The conformational heterogeneity of backbone N-substituted peptides limits their ability to adopt stable secondary structures. Herein, we describe a practical synthesis of backbone aminated peptides that readily adopt β-sheet folds. Data derived from model N-amino peptides suggest that extended conformations are stabilized through cooperative steric, electrostatic, and hydrogen-bonding interactions.
Backbone N-methylation of α-peptides has been widely employed to enhance the bioavailability and bioactivity of parent sequences. Heteroatomic peptide amide substituents have received less attention due, in part, to the lack of practical synthetic strategies. Here, we report the synthesis of α-hydrazino acids derived from 19 out of the 20 canonical proteinogenic amino acids and demonstrate their use in the solid-phase synthesis of N-amino peptide derivatives.
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.
The conformational heterogeneity of backbone Nsubstituted peptides limits their ability to adopt stable secondary structures.H erein, we describe ap ractical synthesis of backbone aminated peptides that readily adopt b-sheet folds. Data derived from model N-amino peptides suggest that extended conformations are stabilized through cooperative steric, electrostatic,and hydrogen-bonding interactions.
The first chemical synthesis of L-156,373 (1), a potent oxytocin receptor antagonist isolated from Streptomyces silvensis, is reported. Assembly of the unusual d-Piz-l-Piz dipeptide subunit was achieved through a sequential electrophilic amination-acylation-deprotection strategy followed by late-stage Piz ring formation. Synthesis and incorporation of a novel N-hydroxy-l-isoleucine building block is also described. This submonomer approach was further applied to the expedient synthesis of a di-δ-oxopiperazic acid analogue of 1 starting from Fmoc-Glu( tBu)-OH building blocks.
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