Synthesis of a Chiral [2]Rotaxane: Induction of a Helical Structure through Double Threading

Article abstract of DOI:10.1021/acs.orglett.8b01727

A helically chiral [2]rotaxane featuring two ammonium ion recognition sites in the dumbbell-like component and a calix-bis-crown ether as the macrocyclic component was synthesized, but with no chirality in either individual component. The enantiomeric nat

Full text of DOI:10.1021/acs.orglett.8b01727

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of a Chiral [2]Rotaxane: Induction of a Helical Structure
through Double Threading
Toshihiro Tsukamoto,† Ryota Sasahara,† Atsuya Muranaka,*,‡ Yuzuki Miura,§ Yu Suzuki,∥
Masaki Kimura,† Shinobu Miyagawa,† Tsuneomi Kawasaki,⊥ Nagao Kobayashi,*,#
Masanobu Uchiyama,§,‡ and Yuji Tokunaga*,†
†Department of Materials Science and Engineering, Faculty of Engineering, Fukui University, Bunkyo, Fukui 910-8507, Japan
‡Elements Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
§Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
∥Tenure-Track Program for Innovative Research, University of Fukui, Bunkyo, Fukui 910-8507, Japan
⊥Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
#Faculty of Textile Science and Technology, Shinshu University, Tokida, Ueda, Nagano 386-8567, Japan
S
* Supporting Information
ABSTRACT: A helically chiral [2]rotaxane featuring two ammonium ion recognition sites in the dumbbell-like component and
a calix-bis-crown ether as the macrocyclic component was synthesized, but with no chirality in either individual component. The
enantiomeric nature of the isomers, separated through chiral HPLC, was apparent in their CD spectra, which were mirror
images for all wavelengths.
axle-shaped and macrocyclic components; here, the chirality
he harmonious conjunction of mathematics and chem-
Tistry can create fascinating structures, for example, when arises from two rotaxane subunits being present in the
interlocked molecule.11,12
using organic and inorganic species as components in
stereochemically interesting interlocked molecules.1,2 Studying
Recently, we reported the formation of pseudo[3]rotaxanes
from the calix-bis-crown ether 1 and two secondary
ammonium ions.13 The two crown ether-like macrocycles in
1, each connected to the rigid calix[4]arene core in a 1,3-
alternate conformation, are positioned relatively perpendicu-
larly. If a 1:1 complex were to form between the calix-bis-
crown ether 1 and a symmetrical linear bis-ammonium ion 2,
the bis-ammonium ion would by necessity adopt a helical
and, therefore, chiralconformation in the pseudo[2]-
rotaxane, even though the individual components lack chirality
themselves (Figure 1). We have used this approach, by way of
intramolecular two-place interlocking, to synthesize a new type
of chiral rotaxane.
We synthesized the bis-ammonium salts 2a−c, differing only
by the length of the spacer between the two ammonium
centers, to examine their ability to construct 1:1 complexes
with the bis-crown ether 1 (Supporting Information). 1H
NMR spectra of mixtures of each bis-ammonium salt 2 (10
mM) and the bis-crown ether 1 (10 mM) revealed the
formation of pseudo[n]rotaxanes (Figures 2 and 3 and the S1);
the chirality of interlocked molecules is a particularly appealing
aspect of supramolecular chemistry.3 Molecular asymmetry
resulting from a rotaxane structure has been paid much
attention, but examples of such stereochemical constructs
remain rare.
̈
The Vogtle group has isolated mechanically planar-chiral
rotaxanes (cycloenantiomeric rotaxanes) comprising both
achiral axle and macrocyclic components.4 These types of
chiral rotaxanes have been exploited in the chiral sensing of
amino acid derivatives,5 and further studies have led to more
efficient syntheses of such chiral rotaxanes.6−8 In addition, the
Ogoshi group reported the synthesis of a chiral rotaxane
featuring a pillar[5]arene derivative containing one π-
conjugated unit as a planar-chiral motif.9 Furthermore, the
Leigh group has synthesized another type of chiral rotaxane
based on the positional difference of the macrocyclic
component on the axle-shaped component;10 although these
individual components were highly symmetrical, restraining
the movement of the macrocyclic component through
acylation of a prochiral OH group produced both enantiomers
in a selective manner. In this present paper, we report the
synthesis of a new type of chiral [2]rotaxane from symmetrical
Received: June 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01727
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
similar functional groups around their ammonium centers,
these values suggest that the bis-ammonium salt 2b was most
likely to form a 1:1 complex with 1. Moreover, two equally
integrated triplets, assignable to protons HM in the pseudo[2]-
rotaxane 3b, were evident at 6.21 and 6.42 ppm (Figure 3c),
consistent with formation of a pseudo[2]rotaxane that breaks
the symmetry of the macrocyclic component (from D2
symmetry to C2 symmetry), confirming that 2b has a suitable
spacer allowing its 1:1 complexation with the bis-crown ether
1.
Next, we performed variable-concentration NMR spectros-
copy of mixtures of 1 and 2b (Figure S2). The two triplets at
6.21 and 6.42 ppm, corresponding to protons HM in the
pseudo[2]rotaxane 3b, were evident in all spectra, consistent
with a relatively strong complex, in which the second threading
event proceeds intramolecularly. Diffusion-ordered NMR
spectroscopy (DOSY) confirmed the structure of the 1:1
complex (Figure S3). Plots of the signal intensities with respect
to the gradient strength gave straight lines; the slopes of these
lines for the signals of the complex gave the same number and
provided a diffusion coefficient (ca. 5.0 × 10−10 m2/s) smaller
than those of both original components.
Figure 1. Schematic representation of the mirror-image helically
chiral (pseudo)[2]rotaxanes 3 formed from the calix-bis-crown ether
1 and a bis-ammonium ion 2.
We examined the synthesis of a [2]rotaxane from the bis-
crown ether 1 and the ammonium salt 2d, featuring the same
spacer as that in 2b, using ester formation as a means of end-
capping (Scheme 1).14 We treated a mixture of 1 and 2d in an
Figure 2. Structures of the calix-bis-crown ether 1 and the bis-
ammonium salts 2.
Scheme 1. Synthesis of the Rotaxane 3d and Numbering of
Its Atoms
aprotic solvent with diphenyldiazomethane, affording the
[2]rotaxane 3d in its doubly protonated form; the mass
spectrum (Figure S10) featured a peak at m/z 1830,
corresponding to the species having lost a HPF6 unit and a
1
Figure 3. Partial H NMR spectra (600 MHz; CDCl3/CD3CN, 3:2,
25 °C) of the bis-crown ether 1 (10 mM) and bis-ammonium salts 2
(10 mM): (a) isolated 2b (2.1−2.5 ppm) and 1 (6.1−6.8 ppm); (b) a
mixture of 1 and 2a; (c) a mixture of 1 and 2b; (d) a mixture of 1 and
2c.
PF6 counterion ([M − HPF6 − PF6]+). NMR spectra were
consistent with the C2-symmetric structure of the [2]rotaxane
3d (Figure 4); for example, all of the signals of the aromatic
protons of the calixarene component were split in two (HM:
6.11; HM*: 6.49 ppm) or four (HN*: 6.72; HN: 6.79; HL: 6.82;
HL*: 6.86 ppm), and four sets of signals for the ethylene glycol
protons (HF and HG) were observed in the 1H NMR spectrum,
while the 13C NMR spectrum featured two or four sets of
signals for the aromatic carbon nuclei of the calixarene moiety
−
−
for example, characteristic upfield-shifted signals were evident
for the hydrogen atoms of the ethylene glycol chains of the bis-
crown ether. Consistent with previous results,13 the signal of
the methyl protons of each dumbbell-shaped component
shifted downfield (from ca. 2.27 to ca. 2.37 ppm) upon
encapsulation within the crown ether. Through integration of
the signal of the methyl protons in the NMR spectrum of each
mixture, we calculated the ratios of pseudorotaxane formation
for the bis-ammonium salts 2a−c to be 36, 59, and 40%,
respectively. Because the bis-ammonium salts 2a−c have
(two sets: CO*, 155.9/CO, 156.0 ppm; CHM, 122.1/CHM*
,
122.6 ppm; four sets: Cp, 133.4, 133.5, 133.7, and 133.8 ppm)
and 12 signals for the carbon nuclei of the ethylene glycol
moieties (CHA−G, though 14 signals should be observed
theoretically, two of the signals appeared to overlap) (Figure
B
DOI: 10.1021/acs.orglett.8b01727
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
rotaxane 3d was a mirror image of the other with respect to the
x-axis and corresponded to the absorption spectrum,
confirming the purity of the two separated enantiomers.
Judging from the intensity of the signals, these CD spectra
appear to have been produced by coupling of a plural number
of chromophores.15 Considering the chiral structure of the
helical axle component of the rotaxane 3d, the two end groups
(benzoate moieties) may have been responsible for the signals
in the CD spectra; nevertheless, the electronic coupling
between the end groups would be small because of relatively
large distance between them, because CD intensity decreases
in proportion to the cube of the interdistance.15 Work is in
hand to assign the absolute configuration of the enantiomers
through calculation of the CD spectra and comparison with the
observed data.
In summary, we have demonstrated the generation of a
chirality, which is based on helical stereogenic element in the
[2]rotaxane though double threading. At first, we have found a
matching bis-ammonium salt for the calix-bis-crown ether 1
that allows the formation of a corresponding pseudo[2]-
rotaxane. Using this recognition system, we applied an ester
capping methodology to synthesize a corresponding chiral
[2]rotaxane (3d) as a racemate, even though both of its
components are achiral in their isolated forms. After separation
of the enantiomers of 3d through chiral HPLC, the two CD
spectra were mirror images over the entire region of
wavelengths.
1
Figure 4. Partial H NMR spectra (600 MHz, CDCl3, 25 °C) of (a)
the calix-bis-crown ether 1 and (b) the rotaxane 3d.
S4). The identities of the nuclei of 3d responsible for these
signals were determined through 2D NMR spectroscopy
(Figures S5−S8).
We subjected the rotaxane 3d to separation through
enantioselective high-performance liquid chromatography
(HPLC) using CHIRALPAK ZWIX(+) as the stationary
phase (Figure S9). The HPLC chromatogram of the rotaxane
3d featured two peaks of equal area, as expected for a 1:1
mixture of its two enantiomers. After separation of these
enantiomers through the chiral column [shorter retention time
(Fr1): 94% ee; longer retention time (Fr2): 95% ee], we
recorded their circular dichroism (CD) spectra.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01727.
Experimental details; NMR spectroscopic titration
experiments of 1 and 2; details of the DOSY
experiments; 2D NMR and MALDI-TOF mass spectra
of the rotaxane 3d; HPLC analysis; characterization data
(PDF)
Figure 5 presents the electronic absorption and CD spectra
of each separated enantiomer of the rotaxane 3d in acetonitrile.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: atsuya-muranaka@riken.jp.
*E-mail: nagaok@shinshu-u.ac.jp.
*E-mail: tokunaga@u-fukui.ac.jp.
ORCID
Atsuya Muranaka: 0000-0002-3246-6003
Tsuneomi Kawasaki: 0000-0002-6332-2096
Masanobu Uchiyama: 0000-0001-6385-5944
Yuji Tokunaga: 0000-0002-4183-7320
Notes
The authors declare no competing financial interest.
Figure 5. CD spectra (CH3CN) of the separated enantiomers of the
[2]rotaxane 3d. Fr1: 94% ee; Fr2: 95% ee.
ACKNOWLEDGMENTS
We thank the Daicel Corp. for supporting the HPLC analysis.
■
In the electronic absorption spectrum, a weak broad
absorption appeared in the region 260−310 nm, with a more
intense absorption in the region 210−250 nm. The rotaxane
3d contains several types of phenyl groups capable of acting as
chromophores. The CD spectrum of each fraction of the
REFERENCES
■
(1) For selected reviews and examples on stereochemical concepts
related to interlocked molecules, see: (a) Wasserman, E.; Frisch, H. L.
J. Am. Chem. Soc. 1961, 83, 3789−3795. (b) Walba, D. M.
Tetrahedron 1985, 41, 3161−3212. (c) Wasserman, E. Chemical
C
DOI: 10.1021/acs.orglett.8b01727
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Topology: Statistical Musings. In Molecular Catenanes, Rotaxanes and
Knots; Sauvage, J.-P., Dietrich-Buchecker, C., Eds.; Wiley-VCH:
Weinheim, 1999; pp 1−6. (d) Flapan, E. A Knot Theoretic Approach
to Molecular Chirality. In Molecular Catenanes, Rotaxanes and Knots;
Sauvage, J.-P., Dietrich-Buchecker, C., Eds.; Wiley-VCH: Weinheim,
(11) For the helical structure of m-ethynylpyridine oligomers
stabilized through the mechanical bonding of [3]rotaxane moieties
to the side chains in the oligomeric structure, see: Hirokane, S.;
Takashima, S.; Abe, H.; Inouye, M. Eur. J. Org. Chem. 2017, 2017,
726−733.
(12) The similar induction of chirality on handcuff catenene was
discussed; see: Hartlieb, K. J.; Blackburn, A. K.; Schneebeli, S. T.;
Forgan, R. S.; Sarjeant, A. A.; Stern, C. L.; Cao, D.; Stoddart, J. F.
Chem. Sci. 2014, 5, 90−100.
(13) Tokunaga, Y.; Hayakawa, K.; Miyashita, J.; Kawasaki, T.;
Miyagawa, S. Tetrahedron Lett. 2013, 54, 6829−6833.
(14) Tokunaga, Y.; Kakuchi, S.; Akasaka, K.; Nishikawa, N.;
Shimomura, Y.; Isa, K.; Seo, T. Chem. Lett. 2002, 31, 810−811.
(15) Kobayashi, N.; Muranaka, A.; Mack, J. Circular Dichroism and
Magnetic Circular Dichroism Spectroscopy for Organic Chemists; The
Royal Society of Chemistry: London, 2012.
̈
1999; pp 7−35. (e) Lukin, O.; Godt, A.; Vogtle, F. Chem. - Eur. J.
2004, 10, 1878−1883. (f) Molokanova, O.; Bogdan, A.; Vysotsky, M.
̈
O.; Bolte, M.; Ikai, T.; Okamoto, Y.; Bohmer, V. Chem. - Eur. J. 2007,
13, 6157−6170. (g) Castle, T.; Evans, M. E.; Hyde, S. T. New J. Chem.
2008, 32, 1484−1492. (h) Amabilino, D. B.; Perez-Garcia, L. Chem.
Soc. Rev. 2009, 38, 1562−1571. (i) Beves, J. E.; Blight, B. A.;
Campbell, C. J.; Leigh, D. A.; McBurney, R. T. Angew. Chem., Int. Ed.
2011, 50, 9260−9327. (j) Forgan, R. S.; Sauvage, J.-P.; Stoddart, J. F.
Chem. Rev. 2011, 111, 5434−5464. (k) Ayme, J.-F.; Beves, J. E.;
Campbell, C. J.; Leigh, D. A. Chem. Soc. Rev. 2013, 42, 1700−1712.
(l) Lim, N. C. H.; Jackson, S. E. J. Phys.: Condens. Matter 2015, 27,
354101. (m) Horner, K. E.; Miller, M. A.; Steed, J. W.; Sutcliffe, P. M.
Chem. Soc. Rev. 2016, 45, 6432−6448. (n) Liu, Y.; O’Keeffe, M.;
Treacy, M. M. J.; Yaghi, O. M. Chem. Soc. Rev. 2018, 47, 4642−4664.
(o) Jamieson, E. M. G.; Modicom, F.; Goldup, S. M. Chem. Soc. Rev.
2018, 47, 5266−5311.
(2) For selected examples of stereochemical concepts related to
interlocked molecules, see: (a) Dietrich-Buchecker, C. O.; Sauvage, J.-
P. Angew. Chem., Int. Ed. Engl. 1989, 28, 189−192. (b) Yamada, S. J.
Graph Theory 1989, 13, 537−551. (c) Nierengarten, J.-F.; Dietrich-
Buchecker, C. O.; Sauvage, J.-P. J. Am. Chem. Soc. 1994, 116, 375−
376. (d) Carina, R. F.; Dietrich-Buchecker, C.; Sauvage, J.-P. J. Am.
Chem. Soc. 1996, 118, 9110−9116. (e) Chichak, K. S.; Cantrill, S. J.;
Pease, A. R.; Chiu, S.; Cave, G. W. V.; Atwood, J. L.; Stoddart, J. F.
Science 2004, 304, 1308−1312. (f) Ronson, T. K.; Fisher, J.; Harding,
L. P.; Rizkallah, P. J.; Warren, J. E.; Hardie, M. J. Nat. Chem. 2009, 1,
212−216. (g) Li, F.; Clegg, J. K.; Lindoy, L. F.; Macquart, R. B.;
Meehan, G. V. Nat. Commun. 2011, 2, 205. (h) Arias, K. I.; Zysman-
Colman, E.; Loren, J. C.; Linden, A.; Siegel, J. S. Chem. Commun.
2011, 47, 9588−9590. (i) Ayme, J.-F.; Beves, J. E.; Leigh, D. A.;
McBurney, R. T.; Rissanen, K.; Schultz, D. Nat. Chem. 2012, 4, 15−
20. (j) Ponnuswamy, N.; Cougnon, F. B. L.; Clough, J. M.; Pantos,̧ G.
D.; Sanders, J. K. M. Science 2012, 338, 783−785. (k) Leigh, D. A.;
Pritchard, R. G.; Stephens, A. J. Nat. Chem. 2014, 6, 978−982.
(l) Lincheneau, C.; Jean-Denis, B.; Gunnlaugsson, T. Chem. Commun.
2014, 50, 2857−2860. (m) Ponnuswamy, N.; Cougnon, F. B. L.;
Pantos,̧ G. D.; Sanders, J. K. M. J. Am. Chem. Soc. 2014, 136, 8243−
8251. (n) Marcos, V.; Stephens, A. J.; Jaramillo-Garcia, J.;
Nussbaumer, A. L.; Woltering, S. L.; Valero, A.; Lemonnier, J.-F.;
Vitorica-Yrezabal, I. J.; Leigh, D. A. Science 2016, 352, 1555−1559.
(3) For selected reviews and examples of chiral rotaxanes, see:
̈
(a) Schalley, C. A.; Beizai, K.; Vogtle, F. Acc. Chem. Res. 2001, 34,
̈
465−476. (b) Lukin, O.; Vogtle, F. Angew. Chem., Int. Ed. 2005, 44,
1456−1477. (c) Neal, E. A.; Goldup, S. M. Chem. Commun. 2014, 50,
5128−5142.
(4) (a) Yamamoto, C.; Okamoto, Y.; Schmidt, T.; Jager, R.; Vogtle,
̈
̈
F. J. Am. Chem. Soc. 1997, 119, 10547−10548. (b) Reuter, C.; Seel,
̈
C.; Nieger, M.; Vogtle, F. Helv. Chim. Acta 2000, 83, 630−640.
(c) Schmieder, R.; Hubner, G.; Seel, C.; Vogtle, F. Angew. Chem., Int.
̈
̈
Ed. 1999, 38, 3528−3530. (d) Radha Kishan, M.; Parham, A.;
̈
Schelhase, F.; Yoneva, A.; Silva, G.; Chen, X.; Okamoto, Y.; Vogtle, F.
Angew. Chem., Int. Ed. 2006, 45, 7296−7299.
(5) Kameta, N.; Nagawa, Y.; Karikomi, M.; Hiratani, K. Chem.
Commun. 2006, 3714−3716.
(6) Makita, Y.; Kihara, N.; Nakakoji, N.; Takata, T.; Inagaki, S.;
Yamamoto, C.; Okamoto, Y. Chem. Lett. 2007, 36, 162−163.
(7) Bordoli, R. J.; Goldup, S. M. J. Am. Chem. Soc. 2014, 136, 4817−
4820.
(8) Hirose, K.; Ukimi, M.; Ueda, S.; Onoda, C.; Kano, R.; Tsuda, K.;
Hinohara, Y.; Tobe, Y. Symmetry 2018, 10, 20.
(9) Ogoshi, T.; Yamafuji, D.; Akutsu, T.; Naito, M.; Yamagishi, T.
Chem. Commun. 2013, 49, 8782−8784.
́
(10) Alvarez-Perez, M.; Goldup, S. M.; Leigh, D. A.; Slawin, A. M. Z.
J. Am. Chem. Soc. 2008, 130, 1836−1838.
D
DOI: 10.1021/acs.orglett.8b01727
Org. Lett. XXXX, XXX, XXX−XXX