazic acid.