Chiral recognition and kinetic resolution of aromatic amines via supramolecular chiral nanocapsules in nonpolar solvents

Article abstract of DOI:10.1021/ja312367k

Herein we report the first example of chiral recognition and kinetic resolution of aromatic amine guests using supramolecular nanocapsules assembled from cyclodextrin derivatives in nonpolar media. With these nanocapsules, an extremely high chiral recognition of 1-(1-naphthyl)ethylamine (1) in cyclohexane was achieved, with a binding selectivity of up to 41 for (S)-1(R)-1. In addition, kinetic resolution of 1 through enantioselective N-acylation was accomplished with an enantiomeric excess of up to 91%.

Full text of DOI:10.1021/ja312367k

Communication
pubs.acs.org/JACS
Chiral Recognition and Kinetic Resolution of Aromatic Amines via
Supramolecular Chiral Nanocapsules in Nonpolar Solvents
Toshiyuki Kida, Takuya Iwamoto, Haruyasu Asahara, Tomoaki Hinoue, and Mitsuru Akashi*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
S
* Supporting Information
kinetic resolution of racemic compounds utilizing selective
sequestration of one enantiomer within the supramolecular CD
nanocapsule.
ABSTRACT: Herein we report the first example of chiral
recognition and kinetic resolution of aromatic amine
guests using supramolecular nanocapsules assembled from
cyclodextrin derivatives in nonpolar media. With these
nanocapsules, an extremely high chiral recognition of 1-(1-
naphthyl)ethylamine (1) in cyclohexane was achieved,
with a binding selectivity of up to 41 for (S)-1 over (R)-1.
In addition, kinetic resolution of 1 through enantiose-
lective N-acylation was accomplished with an enantiomeric
excess of up to 91%.
(R)- and (S)-1-(1-naphthyl)ethylamine [(R)- and (S)-1] and
(R)- and (S)-1-(2-naphthyl)ethylamine [(R)- and (S)-2] were
used as chiral guests to examine the effect of the guest structure
on the binding and chiral recognition by the supramolecular
TIPS-β-CD capsule in nonpolar media. The chiral recognition
ability of the supramolecular TIPS-β-CD capsule toward these
aromatic amine guests was evaluated on the basis of the
association constants (K) between two TIPS-β-CD molecules
and one molecule of the chiral guests in benzene-d6 and
cyclohexane-d12 (Scheme 1), which were determined by the 1H
upramolecular nanocapsules constructed by the self-
Sassembly of molecular building blocks have attracted
considerable attention in the fields of supramolecular and
synthetic chemistry1 because they exhibit unique guest
discrimination properties2 as well as a high stabilization effect
toward reactive intermediates3 by utilizing their isolated
nanocavity from the bulk solution. To date, a variety of
supramolecular nanocapsules have been employed as molecular
selectors4 and reaction vessels.5 However, reports on chiral
recognition6 and enantioselective reactions7 with supramolec-
ular chiral nanocapsules bearing asymmetric cavities are limited,
even though well-designed supramolecular chiral nanocapsules
should effectively recognize chiral guests because of the
confined chiral environment and also should function as potent
reaction tools for enantioselective reactions via the selective
sequestration of one enantiomer.
Scheme 1. Formation of an Inclusion Complex between a
Supramolecular TIPS-β-CD Nanocapsule and a Chiral
Aromatic Amine in a Nonpolar Solvent
We recently reported that a supramolecular nanocapsule
formed by self-assembly of 6-O-triisopropylsilyl-β-cyclodextrin
(TIPS-β-CD) exhibited a high affinity for pyrene in benzene or
cyclohexane.8 Because this nanocapsule possesses an asym-
metric cavity derived from the constituent D-glucose units, it
has potential for enantioselective recognition of specific chiral
guests (e.g., chiral aromatic amines and chiral aromatic
alcohols) in nonpolar solvents through multipoint interactions,
including hydrogen bonding between the CD hydroxyl groups
and the guest polar groups as well as inclusion of the guest
aromatic moiety into the CD cavity. Herein we report the
extremely high chiral recognition of an aromatic amine by a
supramolecular chiral nanocaspsule assembled from TIPS-β-
CD in a nonpolar solvent. In addition, the selective
sequestration of one enantiomer by the supramolecular chiral
nanocapsule in the nonpolar solvent enabled the successful
kinetic resolution of racemic aromatic amines. To the best of
our knowledge, this is the first example of chiral recognition by
a supramolecular CD nanocapsule in a nonpolar medium and
1
NMR method. Figure 1 shows the changes in the H NMR
signals of TIPS-β-CD induced by the addition of (R)- or (S)-1
in benzene-d6 at 25 °C. Upon the addition of (R)- or (S)-1,
new signals appeared at 4.1 and 5.2 ppm. As the ratio of (R)- or
(S)-1 to TIPS-β-CD increased, the intensities of these new
signals increased, while the original proton signals of TIPS-β-
CD decreased. These observations suggest that complexation
between TIPS-β-CD and (R)- or (S)-1 occurs in benzene-d6
and that the complexation equilibrium at 25 °C is slow on the
NMR time scale. When the (S)-1/TIPS-β-CD ratio reached
2:1, the original proton signals of TIPS-β-CD almost
disappeared (Figure 1b). On the other hand, in the case of
the (R)-1 guest, the original signals of TIPS-β-CD remained
visible even with a (R)-1/TIPS-β-CD ratio of 2:1. These results
suggest that TIPS-β-CD binds (S)-1 with a higher association
Received: December 28, 2012
Published: February 21, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
TIPS-β-CD upon the addition of (R)- or (S)-1. In these
solvents, the supramolecular TIPS-β-CD capsule shows a clear
binding selectivity for (S)-1. It is noteworthy that an extremely
high chiral selectivity (KS/KR) of up to 31 was achieved.
Decreasing the temperature to 10 °C further enhanced the
chiral selectivity in cyclohexane-d12 to 41, which is much higher
than the chiral selectivities of CDs and CD derivatives toward
racemic aromatic guests in aqueous media.9 These results
demonstrate that the supramolecular capsule assembled from
TIPS-β-CD in a nonpolar solvent is highly effective for the
chiral recognition of 1. The thermodynamic parameters for
complexation of TIPS-β-CD with (R)- and (S)-1 in benzene-d6
and cyclohexane-d12, which were calculated from the
association constants at different temperatures (see Tables
S1−S3 in the SI), reveal that the complexation is enthalpy-
driven. When (R)- or (S)-2 was used as the guest, an inclusion
complex with TIPS-β-CD was not formed in benzene-d6. On
the other hand, clear associations between TIPS-β-CD and
those guests were observed in cyclohexane-d12, although the
chiral selectivity was lower than in the case of 1. These results
reveal that the substitution position of the 1-aminoethyl group
on the naphthalene ring of the guest significantly influences the
guest inclusion within the supramolecular capsule cavity in
nonpolar solvents.
Two-dimensional NMR spectroscopy effectively provides
information about the structure of the inclusion complex in
solution. The resonances of the protons of (R)- and (S)-1 and
the H3 and/or H5 protons of TIPS-β-CD in the nuclear
Overhauser effect spectroscopy (NOESY) spectra of the
inclusion complexes in benzene-d6 or cyclohexane-d12 (Figures
S7−10) are clearly correlated, confirming that (R)- and (S)-1
are incorporated within the cavity of the supramolecular TIPS-
β-CD capsule in these solvents. In benzene-d6, the cross-peaks
between the H3 protons of the host and all of the naphthalene
protons of (R)- or (S)-1 were clearly observed, whereas the
cross-peaks between the H5 protons of the host and the
protons of the (R)- or (S)-1 were much weaker. This result
indicates that an (R)- or (S)-1 molecule is included in the
TIPS-β-CD capsule cavity with the long axis of the naphthalene
ring almost perpendicular to the cavity axis, which is similar to
the case for pyrene inclusion.8 On the other hand, in
cyclohexane-d12, stronger cross-peaks were observed between
the H5 protons as well as the H3 protons of the host and almost
all of the naphthalene protons of (R)- and (S)-1, suggesting
that the long axis of the incorporated (R)- or (S)-1 molecule is
tilted toward the axis of the TIPS-β-CD capsule cavity.
Consequently, the (R)- or (S)-1 molecule penetrates deeper
into the CD cavity compared with the case of benzene-d6 as a
solvent. The calculated ratios of the volume integrals of the
correlation peaks between the host H5 protons and the guest
1
Figure 1. H NMR spectral changes observed for TIPS-β-CD (1.0 ×
10−3 M) upon addition of (a) (R)-1 and (b) (S)-1 in benzene-d6 at 25
°C. Red circles denote new signals that appeared upon addition of 1.
constant than for (R)-1. The Job plots using an NMR method
showed a maximum at a [TIPS-β-CD]/[(R)- or (S)-1] molar
ratio of 2:1 [Figure S4 in the Supporting Information (SI)],
clearly indicating that TIPS-β-CD forms a 2:1 complex with
(R)- or (S)-1 in benzene-d6. This result also suggests that a
supramolecular dimer capsule of TIPS-β-CD incorporates these
chiral guests inside the cavity. In the case of cyclohexane-d12 as
1
the solvent, similar H NMR spectral changes occurred upon
the addition of (R)- or (S)-1 (Figure S1). Additionally, the Job
plots (Figure S5) confirmed the complexation between the
supramolecular dimer capsule of TIPS-β-CD and (R)- or (S)-1.
Table 1 shows the K values for association of two TIPS-β-
CD host molecules and one (R)- or (S)-1 guest molecule (KR
or KS, respectively) in benzene-d6 and cyclohexane-d12 at 25 or
1
10 °C as estimated from the H NMR spectral changes of
Table 1. Association Constants for TIPS-β-CD and Chiral Aromatic Amines in Benzene-d6 and Cyclohexane-d12 at 25 or 10 °C
association constant (L2 mol−2
)
selectivity
solvent
T (°C)
KR
KS
KS/KR
(R)- or (S)-1
C6D6
25
25
10
(1.5 0.31) × 106
(4.2 0.96) × 106
(1.5 0.52) × 108
(1.8 0.41) × 107
(1.3 0.20) × 108
(6.1 2.1) × 109
12 2.6
31 6.1
41 13
c-C6D12
c-C6D12
(R)- or (S)-2
C6D6
25
25
∼0
∼0
−
c-C6D12
(1.2 0.12) × 107
(2.7 0.18) × 107
2.3 0.21
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Journal of the American Chemical Society
Communication
naphthalene protons to those between the host H3 protons and
the guest naphthalene protons were 0.42 and 0.22 for the TIPS-
β-CD−(S)-1 and TIPS-β-CD−(R)-1 complexes, respectively,
in cyclohexane-d12. Because the ratio indicates how deep the
naphthalene ring penetrates into the CD cavity, these values
show that the naphthalene ring of (S)-1 penetrates deeper into
the CD cavity than the naphthalene ring of (R)-1. Additionally,
the higher chiral selectivity in cyclohexane-d12 can be explained
in terms of the larger difference in the extents of penetration of
(R)- and (S)-1 into the CD cavity in cyclohexane-d12 compared
with benzene-d6.
In view of the high chiral recognition ability of the
supramolecular TIPS-β-CD capsule toward 1 in nonpolar
solvents, a nonenzymatic kinetic resolution of 1 via
enantioselective N-acylation was expected to proceed. The
selective inclusion of (S)-1 over (R)-1 within the supra-
molecular capsule cavity should predominantly shield the S
isomer from the acylation reagents in the bulk solution,
resulting in the kinetically preferential N-acylation of the R
isomer over the S isomer.
On the basis of this hypothesis, we examined the
enantioselective N-acylation of racemic 1 with acetic anhydride
or benzoic anhydride in the presence of TIPS-β-CD in
cyclohexane. A mixture of racemic 1 and TIPS-β-CD in
cyclohexane was stirred for 1 h to reach complexation
equilibrium. The acid anhydride was then added at 10 °C,
and the mixture was stirred at 10 °C for 1 h (for acetic
anhydride) or 40 h (for benzoic anhydride). Table 2
The X-ray crystal structure of the inclusion complex between
a supramolecular TIPS-β-CD capsule and (S)-1 in benzene
solution (Figure 2) shows that the (S)-1 molecule is
Table 2. Kinetic Resolution of 1 via Enantioselective N-
Acylation with Acid Anhydride in the Presence of TIPS-β-
a
CD in Cyclohexane
Figure 2. Crystal structure of the supramolecular TIPS-β-CD
capsule−(S)-1 inclusion complex. (a) Side view. TIPS-β-CD is
shown with a cylinder representation, whereas (S)-1 and benzene
are shown with space-filling representations. The O atoms in H2O are
shown as orange balls. H atoms except for the α-methine hydrogen of
(S)-1 have been omitted for clarity. (b) Top view. TIPS-β-CD is
shown with a cylinder representation, whereas (S)-1 and benzene are
shown with ball-and-stick representations. O atoms in H2O are shown
as orange balls. Color labels: gray, carbon in TIPS-β-CD and aliphatic
carbon in (S)-1; cyan, silicon; red, oxygen in TIPS-β-CD; yellow,
naphthalene ring; violet, benzene molecule; orange, oxygen in H2O.
acid anhydride
equiv of
conv.
b
ee
b
entry
TIPS-β-CD
R
equiv
(%)
(%)
s
1
2
none
1.0
CH3
CH3
CH3
CH3
CH3
CH3
Ph
0.50
0.10
0.10
0.10
0.35
0.50
0.50
0.10
0.20
0.50
48
10
9
−
50
72
83
70
59
−
91
87
75
−
3.2
6.7
11
3
2.0
4
5.0
7
5
5.0
29
42
48
7
7.5
5.7
6
5.0
7
none
5.0
−
8
Ph
23
17
15
9
5.0
Ph
18
49
incorporated within the supramolecular capsule cavity formed
by the two TIPS-β-CD molecules through hydrogen bonding
between the secondary hydroxyl groups. Interestingly, as in the
case of a pyrene guest,8 the (S)-1 molecule forms a sandwich-
type complex with two benzene molecules through π−π
interactions and is located at the center of the capsule cavity.
Hydrogen bonding between the NH2 group of (S)-1 and the 3-
OH group of TIPS-β-CD with a N···O distance of 2.88 Å also
occurs (Figure S13). Unlike the case of a pyrene guest,8 two
H2O molecules, which are possibly originated from TIPS-β-
CD−bound water or a trace amount of water in the solvent, are
present between the two TIPS-β-CD molecules, acting as
connecting linkers through hydrogen bonding. This difference
is probably due to the steric effect of the aminoethyl group of
(S)-1. The location of (S)-1 in the crystalline state reasonably
agrees with the proposed location of (S)-1 in the benzene
solution. Although X-ray analysis of a crystal of the inclusion
complex between a supramolecular TIPS-β-CD capsule and
(R)-1 in benzene has not yet been successful, the interactions
between the guest and the solvent molecules inside the
supramolecular capsule cavity as well as hydrogen bonding
between the NH2 group of the guest and the OH group of
TIPS-β-CD appear to affect the inclusion mode of the guest
molecule within the capsule cavity, resulting in the high chiral
selectivity in the guest inclusion.
10
5.0
Ph
a
Acylation of 1 (6.0 × 10−4 mmol) was carried out with acid anhydride
in cyclohexane (0.6 mL) at 10 °C for 1 h (R = CH3) or 40 h (R = Ph)
in the presence of triethylamine (1.0 equiv) and TIPS-β-CD. The
conversion of 1 and enantiomeric excess of N-acyl-(R)-1 were
b
determined by HPLC.
summarizes the conversion of 1, the enantiomeric excess (%
ee) of the resulting N-acyl-(R)-1, and the s factor10 as functions
of the amount of TIPS-β-CD and acid anhydride added. In all
cases, enantioselective N-acetylation of (R)-1 exceeded 50% ee
in the presence of TIPS-β-CD. The enantioselectivity was
enhanced as the amount of TIPS-β-CD increased (entries 2−
4), confirming that the selective inclusion of (S)-1 within the
TIPS-β-CD capsule cavity is responsible for the enantiose-
lective N-acetylation. On the other hand, increasing the amount
of acetic anhydride lowered the enantioselectivity (entries 4−
6). With benzoic anhydride, which possesses a bulkier acyl
group than acetic anhydride, N-acylation proceeded with higher
enantioselectivity. In particular, the highest enantioselectivity
for N-benzoylation of (R)-1 occurred with a combination of 5.0
equiv of TIPS-β-CD and 0.10 equiv of benzoic anhydride (91%
ee, s = 23). Generally, it is considered that nonenzymatic
kinetic resolution of racemic primary amino compounds is
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Journal of the American Chemical Society
Communication
(7) Nishioka, Y.; Yamaguchi, T.; Kawano, M.; Fujita, M. J. Am. Chem.
Soc. 2008, 130, 8160−8161.
(8) Kida, T.; Iwamoto, T.; Fujino, Y.; Tohnai, N.; Miyata, M.; Akashi,
M. Org. Lett. 2011, 13, 4570−4573.
difficult because of the higher reactivity of primary amino
groups.11 Thus, this supramolecular capsule should be a
powerful tool for nonenzymatic kinetic resolution of racemic
amino compounds.
(9) (a) Rekharsky, M.; Inoue, Y. J. Am. Chem. Soc. 2000, 122, 4418−
4435. (b) Rekharsky, M.; Inoue, Y. J. Am. Chem. Soc. 2002, 124, 813−
826. (c) D’Anna, F.; Riela, S.; Gruttadauria, M.; Meo, P. L.; Noto, R.
Tetrahedron 2005, 61, 4577−4583. (d) Cyclodextrins and Their
Complexes; Dodziuk, H., Ed.; Wiley-VCH: Weinheim, Germany,
2006. (e) Kumar, V. P.; Kumar, P. A.; Suryanarayana, I.; Venkata, Y.;
Nageswar, D.; Rao, K. R. Helv. Chim. Acta 2007, 90, 1697−1704.
(10) The s factor is defined as s = (rate of the faster-reacting
enantiomer)/(rate of the slower-reacting enantiomer). Values of s
were calculated using Kagan’s method. See: Kagan, H. B.; Fiaud, J. C.
Top. Stereochem. 1988, 18, 249−330.
(11) For selected examples, see: (a) Mittal, N.; Sun, D. X.; Seidel, D.
Org. Lett. 2012, 14, 3084−3087. (b) Kolleth, A.; Christoph, S.;
Arseniyadis, S.; Cossy, J. Chem. Commun. 2012, 48, 10511−10513.
(c) Min, C.; Mittal, N.; De, C. K.; Seidel, D. Chem. Commun. 2012, 48,
10853−10855. (d) Krasnov, V. P.; Gruzdev, D. A.; Levit, G. L. Eur. J.
Org. Chem. 2012, 1471−1493.
In conclusion, we have demonstrated that high chiral
recognition of aromatic amines can be realized by using
inclusion within the cavity of a supramolecular CD nanocapsule
in nonpolar solvents. In particular, an extremely high binding
selectivity for (S)-1-(1-naphthyl)ethylamine [(S)-1] over the
corresponding R isomer was achieved. A crystallographic study
of the complex between the supramolecular nanocapsule and
(S)-1 obtained from benzene solution showed that hydrogen
bonding between the guest and the CD host as well as the
interactions between the guest and the solvent molecules inside
the capsule cavity play crucial roles in the enantioselective guest
inclusion. Moreover, through chiral recognition with the
supramolecular nanocapsule in cyclohexane, a nonenzymatic
kinetic resolution of racemic 1 via enantioselective N-
benzoylation is attained with up to 91% ee and an s factor of
23. This supramolecular nanocapsule should be applicable as a
powerful chiral selector and a potent reaction tool for various
enantioselective reactions.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
akashi@chem.eng.osaka-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Funding Program for Next
Generation World-Leading Researchers (GR067).
■
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