Tuning selectivity in macrotricyclic carbohydrate receptors; CH → N mutations in aromatic spacers

Article abstract of DOI:10.1039/b315447e

Dipicolinoyl spacer groups are used to control the conformational and H-bonding properties of tricyclic carbohydrate receptors 3 and 4. Binding selectivities are changed in relation to all-isophthaloyl system 1b.

Full text of DOI:10.1039/b315447e

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Tuning selectivity in macrotricyclic carbohydrate receptors;
CH N mutations in aromatic spacers†
Trinidad Velasco,a Gregory Lecollinet,a Theo Ryanb and Anthony P. Davis*a
a School of Chemistry, University of Bristol, Cantock’s Close, UK BS8 1TS.
E-mail: Anthony.Davis@bristol.ac.uk; Fax: (ϩ44)117-929-8611
b Department of Chemistry, Trinity College, Dublin 2, Ireland
Received 1st December 2003, Accepted 12th January 2004
First published as an Advance Article on the web 26th January 2004
Dipicolinoyl spacer groups are used to control the
conformational and H-bonding properties of tricyclic
carbohydrate receptors 3 and 4. Binding selectivities are
changed in relation to all-isophthaloyl system 1b.
pyridine-based analogues. By participating in hydrogen bond-
ing, the pyridine nitrogen is likely to affect both the geometry of
the macrocycle and the array of H-bonding groups presented
to the interior. We now report the synthesis and recognition
properties of two macrotricycles 3 and 4 which feature this
“mutation”. The introduction of the pyridines is shown to
invoke significant changes in binding selectivity.
Carbohydrate recognition is a central biological phenomenon,
mediating carbohydrate metabolism, cell infection, cell–cell
recognition and many aspects of the immune response.1 This
importance, coupled to poor understanding of the underlying
principles, has fuelled research into saccharide binding by
synthetic, potentially biomimetic receptors.2 However, there are
still few systems which show high affinities and selectivities
towards closely related carbohydrate substrates. A recent
example from this group is the tricyclic octa-amide 1. The first
version 1a was shown to bind octyl glycosides in chloroform
with unusual strength and discrimination.3 Later variant 1b
proved capable of extracting the common hexoses from water
into chloroform,
a feat unprecedented for preorganised
receptors operating through non-covalent bonding.4 In both
cases, particular selectivity was shown for equatorial sub-
stitution patterns. 1a preferred β-glucoside 2 over the α anomer
by a factor of 50, while 1b extracted xylose in preference to
ribose, and glucose in preference to galactose and mannose.
The synthesis of receptors 3 and 4 is summarised in Scheme 1.
Biphenyl unit 5 and isophthaloyl derivative 6 were prepared as
previously reported.4 The novel pyridine-based spacer 11 was
synthesised from chelidamic acid 7 via esterification to give 8,
O-alkylation to 9, hydrogenolysis to 10, and treatment with
DCC/pentafluorophenol. Formation of the tricyclic “cages”
was accomplished through sequential [2ϩ2] macrolactam-
isations. Hydrogenolysis of the Cbz groups in 5 gave a diamine
which was cyclised with 6 to give 12, and 11 to give 13. Acid-
induced deprotection and cyclisation with 11 then gave 3 and 4.
The affinities of receptors 3 and 4 for saccharide guests were
investigated firstly by titration studies in organic media with
octyl β--glucopyranoside 2. Upon addition of the glucoside to
3 in CDCl3/CD3OH (96 : 4), or 4 in CDCl3/CD3OH (99 : 1),
significant changes in the receptor 1H-NMR spectra were
observed.† However, signal broadening and the relatively small
∆δ precluded quantitative analysis. Fluorescence titrations
in CHCl3 revealed ≥65% decreases in emission intensity from
both receptors on addition of 2, with saturation at close to 1
equivalent.† Analyses of the data at the emission maxima,
assuming a 1 : 1 binding model, gave very high binding
constants (>107 Ϫ1 in each case). However, the fits were
poor and changes in the emission profiles during the titrations
suggested interference from other stoichiometries. Accurate
and reliable Ka values were therefore unobtainable.
Given the diversity of carbohydrate structures, alternative
selectivities are clearly of interest. Accordingly, we are investi-
gating changes to 1 which might alter binding preferences while
maintaining the same general architecture.5 One possibility
is the replacement of the isophthaloyl spacer groups with
† Electronic supplementary information (ESI) available: experimental
details for the synthesis of receptors 3 and 4, binding studies of recep-
tors 3 and 4 with monosaccharide 2, and extraction experiments. See
http://www.rsc.org/suppdata/ob/b3/b315447e/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 6 4 5 – 6 4 7
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Table 1 Extractabilities of aldohexoses 14–16 from aqueous solutions into CHCl3 by receptors 1b, 3 and 4a
-Glucose 14 -Galactose 15
-Mannose 16
1 b
1 b
0.5 b
0.1 b
1 b
0.5 b
0.1 b
1b
3
4
1
0.55
0.15
0.5
0.2
<0.1c
n.d.d
0.2
0.6
<0.1c
0.17
n.d.d
n.d.d
<0.1c
0.3
<0.1c
n.d.d
a Values in mole equivalents with respect to receptor, as determined by 1H-NMR (integration of anomeric CH vs. receptor protons). Estimated error
ϩ20%. Results for 1b from ref. 4. b Concentration of substrate in aqueous phase. c Carbohydrate detectable, but amount too small for quantification
by NMR integration. d None detectable.
As a result, galactose and glucose are extracted to similar
extents, in contrast to the strong preference of 1b for glucose.
While it might appear that 3 is simply less selective than 1b, it
should be noted that the monosaccharides are not equally
hydrophilic. Indeed, physical chemical measurements have sug-
gested that galactose is more strongly hydrated than glucose,6
implying that 3 may be intrinsically galactose-selective.
Control experiments with tetra N-Boc protected macrocyclic
intermediates 12 and 13 were carried out with -glucose 14 (1 
aqueous solution). No sugar was detected in the organic phase,
confirming that the macrotricyclic frameworks of 3 and 4 are
necessary for efficient extraction.
The selectivity differences between 1b and 3 are probably due
to the conformational properties of the spacers. It is established
that the dipicolinamide unit prefers the syn–syn conformation
17 because of electrostatic interactions between the NH groups
and the pyridine N. In contrast, the isophthalamide unit prefers
the syn–anti arrangement 18.7 The two spacers will thus tend
to present different arrays of H-bonding groups to a bound
substrate, and will also promote different cavity dimensions.
Scheme 1 Synthesis of receptors 3 and 4. Reagents, conditions and
yields: a) i) (COCl)2, DMF, THF, ii) BnOH, iPr2NEt, 72%; b) K2CO3,
pentyl bromoacetate, (CH3)2CO, 97%; c) H2, Pd/C, EtOAc, 97%; d)
DCC, DMAP, C6F5OH, iPr2NEt, THF, 56%; e) H2, Pd/C, DCM/
CH3OH, 72%; f ) 6, iPr2NEt, THF, high dilution, 80%, or 11, iPr2NEt,
THF, high dilution, 62%, g) CF3CO2H, DCM; h) 11, iPr2NEt, THF,
high dilution, 23% (3) or 11% (4).
Financial support from the European Commission (Network
contracts ERB-FMRX–CT98-0231 and HPRN-CT-2002-
00190) and Enterprise Ireland is gratefully acknowledged.
The extraction of substrates from water into non-polar
solvents provides an alternative means of studying carbo-
hydrate recognition. Such experiments allow straightforward
Notes and references
comparisons between receptors under conditions which mimic,
1 Leading references: T. Feizi and B. Mulloy, Curr. Opin. Struct. Biol.,
to some extent, the cytosol–membrane interface in biology.
2001, 11, 585; C. R. Bertozzi and L. L. Kiessling, Science, 2001, 291,
Receptors 3 and 4 were tested using the procedure previously
2357; S. J. Williams and G. J. Davies, Trends Biotechnol., 2001, 19,
356.
applied to 1b.4 Solutions of receptor in chloroform (0.35 m)
were warmed to 30 ЊC then shaken vigorously with aqueous
carbohydrate. The phases were separated, and the organic
phase was passed through hydrophobic filter paper to remove
residual aqueous solution. The chloroform was evaporated and
2 For an overview, see: A. P. Davis and R. S. Wareham, Angew. Chem.,
Int. Ed., 1999, 38, 2978. For recent examples see: T. Ishi-i,
M. A. Mateos-Timoneda, P. Timmerman, M. Crego-Calama,
D. N. Reinhoudt and S. Shinkai, Angew. Chem., Int. Ed., 2003, 42,
2300; R. Welti and F. Diederich, Helv. Chim. Acta, 2003, 86, 494;
R. Welti, Y. Abel, V. Gramlich and F. Diederich, Helv. Chim. Acta,
2003, 86, 548; M. Mazik, W. Radunz and W. Sicking, Org. Lett., 2002,
4, 4579; Y. H. Kim and J. I. Hong, Angew. Chem., Int. Ed., 2002, 41,
2947; K. Ladomenou and R. P. Bonar-Law, Chem. Commun., 2002,
2108; R. D. Hubbard, S. R. Horner and B. L. Miller, J. Am. Chem.
Soc., 2001, 123, 5810; S. Tamaru, M. Yamamoto, S. Shinkai,
A. B. Khasanov and T. W. Bell, Chem. Eur. J., 2001, 7, 5270;
J. H. Liao, C. T. Chen, H. C. Chou, C. C. Cheng, P. T. Chou,
J. M. Fang, Z. Slanina and T. J. Chow, Org. Lett., 2002, 4, 3107;
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1
the residue analysed by H NMR in (CD3)2SO. -Glucose 14,
-galactose 15 and -mannose 16 were used as substrates. The
results are shown in Table 1, along with the data obtained
earlier for 1b. Both 3 and 4 succeeded as monosaccharide
extractors. The symmetrical cage 4 proved relatively weak,
while the asymmetrical receptor 3 was found to be roughly
similar in affinity to 1b. Significantly, however, the selectivities
observed for 3 were quite different to those of the earlier
system. Compared to 1b, receptor 3 showed increased affinity
to galactose and -mannose, but decreased affinity to glucose.
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3 A. P. Davis and R. S. Wareham, Angew. Chem., Int. Ed., 1998, 37,
2270.
4 T. J. Ryan, G. Lecollinet, T. Velasco and A. P. Davis, Proc. Natl. Acad.
Sci. USA, 2002, 99, 4863.
5 For a variation giving disaccharide selectivity, see: G. Lecollinet,
A. P. Dominey, T. Velasco and A. P. Davis, Angew. Chem., Int. Ed.,
2002, 41, 4093.
6 S. A. Galema and H. Hoiland, J. Phys. Chem., 1991, 95, 5321;
S. A. Galema, M. J. Blandamer and J. Engberts, J. Org. Chem., 1992,
57, 1995.
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31, 792; K. Kavallieratos, C. M. Bertao and R. H. Crabtree, J. Org.
Chem., 1999, 64, 1675.
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