Sugar recognition by C3-symmetric oxazoline hosts

Article abstract of DOI:10.1016/S0040-4039(01)00915-7

C₃-Symmetric tris(oxazoline) derivatives (2S,2R) were designed to complex sugars and alcohols in nonpolar organic solvent through complementary intermolecular hydrogen-bonding interactions. ¹H NMR titration demonstrated that the C₃-symmetric hosts were capable of anomer-selective recognition for n-octyl-D-glucopyranoside. ¹H NMR data revealed intermolecular hydrogen bonds between 2S and glucopyranosides.

Full text of DOI:10.1016/S0040-4039(01)00915-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5049–5052
Sugar recognition by C3-symmetric oxazoline hosts
Hae-Jo Kim, Yeon-Hwan Kim and Jong-In Hong*
School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-742, South Korea
Received 6 April 2001; revised 21 May 2001; accepted 25 May 2001
Abstract—C3-Symmetric tris(oxazoline) derivatives (2S,2R) were designed to complex sugars and alcohols in nonpolar organic
solvent through complementary intermolecular hydrogen-bonding interactions. 1H NMR titration demonstrated that the
C3-symmetric hosts were capable of anomer-selective recognition for n-octyl-
intermolecular hydrogen bonds between 2S and glucopyranosides. © 2001 Elsevier Science Ltd. All rights reserved.
D
-glucopyranoside. 1H NMR data revealed
Carbohydrate recognition through non-covalent inter-
actions is one of the challenging goals of biomimetic
and supramolecular chemistry.1 This is ascribed to the
complex structural diversity of carbohydrates and to
their important roles in biological regulation.2 As
revealed by the X-ray crystal structures of carbohy-
drate–protein complexes,3 the most effective approach
to carbohydrate recognition is to surround the polar
hydroxyl groups with complementary hydrogen-bond-
ing groups and place aromatic surfaces against carbo-
hydrate CH moieties. Despite considerable efforts in
the development of artificial carbohydrate receptors,
there are only a few effective hydrogen-bonding recep-
tors for sugars in organic solvents reported to date and
anomeric-selective artificial receptors for monosaccha-
rides are far less developed.4
We describe here oxazoline-based C3-symmetric hosts
having three oxazoline nitrogens as H-bonding accep-
tors and a central phenyl group as a p-donor for CH-p
interactions, and focus on the anomer-selective recogni-
tion for octyl-D-glucopyranoside in chloroform.
C3-Symmetric chiral tris(oxazoline) derivatives were
synthesized from 1,3,5-benzenetricarboxylic acid as
shown in Scheme 1.5 Treatment of triacid with oxalyl
R2 R1
OH
1) (COCl)2 , cat DMF
O
HN
HO2C
CO2H
R1
OH
N
H
O
R2
Ph
2)
H2N
OH
CO2H
1S (R1 = Ph, R2 = H)
1R (R1 = H, R2 = Ph)
*
(S or R)
TEA
O
NH
HO
R1
R2
R1
R2
O
N
3eq. MsCl
6eq. TEA
R1
N
O
R2
2S (R1 = Ph, R2 = H)
2R (R1 = H, R2 = Ph)
O
N
R2
R1
Scheme 1. Synthetic scheme for oxazoline derivatives 2S and 2R.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00915-7

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H.-J. Kim et al. / Tetrahedron Letters 42 (2001) 5049–5052
1H NMR titration in CDCl3 shows
a dramatic
chloride under cat. DMF in dichloromethane afforded
triacid chloride which was subsequently added to
amino alcohol to give rise to tris(amides) in good yield.
Reaction of the resulting amide with mesyl chloride
in the presence of TEA afforded the desired
tris(oxazolines).6
downfield shift of aromatic protons at the center of the
host 2S, which may be caused by the decrease of charge
density in a nitrogen lone pair (Fig. 1). This results
from intermolecular H-bonding interactions between
H-bond acceptor N of host and H-bond donor OH of
guest.
Curve fitting of the host signals to a 1:1 binding
isotherm gave apparent binding constants listed in
Table 1. The 1:1 binding ratio was confirmed by a Job’s
plot (Fig. 2). The binding constants between 2S and
n-octyl- -glucopyranoside were found to be 270 for a
D
anomer and 1120 for b anomer. Although the binding
affinity of 2S is weaker than that of Mazik’s C3-sym-
metric polypyrimidine receptors due to the decreased
number of the H-bonding donors and acceptors in 2S,7a
the selectivity between a and b anomers increases from
1.1 to 4.1 (b/a) presumably because of the steric inter-
actions of the phenyl substituents in the oxazoline
rings. The binding affinity of 2S to n-octyl-b-
galactopyranoside is four times weaker than to n-octyl-
b- -glucopyranoside. This anomeric selectivity and
diastereoselectivity for sugars are mostly likely to result
from the slight energetic difference in the intermolecu-
lar H-bonding patterns due to the varying degree of
steric interaction between sugars and 2S. cis-1,2-Cyclo-
D-
Figure 1. 1H NMR titration curves between host 2S and
D
guests in CDCl3 at 295 K. [H]0=1.5 mM, 1=n-octyl-b-
glucopyranoside, 2=n-octyl-a- -glucopyranoside, 3=n-
-galactopyranoside,4=N-octylthymidine,5=N-octy-
D-
D
octyl-b-
D
luridine, 6=cis-1,2-cyclohexanediol.
Table 1. Binding constants between hosts and guestsa
a 1H NMR titration of 1.5 mM of [2] in CDCl3 at 295 K.

H.-J. Kim et al. / Tetrahedron Letters 42 (2001) 5049–5052
5051
particular, 3-OH and 4-OH protons of b-
D
-glucopyrano-
side show the more pronounced changes compared to
those of a-anomer. This implies that those protons of
b-D-glucopyranoside are more strongly involved in H-
bonds with 2S than those of a-anomer. Furthermore,
1
inverse H NMR titration experiments show that 1-H
and 5-H of a- or b-D-glucopyranoside experience
upfield shifts upon addition of 2S, which indicates that
these protons are likely to be placed in the shielding
region of the aromatic ring of the host due to the
hydrogen bonding interactions. However, since hosts
2S and 2R give essentially the same binding constants
for both a- and b-isomers of the sugar derivatives, the
chirality of the hosts turns out to have no effect on the
chiral discrimination.
Figure 2. Job’s plot between host 2S and
D-glucopyranosides
at 295 K. [H]+[G]=1.0 mM, each in 500 mL. Rectangular and
circle represent b-glucopyranoside and a-glucopyranoside,
respectively.
Calculated structures revealed three intermolecular H-
bonds between three oxazoline nitrogens of 2S and
three OH groups in the 2,4,6-positions of b-D-glucopy-
ranoside (AAA…DDD).8 In contrast, only one H-bond
-glucopy-
hexanediol, N-octylthymidine and N-octyluridine with
fewer numbers of hydroxyl groups show weaker bind-
ing affinities to the host, which implies that not only
geometrical complementarity of H-bonding partners
but also the number of H-bonds are crucial in H-bond
based molecular recognition system.
is shown in the complex between 2S and a-
D
ranoside due to the steric hindrance between phenyl
groups of 2S and axial OR in the anomeric position of
a-
D
-glucopyranoside (Fig. 3). In addition, 1-H and 5-H
of b-
D
-glucopyranoside are directed toward the central
phenyl surface of 2S as shown in Fig. 3 (a). This is in
accordance with inverse H NMR titration experiments
1
In order to elucidate the intermolecular binding mode,
in which those protons show upfield shifts upon addi-
tion of increasing amounts of 2S. In the case of com-
plexation of 2S with b-D-galactopyranoside, only two
H-bonds are observed as expected from its weaker
binding affinity to 2S compared to the complexation
with b-D-glucopyranoside.
1
we performed inverse H NMR titrations of 2S with
sugar guests in CDCl3 (Table 2). Resonance changes in
OH protons of sugar derivatives were compared upon
addition of 0.3 equiv. of 2S to each sugar guest. In
Table 2. Complexation-induced shifts (CIS) of guests
upon addition of 2Sa
In conclusion, we have developed benzene-based tripo-
dal tris(oxazolines) as artificial receptors for sugars and
alcohols. This is one of the rare examples of anomer-
selective molecular recognition of alkylglycosides by
noncovalent interactions.4f
Dlmax of CIS (l of free ligand) in ppm
a-Glc
b-Glc
b-Gal
1-H
−0.168 (4.85)
+0.286 (1.96)
+1.45 (2.52)
+1.24 (2.44)
+0.084 (1.88)
−0.042 (4.29)
+0.033 (2.38)
+0.907 (2.63)
+0.795 (2.52)
+0.021 (1.97)
−0.061 (4.25)
+0.291 (2.37)
+0.726 (2.60)
+0.436 (2.76)
+0.149 (2.08)
2-OH
3-OH
4-OH
6-OH
Acknowledgements
Financial support from CMDS (KOSEF) is gratefully
acknowledged. H.J.K. and Y.H.K. thank the Ministry
of Education for the BK 21 fellowship.
a 1H NMR reverse titration of 1.5 mM of [G]0 in CDCl3 at 295 K.
Extrapolated to maximum complex formation from the CIS values.
Figure 3. Minimized structures between 2S and guests; (a) 2S and b-Glc, three intermolecular H-bonds (AAA···DDD) (b) 2S and
a-Glc, one intermolecular H-bond (A···D) (c) 2S and b-Gal, two intermolecular H-bonds (AA···DD). Hydrogens except OHs are
omitted for clarity.

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H.-J. Kim et al. / Tetrahedron Letters 42 (2001) 5049–5052
mmol) of MsCl at 0°C under N2. Resulting white suspen-
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