Nonpeptidic foldamers from amino acids: Synthesis and characterization of 1,3-substituted triazole oligomers

Article abstract of DOI:10.1021/ja056406z

Nonpeptidic foldamers capable of displaying protein-like functionality were prepared by swapping amide bonds with 1,2,3-triazole rings. The overall conformation of these triazole oligomers is largely dictated by dipole-dipole interactions between adjacent

Full text of DOI:10.1021/ja056406z

Published on Web 11/12/2005
Nonpeptidic Foldamers from Amino Acids: Synthesis and Characterization of
1,3-Substituted Triazole Oligomers
Nicholas G. Angelo and Paramjit S. Arora*
Department of Chemistry, New York UniVersity, New York, New York 10003
Received September 17, 2005; E-mail: arora@nyu.edu
The intrinsic instability of peptides limits their potential as
reagents in molecular biology and drug discovery. Nonpeptidic
scaffolds that adopt well-defined conformations and display protein-
like side chains would be invaluable alternatives to peptides.1,2
Biomimetic oligomers,2,3 such as â-peptides,4 have been intensively
studied because they possess a high propensity to adopt defined
secondary structures and resist degradation by proteolytic enzymes.
These oligomers also retain perhaps the most important asset offered
by peptides, namely, access to a diverse set of side chain functional
groups needed for molecular recognition and catalysis. We con-
jectured that it may be possible to increase the number of defined
backbone conformations possible from R- and â-amino acids and
introduce “drug-like” character into these oligomers by swapping
the amide bond with aromatic rings and by projecting the attached
main chains at different angles from a given ring (Figure 1).5,6
Several nonpeptidic oligomers composed of carbamates, sulfon-
amides, ureas, hydrazino acids, aminoxy acids, anthranilamides,
oligophenylacetylenes, and pyrrolinones, among others, have been
described.2,3 Here we report a new class of distinctly folded
nonpeptidic oligomers in which the amide bond is replaced by
aromatic rings yet the chiral main chain and amino acid side chains
are maintained (Figure 1). These molecules potentially afford
specific conformations featuring a diverse set of side chains without
the limitations imposed by the secondary amide bond.5
We were inspired in this endeavor by previous efforts,6,7 in which
the amide bond is substituted with heteroaromatic rings to generate
peptidomimetics, and sought to extend these methodologies to the
synthesis of nonpeptidic oligomers directly from amino acids.
Figure 1. (a) Development of nonpeptidic foldamers by replacement of
Although several ring systems are synthetically accessible, we began
by swapping the amide bonds with triazole rings for two reasons:
(1) dipeptides bearing both 1,2,3-triazole8 and 1,2,4-triazole9 rings
(Figure 1a) have been described in the literature, and (2) we were
intrigued by the large dipole moment (∼5 D)10 in these rings and
wondered whether defined conformations could be obtained through
forces, such as dipole-dipole interactions and torsional effects.
This report presents the design, synthesis, and initial structural
studies on the 1,3-substituted oligomers derived from the 1,2,3-
triazoles (Figure 1b).11 Solution NMR studies on trimers and
tetramers suggest that these oligomers adopt zigzag conformations
reminiscent of peptide â-strands. Dipole-dipole interactions be-
tween neighboring triazole rings appear to play a critical role in
stabilizing the observed conformations in polar solvents, such as
DMSO and acetone.
the amide bond with triazole rings. (b) A 1,3-substituted triazolamer. (c)
Synthesis of the triazole oligomers from amino acids.
Figure 2. Conformations adopted by the triazole dimer (5). The syn and
anti conformations are defined by the dipole-dipole interactions between
adjacent triazole rings. The anti conformations are calculated to be roughly
4 kcal/mol lower in energy than the syn conformations.14
The 1,3-substituted oligomers were prepared from amino acid
methyl esters through an iterative reaction sequence consisting of
conversion of the amine to the corresponding azide,12 copper(I)-
catalyzed azide-alkyne [3+2] cycloaddition13 with the suitable
amino alkyne 1 followed by removal of the protecting group (Figure
1c). To examine the solution conformations of short 1,3-substituted
triazole oligomers, we prepared and studied two trimers 3a,b and
two tetramers 4a,b.
Molecular mechanics and ab initio calculations were used to
predict the conformations of these oligomers,14 and the predictions
were confirmed by 2D NMR analysis. We began our studies by
calculating the conformational preferences of the triazole dimer (5),
which can adopt two anti and two syn conformations (Figure 2).
The syn and anti conformations are defined based on the relative
direction of the dipoles in adjacent rings. Both molecular mechanics
and ab initio studies predict that the anti conformations are ∼4
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10.1021/ja056406z CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
In summary, we have reported an approach for the synthesis of
nonpeptidic scaffolds capable of displaying protein-like side chains
by swapping amide bonds with 1,2,3-triazole rings. The overall
conformation of these triazole oligomers appears to be dictated by
dipole-dipole interactions between adjacent rings. Solution NMR
studies suggest that a zigzag conformation, which closely mimics
the â-strand structure, predominates in two different tetramers.
Acknowledgment. We thank Prof. Samuel Gellman for insight-
ful comments, Prof. M. G. Finn and Prof. Scott Rajski for helpful
discussions and generous donations of the TBTA ligand, and Po
Hu and Prof. Yingkai Zhang for performing the ab initio calcula-
tions. P.S.A. is grateful for financial support from the Research
Corporation (Cottrell Scholar Award) and NYU (Whitehead Fel-
lowship). We thank the NSF for equipment Grants MRI-0116222
and CHE-0234863, and the NCRR/NIH for Research Facilities
Improvement Grant C06 RR-16572.
Supporting Information Available: Detailed conformational analy-
ses, synthetic procedures, and characterization of monomers and
oligomers (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 3. (a) A cross-section of the ROESY spectra of 4b (in DMSO-d6)
displaying cross-peaks between the aromatic and the CR protons. (b)
Predominant triazolamer conformation revealed by ROESY experiments.
Solid and dashed lines indicate observed strong and weak NOE cross-peaks,
respectively. (c) Comparison of triazolamer 4b in a zigzag conformation
(top) to a peptide â-strand (tetraalanine) (bottom). The triazolamer mimics
a peptide â-strand with similar axial distances between the i and i + 2 side
chains. For clarity, side chains are depicted as methyl groups.
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kcal/mol more stable than the syn conformations. We anticipated
that the restriction imposed by the anti conformation on the possible
number of rotamers may lead to a specific set of defined backbone
structures.
Examination of the 2D NMR spectra reveals that the backbones
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1
assign H NMR resonances. The anti conformation can also lead
to a turn backbone structure, which was ruled out through NMR
studies (see Supporting Information for details). It remains to be
determined what specific backbone structure will predominate in
longer oligomers or in compounds with different side chain groups.
The zigzag triazolamer structure is reminiscent of peptide
â-strand conformation (Figure 3c) and oligopyrrolinones described
by Smith and Hirschmann.6 The axial distance between i and i +
2 residues in â-strands is 7.2 Å; this distance is roughly 7.9 Å in
the zigzag triazolamer. The Câ to Câ distances in adjacent residues
are 5.5 Å in â-strands and a little longer (6.8 Å) in the triazolamer.
Thus, one surface of the zigzag triazolamer may effectively mimic
a â-strand and prove useful for targeting protein pockets and
surfaces involved in â-strand recognition.16 Although the triazolamer
backbone does not offer a â-strand’s hydrogen bond functionality,
the N-2 and N-3 electron pairs may serve as hydrogen bond
acceptors.8a
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force field in chloroform), and ab initio calculations were conducted with
the Gaussian 03 program package (DFT B3LYP method at 6-31G* level).
(15) Acetone and DMSO were chosen because the aromatic protons were well
dispersed in these solvents.
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