Synthesis of a water-soluble molecular tweezer and a recognition study in an aqueous media

Article abstract of DOI:10.1016/j.tetlet.2004.12.002

Synthesis of a 1,10-diphenanthryl all-trans fused perhydrophenanthrene derivative and a recognition study in an aqueous media were carried out. A water-soluble derivative recognized certain benzene derivatives with 10 ⁴-10⁵ M^-1 of binding constant.

Full text of DOI:10.1016/j.tetlet.2004.12.002

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 551–553
Synthesis of a water-soluble molecular tweezer and a
recognition study in an aqueous media
Hisao Nemoto,a,* Tomoaki Kawano,a Nobuo Ueji,a Nobutaka Sakamoto,a
Takaaki Araki,a Norikazu Miyoshi,b Ichiro Suzukia and Masayuki Shibuyaa
aDepartment of Molecular Design and Synthesis, Division of Pharmaceutical Sciences, Graduate School of The University of
Tokushima, Sho-machi 1-78, Tokushima 770-8505, Japan
bDepartment of Chemistry, Faculty of Integrated Arts and Sciences, The University of Tokushima,1-1, Minamijosanjima-cho,
Tokushima 770-8502, Japan
Received 1 November 2004; revised 28 November 2004; accepted 1 December 2004
Abstract—Synthesis of a 1,10-diphenanthryl all-trans fused perhydrophenanthrene derivative and a recognition study in an aqueous
media were carried out. A water-soluble derivative recognized certain benzene derivatives with 104–105 MÀ1 of binding constant.
ꢀ 2004 Elsevier Ltd. All rights reserved.
During the last quarter of the century, recognition stud-
H N C
CN H
4
2
2
4
N
ies using artificially designed molecular tweezers1 involv-
ing a pair of electron sufficient aromatic plates have
been demonstrated.2–21 In most of these publications,
including our previous paper,2 recognition studies be-
tween an electron-deficient aromatic compound and a
pair of electron-sufficient aromatic plates were carried
out in organic solvents. Kreb and Jørgensen argued that
the value of 490 MÀ1 reported by them was the highest
recorded value for the binding constant under those
conditions.3 Until now, it was considered that these rec-
ognitions could be based on strong p–p interactions.3
Accordingly, neither molecular recognition of electron-
sufficient aromatic compounds as an analyte, nor recog-
nition study in aqueous solvent22 has been reported until
now. In other words, when tweezers were used as a host
molecule, other typical interactions such as a hydropho-
bic interaction between aromatics, were not
demonstrated.
N
-
-
CF CO
2
CF CO
3
N
N
3
2
O
O
H
H
H
H
H
H
4
5
6
7
2
9
12
11
10
1
O
O
O
O
1
Figure 1.
tional ionic groups are conformationally located far
from this cavity.
First, we synthesized the diacid 10 from the diketone 22
as shown in Scheme 1. Reduction of 2 was carried out
23
with AlH3 in THF at 0 ꢁC for 10 min, which gave a
pure equatorial diol 3 in 61% yield along with a mixture
of its diastereomers. The obtained purified major diaste-
reomer 3 was treated with a mixture of acetic anhydride,
pyridine, and 4-(N,N-dimethylamino)pyridine (DMAP)
in dichloromethane at 0 ꢁC for 13 h to give the diacetate
4 in 88% isolated yield. Two tolyl moieties of 4 were oxi-
dized2 with N-bromo succinimide (NBS), CaSO4/H2O,
and pyrodinium chlorochromate (PCC) to obtain the
dialdehyde 5 in 55% overall yield. The Honnor–
Emmons–Wittig reaction of 5 was performed with
diethyl benzylphosphate/NaH in THF at reflux for 8 h.
In this letter, we report the synthesis of a water-soluble
molecular tweezer 1, and its recognition study in an
aqueous media (Fig. 1). The cavity between two phen-
anthrenes of 1 is perfectly hydrophobic, and the addi-
Keywords: Molecule recognition; Tweezers; Perhydronaphthacene;
Water soluble; Binding constant; Hydrophobic interaction.
*
Corresponding author. Tel./fax: +81886337284; e-mail: nem@ph.
tokushima-u.ac.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.002

552
H. Nemoto et al. / Tetrahedron Letters 46 (2005) 551–553
CO H
2
CO H
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
LiAlH /AlCl
4
3
1
1
O
O
R O
OR
O
O
O
O
H
H
H
CN
2
2
R
R
2
O N
2
NO
2
1
2
3: R =H, R =CH
3
1
2
4: R =COCH , R =CH
3
3
11
12
10
1
2
5: R =COCH , R =CHO
3
1
2
CO R
2
CO R
2
6: R =H, R = CH=CHPh
H
H
H
H
1
7: R =COCH CH CO H,
2
2
2
2
58M-1
(CDCl3/CD3CO2D=3:1)
R =CH=CHPh
1
34M-1
(CDCl3)
8: R =COCH CH CO CH CH SiMe ,
O
O
O
O
2
2
2
2
2
3
H
H
2
R =CH=CHPh
Figure 2.
in CDCl3.2 Using the titration method,25 measured by
1H NMR at 25 ꢁC, the binding constant of 10/12 was
determined to be 58 MÀ1, which was not in a different
class from the binding constant of 11/12 (34 MÀ1 at
25 ꢁC in CDCl3)2.
9: R=CH CH SiMe
3
2
2
10: R=H
Scheme 1.
This resulted in the production of trans-distyrene 6 in
82% yield. Treatment of 6 with succinic anhydride and
DMAP gave the diacid 7 in 91% yield. The diacid 7
was transformed into the diester 8 with 2-(trimethylsil-
yl)ethanol, 1-dimethylaminopropyl-3-ethyl carbodi-
imide hydrochloride salt (EDC Æ HCl), and DMAP in
71% yield. Oxidative cyclization of two bis-styryl moie-
ties24 of 8 was carried out by a mercury lamp with iodine
and propene oxide in argon-bubbled benzene for 4 h to
give the bis-phenanthrene 9 in 44% yield. Finally, depro-
tection of 2-silylethyl moieties of 9 with tetrabutylam-
monium fluoride in N,N-dimethylformamide (DMF)
was carried out to give the diacid 10 in 86% yield.
Thus, the diacid 10 was transformed to bis-guanidine
salt 1 as shown in Scheme 2. Condensation of 10 with
1326 was carried out with EDC Æ HCl and N-hydroxy-
benzotriazol (HOBt) to give 14 in 93% yield. Finally,
deprotection of four tert-butyloxycarbonyl groups
(Boc) quantitatively yielded 1 with trifluoroacetic acid
(TFA) in chloroform.
The TFA salt 1 was sufficiently soluble in both metha-
nol-d4 and deuterium oxide for the measurement by
1H and 13C NMR. However, as no clear sharp peaks
were obtained at 25 ꢁC in each solvent, we chose UV
measurement instead.
The water-solubility of 10 was very low even though two
free carboxylic acids were present. However, we inciden-
tally attempted our binding study in a solvent more
polar than CDCl3 for comparing the obtained results
First, the UV spectra of 1 in various concentrations in
water were examined and were found to be strongly
influenced by the concentration. This indicates the pres-
ence of self intermolecular interactions of 1. In such a
case, the binding study between 1 and a certain guest
molecule could not be clearly determined based on Lam-
bert–Beer rule alone. Unfortunately, the UV peaks indi-
cated self interaction even at the lowest concentration
for the acceptable measurable range. Therefore, we con-
cluded that binding study of 1 in water could not be
taken into account. Fortunately, the above problem
was solved when solution of 1 in water/methanol
(v/v = 4/1) was prepared. Difference between the UV
spectra of 1 at 5 · 10À5 M and that at 2 · 10À5 M was
negligible. Thus we carried out the binding study of 1
at 5 · 10À5 M.
1
with our previous result using 11.2 (Fig. 2) H NMR
of the saturated solution of 10 in several polar solvents
such as acetone-d6, methanol-d4, and acetic acid-d4
was measured. A satisfactory signal/noise range of H
1
NMR was obtained from the solution of 10 in acetic
acid-d4, although all the NMR peaks of 10 were too
broad to determine the binding constant. Finally, clear
sharp peaks were observed in CDCl3/acetic acid-d4
(v/v = 3/1). This enabled us to carry out the binding
study of 10 with 3,5-dinitrobenzonitrile (12). The molar
ratio of the complex of 10/12 at 25 ꢁC was determined to
be 1:1 by Job plot,25 which was similar to that of 11/12
Boc
Boc
HN
NH
H
N
N
N
N
N
N
Boc
Boc
N
Boc
N
Boc
N
O
O
H
H
H
H
H
H
CF CO H/CH Cl
2
N
H
13
3
2
2
1
10
O
O
O
O
EDC•HCl, HOBt
14
Scheme 2.

H. Nemoto et al. / Tetrahedron Letters 46 (2005) 551–553
553
2. Nemoto, H.; Kawano, T.; Ueji, N.; Bando, M.; Kido, M.;
Suzuki, I.; Shibuya, M. Org. Lett. 2000, 2, 1015–1017.
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4. Harmata, M.; Murray, T. J. Org. Chem. 1989, 54, 3761–
3763.
CN H
2
4
N
-
N
N
2CF CO
O
N
3
2
O
O
CN H
2
4
N
18
O
5. Harmata, M.; Barnes, C. L. Tetrahedron Lett. 1990, 31,
1825–1828.
Figure 3.
6. Harmata, M.; Barnes, C. L. J. Am. Chem. Soc. 1990, 112,
5655–5657.
We could not choose 12 as an analyte as it is insoluble in
water/methanol. Therefore, benzene 1,3-disulfonic acid
(15) and 4-methoxyphenol (16) were chosen as guest
molecules as both are sufficiently soluble in water/meth-
anol (v/v = 4/1), and the maximum UV peaktop for
these two molecules was sufficiently far away from that
of 1 (256 nm).
7. Harmata, M.; Barnes, C. L.; Karra, S. R.; Elahmad, S. J.
Am. Chem. Soc. 1994, 116, 8392–8393.
8. Fleischhauer, J.; Harmata, M.; Kahraman, M.; Koslow-
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9502.
The molar ratio of both complexes of 1/15 and 1/16 were
determined to be 1:1 by Job plot.25 The binding constant
of 1/15 was determined to be 3.3 · 104 MÀ1 by the titra-
tion method.25 Similarly, the binding constant of 1/16
was determined to be 4.0 · 104 MÀ1. In contrast, a UV
spectrum of 18 (Fig. 3) at 5 · 10À5 MÀ1 in a water–
methanol (v/v = 4/1) was not altered significantly upon
titration with 15.
11. Maitra, U.; DꢀSouza, L. J.; Kumar, P. V. Supramol. Chem.
1998, 10, 97–106.
12. Jeong, K. S.; Tjivikua, T.; Muehldorf, A.; Deslong-
champs, G.; Famulok, M.; Rebek, J., Jr. J. Am. Chem.
Soc. 1991, 113, 201–209.
13. Blake, J. F.; Jorgensen, W. L. J. Am. Chem. Soc. 1990,
112, 7269–7278; Zimmerman, S. C.; VanZyl, C. M.;
Hamilton, G. S. J. Am. Chem. Soc. 1989, 111, 1373–1381.
14. Zimmerman, S. C.; Zeng, Z.; Wu, W.; Reichert, D. E. J.
Am. Chem. Soc. 1991, 113, 183–196.
Therefore, we can conclude that perhydronaphthacene
moiety is essential for the recognition property of 1.
Additionally, the ionic interaction between guanidine
moiety and either sulfonic acid or aromatic-OH could
be ignored in water/methanol. The main driving force
of recognition is strongly due to the elaborately designed
cavity27 of 1 that fits both the width and depth of the
benzene ring.
15. Zimmerman, S. C.; Wu, W.; Zeng, Z. J. Am. Chem. Soc.
1991, 113, 196–201.
16. Zimmerman, S. C. Top. Curr. Chem. 1993, 165, 71–102.
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8054–8055.
20. Zimmerman, S. C.; VanZyl, C. M. J. Am. Chem. Soc.
1987, 109, 7894–7896.
In conclusion, we have designed and synthesized a
water-soluble tweezer that exceeds the previous highest
record of the binding constant.3 The currently obtained
binding constants, 104–105 MÀ1, could be a significant
quantitative index for the hydrophobic interacting force
of parallelly organized aromatic plates27,28 in an aque-
ous media.
21. Muhammad, F.; Richards, N. G. J.; Guide, W. C.;
Liskamp, R.; Caufield, C.; Chang, G.; Hendrickson, T.;
Still, W. C. J. Comput. Chem. 1990, 11, 440–467.
22. In this publication, synthesis and the recognition study of
a water-soluble tweezer was reported. However, the
driving force of binding might be mainly ionic interations.
Scrimin, P.; Tecilla, P.; Tonellato, U.; Vignaga, N. J.
Chem. Soc., Chem. Commun. 1991, 449–451.
23. Brown, H. C.; Yoon, N. M. J. Am. Chem. Soc. 1966, 88,
1464–1472.
24. Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org.
Chem. 1991, 56, 3769–3775.
25. Blanda, M. T.; Horner, J. H.; Newcomb, M. J. Org.
Chem. 1989, 54, 4626–4636.
26. The guanidine derivative 13 was prepared from piperadine
and BocN@C(NHBoc)-NH-SO2CF3.
Acknowledgments
This work was in part supported by research grants
from Faculty of Pharmaceutical Sciences, The Univer-
sity of Tokushima.
27. b-Cyclodextrin has a cone-shaped cavity. In contrast, the
tweezer 1 has a rectangular-shaped cavity that is fit for the
thickness of benzene ring. We carried out the recognition
study of 4-methoxyphenol with b-cyclodextrin in water/
methanol (4/1), and observed no recognition.29
28. Smiththrud, D. B.; Wyman, T. B.; Diederich, F. J. Am.
Chem. Soc. 1991, 113, 5410–5419; Ferguson, S. B.;
Sanfold, E. M.; Seward, E. M.; Diederich, F. J. Am.
Chem. Soc. 1991, 113, 5420–5426.
Supplementary data
IR, 1H NMR, 13C NMR, HRMS data of 1, 3, 5–10, 13,
14 and 18 are available. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2004.12.002.
29. The binding constant between b-Cyclodextrin and 4-
nitrophenol was reported (6 · 103 MÀ1 in D2O; no recog-
nition in methanol). Kanda, Y.; Yamamoto, Y.; Inoue,
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