Promoting helicity in carbohydrate-containing foldamers through long-range hydrogen bonds

Article abstract of DOI:10.1039/b614294j

A sensor system to probe the propensity of carbohydrates to induce helical structures through long-range hydrogen bonds, based on a C₂-symmetric xylylene bis(thiourea) arrangement, is reported; the formation of intermolecular complexes with ben

Full text of DOI:10.1039/b614294j

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Promoting helicity in carbohydrate-containing foldamers through long-
range hydrogen bonds{
David Rodr´ıguez-Lucena,a Juan M. Benito,b Carmen Ortiz Mellet*a and Jose´ M. Garc´ıa Ferna´ndez*b
Received (in Cambridge, UK) 2nd October 2006, Accepted 8th November 2006
First published as an Advance Article on the web 27th November 2006
DOI: 10.1039/b614294j
intermolecular multipoint hydrogen bonds with complementary
guests in a specific and predictable manner.6 The influence of
definite folding patterns on the complexing activity can be
correlated, thus, to the stability of the corresponding secondary
structure (Fig. 1 C).
A sensor system to probe the propensity of carbohydrates to
induce helical structures through long-range hydrogen bonds,
based on a C2-symmetric xylylene bis(thiourea) arrangement, is
reported; the formation of intermolecular complexes with
benzoate anion promotes helix uncoiling, the free energy of
the process being related to helix stability.
In order to test the suitability of the above design criteria to
…
assess 15-membered O(sugar) HN hydrogen bond patterns,
Emulating the close relationships between conformational and
functional aspects typical of biological systems represents a
challenging goal in supramolecular chemistry. Foldamers, oligo-
mers that fold into a conformationally ordered state, offer a good
opportunity to learn about such processes. Although the field has
experienced significant progress during the last years, designability
of definite folding patterns resulting in precise secondary structures
is still limited to a few systems, among which b- and c-peptides are
paradigmatic examples.1 Several carbohydrate–peptide foldamers
have also been reported. The presence of the rigid sugar units
usually exerts a drastic effect in the folding properties due to
configurational and conformational biases. In all cases, however,
the conformational properties of the ditopic m-xylylene derivatives
2a–c in chloroform-d solution and their complexing abilities
towards benzoate anion were examined. The homologous
monotopic benzylthioureas 1a–c were also included in our study
as reference compounds. In the absence of any definite secondary
structure, the conformational behaviour of a bis-thiourea deriva-
tive should be the result of a statistic distribution per branch of the
rotameric populations encountered in the monotopic counterpart.
On the contrary, detection of a single conformer would necessary
imply intramolecular interbranch interactions (Fig. 2).
In the D-xylopyranosyl derivative 2a, the oxygen atom O-4 is
located at 14 covalent bonds from the benzylic NH proton at the
opposite branch. Notwithstanding, comparison of the low
temperature NMR spectra for 1a and 2a discarded the existence
…
long-range CLO HN hydrogen bonds are the primary intramo-
lecular interactions driving folding, the sugar oxygens playing only
a minor role.2
Recently, we have reported the synthesis of pseudoamide (urea,
thiourea, guanidine)-linked carbohydrate oligomers as phosphate
anion binders.3 Preliminary results suggested that such glycooli-
gomers tend to take on 15-membered hydrogen-bond held helical
conformations involving the sugar oxygens. We anticipated that
the folding effect of preferred hydrogen bond patterns would be
amplified in conjugates with a pseudo-C2-symmetry axis, by virtue
of concerted interactions, leading to helical arrangements. To
prove this concept, the highly flexible m-xylylene unit has been
chosen as helix handedness inversion centre, since it allows the
formation of both left-handed (M) and right-handed (P) isomers.4
Fixation of a secondary structure would anchor the conformation
about the NH–C(LS) bonds. The rotameric E–Z conformational
equilibrium in thioureas being slow in the chemical shift time scale,
this fact makes it conceivable to structurally characterize the
capability of a monosaccharide template to dictate a given
sense upon hydrogen bonding by dynamic NMR spectroscopy
(Fig. 1 A, B).5 Interestingly, thiourea receptors can also establish
Fig. 1 Schematic representation of a sensor to probe the propensity of
monosaccharides to induce long-range hydrogen bonds based on the
xylylene bis(thiourea) core. (A) In the unfolded state, all rotameric
configurations about the NH–(CLS) bonds are possible. (B) Cooperative
long-range hydrogen bonds resulting in helical foldings would anchor the
Z,Z configuration at both thiourea segments. (C) The formation of an
intermolecular six-centre hydrogen-bonded complex with carboxylate
guests should promote helix uncoiling, the free energy of the process being
related to helix stability.
aDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad
de Sevilla, Apartado 553, E-41071 Sevilla, Spain. E-mail: mellet@us.es;
Fax: +34 954624960; Tel: +34 954551519
bInstituto de Investigaciones Qu´ımicas, CSIC, Ame´rico Vespucio 49, Isla
de la Cartuja, E-41092 Sevilla, Spain. E-mail: jogarcia@iiq.csic.es;
Fax: +34-954460565; Tel: +34-954489559
{ Electronic supplementary information (ESI) available: general proce-
dures, NMR and titration data. See DOI: 10.1039/b614294j
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 831–833 | 831

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Fig. 2 Structures of the monotopic (1a–c) and ditopic thiourea
derivatives (2a–c) considered in this study. Their synthesis was accom-
plished by coupling of the corresponding sugar isothiocyanate with
benzylamine or m-(bis-aminomethyl)benzene, (see Supplementary
Information{). The key oxygen centre located at 14 covalent bonds from
the PhCH2NH proton at the opposite branch is shown in boldface.
Fig. 3 Schematic representation and computer generated model of the
P-helical conformation of compound 2b.{1 The two key 15-membered
H-bonds are indicated. Only the CH protons relevant for structural
assignment (NOE) are depicted. The acetate groups at secondary carbons
have been omitted for clarity.
up to six conformations are accessible for the ditopic homologue
2c in the unfolded state. Instead, only two species, in relative
proportions close to 1:1, were detected in the low temperature
NMR spectra, both of them displaying the (Z,Z:Z,Z) configura-
tion at the thiourea segments as confirmed by NOE, correspond-
ing to the P and M helical foldings (Fig. 4).
of any defined folding (Table 1). In stark contrast, whilst the
monotopic D-glucopyranosyl derivative 1b existed as a mixture of
the Z,Z and Z,E rotamers in chloroform-d solutions, a single
conformer, having the Z,Z configuration at both thiourea
segments, was detected in the case of 2b, independently of the
sample concentration. Moreover, the NH proton resonances in 2b
were significantly downfield shifted as compared to 1b, with
particularly low chemical shift temperature coefficients in the case
of those located at benzylic positions, strongly supporting their
participation in intramolecular hydrogen bonding, with the O-6
atoms as acceptors, in an overall helical architecture (Fig. 3).
It is noteworthy that only one of the two possible diastereomeric
helices for 2b was detected. In fact, the anomeric carbon (C-1)–
NH–C(LS) segment is set in the anti-Z conformation in
glycosylthioureas. According to molecular modelling, this rigid
arrangement is only compatible with the P-handeness in the
xylylene bis(thiourea) system. The existence of a fixed gauche-
trans conformation at the C-5–C-6 bond (J5,6a and J5,6b 9.3 and
,1.5 Hz, respectively) instead of the usual equilibrium between
staggered rotamers, as well as diagnostic NOE contacts,
additionally supported this assignment.
In order to get information on the energy of the 15-membered
hydrogen bonds responsible for helical folding, a comparative
analysis of the complexing properties of the mono (1a–c) versus the
ditopic (2a–c) receptors was carried out. Benzoate anion was used
as an external probe for this purpose. In the absence of any
intramolecular interaction, an above 10-fold increase in the
association constant (Kas) on going from the four-centre to
the six-centre 1:1 complex (Fig. 5) was expected.7 Consistently, the
Job’s plots and binding isotherms for 1a and 2a were indicative of
1:1 stoichiometries, with Kas values of 1749 ¡ 34 and 18140 ¡
180 M21, respectively (Table 1).8
Titration experiments for the 1b/2b and 1c/2c pairs against
benzoate revealed a totally different scenario. Whereas the
In the bis(thiourea) derivative 2c the relative disposition of the
key oxygen and nitrogen atoms has been exchanged as compared
to 2b. This subtle modification does not alter the distance between
donor and aceptor centres. Yet, it has a dramatic influence on the
chain flexibility, the C-5–C-6–NH–C(LS) segment exhibiting a
broad conformational freedom. Thus, the three possible rotameric
forms, Z,Z, Z,E and E,Z contribute to the conformational
equilibrium of the monotopic thiourea 1c in CDCl3, meaning that
Table 1 Thermodynamic data for 1a–c and 2a–c and their benzoate
complexes
Receptor Rotameric populationsa Kas(1:1) /M21 Kas(2:1) /M21
b
b
1a
2a
1b
2b
1c
2c
a
Z,E/Z,Z 1.0:2.5
n.d.c
Z,E/Z,Z 1.0:3.6
(Z,Z:Z,Z) 100%
Z,E/Z,Z/E,Z 1.6:1.2:1.0 625 ¡ 14
(Z,Z:Z,Z) 100% 1930 ¡ 80
1749 ¡ 34
18140 ¡ 180
929 ¡ 8
—
—
—
87 ¡ 6
—
30 ¡ 5
1106 ¡ 49
Fig. 4 Computer generated helical conformations for 2c. The curve
arrows in the P-isomer indicate the aromatic ring flipping, approaching
the sugar protons at the b-face, which allows helix assignment (see
Supplementary Information{). In the left-side structures, CH protons and
acetate groups have been omitted for clarity.
Obtained by digital integration at 233 K. The first stereochemical
sign refers to the N–C(LS) bond next to the monosaccharide residue.
At 298 K. Average values from at least three separate experiments.
Not determined due to extensive overlapping.
b
c
832 | Chem. Commun., 2007, 831–833
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free energy associated to the helical folding pattern can be
estimated at 60 and 25 J mol21 for 2b and 2c, respectively.
The above differences in the propensity of different orientations
of equivalent structural motifs to induce a given secondary
structure are remarkable and underline the potential of carbohy-
drates as conformational modulators. Particularly notable is the
conformational uniqueness and stability associated to the
N-glucopyranosyl derivative 2b. Additional dynamic NMR studies
confirmed that the 15-membered intramolecular hydrogen bonds
holding the helix structure survived in the presence of up to 30%
dimethyl sulfoxide, which is consistent with previous observations
for natural N-glycopeptides in non aqueous solvents.9 The
conclusions of this study should make the rational design of this
new family of carbohydrate-based foldamers feasible.
Fig. 5 Structures of the 1a:benzoate (four-centre) and 1b:benzoate (six-
centre) complexes.
We thank the Spanish Ministerio de Educacio´n y Ciencia for
financial support (contracts number CTQ2006-15515-C02-01/
BQU and CTQ2004-05854/BQU) and for a doctoral fellowship
(to DR-L).
Notes and references
{ Calculations were performed with the MACROMODEL 6.0 package
and the GB/SA continuous solvent model for chloroform.
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Fig. 6 Job’s plot (A) and binding isotherm (B) for the complexation of
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represented).
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helix-forming derivatives 2b and 2c provided sigmoid binding
isotherms and Job’s plots consistent with 2:1/1:1 host:guest
equilibria (Fig. 6 A, B).8 Although probably both NH protons
at each thiourea segment contribute to helix stability, just those
located at 14-bonds from the oxygen acceptors are strictly
necessary, the other two remaining accessible for intermolecular
interactions in the 2:1 complex (Fig. 6 C). In the presence of excess
benzoate, the six-centre hydrogen-bonded 1:1 complex is formed.
Yet, this process has a significant penalty associated to helix
disruption. The lower increment in the Kas(1:1) values on going
from 1b:benzoate (929 ¡ 8 M21) or 1c:benzoate (625 ¡ 14 M21
)
to 2b:benzoate (1106 ¡ 49 M21) or 2c:benzoate (1930 ¡ 80 M21),
as compared with the corresponding data for 1a and 2a, reflects
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Chem. Commun., 2007, 831–833 | 833