Cyclodextrin-Isolated Alkynylpyrenes as UV-Stable and Blue-Light-Emitting Molecules even in Condensed States

Article abstract of DOI:10.1021/acs.orglett.6b00420

Encapsulation of highly emissive alkynylpyrenes with permethylated α-cyclodextrin (PM-α-CD) followed by capping reaction yielded alkynylpyrene-based [3]rotaxanes. The [3]rotaxane emitted only blue light of monomeric pyrene under various circumstances such

Full text of DOI:10.1021/acs.orglett.6b00420

Letter
pubs.acs.org/OrgLett
Cyclodextrin-Isolated Alkynylpyrenes as UV-Stable and Blue-Light-
Emitting Molecules Even in Condensed States
Masahiko Inouye,*,† Atsushi Yoshizawa,† Mari Shibata,† Yuki Yonenaga,† Kazuhisa Fujimoto,‡
Takuma Sakata,§ Shinya Matsumoto,§ and Motoo Shiro∥
†Graduate School of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
‡Department of Applied Chemistry and Biochemistry, Kyushu Sangyo University, Fukuoka 813-8503, Japan
§Graduate School of Environment and Information Sciences, Yokohama National University, Yokohama 240-8501, Japan
∥Rigaku Corporation, Matsubaracho, Akishima, Tokyo 196-8666, Japan
S
* Supporting Information
ABSTRACT: Encapsulation of highly emissive alkynylpyrenes with
permethylated α-cyclodextrin (PM-α-CD) followed by capping
reaction yielded alkynylpyrene-based [3]rotaxanes. The [3]rotaxane
emitted only blue light of monomeric pyrene under various
circumstances such as lipophilic, hydrophilic, and even condensed
states and exhibited extremely high stability for UV irradiation.
These properties would result because PM-α-CD, like bulletproof
glass, protected the alkynylpyrene core from the attack of another
excited alkynylpyrene and singlet oxygen generated by the energy transfer from the excited alkynylpyrene.
Bisalkynylpyrenes such as 1 exhibited strong blue emissions in
lue-light-emitting molecules occupy a cardinal position not
Bonly in optoelectronics but also in bioprobes, in which they the wavelength region ranging from 450 to 390 nm in dilute
solutions. At high concentrations in lipophilic solvents and even
at low concentrations in water, they showed yellow-green
excimer emissions with maxima of at least 520 nm. For the
construction of the desired blue-emitting fluorophore, we
devised rotaxane-type alkynylpyrenes (Scheme 1). In the
rotaxane, the single alkynylpyrene core is completely encapsu-
lated within macrocycles, and the resulting complex is prohibited
from dissociation by attaching appropriate stopper molecules.
This encapsulation would prevent the alkynylpyrene core from
aggregations of themselves and interactions with other photo-
chemically induced reactive species of outside. CDs were
selected as the macrocycle because of their well-known
encapsulation ability for the hydrophobic fluorophores in
aqueous solutions8 and optical transparency above 200 nm.
We recently reported a new class of [4]rotaxanes that exhibited
strong circularly polarized luminescence in their excimer
emission region, in which two alkynylpyrenes were threaded
into two γ-CDs.9 However, single alkynylpyrene-threaded
[3]rotaxanes could not be synthesized not only in this study
but also in any ones using α- and β-CDs. Indeed, unlike other
fluorophores,10 a few [3]rotaxanes have been prepared for
pyrenes as an axle component.11
act as a donor materials for other fluorescence acceptors of longer
wavelengths.1 Among the blue-light-emitting molecules, pyrene
and its derivatives have long been attractive in terms of their
chemical usability.2 However, pyrene itself possesses a robust
tendency to form an aggregated state, which dooms a
substantially red-shifted emission as well as the fatal decrease
for the luminescent efficiency particularly in aqueous and
condensed conditions. These troublesome phenomena are
seen not only for pyrenes but also for most organic hydrophobic
fluorophores. More seriously, purely organic blue-light emitters
still rquire improved optical stability due to their large HOMO−
LUMO energy gaps.3 Indeed, the prolonged irradiation usually
results in photobleaching of the fluorophores mostly by the
reaction with singlet oxygen generated by the energy transfer
from the excited fluorophores to dissolved oxygen.
During the course of our studies for finding a new class of
pyrene derivatives, we developed alkynylpyrenes possessing the
advantage of high fluorescence quantum yields even in the
presence of oxygen in water.4 To reach the alkynylpyrenes near
the ideal blue-emitting molecules, we additionally planned to
encapsulate the fluorophore with “bulletproof glass” at the
molecular level in order to no longer suffer from uncertainty due
to its unfavorable aggregation even in the condensed states. This
bulletproof glass isolated fluorescent core will also be protected
from photochemically induced reactive species present out-
side.5−7 Here, we report rotaxane-type alkynylpyrenes fully
shielded with cyclodextrins (CDs), which show intensely blue-
emitting characteristics under universal circumstances and
extremely high stabilities against photoirradiation.
Returning to the basis, we thoroughly investigated the
complex-forming ability of 1 with native and various chemically
modified CDs by 1H NMR titration experiments in D2O. Among
the CDs tested, permethylated α-CD (PM-α-CD) showed the
Received: February 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00420
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Capping Reaction for Synthesizing [3]Rotaxane 3
most drastic changes in the 1H NMR spectrum. In the 1H NMR
spectrum of 1a (6 × 10−3 M) in D2O, the aromatic proton signals
shifted upfield compared to those in CDCl3 because amphiphilic
1a readily aggregates by using the large plane of the pyrene cores
in an aqueous circumstance (Figure S1). Upon addition of PM-
α-CD, a new set of signals appeared at a similar region in CDCl3,
indicating the existence of a nonaggregated alkynylpyrene
independently on the 1H NMR time scale against the aggregated
species. When the molar ratio of PM-α-CD/1a increased up to 2,
the original proton signal of 1a disappeared completely and
converged into the well-resolved four doublets of the non-
aggregated alkynylpyrene. These NMR data including the DOSY
spectrum (Figure S2) proved that one molecule of alkynylpyrene
1a was included in the cavities of two PM-α-CD molecules to
form a ternary complex, 1a⊂(PM-α-CD)2.
The capping reaction of 1a⊂(PM-α-CD)2 for constructing a
[3]rotaxane needs to be performed at relatively low temperature
because the inclusion complex will dissociate above 60 °C
(Figure S3). The succinimidyl ester of bulky benzoic acid 2a was
selected as a stopper moiety of the [3]rotaxane, which could react
with the terminal amines of 1a at room temperature. When 2a
was added to a solution of 1a⊂(PM-α-CD)2 in water at 25 °C
around pH 11, the reaction gave [3]rotaxane 3a (9%) and PM-α-
CD-free dumbbell 4a (28%) (Scheme 1). To improve the water
solubility of the stopper molecule, the hydroxyl group of 2a was
modified with oxyethylene chains to afford 2b and 2c. These
stopper molecules fairly increased the isolated yields of the
corresponding [3]rotaxanes, 15% and 20% for 3b and 3c,
respectively, while those for both dumbbells 4b and 4c decreased
to 26% and 25%. The formation of [2]rotaxanes that possess only
one PM-α-CD was also confirmed on the basis of ESI-TOF-MS
(Figure S4). All of the [3]rotaxanes 3 had good solubility not
only in water but also in many organic solvents such as CHCl3,
MeOH, EtOH, NMP, DMF, DMSO, and MeCN. The good
solubility for various solvents is essential for applying them to
materials of optical interest using inkjet printing technology.12
No unthreading of the dumbbell part was confirmed by heating a
DMSO solution of 3a at 100 °C for 18 h (Figure S5). A rather
good yield was attained for a reversely connected [3]rotaxane 3d
synthesized from the carboxylic acid terminated alkynylpyrene
1b and the stopper 2d possessing an amino group in its reaction
site. The short linkage in 3d was introduced between the
alkynylpyrene core and the stopper for reducing the flexibility of
the axle in order to subject the rotaxane to X-ray structure
analysis.
in the alkynylpyrene and the C−H protons (H1−6) in the PM-α-
CDs (Scheme 1 and Figures S6 and S7). Chemical shifts of the
three methoxy protons (CH32,3,6O) were decided by super-
1
imposing the H NMR spectra of separately synthesized 3b
parallel to the corresponding PM-α-CDs possessing partially
deuterated methoxy groups (CD33,6O: Figure S8). The signals of
2
3
CH3 O (−0.16 ppm) and CH3 O (−0.61 ppm) shifted upfield,
whereas that of CH3 O (+0.03 ppm) shifted downfield in the 1H
6
NMR spectrum of 3b at 400 MHz (Figures S8 and S9).
Unexpectedly, not the inward substituent at C2 but the outward
one at C3 largely shifted by the anisotropy from the inner
alkynylpyrene, and this phenomenon was disclosed by the crystal
structure of 3d (vide infra). In the NOESY spectrum of 3b,
strong NOEs were detected between all the alkynylpyrene
protons and the protons of H3 and CH32,3O in the PM-α-CDs,
while no NOEs for the narrow rim and outward protons of
H1,2,4‑6,6′ and CH3 O (Figure S10). The NOEs illustrate that the
6
alkynylpyrene moiety was fully encapsulated within the cavity of
the two PM-α-CDs and located near wide rims of them as
depicted in Scheme 1.
MacroModel-based Monte Carlo simulations followed by
B3LYP/6-31G reinforced the spatial correlation, in which the
two PM-α-CDs tightly wrapped the alkynylpyrene axle, and the
stoppers were large enough to prevent unthreading in the
designed manner (Figure S11). Conclusive proof for the
rotaxane structure was obtained on the basis of the X-ray
structure analysis for 3d (Figure 1). The pyrene unit was largely
Figure 1. Structures of [3]rotaxane 3d obtained from X-ray analyses: (a)
side and (b) top views. The single crystal was obtained by
recrystallization from DMSO and H2O.
separated from the neighboring pyrene units because of the
wrapping CD units as well as the stopper moiety (Figure S12).
The two PM-α-CDs were found to completely screen the inner
alkynylpyrene fluorophore from the outer world in a head-to-
head dimerization manner as speculated. There should not be
enough space even for small reactive species to approach the
inner alkynylpyrene. These structural aspects will guarantee the
spatial isolation of the emitting core against other alkynylpyrenes
and photochemically induced reactive species. The methoxy
Various NMR experiments revealed the spatial correlation
between the PM-α-CD wheels and the alkynylpyrene axle of the
[3]rotaxane 3b in solutions. COSY and long-range COSY
spectra of 3b allowed assignment of the aromatic protons (Ha−d
)
B
DOI: 10.1021/acs.orglett.6b00420
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
oxygen at C2 was located inward and that at C3 outward in PM-
α-CD; on the other hand, the next methyl groups were reversed
(Figure S13). This is a reason why the methoxy protons at C3
suffered more from the anisotropy by the inner alkynylpyrene in
the 1H NMR spectra of the rotaxanes (vide supra).
(Table S1). The fluorescence intensity of 3b increased according
to Beer’s law up to a concentration of 5.5 × 10−6 M by
monitoring at 397 nm, then began to saturate, and finally
decreased above 1.1 × 10−5 M (Figure S17a). The deviation from
Beer’s law at higher concentrations would result not from the
concentration quenching by aggregation but from the
fluorescence reabsorption on 3b by crosstalk between the
absorption and emission bands ranging from 400 to 375 nm
(Figure S17b). This was partly validated from the fact that the
peak intensity of the shortest fluorescence band at 397 nm mainly
weakened relative to the concentrations (Figure S17c). The thin
film state of 3b also emitted blue light, while the peak intensity at
397 nm was reduced because of the fluorescence reabsorption
(Figure 2b, red line). Nevertheless, the [3]rotaxane 3b proved to
be an intensely blue-light-emitting molecule regardless of their
circumstances. Other [3]rotaxanes 3a,c,d also exhibited similar
fluorescence properties (Figure S16).
The [3]rotaxanes 3 can be regarded as an “isolated”
fluorophore by the encapsulation with visible-light-transparent
shells. The shell, PM-α-CD, consists only of C−C, C−O, and C−
H single bonds and never of unsaturated bonds that will be
targets for reactive oxygen species as a major causative substance
inducing photobleaching. Expecting that the shells will act as a
bulletproof glass, we examined the stabilities of 3b and 4b under
photoirradiation. While quartz cells containing air-saturated
aqueous solutions of 3b and 4b were continuously irradiated with
>300 nm light using a 150 W high-pressure mercury lamp with a
UV-30 filter, the UV−vis spectra were monitored over time
(Figure 3). The dumbbell 4b was rapidly photobleached with the
Optical properties of the [3]rotaxanes 3 proved to be highly
independent of solvents used and of their concentrations because
the emitting core was isolated from external environments by the
two PM-α-CDs. A dilute solution of the dumbbell such as 4b
bearing an exposed alkynylpyrene moiety displayed sharp
absorption bands at 388, 366, and 348 nm in organic solvents,
which were attributed to the π → π* transition of the
alkynylpyrene core. However, 4b easily aggregated by using the
hydrophobic plane to afford the broad absorption band around
390 nm in an aqueous solution and in a thin film state (Figure
S14a). By contrast, the absorption spectra of the [3]rotaxane 3b
were almost the same in CH2Cl2, EtOH, and water with
absorption bands at 388 nm (Figure 2a). Noteworthy is that the
Figure 2. Electronic spectra of [3]rotaxane 3b under various
circumstances at 25 °C: (a) absorption (2.0 × 10−5 M) and (b)
fluorescence spectra (2.0 × 10−6 M) in CH2Cl2 (orange), EtOH
(green), H2O (blue), and H2O/DMSO = 9:1 (purple). Both of the red
spectra were obtained in a thin film state. Excitation wavelengths are 366
and 388 nm for red and the others, respectively.
shape of absorption band of 3b remained unchanged even in its
thin film state (Figure 2a, red line), which was verified by optical
waveguide spectroscopy measurements (Figure S15). The
notable insensitivity of 3b against the measurement media
most likely results from the spatial isolation of the emitting core
by the optically transparent, amphiphilic PM-α-CD. This was
also seen in other [3]rotaxanes, so that the spectra of 3a−d in any
media are similar (Figure S16).
Figure 3. Absorption spectral changes of (a) [3]rotaxane 3b (2.0 × 10−5
M) and (b) dumbbell 4b (2.0 × 10−5 M) for 48 h at 25 °C in a mixed
solvent (H2O/MeOH = 6:4) under photoirradiation with >300 nm light
using a 150 W high-pressure mercury lamp with a UV-30 filter.
A striking difference between the [3]rotaxane 3 and the
dumbbell 4 arose from their fluorescence spectra. For the
dumbbell 4b, blue light of monomeric pyrene was emitted in a
dilute EtOH solution at 396 and 417 nm, while yellow-green
emission became predominant around 520 nm in an aqueous
solution and in a thin film state, which must originate from the
excimer (Figure S14b). Hydrophilic and condensed environ-
ments should make the excited alkynylpyrene core easy to match
up with another, usually that of the ground state. On the other
hand, the rotaxane 3b illuminated only blue light of monomeric
pyrene not only in solvents but also in a thin film state (Figure
2b). The PM-α-CD shells would inhibit the alkynylpyrene core
from crossing over to each other, so that the excited core no
longer formed an excimer. Furthermore, the quantum yield of 3b
(Φf = 0.76) was substantially higher than that of 4b (Φf = 0.60) in
EtOH, being due to the reduced rate of nonradiative decay by
restricting the rotation of the alkynylpyrene core within the PM-
α-CD shells. Thus, the measurement media scarcely affected
emitting efficiencies of all the [3]rotaxanes 3, the quantum yields
of which fell within the range from 0.77 to 0.60 in any media
absorption decay half-life of 3 h, whereas the absorption
spectrum of 3b remained unchanged after 48 h irradiation.
Anderson6 and Smith7 also reported photodurabilities of singly
CD- and synthetic macrocycle-encapsulated fluorophores,
respectively. Although those rotaxanes showed the increased
photodurabilities compared with the corresponding dumbbells,
most of them photobleached within several hours. The far
superior photodurability of our rotaxanes is certainly caused by
the doubly CD-encapsulated [3]rotaxane structure that near
completely shields the fluorophore core from reactive oxygen
species. On the other hand, the previous examples might be
insufficient in terms of the shielding.
Singlet oxygen is known to play a chief role in photobleaching
for fluorescent aromatic hydrocarbons.13 The bulletproof glass,
PM-α-CD, seems to protect the alkynylpyrene core from the
attack of singlet oxygen generated by the energy transfer from the
excited alkynylpyrene to dissolved oxygen.14 However, there, is
still another possibility for the photodurability of the [3]-
rotaxanes, i.e., no chance for the energy transfer because of the
C
DOI: 10.1021/acs.orglett.6b00420
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
spatial separation between the alkynylpyrene core and oxygene
by the bulletproof glass. To rule out this, trapping experiments
were executed using 1,3-diphenylisobenzofuran (DPBF) that is
known to rapidly react with singlet oxygen. The generation of
singlet oxygen was evaluated from the decrease in the absorption
band of DPBF during the photoirradiation.15 Air-saturated
aqueous solutions of 3b and 4b containing DPBF were irradiated
by using a 150 W high-pressure mercury lamp with a UV-30 filter,
located 10 cm away from the sample quartz cell, and the
consumption of DPBF was monitored at 415 nm (Figure S18a).
The absorption band of DPBF decreased quickly both in the
presence of 3b and 4b with a decay half-life of around 120 s,
which is 5 times as fast as that in the absence. The [3]rotaxane did
generate singlet oxygen with the quantum yield for singlet
oxygen generation of ΦΔ = 0.04 (Figure S18b) but did not permit
the approach of the singlet oxygen to its alkynylpyrene core by
the bulletproof glass. From the other viewpoint of this
experiment, the [3]rotaxane could be utilized as a highly stable
singlet oxygen generator.
The blocking ability of PM-α-CD was reconfirmed by
fluorescence quenching experiments through intermolecular
photoinduced electron transfer (PET). For this purpose, we used
maleimide that had been known to quench the fluorescence of
alkynylpyrenes.4a From the Stern−Volmer plot of the dumbbell
4 in EtOH, the kq value was estimated to be ca. 1.4 × 1010 M−1 s−1
that is larger than the diffusion-controlled rate constant (6.0 ×
109 M−1 s−1) in EtOH. Furthermore, the quenching efficiency
increased by increasing the temperature of the solution, meaning
the quenching being induced by intermolecular PET (Figure
S19).16 In contrast to the shell-free 4a, the [3]rotaxane 3a
suffered little from the fluorescence quenching with the
concentration up to as high as 0.2 M of maleimide. The PM-α-
CD shell proved to inhibit the approach of maleimide to the
alkynylpyrene core within the distance that allows the
intermolecular PET.17
from The Fugaku Trust for Medicinal Research and by MEXT
Grants-in-Aid for Scientific Research on Innovative Areas,
“Stimuli-responsive Chemical Species for Creation of Functional
Molecules”.
REFERENCES
■
(1) (a) Michalet, X.; Weiss, S.; Jager, M. Chem. Rev. 2006, 106, 1785−
1813. (b) Reineke, S.; Thomschke, M.; Lussem, B.; Leo, K. Rev. Mod.
̈
̈
Phys. 2013, 85, 1245−1293. (c) Sasabe, H.; Kido, J. Eur. J. Org. Chem.
2013, 7653−7663. (d) Kim, N. H.; Kim, Y.-H.; Yoon, J.-A.; Lee, S. Y.;
Ryu, D. H.; Wood, R.; Moon, C.-B.; Kim, W. Y. J. Lumin. 2013, 143,
723−728.
(2) Figueira-Duarte, T. M.; Mullen, K. Chem. Rev. 2011, 111, 7260−
̈
7314.
(3) Zhu, M.; Yang, C. Chem. Soc. Rev. 2013, 42, 4963−4976.
(4) (a) Maeda, H.; Maeda, T.; Mizuno, K.; Fujimoto, K.; Shimizu, H.;
Inouye, M. Chem. - Eur. J. 2006, 12, 824−831. (b) Shimizu, H.;
Fujimoto, K.; Furusyo, M.; Maeda, H.; Nanai, Y.; Mizuno, K.; Inouye,
M. J. Org. Chem. 2007, 72, 1530−1533. (c) Chiba, J.; Takeshima, S.;
Mishima, K.; Maeda, H.; Nanai, Y.; Mizuno, K.; Inouye, M. Chem. - Eur.
J. 2007, 13, 8124−8130. (d) Fujimoto, K.; Shimizu, H.; Furusyo, M.;
Akiyama, S.; Ishida, M.; Furukawa, U.; Yokoo, T.; Inouye, M.
Tetrahedron 2009, 65, 9357−9361.
(5) Dsouza, R. N.; Pischel, U.; Nau, W. M. Chem. Rev. 2011, 111,
7941−7980.
(6) (a) Buston, J. E. H.; Young, J. R.; Anderson, H. L. Chem. Commun.
2000, 905−906. (b) Stone, M. T.; Anderson, H. L. Chem. Commun.
2007, 2387−2389.
(7) (a) Arunkumar, E.; Fu, N.; Smith, B. D. Chem. - Eur. J. 2006, 12,
4684−4690. (b) Fu, N.; Baumes, J. M.; Arunkumar, E.; Noll, B. C.;
Smith, B. D. J. Org. Chem. 2009, 74, 6462−6468.
(8) (a) Nepogodiev, S. A.; Stoddart, J. F. Chem. Rev. 1998, 98, 1959−
1976. (b) Wenz, G.; Han, B.-H.; Muller, A. Chem. Rev. 2006, 106, 782−
̈
817.
(9) Inouye, M.; Hayashi, K.; Yonenaga, Y.; Itou, T.; Fujimoto, K.;
Uchida, T.; Iwamura, M.; Nozaki, K. Angew. Chem., Int. Ed. 2014, 53,
14392−14396.
(10) (a) Craig, M. R.; Claridge, T. D. W.; Hutchings, M. G.; Anderson,
H. L. Chem. Commun. 1999, 1537−1538. (b) Qu, D.-H.; Wang, Q.-C.;
Ma, X.; Tian, H. Chem. - Eur. J. 2005, 11, 5929−5937. (c) Daniell, H. W.;
Klotz, E. J. F.; Odell, B.; Claridge, T. D. W.; Anderson, H. L. Angew.
Chem., Int. Ed. 2007, 46, 6845−6848.
(11) Inouye, M.; Fujimoto, K.; Yonenaga, Y. Water-Soluble Rotaxane-
Type Fluorescent Dye And Fluorescent Organic Molecule. WO2010/
026957A1 11032010, 2010.
(12) (a) Chang, S.-C.; Liu, J.; Bharathan, J.; Yang, Y.; Onohara, J.; Kido,
J. Adv. Mater. 1999, 11, 734−737. (b) Suzuki, M.; Fukagawa, H.;
Nakajima, Y.; Tsuzuki, T.; Takei, T.; Yamamoto, T.; Tokito, S. J. Soc. Inf.
The present alkynylpyrene-based [3]rotaxanes only emitted
blue light of monomeric pyrene under various circumstances and
endured the UV irradiation for a long stretch of time. These
photophysical characteristics resulted from the spatially isolated
fluorophore by the rotaxane architecture. The [3]rotaxane could
be a superior molecular basis of purely organic blue-light emitters
and a highly stable singlet oxygen generator.
ASSOCIATED CONTENT
* Supporting Information
■
S
Disp. 2009, 17, 1037−1042. (c) Sandstrom, A.; Dam, H. F.; Krebs, F. C.;
̈
Edman, L. Nat. Commun. 2012, 3, 1002.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00420.
(13) (a) Foote, C. S. Science 1968, 162, 963−970. (b) Fudickar, W.;
Linker, T. J. Am. Chem. Soc. 2012, 134, 15071−15082.
Full experimental and characterization data for all
compounds (PDF)
(14) Lang, K.; Mosinger, J.; Wagnerova,
248, 321−350.
́
D. M. Coord. Chem. Rev. 2004,
(15) Zhang, X. F.; Li, X. J. Lumin. 2011, 131, 2263−2266.
(16) Lakowicz, J. R. Principles of Fluorescence Spectroscopy; Springer:
New York, 2010; pp 278−280.
(17) Taylor, P. N.; Hagan, A. J.; Anderson, H. L. Org. Biomol. Chem.
2003, 1, 3851−3856.
X-ray crystallographic data for compound 3d (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: inouye@pha.u-toyama.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Tatsuya Itou (Graduate School of Pharmaceutical
Sciences, University of Toyama) for experimental assistance and
helpful discussions. This work was supported by the foundation
D
DOI: 10.1021/acs.orglett.6b00420
Org. Lett. XXXX, XXX, XXX−XXX