Allosteric function facilitates template assisted olefin metathesis

Article abstract of DOI:10.1039/b512805f

Template assisted olefin metathesis of an allosteric host 1b to give the corresponding bicyclic compound 1c was achieved and 1c can allosterically bind the template guest diamines, 2 and 3 with different affinity and cooperativity. The Royal Society of Ch

Full text of DOI:10.1039/b512805f

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Allosteric function facilitates template assisted olefin metathesis{
Rie Wakabayashi, Yohei Kubo, Osamu Hirata, Masayuki Takeuchi* and Seiji Shinkai*
Received (in Cambridge, UK) 9th September 2005, Accepted 16th September 2005
First published as an Advance Article on the web 20th October 2005
DOI: 10.1039/b512805f
Template assisted olefin metathesis of an allosteric host 1b to
give the corresponding bicyclic compound 1c was achieved and
1c can allosterically bind the template guest diamines, 2 and 3
with different affinity and cooperativity.
The design of artificial allosteric systems is of great significance to
regulate the complexation ability or the catalytic activity of
artificial receptors in a nonlinear fashion.1,2 Among them, positive
homotropic allosterism is the most attractive but most difficult one
Scheme 1
because the guest binding information in a subunit should be
passed to other all subunits in unison.3,4 We recently designed a
same stabilities by a computational method (Insight II, Discover)
as shown in Scheme 1 and Fig. S1 (ESI{); without the aid of the
allosteric effect, the unfavorable reaction to produce mono-bridged
1b should also proceed. Compound 1c would show different
affinity and cooperativity to guest diamines from those of 1b.
Compound 1b was synthesized according to Scheme 2 and
identified by 1H NMR, MALDI TOF MS spectroscopic evidence
and elemental analysis.{
zinc porphyrin tetramer 1a with a butadiyne axle moiety, where
two pairs of cofacial zinc porphyrin tweezers can bind two
diamines in an allosteric manner and the rotational angle of a
butadiynyl axis can adjust the cleft size to a variety of guest
molecules.5 This cooperativity is ascribed to the favoured spacing
and orientation of the second binding site for the second guest
molecule. In other words, the cofacial zinc porpyrin tweezers in
1a?(diamine)2 complex are arranged at the specific spatial position
by guest diamines. It occurred to us that in 1b the ring closing
olefin metathesis (RCM) reaction to produce new bicyclic host
molecules would efficiently take place in the presence of guest
diamines with the aid of the allosteric function.6,7
The binding of guest diamines, 2,5-diiodo-1,4-bis(N-methylami-
nomethyl)benzene (2) and its bis(2,5-didodecyloxyphenylethynyl)
derivative (3), to 1b was confirmed by UV-vis spectroscopy. Upon
addition of 2 to the solution of 1b (2.00 mM) in chloroform at
25 uC, the Soret band and Q bands of 1b shifted from 429.0, 556.5
and 599.0 nm to longer wavelengths, 432.5, 564.5 and 607.0 nm,
respectively, with clear isosbestic points (Fig. 1). Addition of
compound 3 also resulted in the similar bathochromic shift of the
Soret band and Q bands of 1b. To obtain insights into the binding
mode, the stoichiometry between 1b and guest molecules (2 and 3)
was estimated by a molar ratio method, which clearly supported
formation of 1:2 1b?(2)2 and 1b?(3)2 complex. The plots of
absorbance against [diamine] were firstly analyzed with the Hill
equation (Figs. S2 and S3, ESI{).8 The Hill plots for 2 and 3
provided evidence for the cooperativity as shown by n (Hill
coefficient) 5 1.8 and 1.3, respectively. It is undoubted, therefore,
that the binding to 1b is taking place cooperatively, although the
cooperativity for the binding of 2 is somewhat higher than that for
the binding of 3. We thus analyzed the binding isotherm with a
nonlinear least-squares method assuming the stepwise formation
of 1:1 and 1:2 complexes. The association constants thus obtained
are K1 5 4.7 6 105 M21 and K2 5 3.6 6 105 M21 for 2 and
K1 5 1.4 6 105 M21 and K2 5 3.9 6 104 M21 for 3, which satisfy
the prerequisite for positive homotropic allosterism, K2 . 0.25K1.8
These association constants and Hill coefficients n obtained for 2
and 3 are sufficiently high to apply this system to the template
assisted olefin metathesis.
Here we describe the synthesis, guest-binding properties, and
template assisted olefin metathesis of a porphyrin tetramer 1b
bearing olefinic groups at the peripheral positions. Four zinc
porphyrins are arranged around a butadiynyl rotational axis and
two pairs of cofacial zinc porpyrin clefts are expected to bind two
equivalents of diamine derivatives in an allosteric manner
(Scheme 1).5 Once 1b binds two diamines in its porphyrin clefts
cooperatively, the peripheral two pairs of olefinic moieties, which
are separated by 5.3 nm from one another, are preorganized and
aligned by guest diamines whereby the RCM reaction would occur
efficiently to produce a bicyclic host molecule (1c) (Scheme 1).
Mono-complexed species (A) and (B) were estimated to have the
Department of Chemistry and Biochemistry, Graduate School of
Engineering, Kyushu University, 6-10-1 Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan. E-mail: taketcm@mbox.nc.kyushu-u.ac.jp;
seijitcm@mbox.nc.kyushu-u.ac.jp; Fax: +81-92-802-2820
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b512805f
A chloroform solution of 1b (0.25 mM) was treated with
Hoveyda–Grubbs catalyst 4 (40 mol% with respect to 1b) at 40 uC
under an Ar atmosphere with and without diamines. It was
5742 | Chem. Commun., 2005, 5742–5744
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Scheme 2 Reagents and conditions: (i) 4-acetoxybenzaldehyde, 4-trimethylsilylethynylbenzaldehyde, TFA, DDQ, CH2Cl2, r.t., 4.5 h (19%); (ii) NBS,
pyridine, CHCl3, 0 uC, 40 min (89%); (iii) Zn(OAc)2?2H2O, CHCl3, MeOH, r.t., 35 min (99%); (iv) 4-butoxyphenylboronic acid, Pd(PPh3)4, K3PO4, THF,
reflux, 24 h (40%); (v) CsF, THF, EtOH, r.t., 26 h (99%); (vi) 6-bromo-1-hexene, K2CO3, KI, DMF, 65 uC, 2 h (76%); (vii) 1-(2,5-diiodophenyl)-1-butyn-3-
methyl-3-ol, Pd(PPh3)4, CuI, THF, i-Pr2NH, r.t., 4.5 h (50%); (viii) NaOH, toluene, reflux, 7 h (70%); (ix) Cu(OAc)2, pyridine, 80 uC, 9.5 h (31%).
Fig. 1 (A) UV-vis spectral change of 1b (2.00 mM) upon addition of 2
and (B) plot of absorbance change at 607 nm for 1b vs. [2]. The solid line in
(B) represents a theoretical curve for 1:2 complex formation.
confirmed by a 1H NMR method that in chloroform-d1 no
decomposition of 4 is induced by added 2. In addition, it was also
confirmed by UV-vis spectroscopy that 1b?(diamine)2 complex is
formed quantitatively under the reaction conditions. The time
course of the reaction was monitored by MALDI TOF MS.
During the reaction, a mass peak of m/z 3973.42 ([M + H]+)
decreased gradually, while a new mass peak of m/z 3945.41 ([M +
H]+ 2 28) appeared, followed by another mass peak m/z 3917.55
([M + H]+ 2 56) (Fig. S4, ESI{). The stepwise loss of m/z 28
(ethylene) from 1b ([M + H]+ 5 3973.42) shows that an
Fig. 2 GPC chromatograms for (A) 1b and for the reaction mixture of
the RCM reaction under the conditions of (B) 1b without 2, (C) 1b + 1.1
equivalent of 2, (D) 1b + 2.4 equivalents of 2.
intramolecular RCM reaction took place to afford a bicyclic host
molecule 1c. The reaction was terminated after 24 h and the
reaction mixture was analyzed and separated by GPC (JAIGEL
as we expected, the percentage of a main product 1c significantly
increased up to ca. 50% (with 1.1 equivalent of 2) and ca. 70% yield
(with 2.4 equivalents of 2) as estimated by the area ratio in GPC
chromatogram (Fig. 2(C) and (D)).
2H-40 and JAIGEL 1H-40, chloroform: Fig. 2). The bicyclic
compound 1c (25%, retention time 51.5 min) as a mixture of E and
Z isomers (E/Z 5 1:3), mono-bridged 1b along with a small
amount of unreacted 1b (49.5 min), and inseparable mixtures
(45.5 min) were isolated by this GPC method. The difference in
retention time of 2.0 min between 1c and 1b was probably due to
the smaller exclusion volume of 1c. Further addition of 4 to a
reaction mixture did not cause any change in the ratio of mono-
bridged 1b and 1c, indicating that the remaining mono-bridged 1b
should be an alternately bridged compound, in which the second
ring closure is sterically impossible (Scheme 1). In the presence of
the template molecule 2 (1.1 and 2.4 equivalents with respect to 1),
When compound 3 (4.0 equivalents with respect to 1b) was used
as a template molecule, the RCM reaction of 1b would proceed
straightforward to produce a double-pseudorotaxane 1c?(3)2 due
to the four bulky dodecyl groups. After 48 h, the reaction mixture
was monitored by UV-vis spectroscopy and MALDI TOF MS. It
was found that 80% of porphyrinatozinc in 1c was still complexed
with 3 by UV-vis spectroscopy. We tried to isolate 1c?(3)2
complex by size exclusion chromatography (SEC; Bio-beads
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(m, 12H), 2.02 (m, 4H), 2.26 (m, 8H), 3.96 (t, J 5 6.2, 8H), 4.15 (t, J 5 6.2,
4H), 4.24 (t, J 5 6.3, 8H), 4.28 (t, J 5 6.3, 4H), 5.06 (d, J 5 5.7, 4H), 5.13
(dd, J 5 16.7, 6.7, 4H), 5.94 (m, 4H), 7.04 (d, J 5 8.3, 8H), 7.07 (d, J 5 7.9,
4H), 7.24 (d, 8H), 7.28 (d, J 5 8.5, 4H), 7.59 (d, J 5 7.6, 2H), 7.65 (d,
J 5 9.3, 2H), 7.66 (d, J 5 8.0, 4H), 7.86 (d, 4H), 7.91 (d, 4H), 7.97 (s, 2H),
8.00 (d, J 5 7.9, 8H), 8.07 (d, J 5 7.9, 8H), 8.11 (d, J 5 8.0, 4H), 8.14 (d,
J 5 7.7, 4H), 8.31 (d, J 5 7.2, 4H), 8.74–8.98 (m, 32H). MALDI TOF MS
[dithranol] m/z calc. for [M + H]+ 5 3973.14, found 3973.42. Anal. Calc. for
SX-1, chloroform). The first fraction, which was identified to be
1c?(3)2, was isolated by SEC. The UV-vis spectrum indicated that
this fraction contains 1c and 3 in a ratio of 1.0:1.8, whereas the
second and the third fractions contains 1c and 3, respectively. The
emission spectrum (lex 5 390 nm) of the first fraction showed that
the emission from 3 (lem 5 429 nm) was quenched by 1c due to
efficient energy transfer from 3 to 1c within the complex, because
the emission wavelength of 3 considerably overlaps with the Soret
band of 1c.
C
256H218N16O12Zn4?2H2O: C, 76.71; H, 5.58; N, 5.59. Found: C, 76.40; H,
5.72; N, 5.45%.
1 For reviews on artificial allosteric systems: (a) L. Kovbasyuk and
R. Kra¨mer, Chem. Rev., 2004, 104, 3161; (b) M. Takeuchi, M. Ikeda,
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The resulting bicyclic compound 1c possessing preorganized and
aligned two cavities should be the host molecule possessing
different affinities with 2 and with 3. Compound 1c was titrated
with 2 and 3 in chloroform by UV-vis spectroscopy. The same
bathochromic shifts in the Soret and Q bands were observed as
those for 1b with 2 or 3. The association constants for 1c with 2
and 3 were estimated by a nonlinear least-squares method to be
K1 5 2.2 6 106 M21 and K2 5 9.0 6 105 M21 for 2 and K1 5
6.2 6 104 M21 and K2 5 1.8 6 104 M21 for 3, respectively (Figs.
S5 and S6, ESI{). Furthermore, Hill coefficients n obtained for 2
and 3 with 1c were both 1.4, indicating that 1c can cooperatively
bind diamines, although a degree of cooperativity is not so high.
The loss of the rotational freedom in the butadynyl axis from 1b by
the RCM reaction resulted in higher affinities with smaller n in the
case of 2 and in lower affinities with almost the same n in the case
of 3. It is known in the MWC model for positive homotropic
allosterism that a degree of cooperativity n is correlated with L
value, where L is [T (an unbound conformation)]/[R (a bound
conformation)] and a higher L value results in a higher n value.3c
The lower n for 1c with 2 would be ascribed to the lower L value
because the binding sites in 1c are already preorganized.
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In conclusion, we have demonstrated that allosteric function of
1b facilitates template assisted olefin metathesis and the resulting
1c can still cooperatively bind the template guest diamines, 2 and 3.
Additionally, the guest molecule 2, which is rationally arranged
around the rotational axis in 1c (2.5 nm apart from each other),
would act as a monomer for polymerization to produce poly-
rotaxanes. These studies are now in progress in our group.
We thank Ms Satsuki Kanae at Kyushu University for 1H
NMR measurements. The present work is partially supported by a
Grant-in-Aid for Scientific Research B (17350071) and the 21st
Century COE Program, ‘‘Functional Innovation of Molecular
Informatics’’ from the Ministry of Education, Culture, Science,
Sports and Technology of Japan.
Notes and references
{ 1H NMR (600 MHz, CDCl3, d/ppm, J/Hz); d 0.98 (t, J 5 7.3 Hz, 12H),
1.10 (t, J 5 7.4 Hz, 12H), 1.50 (m, 8H), 1.66 (m, 8H), 1.75 (m, 16H), 1.97
8 (a) B. Perlmutter-Hayman, Acc. Chem. Res., 1986, 19, 90; (b)
K. A. Connors, Binding Constants, John Wiley & Sons, New York,
1987.
5744 | Chem. Commun., 2005, 5742–5744
This journal is ß The Royal Society of Chemistry 2005