Reverse Turn and Loop Secondary Structures in Stereodefined Cyclic Peptoid Scaffolds

Controlling the network of intramolecular
interactions encoded
by Nα-chiral side chains and the equilibria
between cis- and trans-amide junctions in cyclic peptoid architectures
constitutes a significant challenge for the construction of stable
reverse turn and loop structures. In this contribution, we reveal,
with the support of NMR spectroscopy, single-crystal X-ray crystallography
and density functional theory calculations, the relevant noncovalent
interactions stabilizing tri-, tetra-, hexa-, and octameric cyclic
peptoids (as free hosts and host–guest complexes) with strategically
positioned N-(S)-(1-phenylethyl)/N-benzyl side chains, and how these interactions influence
the backbone topological order. With the help of theoretical models
and spectroscopic/diffractometric studies, we disclose new γ-/β-turn
and loop structures present in α-peptoid-based macrocycles and
classify them according ϕ, ψ, and ω torsion angles.
In our endeavor to characterize emergent secondary structures, we
solved the solid-state structure of the largest metallated cyclic
peptoid ever reported, characterized by an unprecedented alternated
cis/trans amide bond linkage. Overall, our results indicate that molecules
endowed with different elements of asymmetry (central and conformational)
provide new architectural elements of facile atroposelective construction
and broad conformational stability as the minimalist scaffold for
novel stereodefined peptidomimetic foldamers and topologically biased
libraries necessary for future application of peptoids in all fields
of science.