Chiral diaminopyrrolic receptors for selective recognition of mannosides, Part 1: Design, synthesis, and affinities of second-generation tripodal receptors

Article abstract of DOI:10.1002/chem.201002871

A new generation of chiral tripodal receptors for recognition of carbohydrates, featuring trans-1,2-diaminocyclohexane as a key structural element, and their recognition properties toward a set of glycosides of biologically relevant monosaccharides is des

Full text of DOI:10.1002/chem.201002871

DOI: 10.1002/chem.201002871
Chiral Diaminopyrrolic Receptors for Selective Recognition of Mannosides,
Part 1: Design, Synthesis, and Affinities of Second-Generation Tripodal
Receptors
Cristina Nativi,[b, c] Oscar Francesconi,[b] Gabriele Gabrielli,[b] Alberto Vacca,[b] and
Stefano Roelens*[a]
Abstract: A new generation of chiral
tripodal receptors for recognition of
carbohydrates, featuring trans-1,2-di-
selectivities, displaying high enantiodis-
crimination levels. These second-gener-
ation diaminopyrrolic tripodal recep-
tors are highly selective for mannose
among other monosaccharides, with
two members of the family being selec-
tive for the a and the b anomers re-
spectively. The measured affinities in
acetonitrile, 83 mm of (S)-7 for the b
mannoside and 127 mm of (R)-5 for the
a mannoside, make them the most ef-
fective synthetic receptors for manno-
sides reported to date. The affinity as-
sessment required a further evolution
of the BC050 parameter, a previously de-
veloped binding descriptor, which in its
ultimate formulation has now been ex-
tended to include, with no restrictions,
complexes of any stoichiometry, and
can thus be generally employed to rank
affinity data from heterogeneous sys-
tems on a common scale.
ACHTUNGTRENNUNGaminocyclohexane as a key structural
element, and their recognition proper-
ties toward a set of glycosides of bio-
logically relevant monosaccharides is
described. The introduction of a chelat-
ing diamino unit into the pyrrolic tripo-
dal architecture markedly enhanced
their binding abilities compared with
the parent aminopyrrolic receptors pre-
viously reported by our group. In addi-
tion, the chirality of the structure had a
clear impact on affinities, as well as on
Keywords: binding descriptors
·
carbohydrates · chiral receptors ·
molecular recognition · NMR spec-
troscopy
Introduction
the basis of intuitive complementarity considerations, one
would expect that the best-matching receptor for a specific
sugar should be a chiral enantiopure structure, appropriately
fitting the functional and geometric requirements of the
target ligand. Following this approach, several chiral syn-
thetic receptors for carbohydrates have been designed,
mostly based on chiral building blocks, such as oligosacchar-
ides and cyclodextrins, peptides, and steroidal units.[2–20]
Quite surprisingly, however, only a few reports in this area
are concerned with the effect of receptorꢀs chirality on the
enantioselective recognition of sugars.[2–8] Indeed, apart from
the systematic studies of Diederich and co-workers with cy-
clophanic and dendrimeric receptors featuring binaphthyl
and spiranic units as chiral fragments,[2] the literature on the
subject is limited to very few reports, specifically dealing
with the enantioselective recognition of glycosides of mono-
saccharides in organic solvents.[3–8] In particular, we are
aware of only two cases of enantioselective recognition of
mannosides, in which 1-octyl-a-d-mannopyranoside binds to
the enantiomers of the receptor with little or no discrimina-
tion.[2b,6]
The last two decades have witnessed the flourishing of a
wide number of synthetic receptors in the field of molecular
recognition of carbohydrates, mostly designed for biomimet-
ic recognition through noncovalent interactions[1] with the
intention of realizing artificial analogues of lectins, the natu-
ral receptors for carbohydrates.
Because carbohydrates are chiral molecules naturally oc-
curring in one enantiomeric form, inspired by lectins and on
[a] Dr. S. Roelens
Istituto di Metodologie Chimiche (IMC)
Consiglio Nazionale delle Ricerche (CNR)
Dipartimento di Chimica, Polo Scientifico e Tecnologico
50019 Sesto Fiorentino, Firenze (Italy)
Fax : (+39)055-457-3570
E-mail: stefano.roelens@unifi.it
[b] Prof. C. Nativi, Dr. O. Francesconi, G. Gabrielli, Prof. A. Vacca
Dipartimento di Chimica, Universitꢁ di Firenze
Polo Scientifico e Tecnologico
50019 Sesto Fiorentino, Firenze (Italy)
Mannosides play a prominent role in glycobiology as epi-
topes in recognition processes. Both the a and the b ano-
AHCTUNGTREGmNNNU ers of d-mannose are ubiquitously found in glycoconju-
gates, where they take part in various biological functions,
among which, for example, acting as markers specifically
recognized by several proteins widespread in living organ-
[c] 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.201002871.
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Chem. Eur. J. 2011, 17, 4814 – 4820

FULL PAPER
isms, from viruses and bacteria to plants and animals, for ex-
ample, the lectin concanavalin A (Con A), the mannose
binding proteins (MBPs) and the human mannose receptor
(hMR).[21] In addition, targeting the glycans of viral glyco-
proteins with carbohydrate-binding agents (CBAs) has re-
cently emerged as a promising strategy for antiviral thera-
pies and vaccines.[22] Because mannose is frequently encoun-
tered as the terminal sugar of N-glycans, and is overex-
pressed in the glycan shield of the viral envelope of several
viral infections of high health risk (HIV, HCV, etc.), termi-
nal oligomannosides have thus become attractive therapeu-
tic targets.[22–24] It is thus clear that having effective and se-
lective receptors for mannosides available would be of para-
mount importance for the development of CBAs.
Despite the biological relevance of mannose, there is not
only a substantial lack of receptors showing enantiodiscrimi-
nation versus mannosides, but also, in general, receptors
showing some level of preference for mannose versus other
monosaccharides are rare,[25] so that neutral biomimetic re-
ceptors specifically and effectively recognizing mannose are
still an open challenge. In this context, in a recent communi-
cation we described a chiral tripodal receptor showing un-
precedented affinities toward mannosides even in polar sol-
vents, as well as marked selectivities with respect to other
monosaccharides.[26] The new receptor not only improved
substantially on the binding ability toward b mannosides
with respect to a tripodal structure previously reported by
our group,[25a] but also exhibited the highest enantioselectivi-
ty ever reported, featuring a remarkable 15:1 enantioselec-
tivity ratio between the two enantiomers of the receptor.
In the present and following paper[27] we report a full ac-
count of our work on a new generation of structures closely
related to this receptor, featuring the most effective recep-
tors for a and b mannosides reported to date. The results
show not only that selectivity toward a and b mannosides
can be tuned by structure variations on the tripodal archi-
tecture, but also clearly demonstrate that chirality plays a
crucial role in the selective recognition of carbohydrates.
the enantiomerically pure (R,R) and (S,S) diamines were
readily available to investigate the enantioselective recogni-
tion of monosaccharides.
The synthesis of the receptors was accomplished as de-
scribed in Scheme 1 from the common intermediate 3,
which was prepared from 1,3,5-tribromomethyl-2,4,6-tri-
AHCTUNGTRENNUNG
ethylbenzene by oxidation with potassium dichromate.[26]
The trialdehyde 3 was reacted with the mono tert-butoxycar-
bonyl (Boc)-protected diamine 2 to give the corresponding
triple Schiff base, which was reduced with sodium borohy-
dride and deprotected with trifluoroacetic acid to afford the
triACTHNUGRTENUNGpodal hexamine 4. Treatment of 4 with pyrrole-2-carbal-
dehyde readily afforded the hexamino-tripyrrolic receptor 5
through Schiff base formation and subsequent sodium boro-
hydride reduction. Quite unexpectedly, reacting 4 with pyr-
role-2,5-dicarbaldehyde afforded the monocyclic receptor 6,
with one pyrrole group bridging two diamino moieties,
rather than the expected bicyclic cage compound or poly-
meric material.[26] Because 6 invariably constituted the
major isolated product from mixtures obtained for different
reactant ratios, it was concluded that replacement of the
amino group with the trans-diamino moiety had biased the
Schiff base equilibrium toward the formation of a pyrrole-
bridged ring, presumably the thermodynamically favored
product regardless of the ratio of reactants. The dipyrrolic
receptor 7 was readily obtained from 6 by treatment with
pyrrole-2-carbaldehyde through the condensation procedure
described above. Compounds 4, 5, 6, and 7 were obtained in
both enantiomerically pure forms by using the commercially
available (R,R) and (S,S) diamines 2 as starting materials,
thus providing a set of 4 pairs of enantiomeric receptors for
carbohydrate recognition, featuring from 0 to 3 pyrrolic
binding units on the same hexamine chiral scaffold.
Results and Discussion
Design and synthesis: The new generation of receptors was
based on the architecture of the aminopyrrolic progenitor 1,
a previously described receptor for monosaccharides,[28] and
was developed by combining a chiral diamino building block
with pyrrolic hydrogen-bonding units on the triethylbenzene
scaffold, in the belief that the potentially chelating diamino
arrangement may result in a more effective hydrogen-bond-
ing motif than the simple parent amine, if the correct bind-
ing geometry could be achieved. Replacement of the trans-
1,2-diaminocyclohexane unit (2) for the amino groups in the
structure of 1, appeared to be the modification of choice.
Indeed, since 2 has been shown to recognize the trans-1,2 ar-
rangement of a number of diols through a well-matched hy-
drogen-bonding network,[29] it may recognize the trans-1,2-
diol arrangement of monosaccharides, and in addition, both
To evaluate the contribution from steric/conformational
effects and to ascertain to what extent the binding ability
toward monosaccharides may be determined by the chirality
of the receptor, structures 8 and 9, two achiral analogues of
5 featuring different degrees of substitution, were prepared
through the described condensation procedure. Thus, the tri-
aldehyde 3 was reacted with mono-Boc-protected ethylene-
diamine and the resulting Schiff base was reduced and de-
protected to afford the unsubstituted hexamine 10. The
latter was condensed with pyrrole-2-carbaldehyde and re-
duced to give 8 in 41% yield. Interestingly, but not unex-
pectedly, reaction of 3 with mono-Boc-protected 2,3-dimeth-
yl-2,3-diaminobutane required prolonged heating to com-
plete, giving a Schiff base that survived acidic deprotection
and chromatographic separation on silica to afford the tri-
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S. Roelens et al.
Scheme 1. Synthesis of receptors. Reagents and conditions: a) N-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-carbaldehyde, CH3OH/CHCl3 1:1, RT, 14 h, then NaBH4, RT, 1 h, 68%;
d) pyrrole-2,5-dicarbaldehyde, CHCl3, 708C, 12 h, then NaBH4, CH3OH, RT, 1 h, 63%; e) pyrrole-2-carbaldehyde, CHCl3, RT, 12 h, then NaBH4,
CH3OH, RT, 1 h, 50%; f) N-tert-butoxycarbonyl-1,2-diaminoethane, CH3OH/CHCl3 1:1, 708C, 7.5 h, then NaBH4, RT, 1 h, 69%; g) CF3COOH, CH2Cl2,
RT, 1.5 h,>99%; h) pyrrole-2-carbaldehyde, CH3OH/CHCl3 1:1, RT, 14 h, then NaBH4, RT, 1 h, 41%; i) N-tert-butoxycarbonyl-2,3-dimethyl-2,3-diamino-
butane, CHCl3, 708C, 36 h, 69%; j) CF3COOH, CH2Cl2, RT, 3 h, 95%; k) pyrrole-2-carbaldehyde, CHCl3 1:1, 708C, 110 h; l) LiAlH4, Et2O, RT, 3 h, 32%
(over 2 steps).
A
tocol,[30] which consists of the simultaneous fit of the com-
plexation-induced shifts of all the available signals from
both the receptor and the glycoside to the appropriate asso-
ciation model by a nonlinear regression analysis. Because
the interaction of the receptors with the glycosides was in
most cases too strong to be measured in CDCl3 by NMR
spectroscopy, as revealed by preliminary testing, association
constants were measured in CD3CN at T=298 K in which,
despite the markedly more polar medium, complex forma-
tion was demonstrated by ESI-MS spectrometry.[26] Having
observed a preference for mannose with some members of
the family,[26] in the first step binding constants were mea-
sured for all the members of the set toward both of the
anomeric mannosides, to single out the receptor showing the
best recognition properties and to ascertain whether any
enantiomer and/or anomer selectivity could be observed.
The results are reported in Table 1 as cumulative association
constants for a set of receptors including, besides those de-
scribed in Scheme 1, also the parent triaminic receptor 1,
the binding properties of which were re-evaluated in the
same medium for direct comparison. Because multiple com-
plex species were found in most cases, affinities were as-
sessed from binding constants through the BC050 parame-
role-2-carbaldehyde, which also required prolonged heating,
and reduction with LiAlH4 eventually gave 9 in 32% yield,
indicating a substantial inertness caused by the introduction
of methyl substituents on the diamine unit.
Binding studies: The binding abilities of the new generation
receptors were tested versus a standard set of monosacchar-
ides, including glucose (Glc), galactose (Gal), mannose
(Man), and N-acetylglucosamine (GlcNAc), which were
used as both the a and the b octyl glycosides, in which the
octyl chain ensured the necessary solubility for binding
measurements in organic media (Scheme 2).
Association constants were measured by 1H NMR spec-
troscopy titrations according to a previously described pro-
Scheme 2. Monosaccharides used in recognition experiments. R=Octyl.
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Chiral Diaminopyrrolic Receptors
FULL PAPER
Table 1. Intrinsic median binding concentration (BC050, mm)[a] and cumulative association constants (logbn)[b]
tiodiscrimination observed be-
tween the (R) and the (S) re-
ceptors of the set (15:1). Nota-
bly, the same receptors 7 did
not show any enantiodiscrimi-
nation in binding to OctaMan,
even though their affinity for
the latter was nearly 50-fold
larger than that of the triaminic
receptor 1. The best affinity for
OctaMan was, instead, shown
by (R)-5, giving a 100-fold im-
provement with respect to 1, to-
gether with a significant a/b se-
lectivity, whereas (S)-5, showed
low a/b selectivity, although
with good affinity. The enantio-
discrimination ability of the
(R)/(S)-5 pair was appreciable
toward both anomers, but not
particularly noteworthy. Com-
parison of 7 with its cyclic mo-
nopyrrolic counterpart 6 shows
for the latter an overall drop in
affinities, which can be ascribed
to the lack of a pyrrolic binding
for receptor to glycoside (R/G) complexes of octyl mannosides in CD3CN.[c]
OctaMan
logb (R/G)
OctbMan
logb (R/G)
Receptor
BC050
BC050
1[d]
(R)-5
13492ꢀ322
127ꢀ3
1.908ꢀ0.009 (1:1)
3.87ꢀ0.01 (1:1)
6.12ꢀ0.05 (1:2)
6.29ꢀ0.05 (2:1)
3.35ꢀ0.02 (1:1)
5.20ꢀ0.16 (2:1)
2.94ꢀ0.01 (1:1)
3.16ꢀ0.02 (1:1)
5.09ꢀ0.10 (2:1)
3.49ꢀ0.01 (1:1)
5.94ꢀ0.02 (2:1)
7403ꢀ93
873ꢀ67
2.152ꢀ0.005 (1:1)
3.01ꢀ0.04 (1:1)
5.14ꢀ0.10 (2:1)
(S)-5
437ꢀ17
566ꢀ15
3.23ꢀ0.01 (1:1)
5.09ꢀ0.09 (2:1)
2.875ꢀ0.004 (1:1)
3.36ꢀ0.02 (1:1)
5.12ꢀ0.16 (2:1)
2.88ꢀ0.02 (1:1)
4.30ꢀ0.18 (2:1)
7.44ꢀ0.08 (3:1)
4.00ꢀ0.05 (1:1)
7.04ꢀ0.13 (1:2)
10.05ꢀ0.15 (1:3)
2.560ꢀ0.006 (1:1)
n.d.[e]
(R)-6
(S)-6
1157ꢀ14
652ꢀ26
1335ꢀ11
424ꢀ18
(R)-7
(S)-7
299ꢀ6
1222ꢀ41
286ꢀ6
3.52ꢀ0.01 (1:1)
5.87ꢀ0.03 (2:1)
83ꢀ7
8
9
3116ꢀ34
2.506ꢀ0.005 (1:1)
2754ꢀ36
n.d.[e]
[a] Calculated from the logb values using the “BC50 Calculator” program (see ref. [28]). [b] Measured by
1H NMR (400–900 MHz) from titration experiments at T=298 K. Formation constants were obtained by non-
linear least-square regression analysis of the NMR data by simultaneous fit of all the available signals from
both reagents. [c] The R and S descriptors are used to designate the receptors of all-R and all-S absolute con-
figuration of the six stereocenters, respectively. [d] Dimerization of the receptor has been observed. The dime-
rization constant has been measured independently (logbdim =0.56ꢀ0.03) and set invariant in the nonlinear re-
gression analysis. [e] Non-detectable.
ter.[28] The BC500 (intrinsic median binding concentration) de-
scriptor is defined as the total concentration of receptor nec-
essary for binding 50% of the ligand when the fraction of
bound receptor is zero, that is, when forming the first com-
plex molecule. This value coincides with the dissociation
constant Kd for 1:1 complexes, whereas it can be viewed as a
“global” dissociation constant when more than one complex
is present in solution (see the following section). The BC500
values calculated from the measured binding constants are
also reported in Table 1.
The two enantiomers of the plain hexaminic receptor 4
did not show recognition properties of interest and were not
reported in Table 1. Indeed, (R)- and (S)-4[31] were tested
versus octyl-b-d-glucoside in CDCl3, giving BC050 values of
(249ꢀ2) and (729ꢀ3) mm, respectively, which compared fa-
vorably with the corresponding triaminic receptor 1,3,5-
unit, although the selectivity pattern is reminiscent of that
of the more effective 7, suggesting a significant contribution
from the cyclic structure of the arms of the tripodal scaffold
to the selectivity features of the receptor. Selectivity may
thus be primarily determined by the cyclic nature of the re-
ceptor, whereas the additional pyrrolic unit would enhance
the overall binding strength.
The role of chirality and of conformational and steric ef-
fects is evidenced by comparison of the chiral receptors 5–7
with the achiral counterparts 8 and 9. A substantial decrease
of binding ability versus both the anomeric mannosides is
observed for the unsubstituted receptor 8, the affinities of
which are intermediate between those of receptors 5–7 and
those of the parent triaminopyrrolic receptor 1. The in-
creased conformational freedom of 8 with respect to the cy-
clohexane derivatives appears to be detrimental for the
binding ability of the receptor, most likely for entropic rea-
sons. On the other hand, the tetramethyl-substituted recep-
tor 9 showed no affinity for mannosides, suggesting that
steric hindrance is detrimental as well for the binding prop-
erties of these structures. In agreement with this evidence,
the binding ability of receptor 9 and the reactivity exhibited
by the tetrasubstitued diamino reactants follow the same
trend, most likely because the amino groups are hardly ac-
cessible. On the contrary, in the structures of receptors 5–7
the amino groups are barely hindered and are kept in a
trans-diequatorial conformation well suited for binding by
the cyclohexane ring, which imparts a chiral twist to the ar-
chitecture. The relevance of such a chiral twist in determin-
ing the correct binding geometry is demonstrated by the sig-
nificantly different recognition abilities exhibited by the two
triethyl-2,4,6-triaminomethylbenzene
(BC050 =(3690ꢀ
50) mm),[28] but was significantly less effective than the tria-
minopyrrolic receptor 1 in the same solvent (BC050 =(24ꢀ
2) mm).[28] On the contrary, with the exception of 9, the affin-
ities exhibited by the other receptors were larger than those
of receptor 1, demonstrating the substantial improvement
achieved by replacing the monoaminic with the chelating di-
aminic unit in the architecture of the receptor. Indeed, affin-
ities increased by up to two orders of magnitude with re-
spect to 1 for all receptors but 9, for which evidence of bind-
ing could not be detected.
The results reported in Table 1 confirm that receptor (S)-
7 exhibits the best affinity of the whole set of data toward
OctbMan, which turned out to be nearly two orders of mag-
nitude larger than that of 1, together with the highest enan-
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S. Roelens et al.
enantiomers of the same receptor. In other words, in addi-
tion to steric and conformational factors favoring the cyclo-
hexane derivatives, the chiral twist of the receptor appears
to play a strategic role in the recognition of mannosides, to
an extent that strongly depends on the match/mismatch
degree achieved between the partners of the specific com-
plex with the sugar.
est match/mismatch observed and may be due to the cyclic
structure of the receptor associated to the correct twist of
the chiral architecture.
Binding descriptors: In the previous section, we assessed the
affinities of a family of receptors toward a set of glycosides
using the BC050 parameter. The treatment of the BC50 de-
scriptor has been developed[28,30,32] with the aim of providing
a general tool to compare, on the same scale, the affinities
of systems featuring different binding models and number
of association constants, thus heterogeneous in nature. We
have clearly pointed out that, except for cases featuring
solely a 1:1 association, in which the affinity is fully defined
by the association constant, in all other cases it is not possi-
ble to assess the affinity of a receptor directly from binding
constant values, as none of the constants alone will give the
overall binding ability of the receptor. The BC50 (median
binding concentration) parameter, which can be calculated
from the measured association constants, represents a gener-
alized affinity descriptor univocally defining on a common
scale the overall binding ability of a species A (a receptor or
a ligand) toward a species B (a ligand or a receptor) in
chemical systems involving any number of complex species.
BC50 directly provides a quantitative measure of binding
ability, since, in analogy to the IC50 parameter, the lower the
value, the higher the affinity.
Because BC50, which is most usefully expressed as a func-
tion of the fraction of bound A (xA), is a conditional param-
eter that depends on the concentration of B, it is particularly
convenient to use its limiting value BC050, the value of BC50
for which xA =0, which we have called the intrinsic median
binding concentration. BC500 depends upon all the equilibri-
um constants involved in the system, but not on specific
(concentration) conditions and represents the affinity of re-
agent A for reagent B in the absence of complex species
formed, that is, when forming the first complex molecule.
Thus, BC050 identifies the maximum binding ability of A
toward B since, with increasing xA, A becomes progressively
Having established that (R)-5 and (S)-7 are the most ef-
fective receptors of the set toward a and b mannosides, re-
spectively, we next turned to investigate the selectivity of 5
and 7 toward the whole set of monosaccharides. In Table 2
the measured binding constants and the corresponding affin-
ities, expressed as BC050 values, are reported for both enan-
tiomers of the receptors, to be compared with the results for
mannosides from Table 1. It is easily appreciated that both
enantiomers of 5 display a preference for the mannosides
with respect to the other monosaccharides; this monosac-
charide selectivity is marked in the case of the a anomers,
especially for (R)-5, whereas it is less pronounced in the
case of the b anomers. a-Monosaccharide selectivity ratios
as high as nearly 10:1 were observed for (R)-5, whereas the
largest ratio observed for (S)-5 was 7:1. The picture is some-
what different for receptor 7. Except for OctbGlcNAc, affin-
ities are in the millimolar range for all glycosides, with little
enantiodiscrimination between the two enantiomers, where-
as micromolar affinities are shown by (R)-7 and (S)-7
toward OctaMan, although without any significant enantio-
discrimination. Although a neat preference for mannosides
is thus confirmed for the a anomer, the behavior of 7
toward the b anomer is quite peculiar. In contrast to the
steep increase of affinity shown by the (S) enantiomer, a
marked decrease is exhibited by the (R) enantiomer, falling
in the range observed for the other monosaccharides, thus
giving rise to the remarkable 15:1 enantiomeric ratio. The
results suggest that the structure of (S)-7 may be particularly
well fitted to bind OctbMan, so that inverting the configura-
tion of the receptor would lead to a dramatic mismatch of
the complex geometry. Whatever the origin, this is the larg-
Table 2. Intrinsic median binding concentration (BC050, mm)[a] and cumulative association constants (logbn)[b] for receptor to glycoside (R/G) complexes
of octyl glycosides in CD3CN.
(R)-5
logb (R/G)
(S)-5
logb (R/G)
(R)-7
logb (R/G)
(S)-7
logb (R/G)
Glycoside
BC050
BC050
BC050
BC050
OctaGlc
1251ꢀ111
2.85ꢀ0.05 (1:1)
4.89ꢀ0.08 (2:1)
3.00ꢀ0.03 (1:1)
4.89ꢀ0.11 (2:1)
2.88ꢀ0.01 (1:1)
4.58ꢀ0.09 (2:1)
2.611ꢀ0.002 (1:1)
1000ꢀ22
3.000ꢀ0.009 (1:1)
3120ꢀ38
2.506ꢀ0.005 (1:1)
2.493ꢀ0.004 (1:1)
2.527ꢀ0.004 (1:1)
2.937ꢀ0.002 (1:1)
2.314ꢀ0.003 (1:1)
2493ꢀ34
2.17ꢀ0.02 (1:1)
5.01ꢀ0.01 (2:1)
2.85ꢀ0.01 (1:1)
4.60ꢀ0.03 (1:2)
2.497ꢀ0.002 (1:1)
OctbGlc
929ꢀ53
1245ꢀ39
2450ꢀ9
1070ꢀ97
905ꢀ133
1819ꢀ50
3186ꢀ11
2542ꢀ164
732ꢀ29
933ꢀ7
2.66ꢀ0.02 (1:1)
4.69ꢀ0.02 (2:1)
2.497ꢀ0.002 (1:1)
3216ꢀ27
2974ꢀ27
1157ꢀ6
4851ꢀ37
763ꢀ27
1248ꢀ28
3183ꢀ15
1532ꢀ34
1573ꢀ14
1298ꢀ23
OctaGal
OctbGal
2.55ꢀ0.03 (1:1)
4.18ꢀ0.13 (2:1)
3.12ꢀ0.02 (1:1)
4.91ꢀ0.08 (2:1)
3.030ꢀ0.003 (1:1)
2.74ꢀ0.01 (1:1)
4.80ꢀ0.05 (2:1)
2.787ꢀ0.003 (1:1)
4.16ꢀ0.08 (2:1)
2.723ꢀ0.008 (1:1)
5.27ꢀ0.03 (2:1)
OctaGlcNAc
OctbGlcNAc
2.92ꢀ0.05 (1:1)
4.99ꢀ0.10 (2:1)
2.99ꢀ0.08 (1:1)
5.11ꢀ0.12 (2:1)
2.87ꢀ0.01 (1:1)
5.62ꢀ0.05 (1:2)
1
[a] Calculated from the logb values using the “BC50 Calculator” program (see ref. [28]). [b] Measured by H NMR (400–900 MHz) from titration experi-
ments at T=298 K. Formation constants were obtained by a nonlinear least-square regression analysis of the NMR data by simultaneous fit of all the
available signals from both reagents.
4818
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Chem. Eur. J. 2011, 17, 4814 – 4820

Chiral Diaminopyrrolic Receptors
FULL PAPER
saturated, losing its binding capability. It has been demon-
strated that, in systems in which a 1:1 association is the only
binding equilibrium, BC050 coincides with the dissociation
constant Kd and can therefore be viewed as a “global” affin-
ity constant in cases involving more than one complex spe-
cies.[28]
for mannosides, that is, (R)-5 and (S)-7, which turned out to
be selective for a and b mannosides, respectively. From the
results presented, which constitute a significant step further
in the design of biomimetic receptors for carbohydrates, it
can be concluded that 1) replacing the amino unit of the
progenitor 1 with a trans-1,2-diamino moiety dramatically
improved the binding ability of the receptor; 2) pyrrolic hy-
drogen-bonding donors contribute substantially to the recog-
nition properties, since affinities increased with the increas-
ing number of pyrrolic units; 3) the chirality of the receptor
plays a key role in determining the recognition properties
by imparting a matched or mismatched twist toward the
chiral ligand, whereas steric hindrance of substituents and
conformational freedom of the structure appear to be detri-
mental; and 4) bridging two arms of the tripodal architec-
ture into a pyrrole-containing cyclic structure completely in-
verts recognition properties from an (S) to an (R) enantio-
meric preference and from a b to an a anomeric preference.
The last conclusion demonstrates that, although architec-
ture, geometry and hydrogen-bonding groups of this family
of receptors could be tuned for selective recognition of
A severe inconvenience in the use of BC050 is that complex
species multinuclear in B, such as AB2, AB3, and so forth,
when present, bring a variable contribution to the BC50
function along xA, which vanishes for xA =0, thus rendering
BC050 insensitive to these species. In such cases, comparing
the entire BC50 curve is required for assessing affinities,
which is not a straightforward process. This is indeed the
case for the results presented in this paper, which feature
several receptor–ligand systems involving RG2 and RG3
complexes that would be neglected by the BC050 parameter.
We have now found a solution to this limitation by applying
a new approach to the calculation of BC050, which restores
the ability of the parameter to describe the full binding af-
finity whatever species is present in solution, including spe-
cies multinuclear in B, that is, in our case, in the glycoside
ligand. The binding affinities reported in Table 1 and 2 as
BC050 values are therefore “corrected” (see below) according
to the new approach. A detailed description of the treat-
ment is reported in an appendix (see the Supporting Infor-
mation).
The principle underlying the new approach is an alterna-
tive procedure for calculating the BC050 value, which consists
of integrating the BC50 function in the whole range of xA,
the fraction of bound A, therefore taking into account the
contribution from all complex species, also including the var-
iable contribution from species multinuclear in B. It is dem-
onstrated (see Appendix in the Supporting Information)
that the value of the integral of 1/BC50 for 0ꢁxA ꢁ1 is pro-
portional to 1/BC050 for all systems and that, in the absence
of complexes multinuclear in B, results from the integration
procedure are consistent with those from the solution of the
analytical equations. Thus, the integration procedure gives
access to BC050 values without any restrictions and in its
most general formulation is given by equation (1):
mannoACTHNURTGNEUsGN ides, the design of receptors for carbohydrates re-
mains a very challenging task, being determined by a subtle
balance of factors not yet amenable to a rational design.
The extension of the BC050 parameter to include complex
species of any stoichiometry represents the ultimate evolu-
tion of the BC50 affinity descriptor. Taking advantage of the
“BC50 Calculator” program as a simple and convenient tool,
BC050 may be easily calculated and employed in molecular
recognition studies to rank binding abilities on a common
scale for a host–guest system of any complexity; BC050 may
therefore represent a general and unifying affinity descriptor
for binding data coming from heterogeneous sources. We
hope this descriptor will find widespread application in
supramolecular chemistry.
Acknowledgements
A research grant to Dr. Oscar Francesconi (grant no. 2008.1475) from
Ente Cassa di Risparmio di Firenze is gratefully acknowledged.
Z
1
1=BC500 ¼ 2
1=BC50ðxAÞdxA
ð1Þ
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family of tripodal architectures as very effective receptors
Chem. Eur. J. 2011, 17, 4814 – 4820
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www.chemeurj.org
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Chem. Eur. J. 2011, 17, 4814 – 4820