A chiral pyrrolic tripodal receptor enantioselectively recognizes β-mannose and β-mannosides

Article abstract of DOI:10.1002/chem.200902514

The prototype of a new family of chiral receptors based on a tripodal scaffold and featuring pyrrolic binding arms containing the trans-1,2- diaminocyclohexane motif, was reported. A cage endowed with a somewhat enlarged cavity was designed, in the belief that fine-tuning of the cage size would lead to a significantly improved affinity even in more polar media. Reaction of the trialdehyde 4 with the mono-BOC-protected diamine 2, followed by reduction of the resulting Schiff base and subsequent deprotection of the amino groups, yielded the tripodal hexaamine 5, which was condensed with pyrrole-2,5- dicarbaldehyde under the conditions used for preparing the bicyclic receptor 1. A preliminary screening indicated that, while Glc, Gal, and GlcNAc were moderately bound, strong recognition occurred with mannosides. βMannose was also extracted in benzene, though to a lesser extent (10%), and αMannose could not be detected.

Full text of DOI:10.1002/chem.200902514

DOI: 10.1002/chem.200902514
A Chiral Pyrrolic Tripodal Receptor Enantioselectively Recognizes
b-Mannose and b-Mannosides
Ana Ardꢀ,[b] Chiara Venturi,[b] Cristina Nativi,[c, d] Oscar Francesconi,[c]
Gabriele Gabrielli,[c] F. Javier CaÇada,[b] Jesffls JimØnez-Barbero,*[b] and
Stefano Roelens*[a]
Biomimetic receptors for carbohydrates have been widely
used to investigate the recognition phenomena occurring in
biological systems.[1] Among the plethora of synthetic recep-
tors for carbohydrates reported in the literature, only a lim-
ited number are chiral. In addition, of the several papers
dealing with recognition of carbohydrates by chiral synthetic
receptors,[2–20] only a few are concerned with the effect of re-
ceptorꢀs chirality on the enantioselective recognition of
sugars.[2–8] This is somewhat surprising because selective rec-
ognition can be expected when enantiomerically pure natu-
ral saccharides bind to opposite enantiomers of a chiral re-
ceptor. Indeed, apart from the extensive work of Diederich
and co-workers on dendritic clefts and cyclophanic and mac-
ropolycyclic receptors,[2] following the first report by Davis
and co-workers,[3] very few investigations were specifically
focused on the enantioselective recognition of monosacchar-
ides by chiral receptors.[4–8] In particular, to our knowledge,
the enantioselective recognition of mannosides has only
been reported in two cases, in which 1-octyl-a-d-mannopyr-
anoside binds to the enantiomers of the receptor with little
or no discrimination.[2b,6] We have recently reported a family
of pyrrolic tripodal receptors possessing distinguished recog-
nition properties towards monosaccharides.[21] We describe
herein the first member of a new generation of chiral tripo-
dal receptors, showing unprecedented affinities towards
mannosides even in polar solvents, and marked selectivities
with respect to other monosaccharides; most remarkably,
the all-S enantiomer of the receptor selectively binds to
b-mannose and b-mannosides with an outstanding enantio-
meric discrimination with respect to the all-R enantiomer,
proving that chirality of the receptor is a key feature in the
selective recognition of mannose.
[a] Dr. S. Roelens
Istituto di Metodologie Chimiche (IMC)
Consiglio Nazionale delle Ricerche (CNR)
Dipartimento di Chimica Organica
Polo Scientifico e Tecnologico
50019 Sesto Fiorentino, Firenze (Italy)
Fax : (+39)055-457-3570
E-mail: stefano.roelens@unifi.it
[b] Dr. A. Ardꢁ, Dr. C. Venturi, Prof. F. J. CaÇada,
Prof. J. Jimꢂnez-Barbero
Chemical and Physical Biology
Centro de Investigaciones Biolꢃgicas
CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain)
Fax : (+34)915-360-432
E-mail: jjbarbero@cib.csic.es
In a previous paper, we described a pyrrolic cage receptor
(1) that specifically recognizes the b-glucosyl residue.[22] Al-
though both b-d-glucose and methyl-b-d-glucoside could be
dissolved in apolar solvents by the receptor, the measured
affinity for octyl-b-d-glucoside in CDCl3 was no larger than
20 mm. We attributed the cause of this relatively modest af-
finity to the size of the cavity, which appeared to be slightly
too tight for the glucosyl residue. In an effort to achieve a
better fit, we tried to design a cage endowed with a some-
[c] Prof. C. Nativi, O. Francesconi, G. Gabrielli
Dipartimento di Chimica Organica
Universitꢄ di Firenze, Polo Scientifico e Tecnologico
50019 Sesto Fiorentino, Firenze (Italy)
[d] Prof. C. Nativi
Centro Risonanze Magnetiche (CERM)
Polo Scientifico e Tecnologico
50019 Sesto Fiorentino, Firenze (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902514.
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Chem. Eur. J. 2010, 16, 414 – 418

COMMUNICATION
what enlarged cavity, in the belief that fine-tuning of the
cage size would lead to a significantly improved affinity
even in more polar media. Replacement of trans-1,2-diami-
nocyclohexane (2) for the amino groups in the structure of
1, leading to the corresponding dodecaamino cage 3, ap-
peared to be the appropriate modification. Since 2 has been
shown to recognize the trans-1,2 arrangement of a number
of diols through a well-matched hydrogen-bonding net-
work,[23] it could be anticipated to recognize the trans-1,2
diol arrangement in monosaccharides and, in addition, both
the enantiomerically pure (R,R)- and (S,S)-diamines were
readily available to investigate the enantioselective recogni-
tion of monosaccarides. The synthesis of 3 was thus attempt-
ed according to Scheme 1.
Reaction of the trialdehyde 4 with the mono-BOC-pro-
tected diamine 2, followed by reduction of the resulting
Schiff base and subsequent deprotection of the amino
groups, yielded the tripodal hexaamine 5, which was con-
densed with pyrrole-2,5-dicarbaldehyde under the conditions
used for preparing the bicyclic receptor 1. Contrary to ex-
pectations, the monocyclic compound 6 was obtained in-
stead of the bicyclic cage 3. Although the best yield was ob-
tained for a 1:1 ratio of reactants, compound 6 always con-
stituted the major product isolated from the oligomeric re-
action mixture, whereas 3 could not be isolated in any case.
Apparently, the described structure modification biased the
Schiff base equilibrium toward the formation of a pyrrole-
bridged ring, regardless of the ratio of the reactants. While
all attempts to prepare the desired cage receptor 3 failed,
the monocyclic compound 6 turned out to be a valuable al-
ternative intermediate. Indeed, condensation of 6 with pyr-
role-2-carbaldehyde readily afforded the hexaamino dipyr-
rolic tripodal compound 7, which from preliminary testing
appeared to be a promising receptor for monosaccharides.
Receptor 7 was thus prepared in both enantiomerically pure
forms, the R,R,R,R,R,R enantiomer ((R)-7) and the
S,S,S,S,S,S enantiomer ((S)-7), which were submitted to
binding tests with the methyl glycosides of a set of monosac-
charides, including glucose (Glc), galactose (Gal), mannose
(Man), and N-acetyl-glucosamine (GlcNAc).
A preliminary screening indicated that, while Glc, Gal,
and GlcNAc were moderately bound, strong recognition oc-
curred with mannosides (see Supporting Information, ex-
traction experiments). Moreover, (S)-7 appeared distinctly
more effective than (R)-7 toward the b anomer. When an
equilibrated mixture of solid mannose, fully insoluble in
chloroform and showing a 2:1 a/b anomeric ratio, was
stirred with an equimolar solution of (S)-7 in CDCl3, 35%
of the solid was dissolved by the receptor in a reversed 1:2
a/b anomeric ratio, showing that bMan was preferentially
extracted into solution. bMan was also extracted in benzene,
though to a lesser extent (10%), and aMan could not be de-
tected. Even stronger evidence of binding was obtained
using the methyl glycosides of mannose (MeaMan and
MebMan: R=Methyl), which are likewise fully insoluble in
chloroform. Indeed, when a 3.1 mm solution of (S)-7 in
CDCl3 was independently treated with an excess of solid
MeaMan and MebMan, a significantly greater amount of
the latter (7.9 mm, 2.5 equiv) than the former (2.6 mm,
0.85 equiv) was found in solution, confirming a strong pref-
erence of the receptor for bMan. It is worth noting that
more than the stoichiometric amount of MebMan is extract-
ed by (S)-7 from the solid, suggesting the occurrence of
Scheme 1. Synthesis of receptor 7. Reagents and conditions: a) tert-butoxycarbonyl-trans-1,2-diaminocyclohexane, CH3OH/CHCl3 1:1, 708C, 7.5 h, then
NaBH4, RT, 1 h, 78%; b) CF3COOH, CH2Cl2, RT, 1.5 h, 91%; c) pyrrole-2,5-dicarbaldehyde, CHCl3, 708C, 12 h, then NaBH4, CH3OH, RT, 1 h, 63%;
d) CHCl3, RT, 12 h, then NaBH4, CH3OH, RT, 1 h, 50%.
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415

S. Roelens, J. Jimꢂnez-Barbero et al.
Table 1. Intrinsic median binding concentration (BC050 [mm])[a] and cumulative
association constants (logb)[b] for receptor to glycoside (R:G) complexes of 7
with octyl mannosides in CD3CN.
complexes of stoichiometry higher than 1:1. This evidence
was confirmed by treating a solid mixture of MeaMan and
MebMan with a 2.9 mm solution of (S)-7 in CDCl3 in a com-
petitive experiment featuring a 1:1:1 mole ratio of reactants;
0.17 equivalents of MeaMan and 0.90 equivalents of
MebMan were extracted from the glycoside mixture, show-
ing a nearly twofold enhancement of selectivity with respect
to the independent extraction of the glycosides. Altogether,
extraction experiments demonstrated that receptor (S)-7 is
able to effectively dissolve bMan and its methyl glycosides
in lipophylic organic solvents with a significant selectivity
over the corresponding a anomers. Eventually, a direct evi-
dence of complexation was obtained by mass spectrometry.
The positive mode ESI-MS spectra of mixtures of either
MeaMan or MebMan with (S)-7, extracted into acetonitrile,
unambiguously showed in both cases the peak of the 1:1
complex (see Supporting Information). The presence of
higher stoichiometry species could not be demonstrated be-
cause of the very dilute conditions in a polar solvent used
for the MS experiments.
OctaMan
logb
OctbMan
logb
Receptor BC050
G
BC050
ACHTUNGTRENNUNG
3.49Æ0.01
5.94Æ0.02
3.52Æ0.01
5.87Æ0.03
N
2.88Æ0.02
4.30Æ0.18
7.44Æ0.08
ACHTUNGTRENNUNG
(R)-7
299Æ6
1.222Æ41
ACHTUNGTRENNUNG
U
ACHTUNGTRENNUNG
4.00Æ0.05
7.04Æ0.13
10.05Æ0.15
ACHTUNGTRENNUNG
(S)-7
286Æ6
83Æ7
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
[a] Calculated from the logb values using the “BC50 Calculator” Program (see
reference [21]). [b] Measured by 1H NMR (400–900 MHz) from
ACHTUNGTRENNUNG
periments at T=298 K. Formation constants were obtained by nonlinear
least-square regression analysis of NMR data by simultaneous fit of all the
available signals from both reagents.
Since, in addition to the 1:1 adducts, formation constants
for complex species of higher stoichiometry were measured,
affinities were assessed using the BC050 parameter, a general-
ized affinity descriptor univocally defining the binding abili-
ty of a receptor in chemical systems involving multiple equi-
libria.[21,24,25] The BC500 descriptor is defined as the total con-
centration of receptor necessary for binding 50% of the
ligand when the fraction of bound receptor is zero, that is,
when forming the first complex molecule and, for 1:1 sys-
tems, coincides with the dissociation constant Kd. Thus, the
BC050 parameter can be used for comparing systems fitting
different models; the lower BC050, the higher the affinity. The
BC050 values calculated from cumulative binding constants
are reported in Table 1, and provide a quantitative evalua-
tion of the binding preference of (S)-7 for OctbMan. From
data of Table 1, it is clearly apparent that while no enantio-
discrimination is observed in the binding of OctaMan, a
15:1 enantioselectivity is apparent in the binding of Octb
Man which, to our knowledge, is the highest value reported
in the literature. The 83 mm value for the affinity observed in
acetonitrile is also worth noting, testifying strong binding
even in a markedly polar medium. We had previously de-
scribed a tripodal achiral receptor featuring selective recog-
nition of OctbMan, which showed an affinity of 680 mm in
acetonitrile;[26] the present, new-generation chiral receptor
exhibits a near tenfold enhancement in affinity, together
with outstanding enantioselectivity, which make (S)-7 the
most effective mannoside receptor up to date.
A quantitative assessment of binding affinities was ob-
1
tained by H NMR titrations of both the (R)-7 and (S)-7 re-
ceptors with octyl a and b mannosides (OctaMan and
OctbMan: R=Octyl) in which the octyl chain ensured the
necessary solubility for the binding measurements. Because
the interaction of the receptors with the glycosides was too
strong to be measured in CDCl3 by NMR spectroscopy,
showing a complex pattern of species in solution, association
constants were measured in CD3CN at T=298 K, for which
the occurrence of complex formation was proven by MS
spectroscopy. The ESI-MS spectrum of a mixture of (S)-7
and OctbMan in acetonitrile is reported in Figure 1, showing
the presence of the 1:1 adduct. Thus, binding interactions
were still evident in the markedly more polar medium.
Titrations were performed according to a previously
ACHTUNGTRENNUNG
established protocol[24] and the results are reported in
Table 1 as cumulative binding constants (see Supporting In-
formation for details).
Conclusive evidence of binding was provided by several
intermolecular NOE contacts, together with clear and signif-
icant changes in both the signals of receptor (S)-7 and of the
glycoside, when both entities were combined in acetonitrile
(Figure S1 and S2 and Tables S1–S3, in the Supporting Infor-
mation), which not only demonstrated the occurrence of re-
ceptor ligand interactions, but also allowed a definition of
the structure of the complex in solution. Indeed, while all at-
tempts to obtain X-ray quality crystals failed, most likely be-
cause of the flexible nature of the receptor, the structure of
the complex of (S)-7 with OctbMan in solution could be
solved by a combination of experimental NMR data and
Figure 1. Positive mode ESI-MS spectrum of a mixture of (S)-7 (0.18 mm)
and OctbMan (0.90 mm) in CH3CN. m/z: 711.58, [(S)-7+H]+;1003.77,
[(S)-7·OctbMan+H]+.
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Carbohydrate Recognition
COMMUNICATION
molecular modeling calculations.[27] Interestingly, although
NMR experiments were acquired at such a concentration
that the 1:1 complex accounted for nearly 50% of the spe-
cies in solution, whereas the 1:2 complex was only 5%, a
single structure did not satisfy all the experimental data,
suggesting the occurrence of two different arrangements of
the partners in the dominant 1:1 complex (Figure S3, Sup-
porting Information). The molecular modeling protocol ap-
plied (see Supporting Information) gave two families of
low-energy conformers for the complex between (S)-7 and
OctbMan: type A, with 12 structures within 4.3 kJmolÀ1
from the global minimum, and type B, with three structures
within 9.0 kJmolÀ1 from the global minimum, both of which
were required to fit with good agreement all the experimen-
tal NMR evidence simultaneously, including the dramatic
upfield shift of the H-4 proton of the mannose moiety,
which in all conformations is located at 2.7–2.8 ꢆ from the
centroid of the benzene ring of the receptor. The two fami-
lies of conformers and the corresponding minimum energy
structures for each family are depicted in Figures 2 and 3,
while the different orientations characterizing the two fami-
lies of structures can be appreciated from the superimposi-
Figure 3. Top: Superimposition of the three energy minima structures as
obtained from the molecular modeling protocol. The relative orientation
(type-B arrangement) of the sugar versus the receptor is depicted. The
flexible arm may adopt different orientations (see Supporting Informa-
tion). Bottom: Structure of the global minimum geometry of the type-B
family.
tion of the minimum energy conformers, depicted in Fig-
ure S4 (see Supporting Information).
Remarkably, the hydrogen-bond between a pyrrolic NH
and the axial mannosyl OH is the most conserved interac-
tion among the whole set of structures; likewise, in both
families the glycosidic chain lies above a pyrrolic ring, in
agreement with the unexpected upfield shift experienced by
the H-7, H-8, and H-9 protons of the octyl chain. Moreover,
in all conformers the b-face of mannose lies on top of the
benzene ring of the receptor, in a roughly face-to-face dispo-
sition. Such an arrangement suggests that strong hydrogen
bonding, particularly to the axial hydroxyl, and additional
CH–p interactions may be responsible for the observed af-
finity for the b anomer of mannosides.
In conclusion, in the present communication we have de-
scribed the prototype of a new family of chiral receptors
based on a tripodal scaffold and featuring pyrrolic binding
arms containing the trans-1,2-diaminocyclohexane motif,
which enantioselectively recognizes b-mannose and b-man-
nosides with remarkable affinity in a polar medium (aceto-
Figure 2. Top: Superimposition of the 12 energy minima structures as ob-
tained from the molecular modeling protocol. The relative orientation
(type-A arrangement) of the sugar versus the receptor is depicted. The
flexible arm may adopt different orientations (see Supporting Informa-
tion). Bottom: Structure of the global minimum geometry of the type A
family.
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S. Roelens, J. Jimꢂnez-Barbero et al.
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Published online: December 8, 2009
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