Remarkably strong, uncharged hydrogen-bonding interactions of polypyridine-macrocyclic receptors for deoxyribofuranosides

Article abstract of DOI:10.1021/ja983539u

Novel macrocyclic saccharide receptors that possess a pyridine-pyridone- pyridine arrangement as a hydrogen-bonding motif are presented. The artificial receptors exhibited a remarkably strong binding affinity for deoxyribofuranoside derivatives in CDCl

Full text of DOI:10.1021/ja983539u

J. Am. Chem. Soc. 1999, 121, 341-345
341
Remarkably Strong, Uncharged Hydrogen-Bonding Interactions of
Polypyridine-Macrocyclic Receptors for Deoxyribofuranosides
Masahiko Inouye,* Kunihide Takahashi, and Hiroyuki Nakazumi
Contribution from PRESTO, Japan Science and Technology Corporation (JST), Department of Applied
Materials Science, Osaka Prefecture UniVersity, Sakai, Osaka 599-8531, Japan
ReceiVed October 6, 1998
Abstract: Novel macrocyclic saccharide receptors that possess a pyridine-pyridone-pyridine arrangement
as a hydrogen-bonding motif are presented. The artificial receptors exhibited a remarkably strong binding
affinity for deoxyribofuranoside derivatives in CDCl3 (Ka ) 19 000 M-1; -∆G298 ) 24.4 kJ/mol), one of the
highest values of artificial receptors having only uncharged hydrogen-bonding sites for monosaccharide
derivatives. Selective extraction of deoxyribose by the receptors was also observed; the extractabilities, or
affinities to the receptors of various pentoses and hexoses, decreased in the following order: deoxyribose >
lyxose = ribose > arabinose = fructose = xylose > glucose > mannose > galactose.
Introduction
bonding abilities of the hydroxyl residues.3,7 We have developed
polypyridine-macrocyclic structures possessing convergent func-
tional groups with hydrogen bond donor/acceptor properties as
efficient synthetic receptors for â-ribofuranosides.8 Another
important pentose is deoxyribose, a component monosaccharide
of DNA. In the deoxyribofuranoside form, however, in addition
to the essentially weak hydrogen bonding ability, only two
hydroxyl residues are expected to take part in the intermolecular
interactions. Here we show remarkably strong uncharged
hydrogen-bonding interactions of novel polypyridine-macrocy-
clic receptors for â-deoxyribofuranoside.
Unlike other intermolecular interactions such as electrostatic
or hydrophobic, the hydrogen bonding interaction is critically
vectorial in solution; thus, the hydrogen bonding plays a leading
role in most biological information-transfer events.1 Thus,
constructing synthetic models employing hydrogen bonding is
a rapidly growing field in current supramolecular chemistry
because it may not only serve as a basic concept to understand
biological functions but also lead to the development of new
pharmaceutical methodologies, new types of biorelevant materi-
als, etc.2-4 Among the many artificial models, however, only a
few of those have been effective even to some extent for the
recognition of saccharides using hydrogen bonds.3-7 This is
possibly because of the three-dimensional complexity of sac-
charide structures and of the weak intermolecular hydrogen-
Results and Discussion
As a starting point for the design of deoxyribofuranoside
receptors, we examined the adaptability of the ribofuranoside
receptor 28 for the recognition of deoxyribofuranoside. To
evaluate the recognition abilities of the receptors for ribofura-
noside and deoxyribofuranoside in aprotic solvents such as
CHCl3, 3-n-octyl derivatives of uridine (1a) and thymidine (1b)
were chosen, respectively (Chart 1). The n-octyl substituents
make the furanosides soluble in such solvents and prevent the
nucleobase residues of 1 from interacting with the hydrogen-
bonding motif of the receptors, so that a net interaction between
the hydroxyl groups of 1 and the receptors will be assessed.
* To whom correspondence should be addressed.
(1) Saenger, W. Principles of Nucleic Acid Structure; Springer-Verlag:
New York, 1984. Fersht, A. Enzyme Structure and Mechanism, 2nd ed.;
Freeman: New York, 1985. Dugas, H. Bioorganic Chemistry -A Chemical
Approach to Enzyme Action, 2nd ed.; Springer-Verlag: New York, 1989.
ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davies, J. E.
D., MacNicol, D. D., Vo¨gtle, F., Eds.; Elsevier: Oxford, 1996.
(2) Hamilton, A. D. In AdVances in Supramolecular Chemistry; Gokel,
G. W., Ed.; JAI: Greenwich, 1990; Vol. 1, pp 1-64. Aoyama, A. In
AdVances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI: Green-
wich, 1992; Vol. 2, pp 65-92. van Doorn, A. R.; Verboom, W.; Reinhoudt,
D. N. In AdVances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI:
Greenwich, 1993; Vol. 3, pp 159-206. Bell, D. A.; Anslyn, E. V. In
ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davies, J. E.
D., MacNicol, D. D., Vo¨gtle, F., Eds.; Elsevier: Oxford, 1996; Vol. 2, pp
439-475. Sessler, J. L.; Wang, B.; Springs, S. L.; Brown, C. T. In
ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davies, J. E.
D., MacNicol, D. D., Vo¨gtle, F., Eds.; Elsevier: Oxford, 1996; Vol. 4, pp
311-336. Simanek, E. E.; Li, X.; Choi, I. S.; Whitesides, G. M. In
ComprehensiVe Supramolecular Chemistry; Atwood, J. L., Davies, J. E.
D., MacNicol, D. D., Vo¨gtle, F., Eds.; Elsevier: Oxford, 1996; Vol. 9, pp
595-621.
(6) Representative examples: Aoyama, Y.; Tanaka, Y.; Sugahara, S. J.
Am. Chem. Soc. 1989, 111, 5397-5404. Kikuchi, Y.; Kato, Y.; Tanaka,
Y.; Toi, H.; Aoyama, Y. J. Am. Chem. Soc. 1991, 113, 1349-1354.
Bhattarai, K. M.; Bonar-Law, R. P.; Davis, A. P.; Murray, B. A. J. Chem.
Soc., Chem. Commun. 1992, 752-754. Bhattarai, K. M.; Davis, A. P.; Perry,
J. J.; Walter, C. J. J. Org. Chem. 1997, 62, 8463-8473. Cotero´n, J. M.;
Vicent, C.; Bosso, C.; Penade´s, S. J. Am. Chem. Soc. 1993, 115, 10066-
10076. Liu, R.; Still, W. C. Tetrahedron Lett. 1993, 34, 2573-2576. Savage,
P. B.; Holmgren, S. K.; Desper, J. M.; Gellman, S. H. Pure Appl. Chem.
1993, 65, 461-466. Eliseev, A. V.; Schneider, H.-J. J. Am. Chem. Soc.
1994, 116, 6081-6088. Das, G.; Hamilton, A. D. J. Am. Chem. Soc. 1994,
116, 11139-11140. Bonar-Law, R. P.; Sanders, J. K. M. J. Am. Chem.
Soc. 1995, 117, 259-271. Anderson, S.; Neidlein, U.; Gramlich, V.;
Diederich, F. Angew. Chem., Int. Ed. Engl. 1995, 34, 1596-1600.
(7) Huang, C.-Y.; Cabell, L. A.; Anslyn, E. V. J. Am. Chem. Soc. 1994,
116, 2778-2792. Cotero´n, J. M.; Hacket, F.; Schneider, H.-J. J. Org. Chem.
1996, 61, 1429-1435.
(3) Schneider, H.-J.; Mohammad-Ali, A. K. In ComprehensiVe Supramo-
lecular Chemistry; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle,
F., Eds.; Elsevier: Oxford, 1996; Vol. 2, pp 89-95.
(4) Fredericks, J. R.; Hamilton, A. D. In ComprehensiVe Supramolecular
Chemistry; Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F.,
Eds.; Elsevier: Oxford, 1996; Vol. 9, pp 565-594.
(5) A review: Aoyama, Y. In ComprehensiVe Supramolecular Chemistry;
Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F., Eds.;
Elsevier: Oxford, 1996; Vol. 2, pp 279-307.
(8) Inouye, M.; Miyake, T.; Furusyo, M.; Nakazumi, H. J. Am. Chem.
Soc. 1995, 117, 12416-12425.
10.1021/ja983539u CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/05/1999

342 J. Am. Chem. Soc., Vol. 121, No. 2, 1999
Inouye et al.
Chart 1
Scheme 1. Synthetic Scheme for 3a
a Reagents: (a) 2-Chloro-1-methylpyridinium iodide, Et3N, CH3CN;
(b) CSA‚H2O, THF, i-PrOH; (c) NaOH, EtOH; (d) 1-hydroxy-2-
pyridinethion, DCC, DMAP, BrCCl3; (e) RhCl(PPh3)3, DABCO,
CH3CN, H2O, EtOH; (f) CH3OCH2Cl, NaH, THF; (g) PdCl2(PPh3)2,
CuI, Et2NH.
modelings revealed the suitable multipoint hydrogen-bonding
arrangement between the two hydroxyl groups of 1b and the
pyridine-pyridone-pyridine motif of 3. Indeed, the association
constant between 1b and 3a displayed 19 000 M-1 (-∆G298
)
24.4 kJ/mol), one of the highest values of synthetic receptors
possessing an uncharged hydrogen bonding site not only for
deoxyribofuranoside but also for other monosaccharide deriva-
tives in CDCl3.13,14
The ribofuranoside receptor 2 revealed Ka values of 10 000 M-1
(-∆G298 ) 22.8 kJ/mol) and 690 M-1 (-∆G298 ) 16.2 kJ/
mol) in CDCl3 for 1a and 1b at 25 °C, respectively.9 The low
association constant between 2 and the deoxyribofuranoside
derivative 1b may be due not only to the decreased number of
hydrogen-bonding interactions compared to that for the ribo-
furanoside derivative 1a but also to the electrostatic repulsion
between the lone electron pairs of the 3-OH groups of 1b and
the receptor nitrogen.
Useful information for the structure of the complex was
obtained by their 1H NMR spectra. Treatment of a CDCl3
solution of 1b (2.5 mM) with 1 equiv of 3a resulted in several
characteristic changes in the spectrum (Figure 1). Large down-
field shifts were observed not only for the OH protons of 1b
(He: 3.6 and Hh: 3.0 ppm) but also for the amide-NH (1.0 ppm)
and the pyridone-NH (2.5 ppm) protons of 3a, while Hi and
N-CH2 protons of the nucleobase residue were shifted upfield
(Hi: 0.3 and N-CH2: 0.2 ppm). The former downfield shifts
reflect the formation of a multipoint hydrogen-bonded complex
as expected, and the latter may be attributed to the fact that the
nucleobase residue of 1b was placed on the diphenylmethane
bridge that is perpendicular to the hydrogen-bonding site.
Furthermore, the receptor signals of the flexible ethylene protons
(-CH2CH2-) showed substantial splits after the recognition of
1b, suggesting the formation of a chiral complex between the
chiral 1b and the achiral 3a. On the basis of the above
observations, a possible recognition mode for the complex (1b‚
3a) is shown in Chart 1.
The extraction of native monosaccharides into CHCl3 con-
taining 3b showed further information for the binding ability
of the receptors. Selective extraction of deoxyribose by the
receptors was observed: the extractabilities or affinities to the
receptors of various pentoses and hexoses decreased in the
following order: deoxyribose > lyxose = ribose > arabinose
= fructose = xylose > glucose > mannose > galactose (Table
1). Noteworthy is the fact that extractability of deoxyribose vs
ribose is reversed to that for the ribofuranoside receptor 2.8
We thought that this difficulty could be overcome by
replacing the central pyridine ring of the receptor by a pyridone
ring; the pyridone-NH protons will change the repulsion into
an attractive hydrogen bond.4,10 For this purpose, the receptors
3 are obvious candidates, in which a novel hydrogen-bonding
donor(amide)-acceptor(pyridine)-donor(pyridone)-acceptor-
(pyridine)-donor(amide) arrangement is convergently incor-
porated in the macrocyclic structures. The new polypyridine-
macrocyclic receptors 3 were synthesized from protected
diaminoterpyridine derivative 5 and dicarboxylic acid derivatives
68 by Mukaiyama’s macrocyclization11 followed by deprotection
of the methoxymethyl groups. The diaminoterpyridine derivative
5 was prepared from known pyridine derivatives 712 and 12.8
n-Undecyl groups in 3b were introduced for solubility problems
in extraction experiments instead of i-Bu groups in 3a (Scheme
1). The spectroscopic properties such as Fourier transform
1
infrared, H and 13C NMR, and fast atom bombardment mass
spectroscopy of 3 were in agreement with the assigned
structures. CPK model examinations and preliminary computer
(9) The binding energy (-∆G298) of 2 for methyl â-(D)-ribofuranoside
in CDCl3 was determined to be 21.7 kJ/mol, so that the nucleobase residues
of 1 were judged to make little contribution to the binding.
(10) Katritzky, A. R.; Jones, R. A. J. Chem. Soc. 1960, 2947-2953.
Meislich, M. In Pyridone and its DeriVatiVes, Part Three; Klingsberg, E.,
Ed.; Wiley: New York, 1962; pp 509-890.
(11) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163-1166.
(12) Markees, D. G.; Dewey, V. C.; Kidder, G. W. J. Med. Chem. 1968,
11, 126-129.
(13) Mizutani and Ogoshi et al. reported strong recognition of â-glu-
copyranoside (-∆G283 ) 25.4 kJ/mol in CHCl3) by a functionalized zinc
porphyrin possessing hydrogen bonding and Lewis acidic sites: Mizutani,
T.; Murakami, T.; Matsumi, N.; Kurahashi, T.; Ogoshi, H. J. Chem. Soc.,
Chem. Commun. 1995, 1257-1258.
(14) Very recently, Davis and Wareham reported a tricyclic polyamide
receptor that shows an unusual level of affinity for â-glucopyranoside
(-∆G298 ) 30.7 kJ/mol in CHCl3): Davis, A. P.; Wareham, R. S. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2270-2273.

Interactions of Deoxyribofuranoside Receptors
J. Am. Chem. Soc., Vol. 121, No. 2, 1999 343
Figure 1. 1H NMR spectra (500 MHz) of (a) 1b (2.5 mM), (b) 1b‚3a, and (c) 3a in CDCl3 at 25 °C. See Chart 1 for proton labeling.
Table 1. Extractabilities of Various (D)-Monosaccharides with 3b (Molar Ratios of (D)-Monosaccharides Extracted to 3b Used)a
deoxyribose
1.00
lyxose
0.66
ribose
0.65
arabinose
0.53
fructose
0.52
xylose
0.52
glucose
0.45
mannose
0.39
galactose
0.32
Monosaccharide/3b
a For details, see Experimental Section.
These results demonstrated the adjustability of the pyridine-
pyridone-pyridine arrangement as a hydrogen-bonding motif
for deoxyribofuranoside.
advantage of the full potential of two hydroxyl groups of
deoxyribofuranoside for hydrogen bonding resembling the
protein-saccharide interactions.
Systematic comparison of experimental -∆G298 for com-
plexation with the number of hydrogen bonds participating the
complexation revealed a substantially constant increment which
is 5 ( 1 kJ/mol per amide-amide type of hydrogen bond in
CHCl3.3 On the other hand, hydrogen-bonding recognition of
saccharides by artificial receptors remains to be investigated
more satisfactorily.7 Indeed, artificial hydrogen-bonding recep-
tors thus far synthesized exhibited rather small binding affinities
for saccharides, in which the stabilization energy of only no
more than 3-4 kJ/mol per hydrogen bond was attained. Recently
developed artificial receptors by Davis et al., however, bind
â-glucosides in CHCl3 with -∆G298 ) 30.7 kJ/mol.14 They
postulated the complex formation of six hydrogen bonds and
therefore 5 kJ/mol per the hydrogen bond. Thus, the observed
-∆G298 of 24.4 kJ/mol for the receptor 3a is a remarkably but
not unusually high value for the substrate having only two
hydroxyl groups. The value implies the substantial participation
of at least four or more hydrogen bonds. A common feature of
the protein-saccharide complexes is that each of the saccharide
hydroxyl groups participates in one donor and one or more
acceptor interactions as elucidated by X-ray crystallography.15
The recognition mode of the polypyridine receptors 3 may take
Conclusions
The novel hydrogen-bonding site, pyridine-pyridone-pyri-
dine structure on the macrocycle was found to be effective for
the recognition of deoxyribose. The binding affinity of the
artificial receptors for â-deoxyribofuranoside was very high. We
are currently investigating the design and synthesis of a
nucleobase recognition site as well as connecting it to the
saccharide receptors, which are expected to bind native nucleo-
sides and deoxynucleosides.
Experimental Section
Instrumentation. H and 13C NMR spectra were recorded at 270
1
and 67.8 MHz, respectively, unless otherwise noted. EI mass spectra
were measured at 70 eV. For FAB mass experiments, Xe was used as
the atom beam accelerated to 8 keV. Melting points are uncorrected.
Materials. The starting materials were all commercially available,
and 6a,8 7,12 and 128 were prepared according to literature procedures.
Methods for the Evaluation of Stoichiometry and Association
Constants. Job’s plot of [complex] vs mole fraction of the receptor
(freceptor) for the complexation of the receptor and 1 was obtained by 1H
NMR in CDCl3 at 25 °C under conditions where [receptor] + [1] is
maintained at 1.0 mM.16 The concentration of a complex in CDCl3
(15) Quiocho, F. A.; Vyas, N. K. Nature 1984, 310, 381-386. Lee, Y.
C.; Lee, R. T. Acc. Chem. Res. 1995, 28, 321-327.
(16) Job, A. Ann. Chem. (Paris) 1928, 9, 113-203.

344 J. Am. Chem. Soc., Vol. 121, No. 2, 1999
Inouye et al.
was evaluated from ∆δobsd for the receptor-NH, according to the
equation, [complex] ) [receptor]t(∆δobsd/∆δsat) (t ) total; obsd )
observed; sat ) saturated). The 1:1 stoichiometry was confirmed by
the plots that contained a maximum at a mole ratio of 0.5 in each case.
Association constants (Ka) were determined by Benesi-Hildebrand
unreacted starting materials. The water phase was acidified to pH 1
with concentrated hydrochloric acid, and the resulting precipitate was
filtered and washed with water. The precipitate was dried in vacuo to
give 8: yield ) 94% (7.79 g); mp 160-161 °C; IR (KBr) 3508, 3104,
1
1927, 1731, 1599, 1336, 1199, 1032 cm-1; H NMR (DMSO-d6) δ
1
analysis of the H NMR shifts in δNH for 2 (0.15 mM) and 3a (0.05
4.84 (d, J ) 4.9 Hz, 2 H), 5.29-5.45 (m, 2 H), 5.98-6.12 (m, 1 H),
7.72 (s, 2 H); 13C NMR (DMSO-d6) δ 69.21, 113.99, 118.54, 132.42,
149.91, 165.44, 166.47; FABMS (in 3-nitrobenzyl alcohol) m/e (relative
intensity) 224 (MH+, 100%). Anal. Calcd for C10H9O5N1: C, 53.82;
H, 4.06; N, 6.28. Found: C, 53.33; H, 4.28; N, 5.89.
mM) in the presence of a 10-20-fold molar excess of the furanoside
derivatives 1 at 25 °C in CDCl3.17 All binding assays were carried out
below the concentration so that the self-association of each substrates
is negligible. In every case, the double reciprocal plots according to
the equation, 1/∆δobsd ) 1/∆δsat + 1/∆δsatKa[1]t gave good linearity
with a correlation coefficient r g 0.99.
Extraction Experiments. The suspension of a large excess of each
monosaccharide (solid) and 3b (0.01 mmol) in CHCl3 (1 mL) was
stirred at 25 °C for 24 h. The suspension was filtered, and the filtrate
(0.85 mL) was added into D2O (0.85 mL). The mixed phases were
stirred at 25 °C for 2 h, and the D2O phase was separated by centrifuge.
To the D2O (0.6 mL) solution was added a D2O (0.06 mL) solution of
TSP (sodium 3-(trimethylsilyl)propionate(2,2,3,3-d4), 0.1 mmol). The
D2O solutions were analyzed by means of 1H NMR spectroscopy. The
amount of monosaccharide re-extracted was evaluated by comparison
of a 1H NMR integration ratio of the total monosaccharide CH proton
resonances to that of TSP (9H) added as the integration standard. Some
monosaccharides are slightly soluble in CHCl3. In such cases, the
extractability of each monosaccharide by 3b was corrected for by
subtracting the value obtained in a blank.
4-Allyloxy-2,6-dibromopyridine (9). A BrCCl3 (160 mL) suspen-
sion of 8 (4.93 g, 22.1 mmol), 1-hydroxy-2-pyridinethion (6.17 g, 48.6
mmol), dicyclohexylcarbodiimide (10.0 g, 48.6 mmol), and 4-(N,N-
dimethylamino)pyridine (5.93 g, 48.6 mmol) was stirred at 110 °C for
2 h. After removal of the solvent, the residue was poured into CH2Cl2,
and the suspension was filtered. The filtrate was evaporated and
chromatographed (silica gel; eluent, CH2Cl2: hexane ) 1:1) to give 9:
yield ) 35% (2.27 g); oil; IR (KBr) 3085, 2931, 1572, 1535, 1417,
1
1373, 1283, 1156, 1072 cm-1; H NMR (CDCl3) δ 4.57-4.59 (m, 2
H), 5.35-5.46 (m, 2 H), 5.91-6.03 (m, 1 H), 6.99 (s, 2 H); 13C NMR
(CDCl3) δ 69.59, 114.04, 119.40, 130.90, 141.15, 166.60; MS m/e
(relative intensity) 293 (M+ + 2, 56%). Anal. Calcd for C8H7ONBr2:
C, 32.80; H, 2.41; N, 4.78. Found: C, 32.78; H, 2.54; N, 4.69.
2,6-Dibromo-4-pyridone (10). A mixture of 9 (994 mg, 3.4 mmol),
(PPh3)3RhCl (188 mg, 0.2 mmol), and DABCO (30.5 mg, 0.27 mmol)
in CH3CN-H2O-EtOH (7 + 7 + 7 mL) was heated at 70 °C for 6 h.
After removal of the solvent, the residue was poured into CH2Cl2, and
the resulting precipitate was filtered. The precipitate was washed with
CH2Cl2 to give 10. Then the filtrate was evaporated and chromato-
graphed (silica gel; eluent, CH2Cl2:AcOEt ) 10:1) to afford additional
10: yield ) 90% (772 mg); mp 209-212 °C; IR (KBr) 3021, 1588,
3-n-Octyluridine (1a). To an EtOH-H2O (10 + 2.5 mL) mixed
solution of uridine (611 mg, 2.5 mmol) and KOH (140 mg, 2.5 mmol)
was added n-octyl bromide (531 mg, 2.8 mmol) dropwise at room
temperature. The reaction mixture was refluxed for 42 h. After removal
of the solvent, the residue was dissolved in CHCl3 and washed with
water to remove the unreacted starting materials. The CHCl3 phase
was evaporated and chromatographed (silica gel; eluent, CH2Cl2:MeOH
) 10:1) to give 1a: yield ) 58% (512 mg); mp 88-90 °C; IR (KBr)
1
1562, 1543, 1415, 1285, 1209, 1151 cm-1; H NMR (DMSO-d6) δ
7.03 (s, 2 H), 11.78 (br s, 1 H); 13C NMR (DMSO-d6) δ 115.06, 140.43,
167.19; MS m/e (relative intensity) 253 (M+ + 2, 100%). Anal. Calcd
for C5H3ONBr2: C, 23.75; H, 1.20; N, 5.54. Found: C, 23.93; H, 1.17;
N, 5.33.
3416, 2918, 1697, 1651, 1619, 1465, 1269, 1103 cm-1 1H NMR
;
(CDCl3) δ 0.88 (t, J ) 6.7 Hz, 3 H), 1.19-1.40 (m, 10 H), 1.55-1.68
(m, 2 H), 2.31 (dd, J ) 5.5, 3.7 Hz, 1 H), 3.00 (d, J ) 3.7 Hz, 1 H),
3.79-4.04 (m, 5 H), 4.25 (q, J ) 3.1 Hz, 1 H), 4.35-4.47 (m, 2 H),
5.64 (d, J ) 4.9 Hz, 1 H), 5.77 (d, J ) 7.9 Hz, 1 H), 7.60 (d, J ) 7.9
Hz, 1 H); 13C NMR (CDCl3) δ 14.12, 22.65, 26.98, 27.56, 29.22, 29.28,
31.81, 41.37, 62.13, 70.99, 75.27, 85.90, 93.73, 101.91, 138.66, 151.84,
162.64; FABMS (in 3-nitrobenzyl alcohol) m/e (relative intensity) 357
(MH+, 60%). Anal. Calcd for C17H28O6N2: C, 57.29; H, 7.92; N, 7.86.
Found: C, 56.95; H, 8.01; N, 7.51.
2,6-Dibromo-4-(methoxymethoxy)pyridine (11). To a THF (12
mL) suspension of NaH (281 mg, 7.0 mmol; commercial 60%
dispersion was washed thoroughly with hexane prior to use) was added
a THF (3 mL) solution of 10 (1.48 g, 5.9 mmol) dropwise at 0 °C.
After the mixture was stirred at that temperature for 30 min, to the
solution was added chloromethyl methyl ether (566 mg, 7.0 mmol)
dropwise at the same temperature. The reaction mixture was stirred at
room temperature for an additional 24 h. The reaction mixture was
filtered, and the filtrate was evaporated and chromatographed (silica
gel; eluent, CH2Cl2:hexane ) 1:1) to give 11: yield ) 90% (1.57 g);
mp 64-65 °C; IR (KBr) 2919, 1574, 1538, 1433, 1373, 1263, 1155,
3-n-Octylthymidine (1b). To an EtOH-H2O (20 + 1 mL) mixed
solution of thymidine (1.21 g, 5.0 mmol) and KOH (281 mg, 5.0 mmol)
was added n-octyl bromide (1.06 g, 5.5 mmol) dropwise at room
temperature. The reaction mixture was refluxed for 20 h. After removal
of the solvent, the residue was dissolved in CH2Cl2 and washed with
water to remove the unreacted starting materials. The CH2Cl2 phase
was evaporated and chromatographed (silica gel; eluent, CH2Cl2:MeOH
) 20:1) to give 1b: yield ) 55% (953 mg); mp 89-90 °C; IR (KBr)
1
1094 cm-1; H NMR (CDCl3) δ 3.48 (s, 3 H), 5.21 (s, 2 H), 7.13 (s,
2 H); 13C NMR (CDCl3) δ 56.85, 94.43, 115.09, 141.13, 165.33; MS
m/e (relative intensity) 297 (M+ + 2, 62%). Anal. Calcd for C7H7O2-
NBr2: C, 28.31; H, 2.38; N, 4.72. Found: C, 28.26; H, 2.41; N, 4.43.
2,6-Bis[(6-aminopyrid-2-yl)ethynyl]-4-(methoxymethoxy)pyri-
dine (5). An Et2NH (27 mL) solution of 11 (2.64 g, 8.9 mmol), 128
(3.16 g, 26.7 mmol), (PPh3)2PdCl2 (125 mg, 0.178 mmol), and CuI
(17 mg, 0.089 mmol) was stirred at 50 °C for 12 h. The resulting
precipitate was filtered and washed with CHCl3 to give 5: yield )
84% (2.77 g); mp 216-219 °C; IR (KBr) 3306, 3180, 2218, 1626,
3513, 2926, 1689, 1668, 1636, 1471, 1291, 1102 cm-1 1H NMR
;
(CDCl3) δ 0.87 (t, J ) 6.7 Hz, 3 H), 1.17-1.42 (m, 10 H), 1.52-1.69
(m, 2 H), 1.93 (s, 3 H), 2.15-2.65 (m, 4 H), 3.79-4.00 (m, 4 H), 4.02
(q, J ) 3.7 Hz, 1 H), 4.61 (dt, J ) 3.7, 7.3 Hz, 1 H), 6.18 (t, J ) 6.7
Hz, 1 H), 7.31 (d, J ) 1.2 Hz, 1 H); 13C NMR (CDCl3) δ 13.29, 14.04,
22.59, 26.96, 27.54, 29.16, 29.22, 31.75, 40.12, 41.55, 62.35, 71.45,
86.93, 110.32, 134.62, 150.97, 163.49; FABMS (in 3-nitrobenzyl
alcohol) m/e (relative intensity) 355 (MH+, 84%). Anal. Calcd for
C18H30O5N2: C, 61.00; H, 8.53; N, 7.90. Found: C, 60.59; H, 8.56; N,
7.75.
4-Allyloxypyridine-2,6-dicarboxylic acid (8). To an EtOH (74 mL)
solution of 712 (12.5 g, 37.2 mmol) was added an EtOH (222 mL)
solution of NaOH (5.96 g, 148.9 mmol) at room temperature. The
reaction mixture became turbid, and the cloudy solution was allowed
to stand for 12 h at this temperature. After removal of the solvent, the
residue was poured into water and washed with CH2Cl2 to remove the
1
1584, 1553, 1466, 1146, 1024 cm-1; H NMR (DMSO-d6) δ 3.41 (s,
3 H), 5.39 (s, 2 H), 6.21 (br s, 4 H), 6.52 (d, J ) 8.5 Hz, 2 H), 6.83
(d, J ) 6.7 Hz, 2 H), 7.29 (s, 2 H), 7.43 (t, J ) 7.9 Hz, 2 H); 13C NMR
(DMSO-d6) δ 57.25, 86.16, 89.84, 94.86, 110.44, 115.93, 117.26,
138.41, 139.98, 144.67, 160.82, 164.27; FABMS (in 3-nitrobenzyl
alcohol) m/e (relative intensity) 372 (MH+, 97%). Anal. Calcd for
C21H17O2N5: C, 67.91; H, 4.61; N, 18.86. Found: C, 68.40; H, 4.44;
N, 18.39.
4,4′-(Tridec-2-ylidene)bis(dihydrocinnamic acid) (6b). This com-
pound was synthesized from the corresponding bisphenol derivative
in a manner similar to that described for 6a.8 To a mixture of phenol
(9.91 g, 50.0 mmol) and 2-tridecanone (14.1 g, 150 mmol) was bubbled
dry HCl gas at 60 °C for 1 week. The reaction mixture was subjected
to column chromatography (silica gel; eluent, CH2Cl2:AcOEt ) 10:1)
(17) Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703-
2707. Foster, R.; Fyfe, C. A. Prog. Nucl. Magn. Reson. Spectrosc. 1969, 4,
1-89.

Interactions of Deoxyribofuranoside Receptors
J. Am. Chem. Soc., Vol. 121, No. 2, 1999 345
to give 4,4′-(tridec-2-ylidene)diphenol: yield ) 60% (11.1 g); oil; IR
added a CH3CN (100 mL) solution of 2-chloro-1-methylpyridinium
iodide (4.83 g, 18.9 mmol) dropwise at 70 °C. The reaction mixture
was stirred at this temperature for 24 h. After removal of the solvent,
the residue was dissolved in water and extracted with CHCl3. The CHCl3
extract was evaporated and chromatographed (silica gel; eluent, CH2Cl2:
AcOEt ) 8:1) to give 4a: yield ) 7% (244 mg); mp 239-242 °C; IR
(KBr) 2953, 2361, 1702, 1573, 1546, 1452, 1365, 1226, 1155, 1141
(KBr) 3285, 2933, 2854, 1612, 1512, 1464, 1375, 1240, 1178 cm-1
;
1H NMR (CDCl3) δ 0.72 (t, J ) 6.7 Hz, 3 H), 0.98-1.37 (m, 18 H),
1.55 (s, 3 H), 1.95-2.01 (m, 2 H), 4.94 (br s, 2 H), 6.71 (d, J ) 8.6
Hz, 4 H), 7.04 (d, J ) 8.6 Hz, 4 H); 13C NMR (CDCl3) δ 14.18, 22.73,
24.76, 27.92, 29.38, 29.61, 29.65, 29.68, 30.44, 31.95, 42.14, 44.94,
114.62, 128.48, 142.51, 153.19; MS m/e (relative intensity) 213 (M+
- C11H23, 100%). To a pyridine (70 mL) solution of 4,4′-(tridec-2-
ylidene)diphenol (11.1 g, 30.1 mmol) was added trifluoromethane-
sulfonic anhydride (19.6 g, 69.2 mmol) slowly at 0 °C. The reaction
mixture was stirred at 0 °C for 5 min and then allowed to warm to
room temperature and stirred at this temperature for 3 h. After removal
of the solvent, the residue was dissolved in water and extracted with
CH2Cl2. The CH2Cl2 extract was washed with 10% aqueous hydro-
chloric acid solution twice, dried over MgSO4, and evaporated. The
residue was subjected to column chromatography (silica gel; eluent,
hexane:CH2Cl2 ) 10:1) to give 4,4′-(tridec-2-ylidene)diphenyl ditri-
flate: yield ) 90% (17.1 g); oil; IR (KBr) 2929, 2856, 1596, 1500,
1426, 1250, 1213, 1142, 1015 cm-1; 1H NMR (CDCl3) δ 0.87 (t, J )
6.7 Hz, 3 H), 0.96-1.37 (m, 18 H), 1.63 (s, 3 H), 2.02-2.08 (m, 2 H),
7.18 (d, J ) 9.2 Hz, 4 H), 7.23 (d, J ) 9.2 Hz, 4 H); 13C NMR (CDCl3)
δ 14.14, 22.73, 24.59, 27.73, 29.38, 29.46, 29.63, 30.21, 31.95, 41.84,
46.22, 116.43, 120.94, 129.14, 147.70, 149.52; MS m/e (relative
intensity) 477 (M+ - C11H23, 100%). To a DMF (80 mL) solution of
4,4′-(tridec-2-ylidene)diphenyl ditriflate (16.5 g, 26.2 mmol), (PPh3)2-
PdCl2 (367 mg, 0.5 mmol), LiCl (6.66 g, 157.2 mmol), and Et3N (21.2
g, 209.6 mmol) was added methyl acrylate (5.08 g, 59.0 mmol) at room
temperature. The reaction mixture was stirred at 75 °C for 12 h. After
removal of the solvent, the residue was dissolved in water and extracted
with CH2Cl2. The CH2Cl2 extract was evaporated and chromatographed
(silica gel; eluent, hexane:AcOEt ) 10:1) to give dimethyl 4,4′-(tridec-
2-ylidene)bis(cinnamate): yield ) 76% (10.0 g); oil; IR (KBr) 3446,
2933, 2853, 1723, 1635, 1436, 1314, 1273, 1170, 1014 cm-1; 1H NMR
(CDCl3) δ 0.87 (t, J ) 6.7 Hz, 3 H), 0.98-1.36 (m, 18 H), 1.62 (s, 3
H), 2.04-2.10 (m, 2 H), 3.79 (s, 6 H), 6.40 (d, J ) 15.9 Hz, 2 H),
7.19 (d, J ) 8.5 Hz, 4 H), 7.42 (d, J ) 8.5 Hz, 4 H), 7.67 (d, J ) 15.9
Hz, 2 H); 13C NMR (CDCl3) δ 14.08, 22.65, 24.57, 27.24, 29.30, 29.44,
29.57, 30.27, 31.87, 41.45, 46.53, 51.60, 117.22, 127.81, 127.85, 131.93,
144.49, 151.99, 167.45; MS m/e (relative intensity) 349 (M+ - C11H23,
100%). An AcOEt (10 mL) solution of dimethyl 4,4′-(tridec-2-ylidene)-
bis(cinnamate) (10.0 g, 19.8 mmol) and 5% Pd/C (1.0 g) was stirred at
room temperature for 24 h under hydrogen (at an initial pressure of 40
atm) in an autoclave. The reaction mixture was filtered through Celite,
and the filtrate was evaporated to give dimethyl 4,4′-(tridec-2-ylidene)-
bis(dihydrocinnamate): yield ) 93% (9.32 g); oil; IR (KBr) 3467, 2928,
1
cm-1; H NMR (CDCl3) δ 0.72 (d, J ) 6.6 Hz, 6 H), 1.54-1.76 (m,
4 H), 2.07 (d, J ) 5.0 Hz, 2 H), 2.66 (d, J ) 7.9 Hz, 4 H), 2.99 (d, J
) 7.9 Hz, 4 H), 3.51 (s, 3 H), 5.27 (s, 2 H), 7.15 (s, 2 H), 7.10 (d, J
) 8.5 Hz, 4 H), 7.13 (d, J ) 8.5 Hz, 4 H), 7.23 (d, J ) 6.6 Hz, 2 H),
7.70 (t, J ) 7.6 Hz, 2 H), 8.05 (br s, 2 H), 8.17 (d, J ) 8.2 Hz, 2 H);
13C NMR (CDCl3) δ 24.67, 25.26, 27.58, 30.78, 40.50, 45.95, 49.52,
56.73, 87.26, 87.81, 94.12, 114.08, 114.16, 122.44, 127.78, 127.81,
137.50, 138.70, 139.91, 143.97, 148.77, 151.48, 163.79, 171.33;
FABMS (in 3-nitrobenzyl alcohol) m/e (relative intensity) 718 (MH+,
100%). Anal. Calcd for C45H43O4N5: C, 75.29; H, 6.04; N, 9.76.
Found: C, 75.84; H, 6.21; N, 9.30.
Receptor 4b. This compound was synthesized from 5 (929 mg, 2.5
mmol) and 6b (1.20 g, 2.5 mmol) in a manner similar to that described
for 4a. 4b: yield ) 7% (145 mg); mp 190-192 °C; IR (KBr) 2923,
2853, 1704, 1573, 1548, 1452, 1365, 1226, 1155 cm-1 1H NMR
;
(CDCl3) δ 0.87 (t, J ) 6.7 Hz, 3 H), 1.09-1.35 (m, 18 H), 1.68 (s, 3
H), 2.05-2.08 (m, 2 H), 2.66 (t, J ) 7.3 Hz, 4 H), 2.99 (t, J ) 7.3 Hz,
4 H), 3.51 (s, 3 H), 5.27 (s, 2 H), 7.11 (s, 8 H), 7.15 (s, 2 H), 7.23 (d,
J ) 7.9 Hz, 2 H), 7.70 (t, J ) 7.9 Hz, 2 H), 8.09 (br s, 2 H), 8.17 (d,
J ) 7.9 Hz, 2 H); 13C NMR (CDCl3) δ 14.14, 22.71, 24.71, 27.06,
29.36, 29.54, 29.63, 29.69, 30.50, 30.82, 31.93, 38.68, 40.50, 41.19,
45.60, 56.71, 87.32, 87.84, 94.17, 114.08, 114.20, 122.45, 127.69,
127.85, 137.47, 138.68, 139.96, 144.02, 148.61, 151.52, 163.81, 171.35;
FABMS (in 3-nitrobenzyl alcohol) m/e (relative intensity) 816 (MH+,
100%). Anal. Calcd for C52H57O4N5: C, 76.54; H, 7.04; N, 8.58.
Found: C, 76.17; H, 7.34; N, 8.21.
Receptor 3a. A mixture of 4a (35 mg, 0.049 mmol) and (+)-(S)-
camphor-10-sulfonic acid monohydrate (85 mg, 0.34 mmol) in THF-
i-PrOH (0.22 + 0.22 mL) was stirred at room temperature for 18 h.
After removal of the solvent, the residue was subjected to column
chromatography (silica gel; eluent, CH2Cl2:AcOEt:MeOH ) 20:2:1)
to give 3a: yield ) 95% (31 mg); mp 209-212 °C dec; IR (KBr)
3379, 2950, 1700, 1593, 1570, 1516, 1452, 1383, 1278, 1229, 1150
1
cm-1; H NMR (CDCl3) δ 0.72 (d, J ) 6.7 Hz, 6 H), 1.49-1.75 (m,
4 H), 2.07 (d, J ) 4.9 Hz, 2 H), 2.64 (t, J ) 7.6 Hz, 4 H), 2.98 (t, J
) 7.6 Hz, 4 H), 6.80 (s, 2 H), 7.08 (d, J ) 8.6 Hz, 4 H), 7.11 (d, J )
8.6 Hz, 4 H), 7.20 (d, J ) 7.3 Hz, 2 H), 7.69 (t, J ) 7.6 Hz, 2 H), 8.01
(br s, 2 H), 8.20 (d, J ) 6.9 Hz, 2 H); 13C NMR (DMSO-d6) δ 24.60,
25.16, 29.88, 45.20, 87.29, 87.35, 114.01, 114.15, 121.99, 126.95,
127.98, 138.45, 139.36, 139.52, 143.34, 147.85, 152.54, 165.11, 171.72;
FABMS (in 3-nitrobenzyl alcohol) m/e (relative intensity) 674 (MH+,
100%). Anal. Calcd for C43H39O3N5: C, 76.65; H, 5.83; N, 10.39.
Found: C, 76.48; H, 5.97; N, 10.01.
Receptor 3b. This compound was synthesized from 4b (136 mg,
0.17 mmol) in a manner similar to that described for 3a. 3b: yield )
82% (106 mg); mp 161-164 °C; IR (KBr) 2926, 2854, 2670, 2369,
1702, 1569, 1527, 1452, 1384, 1279, 1151 cm-1; 1H NMR (CDCl3) δ
0.87 (t, J ) 6.7 Hz, 3 H), 1.07 (m, 18 H), 1.64 (s, 3H), 2.02 (m, 2 H),
2.64 (t, J ) 7.3 Hz, 4 H), 2.98 (t, J ) 7.3 Hz, 4 H), 6.74 (s, 2 H), 7.09
(s, 8 H), 7.19 (d, J ) 7.3 Hz, 2 H), 7.67 (t, J ) 7.9 Hz, 2 H), 8.09 (br
s, 2 H), 8.21 (d, J ) 8.6 Hz, 2 H); 13C NMR (CDCl3) δ 14.18, 22.32,
25.88, 28.92, 29.21, 29.93, 29.98, 31.51, 44.89, 87.35, 87.39, 114.04,
114.22, 122.05, 126.85, 128.11, 138.49, 139.45, 139.55, 143.38, 147.55,
152.58, 165.16, 171.74; FABMS (in 3-nitrobenzyl alcohol) m/e (relative
intensity) 772 (MH+, 100%). Anal. Calcd for C50H53O3N5: C, 77.79;
H, 6.92; N, 9.07. Found: C, 77.99; H, 7.37; N, 9.53.
2857, 1741, 1511, 1438, 1253, 1196, 1165 1020 cm-1 1H NMR
;
(CDCl3) δ 0.87 (t, J ) 6.7 Hz, 3 H), 0.98-1.37 (m, 18 H), 1.58 (s, 3
H), 1.99-2.05 (m, 2 H), 2.61 (t, J ) 7.3 Hz, 4 H), 2.91 (t, J ) 7.3 Hz,
4 H), 3.67 (s, 6 H), 7.08 (s, 8 H); 13C NMR (CDCl3) δ 14.16, 22.73,
24.73, 27.62, 29.38, 29.57, 29.65, 29.69, 30.45, 31.95, 35.65, 41.92,
45.64, 51.62, 127.44, 127.75, 137.51, 147.92; MS m/e (relative intensity)
353 (M+ - C11H23, 100%). To an EtOH (18 mL) solution of dimethyl
4,4′-(tridec-2-ylidene)bis(dihydrocinnamate) (9.32 g, 18.3 mmol) was
added an EtOH (110 mL) solution of KOH (6.17 g, 110.0 mmol) at
room temperature. The reaction mixture became turbid, and the cloudy
solution was allowed to stand for 12 h at this temperature. After removal
of the solvent, the residue was poured into water and washed with
CHCl3 to remove the unreacted starting materials. The water phase
was neutralized to pH 5 with 10% aqueous hydrochloric acid solution
and extracted with CHCl3. The CHCl3 extract was evaporated to give
6b: yield ) 99% (8.70 g); oil; IR (KBr) 2932, 2855, 1712, 1511, 1414,
1300, 1215, 1106 cm-1; 1H NMR (CDCl3) δ 0.87 (t, J ) 6.7 Hz, 3 H),
0.99-1.36 (m, 18 H), 1.59 (s, 3 H), 1.99-2.08 (m, 2 H), 2.66 (t, J )
7.3 Hz, 4 H), 2.92 (t, J ) 7.3 Hz, 4 H), 7.09 (s, 8 H); 13C NMR (CDCl3)
δ 14.16, 22.73, 24.75, 27.62, 29.40, 29.57, 29.69, 30.09, 30.44, 31.95,
35.57, 41.92, 45.68, 127,51, 127.77, 137.17, 148.04, 179.42; MS m/e
(relative intensity) 325 (M+ - C11H23, 100%). Anal. Calcd for
C31H44O4: C, 77.46; H, 9.23; N, 13.31. Found: C, 77.05; H, 9.41; N,
12.85.
Acknowledgment. The preliminary work in this paper was
supported by Saneyoshi Scholarship Foundation and by Mit-
subishi Chemical Corporation Foundation. This paper is dedi-
cated to M.I.’s teacher, Professor Yoshihiko Ito (Kyoto Uni-
versity) on the occasion of his 60th birthday.
Receptor 4a. To a CH3CN (600 mL) solution of 5 (1.76 g, 4.73
mmol), 6a8 (1.81 g, 4.73 mmol), and Et3N (7.66 g, 75.7 mmol) was
JA983539U