Enantioselective inclusion of pyrene-1-sulfonate salts of α-amino acids with crystals of α-cyclodextrin

Article abstract of DOI:10.1016/j.tet.2020.131100

Enantioselective inclusion of α-amino acids with crystals of α-cyclodextrin (α-CD) has been achieved by converting the amino acids into sulfonate salts with pyrene-1-sulfonic acid (PyS). For example, crystals of α-CD selectively include L-leucine/PyS (1:1) salt in a host/guest ratio of ～1 with 92%ee from a solution of the racemic salt in ethanol/N-methylformamide (91:9) at 40 °C. Under conditions optimized for individual amino acids, the PyS salts of valine, phenylalanine, and methionine are also included with good enantioselectivities (up to 86%ee). Mechanistic studies for the inclusion of leucine/PyS salt reveals that the enantioselectivity originates from the difference in stability between the inclusion complexes of D- and L-leucine/PyS salts with α-CD in crystals.

Full text of DOI:10.1016/j.tet.2020.131100

Journal Pre-proof
Enantioselective inclusion of pyrene-1-sulfonate salts of α-amino acids with crystals of
α-cyclodextrin
Ikuko Miyoshi, Yuichi Kitamoto, Maeda Tetsuya, Naoya Morohashi, Tetsutaro Hattori
PII:
S0040-4020(20)30221-0
https://doi.org/10.1016/j.tet.2020.131100
TET 131100
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 December 2019
Revised Date: 28 February 2020
Accepted Date: 1 March 2020
Please cite this article as: Miyoshi I, Kitamoto Y, Tetsuya M, Morohashi N, Hattori T, Enantioselective
inclusion of pyrene-1-sulfonate salts of α-amino acids with crystals of α-cyclodextrin, Tetrahedron (2020),
doi: https://doi.org/10.1016/j.tet.2020.131100.
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Graphical Abstract
1

Enantioselective inclusion of pyrene-1-sulfonate salts of
-amino acids with crystals of -cyclodextrin
α
α
Authors
Ikuko Miyoshi, Yuichi Kitamoto,* Tetsuya Maeda, Naoya Morohashi,* and Tetsutaro Hattori
Affiliations
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University,
6-6-11 Aramaki-Aoba, Aoba-ku, Sendai 980-8579, Japan
* E-mail: yuichi.kitamoto.d3@tohoku.ac.jp; morohashi@orgsynth.che.tohoku.ac.jp
1

Abstract:
Enantioselective inclusion of α-amino acids with crystals of α-cyclodextrin (α-CD) has been achieved
by converting the amino acids into sulfonate salts with pyrene-1-sulfonic acid (PyS). For example,
crystals of -CD selectively include L-leucine/PyS (1:1) salt in a host/guest ratio of ~1 with 92%ee
α
from a solution of the racemic salt in ethanol/N-methylformamide (91:9) at 40 °C. Under conditions
optimized for individual amino acids, the PyS salts of valine, phenylalanine, and methionine are also
included with good enantioselectivities (up to 86%ee). Mechanistic studies for the inclusion of
leucine/PyS salt reveals that the enantioselectivity originates from the difference in stability between the
inclusion complexes of D- and L-leucine/PyS salts with α-CD in crystals.
Keywords:
Cyclodextrin, Nanoporous molecular crystal, Enantioselective inclusion, Amino acid
2

1. Introduction
The development of solid materials that can capture particular inorganic gases and organic molecules
by precisely recognizing their molecular structures is an important subject from the view point of
reducing environmental load and energy costs through the simplification of separation and purification
processes. Nanoporous materials, such as zeolite,1 metal–organic frameworks (MOFs),2 covalent
organic network polymers (COFs),3 and nanoporous molecular crystals (NMCs),4 are widely
investigated for the separation materials. Molecular crystals of calix[4]arenes are representative NMCs
with “porosity without pores”5 that include guest molecules into their disconnected spatial voids,
accompanied by a structural change in the crystal packing.6–10 We have been engaged in the
development of this type of NMCs11 and recently succeeded in the selective inclusion of various
molecules, such as alcohols,12a,b amines,12c carboxylic acids,12d aromatic compounds,12e and alkanes,12f
using crystals of p-tert-butylcalix[4]arene and its sulfur-bridged analogue. These studies substantiated
that this type of NMCs have potential to precisely discriminate molecules not only by the difference in
the stabilities of their inclusion crystals (thermodynamic factor) but also by the difference in the
activation energies for the structural change of the crystal packing (kinetic factor).
The success in discriminating the achiral compounds with the calixarene crystals motivated us to
extend this methodology to a chiral system. In relation to this, Toda et al. have reported a pioneering
work of the enantioselective inclusion of chiral compounds with crystals of tartaric acid derivatives.13
Crystals of acyclic hosts, such as amino acids, steroids, and carboxylate salts of chiral amines, have also
been employed for the enantioselective inclusion of racemic alcohols and sulfoxides.14 These are based
on the formation of a clathrate-type inclusion crystal, in which guest molecules are disposed in the host
lattice. On the other hand, to the best of our knowledge, there is no precedent of chiral recognition based
on the formation of a complex-type inclusion crystal constructed by discrete host/guest complexes like
the inclusion crystals of calix[4]arenes.15
Cyclodextrins (CDs) are representative chiral hosts widely used as chiral discriminators, such as those
of chiral stationary phases for HPLC.16,17 However, research on the optical resolution through the
3

formation of inclusion crystals with CDs is scarce in the literature.18 In addition, there is no report on the
inclusion of chiral compounds with CD crystals, despite the fact that the crystals have been used to
include chlorinated aromatic compounds,19 volatile organic compounds (e.g., aniline and toluene),20 and
other achiral compounds.21 This is partly because inclusion crystals of CDs adopt a variety of packing
structures;16b,c,22 as a result, the uniformity of the packing structure, which is necessary to achieve high
guest selectivity, cannot be secured. Yet another reason may be that it is difficult to fix the orientation of
guest molecules in the large hydrophobic cavities of CDs with no coordinating groups. In this paper, we
wish to report that crystals of
α-CD enantioselectively include amino acids by converting the amino
acids into sulfonate salts with bulky pyrene-1-sulfonic acid (chart 1).
Chart 1
4

2. Results and Discussion
Enantioselective inclusion of arylsulfonate salts of α-amino acids with crystals of α-CD was carried
out as follows. Powdery crystals of
α-CD were suspended in an ethanol solution of a racemic
arylsulfonate salt, which was prepared in advance by the reaction of a DL-amino acid with a small
excess of an arylsulfonic acid (1.05 molar equiv), and the suspension was stirred at a fixed temperature
until inclusion reached equilibrium (24–48 h). The resulting crystals were collected by filtration and
1
analyzed by H NMR spectroscopy to determine the inclusion ratio (nꢀ), which is defined as the mean
number of guest molecules included into the crystals per
α
-CD molecule. The arylsulfonate salt was
1
desorbed from the crystals by guest exchange with ethanol; H NMR analysis of the resulting crystals
revealed that they contained no arylsulfonate salt of the amino acid, i.e., the guest exchange was
quantitative. The enantiomeric excess (ee%) of the amino acid was determined by HPLC analysis on a
chiral stationary phase, after conversion into the N-benzyloxycarbonyl (Cbz) derivative.
First, the inclusion of arylsulfonate salts of DL-leucine (Leu) was investigated, varying the sulfonic
acid (Table 1). The p-toluenesulfonate salt of DL-Leu was included with nꢀ of ~1.0 from a 0.80 M
solution of the racemic salt in ethanol (entry 1); an ethanol molecule was coinlcluded into the crystals.
The nꢀ value indicates the formation of a 1:1 (host/guest) inclusion complex. The L-isomer was slightly
enriched in the crystals (6%ee). The enantioselectivity was improved to 14%ee and 25%ee by changing
the acid to 1- and 2-naphthalenesulfonic acid, respectively (entries 2 and 3). Further increase in the
bulkiness of the sulfonic acid by replacing the aryl group with a 1-pyrenyl group afforded good
enantioselectivity (79%ee) with almost quantitative inclusion (nꢀ = ~1.0) (entry 4). The bulky and rigid
sulfonic acid seems to fix the orientation of the D- and L-Leu molecules in the cavity of α-CD, which
enables the precise discrimination of the two enantiomers, though the structures of the resulting
diastereomeric inclusion complexes could not be determined in this study.
5

Table 1. Inclusion of arylsulfonate salts of DL-Leu with crystals of
α
-CDa
nꢀ
entry
sulfonic acid
ee% (L)
sulfonic
acid
Leu
EtOH
1.01
1
2
0.92
0.93
1.04
6
1.06
0.44
1.03
1.86
0.95
2.40
14
3b
4
0.44
1.05
25
79
a Conditions: powdery crystals of
α-CD (51.4 ꢀmol), a sulfonate salt of DL-Leu (0.80 M),
EtOH (1.1 mL), 30 °C, 24 h. b 0.34 M sulfonate salt was used because of its low solubility
in EtOH.
The inclusion conditions were further investigated for the Leu salt of pyrene-1-sulfonic acid (PyS)
(Table 2). We found that the concentration of the sulfonate salt in ethanol is a key parameter for the
enantioselective inclusion. The inclusion from a low concentration solution (0.09 M) showed poor
selectivity (27%ee) with a low nꢀ value (~0.15) (entry 1). The enantioselectivity and nꢀ value increased
with increasing the concentration and reached to 79%ee and ~1.0, respectively, at the concentration of
0.80 M (entries 2–5). These results indicate that the concentration of the salt changes the partition ratios
of the D- and L-enantiomers between the solid and liquid phase at different magnitudes, which causes a
change in the enantioselectivity of Leu.
6

Table 2. Effect of salt concentration on the enantioselectivity for the
inclusion of DL-Leu/PyS salt with crystals of α
-CDa
nꢀ
[DL-Leu/PyS salt]
entry
(M)b
ee% (L)
Leu
PyS
0.16
0.33
0.63
0.76
1.05
EtOH
1.01
1.12
1.90
2.34
2.40
1
0.09
0.23
0.42
0.61
0.80
0.15
0.32
0.63
0.77
1.03
27
58
69
71
79
2
3
4
5c
a Conditions: powdery crystals of
α-CD (51.4 ꢀmol), EtOH (1.1 mL), 30 °C, 24 h.
b Initial concentration of DL-Leu/PyS salt. c Data from Table 1 (entry 4).
We envisaged that the enantioselectivity would be tuned by solvent because the partition ratios of the
two enantiomers between the solid and liquid phase may be changed at different magnitudes also by
solvent polarity. In relation to this, we recently succeeded in switching the guest selectivity in the
competitive inclusion between dimethylamine and trimethylamine with crystals of p-tert-
butylthiacalix[4]arene by changing solvent polarity.12c We then examined the effect of solvent polarity
on the enantioselectvity in the inclusion of Leu/PyS salt, using ethanol/N-methylformamide (NMF)
(Table 3). Solvent permittivity (
ε) was used as a measure of solvent polarity, which was varied by
changing the volumetric ratio of the two components.23–25 The enantioselectivity in the inclusion of
Leu/PyS salt increased with increasing the solvent permittivity and reached a plateau (89%ee) at
38.6 and then decreased with further increasing the solvent permittivity (entries 1–5). The use of
methanol ( = 32.6), instead of ethanol/NMF (95:5) ( = 31.8), drastically decreased the enantiopurity
with the coinclusion of methanol (entry 6 compared with entry 2). This indicates that the
enantioselectivity is also affected by the molecular structure of the solvent coincluded in the -CD
crystals; a similar observation has been made in a crystallization-based optical resolution of a
ε =
ε
ε
α
7

diastereomeric binaphthalene.26 Increasing the temperature to 40 °C slightly improved the
enantioselectivity (92%ee) in the ethanol/NMF with a volumetric ratio of 91:9 (entry 7).
Table 3. Dependence of the enantioselectivity on solvent permittivity (ε) for the inclusion of
DL-Leu/PyS salt with crystals of
α
-CDa
nꢀ
entry
solvent
ee% (L)
ε
Leu
PyS
1.05
1.07
1.00
1.05
1.04
0.51
1.06
alcohol
2.40
2.49
1.18
2.00
1.10
1.52
1.25
NMF
–
1b
2
EtOH
24.3
31.8
38.6
42.4
55.8
32.6
38.6
1.03
1.03
1.01
1.04
1.01
0.52
1.03
79
84
89
83
69
50
92
EtOH/NMF (95:5)
EtOH/NMF (91:9)
EtOH/NMF (88:12)
EtOH/NMF (80:20)
MeOH
0.91
1.43
1.57
1.82
–
3
4
5
6
7c
EtOH/NMF (91:9)
1.34
a Conditions: powdery crystals of
α-CD (51.4 ꢀmol), DL-Leu/PyS salt (0.80 M), solvent (1.1 mL),
30 °C, 24–48 h. b Data from Table 1 (entry 4). c At 40 °C.
Enantioselective inclusion of PyS salts of various amino acids was investigated (Table 4); on the basis
of the findings described above, experimental parameters, i.e., salt concentration, solvent and its polarity,
and temperature, were optimized for each amino acid. Valine (Val) exhibited high enantioselectivity
(82%ee) toward the L-isomer with nꢀ of ~1.0 (entry 1). Interestingly, the addition of an excess amount of
PyS improves the enantioselectivities of some amino acids, giving inclusion crystals containing about
two or four times excess of PyS over the amino acids. For example, phenylalanine (Phe) was not
included as the PyS salt in α-CD crystals but solely precipitated from a Phe/PyS (1:1) salt solution (0.41
M) in ethanol/DMF (10:1). However, the addition of PyS (3.5 molar equiv) suppressed the precipitation
and afforded inclusion crystals with a molar ratio of 1.6 (PyS/Phe) with 86%ee (D) (entry 2). The
enantioselectivity of methionine (Met) was improved from 40%ee to 86%ee by the addition of PyS (1.0
8

molar equiv) (entries 3 and 4). A similar observation was made for norvaline (Nva) and tryptophan
(Trp) but the enantioselectivities after the addition of PyS were poor to moderate (entries 5–8).
Table 4. Enantioselective inclusion of PyS salts of various amino acids with crystals of α
-CDa
n
ꢀ
[DL-amino
acid/PyS
salt] (M)
amino
acid
temp
(°C)
entry
solvent
ee%b
amino
acid
PyS
1.13
EtOH
3.15
cosolvent
EtOH/
DMSO
(10:2)
1
Val
Phe
Met
Met
Nva
Nva
Trp
Trp
0.80
0.41
0.59
0.65
0.65
0.40
0.30
0.80
30
70
30
50
30
30
50
50
1.12
0.57
0.91
0.31
0.93
0.51
0.72
0.78
3.75
1.10
4.90
4.26
4.40
4.02
4.02
3.48
82 (L)
86 (D)
40 (L)
86 (L)
13 (L)
44 (L)
0
EtOH/
DMF
(10:1)
2c
3
0.91
0.92
1.25
1.05
1.10
0.42
1.40
0.61
2.61
0.92
1.82
0.97
0.80
1.24
EtOH/
DMSO
(10:5)
EtOH/
DMSO
(10:5)
4d
5
EtOH/
DMSO
(10:5)
EtOH/
DMSO
(10:5)
6d
7
EtOH/
NMF
(10:32)
EtOH/
DMSO
(10:5)
8d
12 (L)
a
Conditions: powdery crystals of
α-CD (51.4 ꢀmol), DL-amino acid/PyS salt, solvent (1.1–1.3 mL),
c
b
24 h. The major enantiomer is shown in parentheses. PyS (3.5 molar equiv to DL-Phe/PyS salt) was
added. d PyS (1.0 molar equiv to the DL-amino acid/PyS salt) was added.
9

We have found that the ee% values of the Leu, Val, and Met salts with PyS in α-CD crystals increase
with time during the inclusion under the optimized conditions (entry 3 in Table 3 for Leu, entries 1 and
4 in Table 4 for Val and Met, respectively). In the early stage of the inclusion of Leu/PyS salt, almost
racemic Leu/PyS salt was included in the α-CD crystals with an excess of PyS (entry 1 in Table 5). The
D-amino acid salt was then gradually desorbed, whereas the L-counterpart was continuously absorbed,
increasing the ee% value to reach 89% (entries 2–4); the molar ratio of PyS to Leu decreased to reach 1
with this change. In each case of Val/PyS and Met/PyS salts, the inclusion ratio of the L-amino acid salt
was almost constant throughout the experiment, whereas that of the D-counterpart decreased with time,
resulting in the selective inclusion of the L-amino acid salt (Tables S1 and S2); the molar ratio of PyS to
the amino acid decreased to reach 1 for Val and increased to reach 4 for Met with this change. These
changes in nꢀ and the PyS/amino acid ratio strongly suggest the inclusion approaching equilibrium.
Therefore, we concluded that the enantioselectivities for these amino acids were controlled by
thermodynamics.
Table 5. Time dependence of the inclusion ratios and enantioselectivity for the
inclusion of Leu/PyS salt with crystals of
α
-CDa
ꢁꢀ
entry
time (h)
ee% (L)
L-Leu D-Leu PyS
EtOH NMF
1
2
3
0.5
6
0.34
0.44
0.51
0.95
0.28
0.20
0.19
0.05
0.83
0.69
0.55
1.15
1.60
1.18
1.13
0.91
1.07
1.43
10
38
45
89
12
24
0.74
4b
1.00
a
Conditions: powdery crystals of
α
-CD (51.4 ꢀmol), DL-Leu/PyS salt (0.80 M),
EtOH/NMF (91:9) (1.3 mL), 30 °C. b Data from Table 3 (entry 3).
10

We next investigated the interaction between amino acid/PyS salts and
for the complexation of D- and L-Leu/PyS salts with -CD in D2O. They revealed that both the D- and
L-salts form 1:1 inclusion complexes with -CD. The association constants (Ka) of the enantiomeric
α-CD. Fig. 1 shows Job’s plots
α
α
Fig. 1. Job’s plots for the complexation of α-CD
with D-Leu/PyS (a) and L-Leu/PyS (b) in D2O.
The sum of the total concentrations of the host
[H]0 and guest [G]0 was adjusted to 10 mM. ∆
δ
denotes the difference in the chemical shift values
of a Leu signal in the presence and absence of
CD.
α-
Leu salts with
α-CD were then calculated, according to the Benesi-Hildebrand equation for 1:1
(host/guest) complexation (eq. 1).27
ꢂ
ꢂ
ꢂ
=
+
ꢃ ꢄ
ꢅ
(1)
ꢃꢄ
ꢃ ꢄꢆ [ꢈ]
ꢅ
ꢇ
ꢅ
Where [H]0 is the total concentration of
α
-CD, and ꢁδ and ꢁ0δ are the difference in the chemical shift
-CD and that between free and complexed states,
values of a Leu signal in the presence and absence of
α
11

respectively; the methyl signal of Leu was used for the analysis. The 1/ꢁδ against 1/[H]0 plots exhibited
linear relationships (Fig. 2), from the slopes and y-intercepts of which Kas were calculated to be 2.84 ×
1
10 mol−1 for L-Leu/PyS and 2.71 × 10 mol−1 for D-Leu/PyS. The H NMR experiments were also
carried out for Val. Job’s plots exhibited the formation of 1:1 inclusion complexes for D- and L-Val/PyS
salts with α-CD in D2O (Fig. S1) but their association constants could not be determined because of
very small peak shifts upon complexation. The small difference in Ka between D- and L-Leu/PyS salts,
combined with the fact that the inclusion selectivity exhibited a time-dependent change characteristic of
an equilibrium system (vide supra), indicates that the enantioselective inclusion originates from the
Fig 2. 1/ꢁδ vs 1/[H]0 plots for D-Leu/PyS·salt (a)
and L-Leu/PyS salt (b) in the complexation with
α
-CD. Conditions: [G]0 = 2 mM, [H]0 = 6–80
mM, D2O.
12

difference in stability between the inclusion complexes of D- and L-Leu/PyS salts with α-CD in crystal
lattices, i.e., not discrete inclusion complexes, which confirms the validity of the present chiral
discrimination method using a crystalline phase.
One may suspect that amino acids are not included in
α-CD crystals as PyS salts. To investigate how
amino acids are included in the crystals, FT-IR analysis was carried. Fig. 3 shows IR spectra measured
by the KBr pellet method for
α-CD, Leu, Leu/PyS salt, and inclusion crystals of Leu/PyS. In the IR
spectrum of
α
-CD (Fig. 3a), a broad absorption is observed at 1643 cm−1, which is assigned to the H–
O–H bending vibration of H2O molecules included in the crystals.28 Zwitterionic Leu shows a stretching
vibration for the carboxylato group and bending vibration for the ammonio group at 1617 and 1589
cm−1, respectively (Fig. 3b). In the spectrum of Leu/PyS salt (Fig. 3c), the C=O stretching vibration
appears at a considerably higher wavenumber (1751 cm−1) than that of Leu, indicating that the carboxyl
group was liberated by the sulfonic acid with stronger acidity. This absorption somewhat shifted to a
lower wavenumber side (1662 cm−1) upon inclusion into
α
-CD (Fig. 3d). This is attributable to the
-CD. Similar observations were made for
-CD appeared at almost the
same wavenumber as that of Met/PyS salt. These results clearly indicate that the amino acids are
included in -CD as PyS salts. However, the IR analysis did not uncover the role of PyS in excess of the
amount used for the 1:1 salt formation with Met.
association of the carboxy group with hydroxy group(s) of
α
Met (Fig. S2), except that the C=O stretching vibration of Met included in
α
α
13

Fig. 3. FT-IR spectra of α-CD (a), Leu (b), Leu/PyS
(c), and inclusion crystals of Leu/PyS (d) measured
by the KBr pellet method. The inclusion crystals
were prepared under the optimized conditions (entry
7 in Table 3).
In CD chemistry, powder X-ray diffraction (PXRD) analysis is a useful technique to know the
arrangement of CD molecules in crystals.16b,c,29–32 Fig. 4 shows the PXRD patterns of the host crystal
and inclusion crystals prepared under the conditions optimized for the individual salts in the competitive
inclusion experiments. The PXRD patterns of the
α
-CD crystal and the inclusion crystal of Leu/PyS salt
= ~10, 14, and 22° (Fig. 4a,b);30–
have three peaks characteristic of a cage-type structure (Fig. 5a) at 2
θ
32 the difference between the two PXRD patterns can be attributed to some change in the arrangement of
the cage-type structure through the inclusion of Leu/PyS salt. On the other hand, the inclusion crystals
of PyS salts of Val, Phe, and Met exhibit a strong diffraction at 2θ = ~20° (Fig. 4c–e), which is
characteristic of a channel-type structure (Fig. 5b).29,31 Although the packing structures must have an
intimate relation to the observed stereoselectivities, as well as the inclusion ratios of the amino acids and
PyS, we could not investigate the relationship because the inclusion complexes did not give single
crystals suitable for X-ray analysis.
14

Fig. 4. PXRD patterns of α-CD (a) and inclusion
crystals of Leu/PyS (b), Val/PyS (c), Phe/PyS (d),
and Met/PyS (e) prepared under the same
conditions optimized for each salt (entry 7 in
Table 3 for Leu/PyS, and entries 1, 2, and 4 in
Table 4 for Val/PyS, Phe/PyS, and Met/PyS,
respectively). Amino acids were used as a racemic
modification.
Fig. 5. Schematic representation for the crystal
structures of
type.
α-CD: (a) cage-type and (b) channel-
3. Conclusion
We have shown here that crystals of
α
-CD include
α
-amino acids with high enantioselectivity by
1
converting the amino acids into sulfonate salts with bulky PyS. H NMR experiments and time course
15

analysis of the ꢁꢀ and ee% values revealed that the selectivity is originated from the difference in
stability between the resulting diastereomeric inclusion complexes of D- and L-amino acid/PyS salts
with α-CD in crystals. This study provides the first example of chiral recognition using an NMC with
porosity without pores through a transition into complex-type inclusion crystals constructed by discrete
host/guest complexes. Further studies on improving the crystallinity of the inclusion complexes by the
chemical modification of α-CD are in progress to clarify the host/guest interaction in crystals.
4. Experimental
4.1. General
1H NMR spectra were recorded on a Bruker Avance-400 spectrometer using D2O as the solvent.
PXRD data were collected on a Rigaku RINT-2200VHF powder X-ray diffractometer using Cu–K
radiation at increments of 0.02° and an exposure time of 1.2 s/step in an angular range (2θ) of 3–30° at
room temperature. -CD crystals were purchased from FUJIFILM Wako Chemicals. Pyrene-1-sulfonic
α
α
acid was prepared by the reaction of pyrene with chlorosulfonic acid, according to the literature
procedure.33 Other materials were used as purchased. Sulfonate salts of amino acids were prepared as
follows. A mixture of a DL-amino acid and arylsulfonic acid (1.05 molar equiv) was stirred in
methanol/H2O (1:1) at 60 °C overnight to give a clear solution. After the solvent was evaporated, the
resulting powder was dried in vacuo (0.5–1.0 kPa) at 70 °C for 2 h to give the sulfonate salt of the
amino acid. The ee% values of amino acids were determined by HPLC analysis on a Daicel
CHIRALCEL OD-H (250 mm × 4.6 mm i.d.), CHIRALPAK AD-H (250 mm × 4.6 mm i.d.), or
CROWNPAK CR-I (+) (150 mm × 3.0 mm i.d.).
4.2. Typical procedure for the inclusion of a sulfonate salt of an amino acid with crystals of
α-CD
Powdery crystals of -CD (50.0 mg, 51.4 µmol) were placed in a screw cap vial equipped with a stir
α
bar and suspended by the addition of a solution of DL-Leu/PyS salt (364 mg, 880 µmol) in ethanol (1.1
16

mL). The suspension was stirred at 30 °C for 24 h, and the resulting crystals were collected by filtration
and dried in vacuo (0.5–1.0 kPa) at room temperature for 2 h. A portion of the crystals was dissolved in
D2O and analyzed by 1H NMR spectroscopy, which determined the nꢀ value to be ~1.0 (entry 4 in Table
1). The enantiomeric excess (ee%) of the Leu included in the crystals was determined as follows. The
residual inclusion crystals were suspended in ethanol/acetonitrile (1:10) at room temperature for 2 h and
the crystals were collected by filtration. This manipulation was repeated four times to desorb the
Leu/PyS salt from the crystals via guest exchange with ethanol. The resulting crystals were analyzed by
1H NMR spectroscopy, indicating that no Leu/PyS salt was left in the crystals. The combined filtrate
was evaporated to leave a residue, which was treated with benzyl chloroformate according to the
literature procedure34 to give N-bezyloxycarbonylleucine (Cbz-Leu). The enantiopurity of the Cbz-Leu
was determined to be 79%ee (entry 4 in Table 1) by HPLC analysis on a Daicel CHIRALCEL OD-H
using 2-propanol/hexane/TFA (15:85:0.1) as the eluent: flow rate = 0.5 mL/min, 30 °C,
(Cbz-L-Leu) = 9.8 min, t (Cbz-D-Leu) = 14.3 min.
λ = 254 nm, t
The ee% values of other amino acids were determined after conversion into their Cbz derivatives by
HPLC. The analysis conditions are as follows. Val: CHIRALCEL OD-H, 2-propanol/hexane/TFA
(10:90:0.1), flow rate = 0.5 mL/min, 30 °C,
min. Phe: CHIRALPAK AD, 2-propanol/hexane/TFA (10:90:0.1), flow rate = 0.5 mL/min, 30 °C,
254 nm, t (Cbz-L-Phe) = 43.4 min, t (Cbz-D-Phe) = 52.1 min. Met: CHIRALCEL OD-H, 2-
propanol/hexane/TFA (15:85:0.1), flow rate = 0.5 mL/min, 30 °C, = 254 nm, t (Cbz-L-Met) = 13.8
min, t (Cbz-D-Met) = 19.5 min. Nva: CHIRALCEL OD-H, 2-propanol/hexane/TFA (15:85:0.1), flow
rate = 0.5 mL/min, 30 °C, = 254 nm, t (Cbz-L-Nva) = 12.9 min, t (Cbz-D-Nva) = 32.2 min. Trp:
λ = 254 nm, t (Cbz-L-Val) = 11.7 min, t (Cbz-D-Val) = 43.6
λ
=
λ
λ
CROWNPAK CR-I(+), aq HClO4 (pH 1.5)/acetonitrile (80:20), flow rate = 0.2 mL/min, 30 °C,
nm, t (L-Trp) = 9.1 min, t (D-Trp) = 16.6 min.
λ
= 200
Acknowledgments
17

This work was supported by JSPS KAKENHI Grant Number 18K05070.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/xxxx.
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22

Highlights:
ꢀ Enantioselective inclusion of
α-amino acids with crystals of α-cyclodextrin (α-CD) has been
achieved by converting the amino acids into sulfonate salts with pyrene-1-sulfonic acid (PyS).
ꢀ Under conditions optimized for individual amino acids, the PyS salts of leucine, valine,
phenylalanine, and methionine are included with good enantioselectivities (up to 92%ee).
ꢀ The enantioselectivity originates from the difference in stability between the inclusion complexes of
D- and L-leucine/PyS salts with α-CD in crystals.
1

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: