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 δ-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 δ position play a dominant role in the conformational
preferences of each analogue. Both δ-azaproline and γ,δ-dehydro-δ-azaproline
exhibit strong trans amide rotamer propensities irrespective
of ring conformation, while a novel residue, γ-oxo-δ-azaproline,
features rapid amide isomerization kinetics and isoenergetic amide
bond geometries influenced by torsional strain and H-bonding interactions.
The introduction of the δ heteroatom in each residue allows
the decoupling of structural effects that are typically linked in
proline and its pyrrolidine-substituted analogues. δ-Azaproline
derivatives thus represent useful probes of prolyl amide isomerism
with potential applications in peptidomimetic drug design and protein
folding.