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.

Synthesis and ß-sheet propensity of constrained N-amino peptides.

The stabilization of ß-sheet secondary structure through peptide backbone modification represents an attractive approach to protein mimicry. Here, we present strategies toward stable ß-hairpin folds based on peptide strand N-amination. Novel pyrazolidinone and tetrahydropyridazinone dipeptide constraints were introduced via on-resin Mitsunobu cyclization between α-hydrazino acid residues and a serine or homoserine side chain. Acyclic and cyclic N-amino peptide building blocks were then evaluated for their effect on ß-hairpin stability in water using a GB1-derived model system. Our results demonstrate the strong ß-sheet stabilizing effect of the peptide N-amino substituent, and provide useful insights into the impact of covalent dipeptide constraint on ß-sheet folding.