An enantiopure cyclophane-type imidazole with no central but planar chirality

Article abstract of DOI:10.1039/b904059e

An enantiopure cyclophane-type imidazole with planar chirality was synthesized, which was expected to serve as a useful component for the development of novel chiral molecular devices, such as ligands, organocatalysts, and receptors.

Full text of DOI:10.1039/b904059e

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An enantiopure cyclophane-type imidazole with no central but planar
chiralityw
Yasuhiro Ishida,* Eriko Iwasa, Yuki Matsuoka, Hiroyuki Miyauchi and Kazuhiko Saigo*
Received (in Cambridge, UK) 26th February 2009, Accepted 26th March 2009
First published as an Advance Article on the web 27th April 2009
DOI: 10.1039/b904059e
An enantiopure cyclophane-type imidazole with planar chirality
was synthesized, which was expected to serve as a useful
component for the development of novel chiral molecular devices,
such as ligands, organocatalysts, and receptors.
shorter bridge seems to be favorable, and therefore, we
targeted a cyclophane-type imidazole with a decamethylene
bridge (Scheme 1, 1a).
For the preparation of such a cyclophane-type imidazole,
two synthetic routes are possible, as illustrated in Scheme 1.10
In the first route, two o-alkenyl substituents are introduced at
the C(2) and C(5) positions of 1-methylimidazole and then
connected by the ring-closing metathesis (Route A), while the
second route includes the transformation of a macrocyclic
ketone into an o-hydroxymethyl lactam, followed by the half-
oxidation of the hydroxy group and subsequent condensation
of the formyl and amido groups with ammonia to form an
imidazole ring (Route B). Although Route A seems to be more
Among the family of heteroaromatics, imidazoles are one of
the most extensively investigated classes.1 Owing to their
unique properties including basicity, nucleophilicity, and
coordination ability, imidazoles have found various applica-
tions. To date, imidazoles with wide structural diversity have
become available. Among them, optically active imidazoles
are of exceptional interest, which would provide useful chiral
materials such as reagents, catalysts, receptors, etc. In fact, a
number of chiral imidazoles are known to work as organo-
catalysts with an excellent chirality-induction ability, as repre-
sented by catalysts for acyl transfer reactions (A, B and E),
conjugated additions (A and D), and cyanohydrin formation
(C and D) (Fig. 1).2–6
straightforward, our previous study revealed
a serious
problem in the macrocycle formation; when 2,5-bis(5-hexenyl)-
1-methylimidazole (3) was employed as a substrate of the
olefin metathesis, an intermolecular reaction proceeded
exclusively to afford a mixture of undesired oligomers even
under highly diluted conditions.9b As a result, this strategy was
found to be applicable only to the formation of cyclophane-
type imidazoles with a bridge longer than an undecamethylene
chain. Therefore, in this study, we adopted the route starting
from a commercially available macrocycle (Route B), which is
expected to be free of such limitation.
For the design of imidazole-based chiral organocatalysts,
the most widely adopted approach is to introduce chiral
substituent(s) to an imidazole core. However, such a strategy
in design usually leads to imidazoles with complicated struc-
ture and/or chemically labile bond(s) (A–E). An alternative
approach is to create imidazoles with ‘topological chirality’,
such as axial, helical or planar chirality. In these cases, a well-
defined dissymmetric structure may be constructed by using
only robust units. Particularly, imidazoles with prochiral faces
should be easily derived into planarly chiral molecules by the
differentiation of the two faces from each other.7 Indeed, a
similar strategy was successfully applied in the cases of other
heteroaromatics such as pyridines8 and imidazoliums.9 At
present, however, such a promising and simple strategy has
not been applied to the synthesis of chiral imidazoles, despite
the potential utility of these species. Such aspects prompted us
to develop novel enantiopure cyclophane-type imidazoles with
planar chirality (F), of which the C(2) and C(5) positions are
bridged by a linker with suitable length. To make full use of
benefits brought by a characteristic cyclophane structure, a
Through Route B, the target imidazole 1a with a cyclophane-
type structure was successfully prepared as follows. Cyclodo-
decanone (5) was readily converted into the keto ester 6 by
the classical Claisen condensation.11 The keto ester 6 thus
obtained was then subjected to ring-expansion by the Schmidt
Department of Chemistry and Biotechnology, Graduate School of
Engineering, The University of Tokyo, Hongo, Bunkyo-ku,
113-8656 Tokyo, Japan. E-mail: ishida@chiral.t.u-tokyo.ac.jp;
Fax: 81 3 5802 3348; Tel: 81 3 5841 7268
w Electronic supplementary information (ESI) available: Experimental
procedures for the synthesis of 1a–d, 7, and 8, X-ray crystal structure
of (S)-1aꢀ(+)-10-camphorsulfonic acid and kinetic resolution of
1-phenylethanol catalyzed by (R)-1a. CCDC 722153. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b904059e
Fig.
1 Selected examples of chiral organocatalysts based on
imidazole.
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to the imidazole C(2)/C(5) split into complicated multiplets,
most likely due to inequivalence of the geminal protons
(Fig. 2(a), indicated with an open circle).9a,b As we expected,
difference in the length of the bridge was a critical factor for
the conformational fixation of the cyclophane-type imidazole;
in the case of the analogous imidazole 9 possessing a longer
bridge, the corresponding bridge-center methylene proton did
not experience the shielding effect from the imidazole ring
current, most likely due to the flexibility of the bridge moiety
(Fig. 2(b)).
Given the fixation of the decamethylene bridge overlaid on
either of the two faces of the imidazole ring, the present
imidazole 1a should exist as a pair of enantiomers in regard
to planar chirality.7 Fortunately, racemic 1a could be easily
resolved into a pair of enantiomers by chiral HPLC on a Dicel
Chiralcel OD-H (Fig. 3(a)). When a semi-preparative column
with the same stationary phase was used, no less than 0.5 g of
the racemate could be perfectly resolved in each injection,
owing to an excellent resolution efficiency (Fig. 3(a), separa-
tion factor a = 3.04). As might be expected, the circular
dichroism (CD) spectra of the enantiomers thus obtained were
mirror images of each other (Fig. 3(b)). Of note is that a
relatively strong Cotton effect was observed for the enantiomers
of 1a, in spite of its simple structure composed of a chromo-
phore (imidazole ring) and an aliphatic chain. The absolute
configuration of the first-eluted isomer ((ꢂ)CD-1a) was
determined unambiguously; (ꢂ)CD-1a was derived into the
salt with (+)-10-camphorsulfonic acid, and the single
crystal of the salt was analyzed by an X-ray crystallographic
study.z As a result, (ꢂ)CD-1a was identified as the S isomer
(Fig. 3(c)).
Scheme 1 Synthesis of the cyclophane-type imidazole 1a.
rearrangement to give the 13-membered lactam 7 bearing an
ethoxycarbonyl group.12 After the N-methylation of the amido
group, the ester moiety was reduced into a hydroxymethyl
group to afford the hydroxymethylated lactam 8. Fortunately,
the Swern oxidation of the hydroxy group of 8 proceeded
smoothly, and subsequent cyclo-condensation of the formylated
lactam with ammonia gave the target imidazole 1a with
a cyclophane-type structure.10a,13 Throughout the synthesis,
neither expensive materials nor special reaction conditions
were required, which allowed us to prepare the cyclophane-
type imidazole 1a in a multi-gram scale.
The 1H NMR spectrum of 1a showed the intriguing
structure characteristic of cyclophane-type compounds. A
resonance attributable to an aliphatic proton at the middle
of the decamethylene chain was observed at an exceptionally
upfield-shifted region, which clearly indicates that the deca-
methylene bridge overlays on the imidazole ring and experi-
ences a shielding effect by the aromatic heterocycle (Fig. 2(a),
indicated with a filled circle).9a,b As an additional evidence for
such an overlaid structure, the signals of methylenes adjacent
In the next stage, the dynamic behavior of the planarly
chiral imidazole 1a was investigated. Generally, planarly chiral
cyclophanes such as 1a, composed of a prochiral planar unit
Fig. 3 (a) Chiral HPLC trace of 1a. Column, Daicel Chiralcel OD-H
(4 ꢃ 250 mm); eluent, hexane–2-propanol = 90 : 10 (v/v). (b) Circular
dichroism spectra of (R)- and (S)-1a in H2O. (c) X-Ray crystal
structure of the salt of (S)-1a with (+)-10-camphorsulfonic acid.
Fig. 2 1H NMR spectra of the cyclophane-type imidazoles 1a and 9.
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catalysts capable of the efficient kinetic resolution of racemic
alcohols has remained as a challenging target. Therefore, the
acylation of racemic 1-phenylethanol was conducted in the
presence of (R)-1a, and a moderate but encouraging kinetic
resolution was observed (at 61% conversion, eealcohol = 50%
and eeester = 32%, s = 3.1). Although the selectivity was not
at an optimal level, it is worth noting that the present
selectivity was achieved by an imidazole catalyst with an
extremely simple structure, having no bulky substituent(s),
asymmetric carbon(s), nor polar functional group(s).
In conclusion, an enantiopure cyclophane-type imidazole
with planar chirality (1a) was efficiently synthesized from an
inexpensive macrocycle 5. As far as we know, 1a is a quite rare
example of an enantiopure imidazole possessing no stereo-
genic center. Considering its well-defined dissymmetric struc-
ture, modifiability at the imidazole N(1)/N(3)/C(4) positions,
and potential utility of the imidazole group, the present
imidazole would be a powerful component for the develop-
ment of chiral molecular devices, such as receptors, catalysts
and ligands.
Scheme 2 Modification of the cyclophane-type imidazole 1a at C(4).
and a bridge unit, can invert their chirality via the rope-
skipping motion of the bridge through the plane.7 Because
such a molecular motion corresponds to racemization, the
estimation of the energy barrier for the rope-skipping motion
is quite important, especially from the viewpoint of the
application of 1 as an optically active material. Therefore,
enantiopure (S)-1a, obtained by the above procedure, was
subjected to extensively heated conditions, and the time course
of the enantiomeric ratio was monitored. As a result, 1a was
proved to be highly tolerant toward heat; after being heated
for 5 h in refluxing o-xylene (144 1C), no detectable loss in the
enantiomeric purity was observed. According to the crystal
structure of 1a, the decamethylene bridge seems to be too
short to go through the imidazole ring at both of the N(1) and
N(3)/C(4) sides.9a,b
Notes and references
z Crystallographic data for (S)-1aꢀ(+)-10-camphorsulfonic acid
(C24H40N2O4S): monoclinic, space group C2, a = 23.772(3), b =
4.7346(13), c = 30.466(5) A, b = 112.7064(18)1, Z = 16, R = 0.0481.
1 M. R. Grimmett, in Comprehensive Heterocyclic Chemistry, ed.
A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon,
Oxford, 1984, vol. 5, p. 77.
2 S. J. Miller, Acc. Chem. Res., 2004, 37, 601.
3 K. Ishihara, Y. Kosugi and M. Akakura, J. Am. Chem. Soc., 2004,
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2006, 443, 67.
5 S. B. Tsogoeva, D. A. Yalalov, M. J. Hateley and C. Weckbecker,
Eur. J. Org. Chem., 2005, 4995.
Thus, a highly efficient method for the synthesis of an
enantiopure cyclophane-type imidazole with planar chirality
((R)- and (S)-1) was established. For the further facile
modification of 1a, the introduction of various functional
groups at the C(4) position was investigated, as illustrated in
Scheme 2. According to an established procedure, the proton
at the C(5) position of racemic 1a was substituted with
bromine by treatment with N-bromosuccinimide to give the
brominated cyclophane-type imidazole 1b.14 As we expected,
the formylated imidazole 1c was successfully obtained from 1b
by successive treatment with butyllithium and N,N-dimethyl-
formamide.15 Since a formyl group can be derived into various
functional groups in general, 1c is also expected to be a
versatile building block for planarly chiral imidazoles. More-
over, phenylated imidazole 1d could be also obtained by the
Suzuki–Miyaura coupling of the brominated imidazole 1b
with phenylboronic acid.16
6 J. Oku and S. Inoue, J. Chem. Soc., Chem. Commun., 1981,
229.
7 S. Grimme, J. Harren, A. Sobanski and F. Vogtle, Eur. J. Org.
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¨
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2003, 658; (d) G. C. Fu, Acc. Chem. Res., 2004, 37, 542.
9 (a) Y. Ishida, D. Sasaki, H. Miyauchi and K. Saigo, Tetrahedron
Lett., 2006, 47, 7973; (b) Y. Ishida, H. Miyauchi and K. Saigo,
Heterocycles, 2005, 66, 263; (c) A. Furstner, M. Alcarazo,
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H. Krause and C. W. Lehmann, J. Am. Chem. Soc., 2007, 129,
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Chem.–Eur. J., 2008, 14, 9215.
10 For selected examples of cyclophane-type azoles with a C(2)–C(4/5)-
bridged structure, see: (a) E. B. Beccalli, L. Majori, A. Marchesini
and C. Torricelli, Chem. Lett., 1980, 659; (b) A. G. J. Commeureuc,
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2006, 1741.
As a preliminary study to prove the utility of these
imidazoles, we applied (R)-1a as an acyl transfer catalyst
(Scheme 3).2–4 Indeed, the development of chiral acyl-transfer
11 J. A. Marshall and V. H. Audia, J. Org. Chem., 1987, 52,
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12 L. J. MacPherson, E. K. Bayburt, M. P. Capparelli, R. S. Bohacek,
F. H. Clarke, R. D. Ghai, Y. Sakane, C. J. Berry, J. V. Peppard
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15 H. Yashioka, T. Choshi, E. Sugino and S. Hibino, Heterocycles,
1995, 41, 161.
16 V. Cerezo, A. Afonso, M. Planas and L. Feliu, Tetrahedron, 2007,
63, 10445.
Scheme 3 Kinetic resolution of 1-phenylethanol catalyzed by (R)-1a.
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