A conformationally reliable spacer for molecular tweezers

Article abstract of DOI:10.1021/ol9913439

A reliable and rigid spacer, trans,trans,trans-perhydronaphthacene, for molecular tweezers was designed. A synthesis and molecular recognition study of its 1,14-disubstituted derivatives was carried out.

Full text of DOI:10.1021/ol9913439

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1015-1017
A Conformationally Reliable Spacer for
Molecular Tweezers
Hisao Nemoto,* Tomoaki Kawano, Nobuo Ueji, Masahiko Bando, Masaru Kido,
Ichiro Suzuki, and Masayuki Shibuya
Faculty of Pharmaceutical Sciences, The UniVersity of Tokushima, 1-78, Sho-machi,
Tokushima 770-8505, Japan
nem@ph2.tokushima-u.ac.jp
Received December 14, 1999
ABSTRACT
A reliable and rigid spacer, trans,trans,trans-perhydronaphthacene, for molecular tweezers was designed. A synthesis and molecular recognition
study of its 1,14-disubstituted derivatives was carried out.
Most of the significant studies on molecular recognition using
“tweezers”, typically constructed with two arms and one
spacer, have been reported in recent years.1 However, it
seems to be difficult to carry out precise analyses, mainly
because of intermolecular unanticipated nonbonded interac-
tions. Additionally, the conformational flexibility of the host
molecules increases the intricacy. Therefore, in recent works
conformational flexibility has been minimized by using
aromatic rings1d and/or fused polycyclic rings involving
bridge heads.1k However, the analysis of steric repulsion
against π-π conjugations as well as the analysis of the
constrained bond should be carried out more discreetly than
that of typical normal bonds should be.
We report the design and synthesis of 1,10-diequatorial-
substituted all-trans-fused perhydronaphthacene derivatives
(Figure 1). We chose them for the following reasons. (1)
Figure 1.
(1) (a) Haino, T.; Yanase, M.; Fukazawa, Y. Angew. Chem., Int. Ed.
1998, 37, 997. (b) Inouye, M.; Fujimoto, K.; Furusho, M.; Nakazumi, H. J.
Am. Chem. Soc. 1999, 121, 1452. (c) Chen, C.-W.; Whitelock, H. W., Jr.
J. Am. Chem. Soc. 1978, 100, 4921. (d) Zimmerman, S. C.; Zeng, Z.; Wu,
W.; Reichert, D. E. J. Am. Chem. Soc. 1991, 113, 183. (e) Magnus, P.;
Morris, J. C.; Lynch, V. Synthesis 1997, 506. (f) D’Souda, L. J.; Maitra,
U. J. Org. Chem. 1996, 61, 9494. (g) Blake, J. F.; Jorgensen, W. L. J. Am.
Chem. Soc. 1990, 112, 7269. (h) van Doorn, A. R.; Bos, M.; Harkema, S.;
van Eerden, J.; Verboom, W.; Reinhoudt, D. N. J. Org. Chem. 1991, 56,
2371. (i) Mink, D.; Deslongchamps, G. Tetrahedron Lett. 1996, 37, 7035.
(j) Rebek, J., Jr. Angew. Chem., Int. Ed. Engl. 1990, 29, 245. (k) Harmata,
M.; Barnes, C. L.; Karra, S. R.; Elahmad, S. J. Am. Chem. Soc. 1994, 116,
8392.
The cyclohexane ring without large axial substituents is one
of the most unstrained molecules. (2) When cyclohexane
rings are trans-fused, the whole conformation becomes rigid
enough. (3) In many of the available programs for confor-
mational analysis, the conformation of cyclohexane deriva-
tives can be optimized with high reliability and reproduc-
ibility. (4) The van der Waals distance between the two
aromatic rings is appropriate for sandwiching a benzene
derivative between them. (5) Lipophilic and/or π-π interac-
tions could turn out to be quite marked, since hydrogen bond
and ionic interactions are completely absent.
(2) 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.
10.1021/ol9913439 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/18/2000

As a contrasting example to the compound 1, we first
carried out the conformational analysis of the compound 2.
We chose MacroModel version 6.022 for this preliminary
examination.
Conformations of 2 were optimized using five calculation
options (MM2′′, MM3′′, OPLS′′, MMFF, and AMBER′′).
The resulting angles of the A/B planes are 60, 70, 70, 89,
and 74°, respectively. The wide dispersion in these results
can be explained by the independent parameters used for
the estimation of the π-conjugation stabilization against steric
repulsion. In contrast, our designed 1 has no π-orbital in the
rigid spacer. In fact, plane angles A/B of 1 were briefly 90°
in all the five calculation options.
5b to 6b was also carried out under conditions similar to
those for 6a in 30% overall yield.
The binding ability of 6a and 6b with regard to a variety
of benzene derivatives was evaluated by a 1H NMR titration
technique in CDCl3. However, no significant change of
chemical shift of the peaks was observed. Therefore, to
increase the interactive π-surface, the phenanthrene derivative
8 was synthesized from 6b as follows (Scheme 2). Bis-
Scheme 2a
Synthesis of bis(p-methoxyphenyl)perhydronaphthacene
(6a) and bis(m-methylphenyl)perhydronaphthacene (6b) was
carried out as shown in Scheme 1. The crude bis(enamine),
Scheme 1a
a Legend: (d) N-bromosuccinimide/CCl4, room temperature, 10
min, then CaCO3/1,4-dioxane/water, room temperature, 19 h, and
then pyridinium chlorochromate/CH2Cl2, room temperature, 2 h;
(e) C6H5CH2PO(OEt)2/NaH/DME, room temperature, 40 h; (f) UV/
1-butene oxide/iodine/benzene, 10 h.
bromination of the m-methyl group of 6b, followed by
hydrolysis with calcium carbonate6 and then oxidation with
pyridinium chlorochromate, gave the dialdehyde 7 in 61%
overall yield. The reaction of 7 with diethyl benzylphos-
phonate gave the trans-stilbene derivative, which was
converted to the phenanthryl derivative 8 with ultraviolet
irradiation in the presence of iodine,7,1e and 1-butene oxide.
The yield was 45% after purification by column chroma-
tography.
a Legend: (a) 3 + pyrrolidine/benzene, room temperature, 21
h, then 4 (1.2 equiv)/benzene, room temperature, 3 h, and then
p-toluenesulfonic acid (TsOH) (cat.)/benzene, 5-24 h; (b) Li/
ammonia/THF, -78 °C, 30 min; (c) 1,2-ethanedithiol/BF3‚OEt2/
CH2Cl2, room temperature, 2-14 h, and then Raney Ni/ethanol,
reflux, 24 h.
The ability of 8 to bind to 1-cyano-3,5-dinitrobenzene (9)
was determined by a 1H NMR titration technique in CDCl3.
Significant changes in peaks ascribable to 8 and 9 were
prepared by condensation of trans-octaline-2,7-dione (3)3
with pyrrolidine, was treated with the enone 4a4 followed
by acidic aldol condensation of the resulting bis(1,4-diketone)
to give the bis(enone) 5a in 43% overall yield from 3. The
bis(enone) 5b was also obtained from 3 with the enone 4b4
in 50% overall yield using reaction conditions similar to those
for 5a.
Treatment of 5a with lithium/ammonia5 gave the corre-
sponding diketone in 40% yield, which was converted to 6a
via the dithioketal in 57% overall yield. Transformation of
(3) Jones, J. B.; Dodds, D. R. Can. J. Chem. 1987, 65, 2397.
(4) The enones 4a and 4b were prepared from the corresponding amides
with vinylmagnesium bromide given in the following paper: Nahm, S.;
Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(5) Although we have used many hydrogenation conditions for 5a, the
cis,trans,cis-fused ring was always obtained exclusively.
Figure 2. Job’s plot and curve-fitting analysis of 8 with 9 using
the ∆δ value of H-6 of phenanthryl groups at 25 °C.
1016
Org. Lett., Vol. 2, No. 8, 2000

observed. A Job’s plot analysis (Figure 2) confirmed the 1:1
stoichiometry of the complex. The association constant of
the complex, which was determined by a nonlinear curve-
fitting analysis using the Gauss-Newton algorithm,8 was 34
( 7.1 M-1 at 25 °C. Although similar titration experiments
were carried out for phenanthrene and 9 for comparison, no
significant changes were observed. Thus, the presence of the
perhydronaphthacene moiety as a spacer is essential for the
recognition of 9.
In conclusion, we have synthesized tweezers bearing a very
rigid and reliable residue, the all-trans-fused perhydronaph-
thacenyl moiety. The bis(phenanthryl) derivative recognizes
1-cyano-3,5-dinitrobenzene. We believe that feedback from
our experimental results will help delineate the relationship
between unanticipated nonbonded interactions and the vari-
ous parameters used by the theoretical methods. We are now
synthesizing other derivatives of perhydronaphthacene for
further study of molecular recognition.
Acknowledgment. We thank Dr. Yoshihisa Fujiwara at
the Graduate School of Science of Hiroshima University for
giving us his original program for the analysis of binding
study. We are grateful to Prof. Yoshimasa Fukazawa and
Dr. Takeharu Haino at the Graduate School of Science of
Hiroshima University for their discussions.
(6) Smith, J. G.; Dibble, P. W.; Sandborn, R. E. J. Org. Chem. 1986,
51, 3762.
(7) Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org. Chem. 1991,
56, 3769.
(8) (a) Conners, K. A. Binding Constants; Wiley: New York, 1987. (b)
Leggett, D. J. Computational Methods for the Determination of Formation
Constants; Modern Inorganic Chemistry Series; Plenum Press: New York,
London, 1985.
Supporting Information Available: Experimental pro-
cedures and characterization data for all the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9913439
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