Influence of achiral units with gem-dimethyl substituents on the helical character of aliphatic oligourea foldamers

Article abstract of DOI:10.1039/c3cc40961a

The structures of various urea oligomers incorporating one or two central achiral 1,2-diamino-1,1-dimethylethane (DADME) units have been investigated in solution and in the crystalline state. These diamine monomers are analogous to the achiral helicogenic

Full text of DOI:10.1039/c3cc40961a

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Influence of achiral units with gem-dimethyl
substituents on the helical character of aliphatic
oligourea foldamers†
Cite this: Chem. Commun., 2013,
4
9, 7415
Received 4th February 2013,
Accepted 21st June 2013
a
a
b
c
Juliette Fremaux, Christel Dolain, Brice Kauffmann, Jonathan Clayden* and
Gilles Guichard*
a
DOI: 10.1039/c3cc40961a
www.rsc.org/chemcomm
3
The structures of various urea oligomers incorporating one or upon homologation, a single b HAib (b-aminoisovaleric acid) being
11
two central achiral 1,2-diamino-1,1-dimethylethane (DADME) units found to prevent b-peptide 14-helix nucleation. Whereas homo-
3
2
have been investigated in solution and in the crystalline state. oligomers of b HAib (or b HAib) do not show propensity to form
8
a
These diamine monomers are analogous to the achiral helicogenic well-defined structures, oligoamides and aminoxypeptides,
amino acid Aib (a-aminoisobutyric acid). Oligomers were found to composed of 1-(aminomethyl)cyclopropylcarboxylic acid and
fold into helical conformations with DADME units inducing local 3-aminoxy-2,2-dimethylpropionic acid, promote the forma-
deviations from the canonical helix geometry of urea foldamers.
tion of folded structures involving H-bonding between nearest
8
b,10
neighbours.
Aliphatic N,N -linked oligoureas bearing proteinogenic side
0
The introduction of a quaternary carbon into an alkyl chain is a
long-recognized way of imposing conformational bias and chains represent another class of peptidomimetic foldamers with
1
12,13
increasing the rate of cyclization reactions. The so-called potential for applications in biology and molecular recognition.
b
a
0
Thorpe–Ingold effect can also be used to control conformations Homooligomers of the general formula [ CH(R)- CH
in short chain a-peptides. The presence of two alkyl groups on adopt a well-defined 2.5-helical structure stabilized by three-centred
the C carbon of an a-amino acid considerably reduces the hydrogen bonds. Recently, we and others have shown that cyclic
conformational space accessible to the amino acid. With (j, c) units such as pyrrolidin-2-ylmethanamine and 1,2-diamino
values around (+601, +301) and (ꢀ601, ꢀ301), a-aminoisobutyric bicyclo[2.2.2]octane are also compatible with a 2.5-helix
acid (Aib), the simplest quaternary a-amino acid, is ideally pre- environment. However, the folding propensity of oligoureas
organized for helix formation. It is a strong promoter of 3 and containing constrained acyclic units has not yet been studied.
2
-NHCON H]
n
2
a
1
4
1
5
10
3
a-helical structures as well as of non-canonical helices such as the
In this work, we set out to investigate whether the helix
homooligomers geometry of aliphatic oligoureas may accommodate the achiral
4
b-bend ribbon spiral. Since Aib is achiral, (Aib)
n
adopt both right- and left-handed helical conformations that units with gem-dimethyl substituents. Two new activated mono-
interconvert rapidly in solution. It is nevertheless possible to mers BB1 and BB2 were prepared starting from 1,2-diamino-
1
6
control the helix screw sense by adding a chiral controller 1,1-dimethylethane (DADME).†
5
,6
(
covalently or non-covalently) at either end of the helix.
7
In the field of foldamers, there have been a few attempts to
use the Thorpe–Ingold effect to enforce non-natural backbones
e.g. b- and g-peptides, aminoxypeptides) to adopt conformationally
(
8–10
defined structures.
Seebach and co-workers showed that the
ability of the Aib residue to nucleate helical structures is not retained
With building blocks BB1 and BB2 in hand, we synthesized
two analogues of urea 7-mer 1 by substituting a DADME unit for
the central canonical residue. The two oligomers 2 and 3 differ
in the relative orientation of the DADME unit in the main
a
Universit ´e de Bordeaux, CNRS, UMR5248, Institut Europ ´e en de Chimie et Biologie,
2
rue Robert Escarpit, 33607 Pessac, France.
b
a
chain, the quaternary carbon being C in 2 and C in 3.
Electronic circular dichroism (ECD) spectra of oligoureas 2
and 3 recorded at 0.2 mM in 2,2,2-trifluoroethanol (TFE) dis-
play the characteristic ECD signature that we previously attri-
buted to the oligourea 2.5-helix, i.e. an intense positive maximum
at B203 nm, zero crossing at B193 nm and a negative maximum
E-mail: g.guichard@iecb.u-bordeaux.fr; Tel: +33 (0)540003020
Universit ´e de Bordeaux, CNRS, UMS3033, INSERM US001, Institut Europ ´e en de
Chimie et Biologie, 2 rue Robert Escarpit, 33607 Pessac, France
School of Chemistry, University of Manchester, Oxford Road, Manchester,
M13 9PL, UK. E-mail: clayden@man.ac.uk
b
c
†
Electronic supplementary information (ESI) available: Synthesis details and
spectral data. CCDC 922576–922578. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3cc40961a
1
4
at 188 nm (Fig. 1). However the lower per residue molar
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Fig. 1 ECD spectra of oligoureas 1–5 recorded in TFE.
ellipticity (PRME) value at 203 nm in 2 and 3 compared to that
in 1 may suggest a lower helical content.
Additional information about the folding character of the
1
DADME unit in 2 and 3 was gained by H NMR spectroscopy in
CD
3
OH. Both compounds 2 and 3 exhibit a number of features
1
4,17,18
typical of 2.5 helical oligoureas
including wide disper-
sion of NH signals (between 5.5 and 7.0 ppm), large vicinal
b
coupling constants between NHs and CH protons of canonical
residues ( J B 10 Hz), and a high degree of anisochronicity (Dd)
Fig. 2 X-Ray diffraction structures of the helix (a) 2 (carbon atoms of the
DADME unit in orange) and (b) 3(I) (carbon atoms of the DADME unit in green);
3
between the diastereotopic main chain CH
2
protons of canonical (c) overlay of the two crystal structures.
residues (in the range 0.88–1.29 ppm for 2 and 0.94–1.22 ppm
for 3).† It is noteworthy that the two methyl groups of the
DADME unit in 2 and 3 also show significant anisochronicity
Table 1 Main backbone torsion angles (1) for DADME units in 2, 3 and 5 and
comparison with values observed in canonical oligourea helices
(Dd = 0.21 ppm and 0.31 ppm, respectively), another indication
of a folded conformation.†
Cmpd
j
y1
+57.81
ꢀ45.61
+56.71
+63.61
y2
+80.81
+174.61
+69.21
+66.71
The presence of unambiguous non-sequential nuclear Over-
hauser enhancements (nOes) between backbones NH(i) and
ref. 18
ꢀ103.81
ꢀ55.31
ꢀ102.61
ꢀ95.11
2
b
a
3
CH(i + 2) repeated along the sequence in 3 provides evidence
b
5
that the DADME containing oligomer adopts a helical confor-
a
b
mation akin to that of 1. The detection of a specific nOe cross
Mean angles for the two independent molecules I and II. Mean
value for the two DADME units in 5.
0
peak between N H(2) and one of the two methyl groups of the
DADME unit in the ROESY spectrum of 3 is also consistent with
the postulated helical structure.† A similar trend was observed
for 2 but a smaller set of nOes was identified unambiguously
because of partial resonance overlaps. Oligomer 2 was found to
differ strongly from 1 in the anisochronicity of the diastereotopic
methylene protons at the central position. The Dd value observed for
the DADME methylene protons in 2 is particularly low (B0.49 ppm)
compared to the corresponding high value in 1 (B1.37 ppm). This
observation supports the view that gem-dimethylation may cause a
local conformational reorganisation in 2.
We obtained single crystals of 2 and 3 and solved their
structures in the P1 and P2 space groups, respectively.† The
1
crystal structure of 3 contains two independent molecules (I)
and (II) in the asymmetric unit. X-ray crystal data confirmed
that both molecules adopt a right-handed helical structure akin
to that of the canonical 2.5-helix. The mean backbone torsion
Scheme 1 Sequences of model urea oligomer 1 (canonical units of (S)-configuration)
and analogues 2–5 incorporating DADME units (in red).
1 2
angles j, y and y of canonical units in the two structures
(
ꢀ97.71, +58.81, +78.01 in 2 and ꢀ98.91, +58.21, +84.81 in 3) (i.e. ꢀ1031, +571, +801). In contrast they all strongly differ in 2 (see
1
8
match well those found in canonical helices. However, a close Table 1) with y of opposite sign (ꢀ45.61) and y close to 1801,
1
2
inspection reveals significant differences between the DADME resulting in a local conformational reorganization with the two
units in the two molecules. Fig. 2 shows the structures of 2 and methyl groups in a plane perpendicular to the helix axis.
3
(I) overlaid by fitting pairs of b-carbons with a root mean
To confirm this trend and evaluate whether the helical structure
square deviation (RMSD) of 0.650 Å (Fig. 2). Values of j, y and y
1
2
propagates across multiple consecutive gem-dimethylated units,
angles in the DADME unit of 3 (ꢀ1031, +571, +691) are close to we prepared 8-mers 4 and 5 with two DADME units flanked by
those generally observed for canonical units in oligourea helices canonical residues (Scheme 1). The typical features previously
7
416 Chem. Commun., 2013, 49, 7415--7417
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formation was found to vary significantly with the orientation of the
a
b
DADME units in the sequence (quaternary C > C). X-ray structure
analyses confirmed that backbone torsion angles of the DADME
a
residue with the two methyl groups on the C match more closely the
geometry of the 2.5-helix. This work is relevant to the design of oligourea
helical structures made of contiguous DADME units for studying
helicity induction in the presence of a chiral controller. It remains
to be seen whether oligoureas composed of an increasing num-
ber of DADME units and a limited number of canonical residues
at one end only are still able to adopt a helical conformation.
This work was supported in part by the CNRS, the Universit´e
de Bordeaux, the R ´e gion Aquitaine and by COST Action CM0803.
The crystallographic data were collected at the IECB X-ray facility
(
UMS3033, CNRS and Universit ´e de Bordeaux, US001 INSERM).
Fig. 3 X-Ray diffraction structures (side and top views) of the helix 5 (carbon
atoms of the DADME units in green).
Notes and references
1
2
M. E. Jung and G. Piizzi, Chem. Rev., 2005, 105, 1735.
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3
b
observed in the NMR spectra of 2 and 3, i.e. large J(NH, CH) and
Dd values for canonical residues, are also present in the spectra of 4
and 5, suggesting persistence of helical folding. It is noteworthy
that in both sequences, the two DADME units differ significantly in
the anisochronicity of their diastereotopic methyl groups, the
Dd values for the second unit being systematically lower: 0.24 vs.
3
(a) J. Venkatraman, S. C. Shankaramma and P. Balaram, Chem. Rev.,
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001, 101, 3131–3152; (b) C. Toniolo and E. Benedetti, Trends
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0
.08 ppm in 4 and 0.33 vs. 0.16 ppm in 5. Comparison of backbone
5
(a) J. Clayden, A. Castellanos, J. Sol `a and G. A. Morris, Angew. Chem., Int.
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nOes in their ROESY spectra† suggests that 5 has a greater folding
propensity than 4. This trend was also confirmed by CD measure-
ments. CD spectra of oligoureas 4 and 5 were recorded in TFE and
compared to those of 1–3 (Fig. 1). The PMRE value at 203 nm in 4
is much smaller than in 2, suggesting that the addition of two
6
7
b
consecutive DADME units with quaternary C increases helix
destabilization. In contrast, the CD spectrum of 5 exhibits a PRME
value at 203 nm which is significantly higher than in 3 and 4,
providing some support for a high helical content in 5.
(
d) G. Guichard and I. Huc, Chem. Commun., 2011, 47, 5933; (e) D.-W.
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(
Helical folding in 5 was also compared to that in a related
-mer oligourea (6) in which the two DADME units are replaced
by two unsubstituted ethylenediamine-derived units.
8 (a) D. Seebach, S. Abele, T. Sifferlen, M. H ¨a nggi, S. Gruner and
P. Seiler, Helv. Chim. Acta, 1998, 81, 2218; (b) S. Abele, P. Seiler and
D. Seebach, Helv. Chim. Acta, 1999, 82, 1559.
8
9
P. G. Vasudev, S. Chatterjee, N. Shamala and P. Balaram, Acc. Chem.
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1
0 (a) D. Yang, Y.-H. Zhang and N.-Y. Zhu, J. Am. Chem. Soc., 2002,
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1
K.-S. Song, Y.-H. Zhang, N.-Y. Zhu, L.-H. Weng and M.-Q. Chen,
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1 D. Seebach, P. E. Ciceri, M. Overhand, B. Jaun and D. Rigo, Helv.
Chim. Acta, 1996, 79, 2043.
Surprisingly, the PRME value at 203 nm is higher in 6 than
in 5 (Fig. 1) thus suggesting that the folding behaviour in these
sequences is largely dominated by the flanking canonical units
and that the Thorpe–Ingold effect may be a less important factor
than expected in promoting the helical structure of oligoureas.
The helical character of 5 was nevertheless confirmed by X-ray
diffraction analysis of single crystals grown in a mixture of MeCN
1
1
2 L. Fischer and G. Guichard, Org. Biomol. Chem., 2010, 8, 3101–3117.
3 P. Claudon, A. Violette, K. Lamour, M. Decossas, S. Fournel,
B. Heurtault, J. Godet, Y. M ´e ly, B. Jamart-Gr ´e goire, M.-C. Averlant-
Petit, J.-P. Briand, G. Duportail, H. Monteil and G. Guichard, Angew.
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1
1
4 J. Fremaux, L. Fischer, T. Arbogast, B. Kauffmann and G. Guichard,
Angew. Chem., Int. Ed., 2011, 50, 11382.
and MeOH (Fig. 3). Both DADME units in 5 adopt backbone 15 B. Legrand, C. Andr ´e , E. Wenger, C. Didierjean, M. C. Averlant-Petit,
J. Martinez, M. Calmes and M. Amblard, Angew. Chem., Int. Ed.,
torsion angles that match those found in 3 and canonical
2012, 51, 11267.
2.5-helices (Table 1). Because of a possible repulsive interaction
1
6 It is noteworthy that the DADME unit has been used previously as an
element of the turn segment for the construction of parallel peptide
b-sheets: J. D. Fisk, D. R. Powell and S. H. Gellman, J. Am. Chem.
Soc., 2000, 122, 5443.
7 A. Violette, N. Lancelot, A. Poschalko, M. Piotto, J.-P. Briand, J. Raya,
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between a methyl group of the DADME unit at P5 and the methyl
side chain at P7, the typical three-centre H-bond interaction is
modified with a water molecule relay causing unusual bending
1
1
1
1
9
of the helix, similar to that found in a-peptide helices.
In conclusion, we have shown that helical folding is maintained
upon insertion of achiral Aib-type (DADME) units into the central
0
region of a canonical N,N -linked oligourea. The extent of helix
This journal is c The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7415--7417 7417