Angewandte Chemie International Edition
10.1002/anie.201804488
COMMUNICATION
potential steric clashes and/or electronic repulsion imposed by
the CHF
hypothesis that the enhanced cis-amide preferences observed in
1-13 arise from the inductive effects imposed by the fluorine
atom(s). As the polarization at C increases the peptoid cis-
amide preference also increases. We propose that this is due to
the fact that the δ +ve on C can form a syn-periplanar
2
/CF
3
groups. Overall, our findings support the
1
α
α
stabilising dipolar interaction with the amide C=O (Figure 3d).
Encouraged by the cis/trans ratios achieved in the model
systems (11-13) we then moved to see if the non-chiral fluoro-
alkyl monomers could be exploited to design stable peptoid
helices. To this end we designed a control 15-mer peptoid,
Pep.1, using non-chiral alkyl ethylamine monomers (Figure 5).
A single NSpe residue was introduced as a chiral reporter for
Circular Dichroism (CD) spectroscopy. The Pep.1 sequence was
then altered by substituting in the various fluorinated monomers
(
6-8) in place of some, but not all of the NEt residues (group 1,
Pep.2-4). In a second group of fluorinated peptoids all of the NEt
residues present were replaced (group 2, Pep.5-7). We were
pleased to see that the structural analysis of the peptoid
oligomers Pep.2-Pep.7 by CD spectroscopy revealed the
presence of stable peptoids helices (Figure 5b-c). In all of the
peptoids studied the substitution of the NEt residues by any of
the fluorinated monomers clearly enhanced the CD minima at
θ
218 nm (M ,218), which is characteristic of an increase in helicity.
When five substitutions (NEt for fluoro-monomer) were made in
non-consecutive positions (group 1, Pep.2-4, nf=5), the overall
increases in molar ellipticity were found to correlate to the
number of fluorine atoms within the side-chain. For example, on-
going from the non-fluorinated peptoid (Pep.1) to the N1fEt
3
Figure 4. Theoretical vs. experimental vicinal
1 a), 12 b) and 13 c) in their preferred cis-conformations (CD
Stick representation of the crystal structures of cis-amide d) 12 and e) 13.
J
H-F coupling constants within
1
3
CN). Ball-and-
[
16]
θ 218
based analogue (Pep.2) a change in molar ellipticity of ΔM , =
2
-1
6
,660 deg cm dmol was observed. Similarly, incorporation of
This result strongly suggested an overall fluorine/amide gauche
orientation within the side-chain. Two staggered conformations
N2fEt (7) and N3fEt (8) produced approximately 2 and 3-fold
higher increases in M
θ
2
,
218 (Pep.3, ΔM
θ
,
218= 12,640; Pep.4,
for 12 were also examined and the experimental value of
-1
ΔM
θ
,
218 = 17,000 deg cm dmol ).
3
J
HF,obs= 14.9 Hz was in perfect agreement with an anti/gauche
When the more heavily substituted peptoids from group 2
conformation (Figure 4b). This finding indicates that only one F-
atom may be actually located gauche to the peptoid amide
group, and this is contrary to the more intuitive (+g / -g)
configuration that would be expected. No significant variations in
were analysed higher values of Mθ,218 were found, indicating that
the secondary structure enhancement induced by the
incorporation of fluorinated side chains has an overall
accumulative behaviour (Pep.5-7, Figure 5d-e). In fact, the
average increases in Mθ,218 produced by each N1fEt (6) and
N2fEt (7) monomer introduced in these sequences were higher
than those observed when only five replacements were made
3
the experimental JHF,obs were seen within each cis/trans pair in
any of the solvents tested, indicating that the fluorine/amide
relative arrangement is retained between conformers. The NMR
results suggest that fluorine gauche effects are not solely
responsible of the cis-isomer preferences observed in 11 and 12.
(
θ f
ΔM ,218/n ; Pep.2 vs Pep.5 and Pep.3 vs Pep.6, Figures 5c-e).
These results revealed a broadly cooperative effect between
neighbouring fluorinated side-chains. Interestingly, this synergy
between consecutive monomers didn’t occur when N3fEt
monomers were used (Pep.4 vs. Pep.7). Based on our crystal
In 13 fast rotation of the CF
3
- group was inferred, as the
3
experimental
JHF,obs greatly deviated from the calculated value
which assumes a static fluorine/amide arrangement (Figure 4c).
We were able to crystallize di-peptoids 12 and 13 from
2
structure data we could evaluate that the volume of the CHF -
[19]
their EtOAc saturated solutions. A perfect agreement between
the solid-state structures for 12 and 13 and the conformations
suggested by NMR analysis was obtained (Figures 4d-e).
Significantly, it is worth noting that from the crystal structures of
3
3
and CF - groups are 29.63 and 40.47 Å respectively. Based on
this we hypothesise that the behaviour seen for Pep.7 may be
related to unfavourable steric and/or repulsive interactions
between the CF - groups of adjacent N3fEt monomers. Overall,
3
the results from the CD studies (Figure 5) are highly
unprecedented due to the fact that none of the fluorinated
monomers investigated are either chiral, aromatic or charged,
and, yet they can support the formation of stable peptoid helices.
In summary we have shown that selective and strategic
incorporation of fluorine atom(s) offers a new route to control the
12 and 13 it would appear that neither fluorine-oxygen repulsive
interactions, nor unfavourable steric clashes contribute
substantially to the cis/trans conformation preferences observed
in these systems. As shown in Figures 4d-e, the fluorinated
groups in 12 and 13 display a well-defined orthogonal orientation
relative to the amide bond planes. This orientation minimizes the
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