Reverse Turn and Loop Secondary Structures in Stereodefined Cyclic Peptoid Scaffolds

Abstract

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)-(1phenylethyl)/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-peptoidbased 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.

The Challenge of Conformational Isomerism in Cyclic Peptoids

“…These large cyclopeptoids, with alternating dyads of cis and trans amide bonds, reveal C 2 ‐symmetric ccttcctt backbones (ΔG ‡ for conformational inversion: ca. 15/16 kcal mol –1 ), , with ϕ and ψ torsion angles within the expected energetic minima (ϕ ≈ ±70°, ψ ≈ ±175°), as in cyclo‐( N ph‐ N ph‐ N pa‐ N me) 2 , cyclo‐( N pa 8 ), cyclo‐( N spe 8 ), a propylazido derivative, congeners of cyclodepsipeptides, cyclo‐( N me 8 ), 6a / 6b , and cyclo‐(Sar 8 ), ( 8a / 8b , Figure A). It is interesting to note that the two trans ‐amide and the two cis ‐amide bonds of the octameric backbone form independent consecutive PPII and PPI helices, justifying the surprising conformational stability of these large cyclooligomers.…”

“…Torsion angles of tetrameric cyclopeptoids vary consistently depending on the position in the sequence. Residues with cis peptoid junctions, as in Sar 1 /Sar 3 , show ϕ ≈ 95°/–95°, ψ ≈ –170°/170° dihedral angles; residues with trans amide bonds, as in Sar 2 /Sar 4 , display ϕ ≈ 120°/–120°, ψ ≈ –65°/65° values (Figure D).…”

“…In particular, the C 3 ‐symmetric all‐ cis “crown” cyclo‐(Sar 3 ), 12a and 12b (Figure E), show ϕ/ψ dihedral angles with opposite values, depending on the conformer (ϕ ≈ 95°, ψ ≈ –95°; and ϕ ≈ –95°, ψ ≈ 95°) . The two cyclotrimers are differentiated by the planar chirality descriptors ( 12a : cyclo‐[( cis , p S )Sar] 3 , and 12b : cyclo‐[( cis , p R )Sar] 3 ), as explained for cyclotrimeric N ‐benzylglycine congeners 4a / 4b in Figure .…”

“…The introduction of chiral N ‐side chains in the primary sequence requires minimum synthetic effort. However, the shift of the stereodirecting element away from the backbone reduces its steric effects …”

“…Synthetic cyclic oligoamides, in their free and complexed form, displayed folding patterns different from classic peptide turn and loop motifs and required a different classification according ϕ, ψ, and ω torsion angles. We suggested the acronym “CP” (from “Cyclic Peptoid”) for these turns or loops, plus a subscript number to identify the type and a prime symbol for “inverse” turns …”