A rigid C3v-symmetrical host for saccharide recognition: 1,3,5-tris(2-hydroxyaryl)-2,4,6-trimethylbenzenes

Article abstract of DOI:10.1021/ol047907c

(Chemical Equation Presented) A rigid C_3v-symmetrical host molecule, syn-1,3,5-tris(2-hydroxy-5-pentylphenyl)-2,4,6-trimethylbenzene, was readily obtained via Suzuki coupling and thermal atropisomerization. The host molecule effectively associa

Full text of DOI:10.1021/ol047907c

ORGANIC
LETTERS
2005
Vol. 7, No. 1
59-61
A Rigid C3v-Symmetrical Host for
Saccharide Recognition:
1,3,5-Tris(2-hydroxyaryl)-2,4,6-
trimethylbenzenes
Hajime Abe,*,†,‡ Yoshinobu Aoyagi,† and Masahiko Inouye*,†
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical UniVersity,
Toyama, 930-0194 Japan, and PRESTO, JST, Japan
abeh@ms.toyama-mpu.ac.jp
Received October 9, 2004
ABSTRACT
A rigid C3v-symmetrical host molecule, syn-1,3,5-tris(2-hydroxy-5-pentylphenyl)-2,4,6-trimethylbenzene, was readily obtained via Suzuki coupling
and thermal atropisomerization. The host molecule effectively associated with various saccharides by multipoint hydrogen bonds, whereas its
anti-atropisomer and analogue lacking in methyl groups showed much weaker association with saccharides. Thermodynamic analyses suggested
that the difference of the association strength was caused by entropic factors.
Hydrogen bonding is one of the fundamental noncovalent
interactions working for assemblies of various natural and
artificial molecules.1 In artificial hydrogen-bonding as-
semblies, it is essential to design proper arrangement of
hydrogen-bonding functionalities on proper frameworks to
make the interaction effective. We have investigated a series
of host molecules bearing multipoint hydrogen-bonding
moieties for recognition of saccharides and nucleobases.2
Herein we wish to report the development of a host molecule,
syn-1,3,5-tris(2-hydroxy-5-pentylphenyl)-2,4,6-trimethylben-
zene (1-syn), which has three phenolic OH groups arrayed
on a very rigid C3V-symmetrical framework (Figure 1).
Recently, various kinds of C3V-symmetrical host molecules
have been developed, for example, by using frameworks of
hexaethylbenzene and its analogues,3,4 and 1,3,5-triarylben-
zenes.5,6 Although the 1,3,5-triaryl-2,4,6-trimethylbenzene
framework of 1-syn would be promising for its higher rigidity
and symmetry, little has been known about its advantage in
molecular recognition.5
† Toyama Medical and Pharmaceutical University.
‡ JST.
(1) ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davies,
J. E. D., MacNicol, D. D., Vo¨gtle, F., Lehn, J.-M., Eds.; Elsevier: Oxford,
1996; Vol. 2. Hamilton, A. D. In AdVances in Supramolecular Chemistry;
Gokel, G. W., Ed.; JAI Press Inc.: Greenwich, 1990; Vol. 1, p 1.
(2) Inouye, M.; Waki, M.; Abe, H. J. Am. Chem. Soc. 2004, 126, 2022.
Takase, M.; Inouye, M. J. Org. Chem. 2003, 68, 1134. Inouye, M.; Chiba,
J.; Nakazumi, H. J. Org. Chem. 1999, 64, 8170. Inouye, M.; Takahashi,
K.; Nakazumi, H. J. Am. Chem. Soc. 1999, 121, 341.
Figure 1. (Left) A C3V-symmetrical host molecule 1-syn and
MOM-derivative 2-syn. (Right) Plausible multipoint hydrogen
bonds of 1-syn with a polyol guest.
10.1021/ol047907c CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/04/2004

When the structure of 1-syn was examined with its CPK
model, the three phenolic rings were found to be no longer
rotatable about the phenol-benzene bonds because of steric
hindrance of the three methyl groups on the center benzene
ring. The three oxygen atoms of the OH groups stand at
intervals of ca. 4-6 Å, which is too far to form intra-
molecular hydrogen bonding efficiently. On the other hand,
intermolecular association with polyols would be preferred
because of the multipoint hydrogen bonding (Figure 1). From
the thermodynamic viewpoint, the high symmetry and
rigidity of 1-syn would be favorable to form host-guest
complexes without suffering entropic loss caused by restruc-
turing. Taking into account these merits, we decided to
develop 1-syn as a host molecule for recognition of saccha-
rides.
ered 2-anti (70%) were easily separated. The conversion
yield was quantitative, so theoretically most of 2-anti can
be converted to 2-syn by repeating this thermal isomerization.
Acidic deprotection of the MOM groups on 2-syn and 2-anti
yielded 1-syn and 1-anti, respectively, which also have very
different Rf values on TLC (silica gel, CH2Cl2, Rf ) 0.06
for 1-syn and 0.65 for 1-anti). The great differences of Rf
values between 1-syn and 1-anti and between 2-syn and
2-anti probably reflect the fitness of the tripodal structure
of 1-syn and 2-syn for interacting with the surface of silica
gel. As the CPK model predicted, the steric hindrance of
the three methyl groups on the center benzene ring is enough
to inhibit easy atropisomerization,5 since no change was
observed under conditions such as 2 months at room
temperature for 1 and 2, at 80 °C in DMSO-d6 for 2-syn, at
160 °C in mesitylene for 6 h for 2-anti, and at 100 °C in
1,4-dioxane for 6 h for 1-anti in the presence of t-BuOK.
To study the effect of the methyl groups in 1 for molecular
recognition, non-methyl analogue 5 was prepared by a similar
procedure from 4 and 1,3,5-tribromobenzene. In the case of
5, no separation of 1H NMR signals caused by atropisomer-
ization was observed in CDCl3 even at -40 °C, because the
rotation about the phenol-benzene bond is fast in 5.
The targeted C3V-symmetrical host molecule 1-syn was
prepared straightforwardly in the way described in Scheme
1. p-Pentylphenol was protected by methoxymethyl (MOM)
Scheme 1. Synthesis of 1-syn, 1-anti, and 5
The self-association tendencies of 1-syn, 1-anti, and 5
were evaluated using 1H NMR analyses in CDCl3. At a dilute
concentration, the signal of the OH protons of 1-syn was
observed as one sharp singlet peak. When the concentration
of 1-syn increased, the OH signal significantly moved
downfield with broadening (Figure S1A). The relationship
between the chemical shift of the OH signal and the
concentration of 1-syn fit with the theoretical curve assuming
self-dimerization (Kdim ) 1.3 ( 0.8 × 102 M-1). When 1-anti
was subjected to a similar NMR experiment, two kinds of
OH signals were observed: the one is the signal of the two
OH protons on the upper side of the triarylbenzene frame-
work shown in Scheme 1, and the other is the signal of the
one OH proton on the opposite lower side. According to the
(3) Pia¸tek, A. M.; Bomble, Y. J.; Wiskur, S. L.; Anslyn, E. V. J. Am.
Chem. Soc. 2004, 126, 6072. Nguyen, B. T.; Wiskur, S. L.; Anslyn, E. V.
Org. Lett. 2004, 6, 2499. Hennrich, G.; Anslyn, E. V. Chem. Eur. J. 2002,
8, 2218 and references therein. Wallace, K. J.; Belcher, W. J.; Turner, D.
R.; Syed, K. F.; Steed, J. W. J. Am. Chem. Soc. 2003, 125, 9699. Yun, S.;
Kim, Y.-O.; Kim, D.; Kim, H. G.; Ihm, H.; Kim, J. K.; Lee, C.-W.; Lee,
W. J.; Yoon, J.; Oh, K. S.; Yoon, J.; Park, S.-M.; Kim, K. S. Org. Lett.
2003, 5, 471. Yun, S.; Ihm, H.; Kim, H. G.; Lee, C.-W.; Indrajit, B.; Oh,
K. S.; Gong, Y. J.; Lee, J. W.; Yoon, J.; Lee, H. C.; Kim, K. S. J. Org.
Chem. 2003, 68, 2467. Ihm, H.; Yun, S.; Kim, H. G.; Kim, J. K.; Kim, K.
S. Org. Lett. 2002, 4, 2897.
(4) Mazik, M.; Radunz, W.; Sicking, W. Org. Lett. 2002, 4, 4579. Mazik,
M.; Sicking, W. Chem. Eur. J. 2001, 7, 664. Mazik, M.; Bandmann, H.;
Sicking, W. Angew. Chem., Int. Ed. 2000, 39, 551.
group to give 3, which was derivatized to boronic acid 4 via
ortho-lithiation. Suzuki coupling of 4 with 2,4,6-triiodo-
mesitylene7 afforded triarylated mesitylene as a mixture of
atropisomers 2-syn and 2-anti in 5% and 74% yield,
respectively. The desired atropisomer is 2-syn, so the major
product 2-anti had to be isomerized to 2-syn. Fortunately,
when 2-anti was heated to 210 °C in xylene for 3 h, partial
isomerization to 2-syn occurred. On TLC analysis (silica gel,
CH2Cl2/hexane ) 2:1), Rf values for 2-syn and 2-anti were
0.15 and 0.73, respectively. By column chromatography
(silica gel, hexane/AcOEt ) 10:1), 2-syn (30%) and recov-
(5) Katz pointed out the potential of the 1,3,5-triaryl-2,4,6-trimethyl
framework for binding units. The rotational barrier of its aryl-aryl bond
was also studied. See: Katz, H. E. J. Org. Chem. 1987, 52, 3932.
(6) Manabe, K.; Okumura, K.; Date, T.; Koga, K. J. Org. Chem. 1993,
58, 6692. Ballester, P.; Capo´, M.; Costa, A.; Deya`, P. M.; Gomila, R.;
Decken, A.; Deslongchamps, G. J. Org. Chem. 2002, 67, 8832. Vo¨gtle, F.;
Michel, I.; Berscheid, R.; Nieger, M.; Rissanen, K.; Kotila, S.; Airola, K.;
Armaroli, N.; Maestri, M.; Balzani, V. Liebigs Ann. 1996, 1697. Kadei,
K.; Moors, R.; Vo¨gtle, F. Chem. Ber. 1994, 127, 897. Pieters, R. J.; Cuntze,
J.; Bonnet, M.; Diederich, F. J. Chem. Soc., Perkin Trans. 2 1997, 1891.
Dyker, G.; Gabler, M.; Nouroozian, M.; Schulz, P. Tetrahedron Lett. 1994,
35, 9697.
(7) Ohshiro, N.; Takei, F.; Onitsuka, K.; Takahashi, S. J. Organomet.
Chem. 1998, 569, 195. See also: Suzuki, H. Organic Syntheses; Wiley:
New York, 1988; Collect. Vol. VI, p 700.
60
Org. Lett., Vol. 7, No. 1, 2005

increase of the concentration of 1-anti, the former signal
moved a little downfield with significant broadening, while
the latter scarcely changed (Figure S1B). The Kdim for 1-anti
was estimated at ca. 10 M-1, which is considerably smaller
than that for 1-syn. These results indicate that the association
strength depends on the number of OH groups on one side
of the triarylbenzene framework to make multipoint hydrogen
bonds efficiently. For non-methyl analogue 5, the downfield
change of the chemical shift of three OH protons was also
small (Figure S1C) and the Kdim was estimated at ca. 3 M-1;
thus the free rotation of the phenol moieties weakens the
association.
Table 1. Association of 1-syn, 1-anti, and 5 with Glycosides
Studied by H NMR Experiments
1
Ka
(M-1
∆G
(kJ mol-1
∆δ(host-OH)c
b
b
host
glycosidea
)
)
(ppm)
1-syn
â-Glc
r-Glc
â-Man
r-Man
â-Gal
â-Fru
â-Rib
â-Glc
6.3 ( 0.2 × 103
2.4 ( 0.1 × 103
1.5 ( 0.3 × 104
3.3 ( 0.2 × 104
2.4 ( 0.1 × 103
1.1 ( 0.1 × 104
1.8 ( 0.5 × 103
<100d
-22
-19
-24
-25
-19
-23
-18
+0.85
+0.80
+1.24
+1.49
+0.80
+1.13
+1.03
+0.16 (2H),
+0.01 (1H)
When 1-syn (2.5 × 10-3 M) was mixed with an equimolar
amount of octyl â-D-glucopyranoside (â-Glc) in CDCl3, the
1H NMR signals of the OH protons on both 1-syn and â-Glc
significantly moved downfield with broadening (Figure 2).
1-anti
5
â-Rib
â-Glc
â-Rib
<100d
<100d
<100d
+0.15
a Glc ) octyl D-glucopyranoside, Man ) octyl D-mannopyranoside, Gal
) octyl D-galactopyranoside, Fru ) octyl D-fructopyranoside, Rib ) methyl
D-ribofuranoside. b Conditions: host (1.0 × 10-4 M), titrated with glycoside,
CDCl3, 22 °C. c Conditions: host (2.5 × 10-3 M) with or without glycoside
(1.0 equiv), CDCl3, 22 °C. Downfield movement of δ(host-OH) is shown.
d Because curve-fitting analysis was not available as a result of the self-
association of both the host and glycoside, Ka values were estimated from
the slope in the initial stage of the titration plot.
and saccharides is comparable to that for many other
hydrogen-bonding host molecules previously reported,2,4,9
although 1-syn has a much simpler structure and is much
more available with ease.
For the association of 1-syn with â-Rib in CDCl3, the
thermodynamic parameters were ∆H ) -35 kJ mol-1, T∆S
) -17 kJ mol-1, and ∆H/T∆S ) 2.1 (300 K) obtained by
van’t Hoff plot. For comparison, the ratios ∆H/T∆S were
estimated for 1-anti and 5 at 1.2 and 1.2 (300 K),
respectively, for the same guest.10 These results suggest that
the differences of the binding constants are mainly due to
the contribution of entropic factors. Probably less symmetry
in 1-anti and less rigidity in 5 caused entropic loss when
they associate with saccharide. The high rigidity and sym-
metry of 1-syn are necessary for efficient saccharide recogni-
tion. For high efficiency and easy availability, the framework
of 1-syn is also attractive as tridentate ligands and triacidic
catalysts, and investigations for versatility of the architectures
are now underway.
Figure 2. 1H NMR spectra of (A) 1-syn (2.5 × 10-3 M), (B) 1-syn
(2.5 × 10-3 M) + â-Glc (1.0 equiv), and (C) â-Glc (2.5 × 10-3
M) in CDCl3, 22 °C, 500 MHz.
1
By contrast, in the cases of 1-anti and 5 in a similar H
NMR experiment, such movement and broadening were very
small. Upon association with â-Glc, the two OH protons on
1-anti became diastereotopic and the separation of 1H NMR
signals was observed. Between 1-syn and a series of alkyl
glycosides soluble in CDCl3, the binding constants were
1
calculated on the basis of H NMR titration (Table 1). The
Supporting Information Available: Figures S1 and S2
and experimental details for the syntheses and analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
titration curves fit with the theoretical curves assuming 1:1
association (for â-Glc, see Figure S2) within the range of
concentration at which the self-associations both of 1-syn
and of the glycosides were negligible. Among the glycosides
examined, octyl R-D-mannopyranoside (r-Man) was found
to associate with 1-syn most strongly. This is possibly
because of the structural fitness for multipoint hydrogen-
bonding between 1-syn and r-Man and/or because of the
relatively weak intramolecular hydrogen-bonding in r-Man.8
Other kinds of the glycosides also showed good association
with 1-syn. On the other hand, the associations of 1-anti
and 5 with â-Glc and methyl â-D-ribofranoside (â-Rib) were
very weak (Ka < 100 M-1). Thus, the C3V structure of 1-syn
is suitable not only for the self-association but also for the
saccharide recognition. The binding strength between 1-syn
OL047907C
(8) Bonar-Law, R. P.; Sanders, J. K. M. J. Am. Chem. Soc. 1995, 117,
259.
(9) For a review on carbohydrate recognition through noncovalent
interactions, see: Davis A. P.; Wareham, R. S. Angew. Chem., Int. Ed.
1999, 38, 2978. For recent examples, see: Velasco, T.; Lecollinet, G.; Ryan,
T.; Davis, A. P. Org. Biomol. Chem. 2004, 2, 645 and references therein.
See also ref 4 for examples using a tripodal host.
(10) In the cases for 1-anti and 5, the accurate values for ∆H and T∆S
could not be acquired because of ambiguity about ∆δsat(host-OH), 1H NMR
downfield movement of δ(host-OH) at the saturating point. The ratio ∆H/
T∆S was estimated from a tentative van’t Hoff plot by assuming ∆δsat(host-
OH) values varied from 0.7 to 2 ppm. For 1-syn, ∆δsat(host-OH) value
was calculated as 1.0 ppm from the titration curve.
Org. Lett., Vol. 7, No. 1, 2005
61