Ferrocene-modified bis(spiropyridopyran)s as synthetic signaling receptors for guanine-guanine dinucleoside derivatives

Article abstract of DOI:10.1039/b107306k

A ferrocene-linked bis(spiropyridopyran) was designed and synthesized, that recognized guanine-guanine dinucleoside derivatives via complementary hydrogen bonds in CH₂Cl₂, resulting in the isomerization of the colorless spiropyridopyran as self-indicating receptors.

Full text of DOI:10.1039/b107306k

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Ferrocene-modified bis(spiropyridopyran)s as synthetic signaling
receptors for guanine–guanine dinucleoside derivatives
Masayoshi Takase and Masahiko Inouye*b
a
a
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
b
Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Toyama
9
30-0194, Japan. E-mail: inouye@ms.toyama-mpu.ac.jp
Received (in Cambridge, UK) 13th August 2001, Accepted 16th October 2001
First published as an Advance Article on the web 30th October 2001
A ferrocene-linked bis(spiropyridopyran) was designed and
synthesized, that recognized guanine–guanine dinucleoside
The 3H-indole derivative bearing ethynyl groups at the 5
position was prepared from 4-bromophenylhydrazine by using
9
derivatives via complementary hydrogen bonds in CH
2
Cl
2
,
the Fischer-indole synthesis followed by Sonogashira reaction.
resulting in the isomerization of the colorless spiropyr-
idopyran as self-indicating receptors.
Further Sonogashira reaction of the indole with 1,1A-diiodo-
ferrocene10 gave ferrocene-linked bis(3H-indole), which was
methylated at the nitrogen and condensed with 6-acetamido-
2-pyridone-3-carbaldehyde4 to yield desired bis(spiropyr-
idopyran) 2 (Scheme 2).† The lipophilic dinucleoside deriva-
7c
a
The recognition and selective binding of nucleobases play
essential roles in entire living systems. For example, com-
plementary hydrogen bonds arise in a very specific fashion
between purine and pyrimidine bases of the two strands of
double-helical DNA in order to store genetic information.1
Thus, the synthetic models that recognize specific nucleobases
and that read-out the recognition event are attracting much
attention from the viewpoint of their uses in biological
8
tives were prepared according to a literature procedure.
The ferrocene-linked bis(spiropyridopyran) 2 showed wine-
2 2
red color in CH Cl , indicating that it exists at least partly as the
1
open merocyanine form. This was demonstrated by the H
NMR spectrum of 2, in which 10% or less of 2 is present as 2A
on the basis of the integration of the spectrum.‡ Futhermore, the
UV-vis spectrum of 2 revealed an absorption maximum around
2
sciences. In this connection, we have reported spiropyridopyr-
3
3
ans 1, isomerization of which to the colored merocyanines 1A
580 nm (e = 6.9 3 10 ) that is unambiguously attributed to the
was induced by recognition of guanosine derivatives.4 To
extend this approach to more challenging projects, we focused
on the recognition of oligonucleotides. Here we describe the
molecular recognition ability and its recognition-induced color-
ation of a ferrocene-modified bis(spiropyridopyran) 2 for
guanine–guanine dinucleosides (Scheme 1).
merocyanine chromophore (Fig. 1a; a line of ‘none’). In
4a
2 2
CH Cl , addition of the guanine–guanine dinucleoside deriva-
tive GG (10 equiv.) to 2 produced changes in the absorption
spectra, and strong absorption bands appeared (lmax = 575 nm,
4
e = 3.8 3 10 ). The change was clearly seen visually, as the
wine-red color of 2 dramatically darkened. Unfortunately, the
1
The choice of ferrocene as a linker was based on the inter-ring
3
H NMR spectrum of the mixture of 2 and GG in CDCl gave
5
spacing of the two Cp rings (0.33 nm), which is near to the
no useful information for the increment of the merocyanine
6
spacing between the stacked base pairs. Another advantageous
point of the ferrocene skeleton is its restricted conformational
flexibility. This may result in the decrease of the entropy loss of
7
2
upon complexation with dinucleotides. To evaluate the
recognition abilities of 2 for dinucleotides in less-polar solvents,
lipophilic dinucleoside derivatives were chosen (Fig. 1b). The
bulky silyl groups at the 5A and 3A ends and the di-n-
hexylsilylene internucleoside linkage make the dinucleoside
soluble in such solvents and prevent their deoxyribofuranoside
residues from interacting with the hydrogen-bonding motif of 2.
The decision for utilizing the silylene linkage was based on the
similarity of covalent bond radius of tetrahedral silicon (0.117
nm) to that of tetrahedral phosphorus (0.110 nm).8
2
2
Fig. 1 (a) Electronic absorption spectra of 2 (3.0 3 10 mM) in the
21
presence of the lipophilic nucleoside derivatives (3.0 3 10 mM) in
CH Cl at 25 °C. (b) The structures of the dinucleoside derivatives. The
guanine–guanine dinucleoside (GG) was used as a mixture with 3A–3A and
A–5A homo-coupling dimers. The guanine mononucleoside (G) is 3A,5A-bis-
O-(tert-butyldimethylsilyl)deoxyguanosine.
2
2
5
Scheme 1
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Chem. Commun., 2001, 2432–2433
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b107306k

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Notes and references
1
†
6
2: H NMR (400 MHz, CDCl
3
, TMS): d 1.18 (s, 6 H, C(CH
3 2
) ), 1.33 (s,
H, C(CH
3
)
2
), 2.12 (s, 6 H, COCH ), 2.77 (s, 6 H, NCH ), 4.31 (s, 4 H, Cp-
3
3
CH), 4.53 (s, 4 H, Cp-CH), 5.67 (d, J = 10.0 Hz, 2 H, pyrane-CH), 6.45 (d,
J = 8.0 Hz, 2 H, benzene-CH), 6.83 (d, J = 10.0 Hz, 2 H, pyrane-CH), 7.18
(
8
s, 2 H, benzene-CH), 7.30 (d, J = 8.0 Hz, 2 H, benzene-CH), 7.41 (d, J =
.0 Hz, 2 H, pyridine-CH), 7.71 (br s, 2 H, NH), 7.72 (d, J = 8.0 Hz, 2 H,
pyridine-CH).
‡
3
2A (diagnostic peaks in 1H NMR): 1.73 (s, C(CH
)
), 2.31 (s, COCH
),
3
2
3
+
.62 (s, N CH
3
a
). Assignments of the peaks of 2 and 2A were based on those
4
for 1 and 1A.
1
General reviews: (a) J. D. Watson, N. H. Hopkins, J. W. Roberts, J. A.
Steitz and A. M. Weiner, Molecular Biology of the Gene, 4th ed.,
Benjamin, Menlo Park, 1987; (b) B. Alberts, D. Bray, J. Lewis, M. Raff
and J. D. Watson, Molecular Biology of the Cell 3rd ed., Garland, New
York, 1994; (c) B. Lewin, Genes V, Oxford University, Oxford, 1994.
A comprehensive review: Comprehensive Supramolecular Chemistry,
ed. J. L. Atwood, J. E. D. Davies, D. D. MacNicol and F. Vögtle,
Elsevier, Oxford, 1996, vol. 2.
General reviews of spiropyrans: (a) R. C. Bertelson, in Photochromism,
ed. G. H. Brown, Wiley-Interscience, New York, 1971, p. 45; (b) R. J.
Guglielmetti, in Photochromism, Molecules and Systems, ed. H. Dürr
and H. Bouas-Laurent, Elsevier, Amsterdam, 1990, p. 314; (c) R. C.
Bertelson, in Organic Photochromic and Thermochromic Compounds,
ed. J. C. Crano and R. J. Guglielmetti, Plenum, New York, 1999, vol. 1,
p. 11.
Scheme 2 Reagents: (a) butan-2-one, AcOH; (b) 2-methylbut-3-yn-2-ol,
(
(
6
Ph
Ph
3
P)
P)
2
PdCl
PdCl
2
, CuI, Et
, Cu(OAc)
2
NH; (c) NaOH, toluene; (d) 1,1A-diiodoferrocene,10
, i-Pr NH; (e) MeI, MeCN, then NaOH, H O; (f)
3
2
2
2
2
2
4
a
-acetamido-2-pyridone-3-carbaldehyde, EtOH.
2
3
form 2A because of much overlap of the peaks between 2A and
GG. The guanine mononucleoside G resulted in similar
changes to the absorption spectrum, while other mononucleo-
side (A, T, C) and dinucleoside (AA and TT) derivatives had
absolutely no influence on it (Fig. 1a). These findings indicated
that the complementary triple hydrogen bond between the
acetamidopyridone anion part of 2A and guanine bases is critical
for selective coloration.
4
(a) M. Inouye, K. Kim and T. Kitao, J. Am. Chem. Soc., 1992, 114, 778;
(b) M. Inouye, Coord. Chem. Rev., 1996, 148, 265; (c) M. Inouye, in
Organic Photochromic and Thermochromic Compounds, ed. J. C.
Crano and R. J. Guglielmetti, Plenum, New York, 1999, vol. 2, p.
393.
The binding constants were estimated by UV titration at 25
°
C using an iterative least-squares curve-fitting with weighting
11
5 General reviews of ferrocene: (a) A. J. Deeming, in Comprehensive
Organometallic Chemistry, ed. G. Wilkinson and F. G. A. Stone,
Pergamon, Oxford, 1982, vol. 4, p. 475; (b) Ferrocenes, ed. A. Togni
and T. Hayashi, VCH, New York, 1995.
of data points according to the error analysis of Deranleau.
The absorbances of the merocyanine forms (575 nm) were
monitored as a function of the concentration of guanosine
derivatives assuming that all the complexed-spiropyrans exist
as merocyanine forms. The association constant between 1A and
6
A comprehensive review: W. Saenger, Principles of Nucleic Acid
Structure, Springer-Verlag, New York, 1984.
4
21
21
G displayed 2.4 3 10 M (2DG298 = 25.0 kJ mol ), while
7
(a) M. Inouye, Y. Hyodo and H. Nakazumi, J. Org. Chem., 1999, 64,
5
21
that of 2A and GG was 4.2 3 10 M (2DG298 = 32.0 kJ
2
704; (b) M. Inouye, M. S. Itoh and H. Nakazumi, J. Org. Chem., 1999,
21
mol ). The increment of the binding energy was lower than
that predicted by the doubled recognition sites; this may partly
result from the electrostatic repulsion between the two zwitter-
ionic merocyanines.
64, 9393; (c) M. Takase and M. Inouye, Mol. Cryst. Liq. Cryst., 2000,
344, 313; (d) M. Inouye and M. Takase, Angew. Chem., Int. Ed., 2001,
40, 1746.
K. K. Ogilvie and J. F. Cormiew, Tetrahedron Lett., 1985, 26, 4159.
Reviews: (a) K. Sonogashira, in Comprehensive Organic Synthesis, ed.
B. M. Trost, I. Fleming, C. H. Heathcock, G. Pattenden, S. V. Ley, S. L.
Schreiber, R. Noyori, M. F. Semmelhack, L. A. Paquette and E.
Winterfeldt, Pergamon, Oxford, 1991, vol. 3, p. 521; (b) K. Sonoga-
shira, in Metal-Catalyzed Cross-Coupling Reactions, ed. F. Diederich
and P. J. Stang, Wiley-VCH, Weinheim, 1998, p. 203.
8
9
In summary, a ferrocene-modified bis(spiropyridopyran) was
developed as a synthetic signaling receptor for guanine–guanine
dinucleoside derivatives. The high selectivity for the coloration
of the receptor is governed by the hydrogen-bonding com-
plementarity between them. In the future, design and synthesis
of the receptors that bind native nucleotides will be expected to
show significant practical value.
10 D. Guillaneux and H. B. Kagan, J. Org. Chem., 1995, 60, 2502.
11 D. A. Deranleau, J. Am. Chem. Soc., 1969, 91, 4044.
Chem. Commun., 2001, 2432–2433
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