δ-Azaproline and Its Oxidized Variants

Peptides featuring backbone N-amino substituents exhibit unique conformational properties owing to additional electrostatic, hydrogen-bonding, and steric interactions. Here, we describe the synthesis and conformational analysis of three delta-azaproline derivatives as potential proline surrogates. Our studies demonstrate stereoelectronic tuning of heterocyclic ring pucker, cis/trans amide propensity, and amide isomerization barriers within a series of oxidation state variants. A combination of NMR, X-ray diffraction, and density functional theory calculations shows that electron density and hybridization at the delta position play a dominant role in the conformational preferences of each analogue. Both delta-azaproline and gamma,delta-dehydro-delta-azaproline exhibit strong trans amide rotamer propensities irrespective of ring conformation, while a novel residue, gamma-oxo-delta-azaproline, features rapid amide isomerization kinetics and isoenergetic amide bond geometries influenced by torsional strain and H-bonding interactions. The introduction of the delta heteroatom in each residue allows the decoupling of structural effects that are typically linked in proline and its pyrrolidine-substituted analogues. delta-Azaproline derivatives thus represent useful probes of prolyl amide isomerism with potential applications in peptidomimetic drug design and protein folding.