Enantioselective inclusion of (R)-phenylglycyl-(R)-phenylglycine with benzyl methyl sulfoxides

Article abstract of DOI:10.1016/j.tet.2004.10.032

A crystalline dipeptide, (R)-phenylglycyl-(R)-phenylglycine (RR-1), recognized p-halobenzyl methyl sulfoxides with high R-enantioselectivity (86-99% ee) to form inclusion compounds. The single-crystal X-ray analyses showed that RR-1 molecules are arranged in parallel and zigzags via hydrogen bonding to construct a pleated sheet. The guest molecules that form hydrogen bond with ⁺NH₃ of RR-1 are accommodated in the channel cavity between the layers. In contrast to the inclusion crystals of parent benzyl methyl sulfoxide, in which a rectangular cavity is formed, the cavity including p-halobenzyl methyl sulfoxides becomes rhomboidal. We also examine the guest exchange in these inclusion compounds and it was found that the guest exchanges occur when the host structure changes. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.10.032

Tetrahedron 60 (2004) 12085–12093
Enantioselective inclusion of (R)-phenylglycyl-(R)-phenylglycine
with benzyl methyl sulfoxides
b
a,b,
Motohiro Akazome,a, Atsushi Hirabayashi and Katsuyuki Ogura
*
*
aDepartment of Materials Technology, Faculty of Engineering, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
bGraduate School of Science and Technology, Chiba University, 1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
Received 6 September 2004; accepted 8 October 2004
Available online 28 October 2004
Abstract—A crystalline dipeptide, (R)-phenylglycyl-(R)-phenylglycine (RR-1), recognized p-halobenzyl methyl sulfoxides with high
R-enantioselectivity (86–99% ee) to form inclusion compounds. The single-crystal X-ray analyses showed that RR-1 molecules are arranged
in parallel and zigzags via hydrogen bonding to construct a pleated sheet. The guest molecules that form hydrogen bond with CNH3 of RR-1
are accommodated in the channel cavity between the layers. In contrast to the inclusion crystals of parent benzyl methyl sulfoxide, in which a
rectangular cavity is formed, the cavity including p-halobenzyl methyl sulfoxides becomes rhomboidal. We also examine the guest exchange
in these inclusion compounds and it was found that the guest exchanges occur when the host structure changes.
q 2004 Published by Elsevier Ltd.
1. Introduction
X-ray analyses, we elucidated the sheet structure of RR-1,
the host-guest interactions, and the origin of the chiral
discrimination. In the inclusion crystals of aryl methyl
sulfoxides, the size and the shape of the included sulfoxides
induced several motifs of benzene–benzene interaction of
RR-1 to create the cavity suitable for one enantiomer of the
Many kinds of organic host molecules that construct a three-
dimensional rigid network or a two-dimensional framework
in a crystal have been designed to include guest molecules.1,
2 However, there are only a few reports on the organic host
molecules that form a precise two-dimensional network
(sheet structure) followed by the inclusion of a guest
molecule.3 Ward and his co-workers developed pillared
two-dimensional hydrogen-bonded networks comprising
guanidinium ions and disulfonate ions, in which the
disulfonate ions act as pillars that connect opposing
hydrogen-bonded sheets with adjustable porosity.4 About
ten years ago,5 we found that a simple dipeptide,
(R)-phenylglycyl-(R)-phenylglycine (RR-1), forms an
inclusion crystal with a sheet structure. The straight
glycylglycine backbones of dipeptide (RR-1) are arranged
in parallel to construct a two-dimensional flat layer by
means of intermolecular salt formation between COOH and
NH2 group (Fig. 1). The phenyl groups stand perpendicular
to the layer to form a chiral cavity for molecular
recognition.
It was also reported by us that RR-1 included several
sulfoxides, which have a chiral center on the sulfur atom,
with high enantioselectivity.6 Based on their single-crystal
Keywords: Inclusion compounds; Peptides; Sulfoxides; Enatiomeric
recognition; Guest exchange.
* Corresponding authors. Tel.: C81 43 290 3388; fax: C81 43 290 3402;
e-mail: katsuyuki@faculty.chiba-u.jp
Figure 1. (a) Structure of (R)-phenylglycyl-(R)-phenylglycine (RR-1).
(b) Sheet structure of dipeptide backbone.
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.10.032

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M. Akazome et al. / Tetrahedron 60 (2004) 12085–12093
sulfoxide by altering the phenyl conformation.6a As
a typical example, the structure of benzyl methyl sulf-
oxide-included crystal of RR-1 is shown in Figure 2.6b
In this inclusion compound, two conformers (vide infra) of
RR-1 are present; consequently the cavities on the upper and
lower sides of the sheet are suitable for the (S)-enantiomer
and (R)-enantiomer, respectively. Since both enantiomers of
benzyl methyl sulfoxide were simultaneously included, the
stereochemistry of recognition became totally
nonenantioselective.
2. Results and discussion
2.1. Enantioselective inclusion of p-substituted benzyl
methyl sulfoxides
Since (R)-phenylglycyl-(R)-phenylglycine (RR-1) is inso-
luble in water and common organic solvents, we obtained an
aqueous solution of RR-1 by carefully neutralizing its acidic
solution (see Section 4). After a methanolic solution of
p-halobenzyl methyl sulfoxide (G1-X, XZF, Cl, Br, or I;
2.2 equiv) was added, the resulting mixture was allowed to
stand for several days. The deposited inclusion crystals,
RR-1$G1-F, RR-1$G1-Cl, RR-1$G1-Br, and RR-1$G1-I,
were collected by filtration and washed with chloroform and
water. The results are summarized in Table 1, which shows
van der Waals radii7 of the halogen substituent, enantios-
electivity, inclusion efficiency (Ef.), and decomposition
temperature (Dec.) measured by TG-DTA. The inclusion
efficiency means the molar ratio of the guest molecule to the
RR-1 molecule in the inclusion compound determined by 1H
NMR. In all cases examined here, the inclusion efficiencies
were 1.00, meaning that a 1:1 inclusion compound was
formed. Enantiomeric excess of the sulfoxide was measured
by chiral HPLC analysis. In any case, the included
p-halobenzyl methyl sulfoxide showed good to high
R-enantioselectivity (86–99% ee). It is noteworthy that
among the inclusion compounds RR-1$G1-F showed the
highest decomposition temperature (190 8C). This is most
likely attributable to significant intermolecular interactions
between the guest molecule and the host framework, which
are disclosed by its crystal structure (vide infra).
As seen from Figure 2, benzyl methyl sulfoxide is fit in size
enough to fill the rectangular cavities above and below the
flat sheet structure of RR-1. If a halogen atom is substituted
at the para-position of the benzyl group, it would receive
steric hindrance and electrostatic repulsion from the phenyl
groups of RR-1 to distort the inclusion cavity for the
inclusion of p-halobenzyl methyl sulfoxides. With this
consideration in mind, we investigated the formation of
inclusion crystals from RR-1 and p-halobenzyl methyl
sulfoxides. Here, we report that the p-halobenzyl methyl
sulfoxides are included in novel cavities, which are different
from those of benzyl methyl sulfoxide-included crystals,
with high R-enantioselectivity. We also report whether the
guest molecules are exchanged in these inclusion
compounds.
2.2. Crystal structures of inclusion compounds of
p-halobenzyl methyl sulfoxides
In the present work, we obtained three inclusion com-
pounds, RR-1$G1-F, RR-1$G1-Br and RR-1$G1-I, as single
crystals suitable for X-ray crystallographic analysis.
Inclusion crystals of RR-1$G1-F has a space group
P212121, but those of RR-1$G1-Br and RR-1$G1-I are
isostructural and their space groups are P21. Their top views
of sheet structures show that p-halobenzyl methyl sulfoxides
(guests) were accommodated in the channel between the
walls that are constructed by the stacked benzene rings of
RR-1 (Fig. 3).
Table 1. Enantioselective inclusion of benzyl methyl sulfoxides by RR-1
a
VDW of X (A)
˚
Entry
G1-X
XZ
RR-1$G1-X
Ef.b (%)
ee (%)
Dec.c (8C)
1
H
F
Cl
Br
I
1.20
1.47
1.75
1.85
1.98
100
100
100
100
100
Rac.d
99 (R)
86 (R)
96 (R)
95 (R)
177
190
173
179
188
2
3
4
5
a Ref. 7.
b Efficiency means mol% of the guest based on the dipeptide in the
inclusion compound.
Figure 2. Inclusion compound of RR-1 (host: backbones in black and
phenyl groups in white) and racemic benzyl methyl sulfoxide (guest in
gray). (a) Side view of layer structure with rectangular cavity (ball and stick
model). (b) Top view of sheet structure (space-filling model).
c Dec. is a decomposition temperature measured by TG-DTA.
d Rac. means enantioselectivity within 10%.

M. Akazome et al. / Tetrahedron 60 (2004) 12085–12093
12087
Figure 4. Dipeptide backbone and atomic distances of intermolecular
hydrogen bonds.
to form another important intermolecular hydrogen bond
(C in Fig. 4), as described below.
Figure 5 shows the included sulfoxide molecule surrounded
by RR-1 molecules. All of RR-1 molecules in the present
inclusion crystals with p-halobenzyl methyl sulfoxides
adopt the similar conformations (conformer I), which are
quite different from those (conformers IIa and IIb) in
RR-1$G1-H (also see Fig. 2). In both of conformer I and
conformer II, the conformations of the N-terminal phenyl-
glycyl moiety are similar; the amide oxygen contacts with
the ammonium hydrogen to provide a well-known five-
membered ring.9,10a In conformer I, the C-terminal
a-hydrogen is close to the amide oxygen and the
carboxylate oxygen. This type of intramolecular C–H/O
hydrogen bonding was often found in the crystals of amino
acids and peptides.10 As a result, the amide hydrogen is free
from the intramolecular hydrogen bonding and contributes
to the intermolecular hydrogen bonding (Bond C in Fig. 4).
In other words, the hydrogen bonding (C) observed in
conformer I compensates the loss of contact between
hydrogen of the amide linkage and the oxygen of the
carboxylate that is seen in conformer II. From the space-
filling models of the inclusion crystals (Fig. 3), it is apparent
that the phenyl groups of RR-1 stack each other in an edge-
to-face manner to construct a wall on the glycylglycine
pleated sheet. These benzene–benzene interactions are seen
in natural proteins11 as well as artificial supramolecular
aggregates.12
Figure 3. Top views of sheet structure of inclusion crystals (CPK model).
(a) RR-1$G1-F. (b) RR-1$G1-Br. (c) RR-1$G1-I.
Interestingly, RR-1 molecules constructed a pleated sheet in
all of the inclusion crystals. The detailed description of the
hydrogen bonding is given in Figure 4. As shown in
Figure 4, the glycylglycine backbone of dipeptide as the
hosting frame arranged in parallel and zigzags to construct a
novel pleated sheet. Intermolecular distances of hydrogen
bonding are comparable in three RR-1$G1-F, RR-1$G1-Br
and RR-1$G1-I. These sheets involve ionic pairing of
carboxyl and amino groups via hydrogen bonding network
(hydrogen bonding A and B in Figure 4): one terminal
COOK contacts with two CNH3 of adjacent dipeptides at
both oxygen sites and, inversely, the CNH3 are also bound
to two adjacent COOK groups (O/N). This hydrogen
bonding mode of RR-1 is also seen in the flat sheet of RR-1
inclusion crystals of alkyl phenyl sulfoxide5,6 as well as
the ether-included (R)-naphthylglycyl-(R)-phenylglycine
crystals.8 It is noteworthy that the present pleated sheet
structure by zigzag arrangement of RR-1 makes it possible
As mentioned above, p-halobenzyl methyl sulfoxides were
recognized in the rhomboidal cavities of RR-1 (also see
Fig. 6). The guest molecules were linked to CNH3 of RR-1
via hydrogen bonding and accommodated between the
adjacent walls of phenyl groups of RR-1 on the pleated
layer. The distances between the ammonium nitrogen and
the sulfinyl oxygen are listed in the table of Figure 4.
Besides hydrogen bonding, benzene–benzene edge-to-face
interaction plays an essential role in the inclusion of the

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M. Akazome et al. / Tetrahedron 60 (2004) 12085–12093
Figure 5. Crystal structure of recognition sites. The list of selected atomic distances and torsion angles of RR-1. (a) RR-1$G1-X (XZF, Br, I). (b) RR-1$G1-H.
guest molecules. These interactions are shown in dotted
lines in Figure 5. The methyl hydrogen of the guest
approaches to the center of another benzene ring of the host
to make weak contact between them as well as RR-1$G1-H.
crystals makes two G1-F molecules on the faced sheets be
paired in an anit-parallel mode. This realizes the edge-to-
face benzene–benzene interaction between the paired G1-F
molecules (shown by a circle in Fig. 6). Furthermore, the
fluorine atom is close (2.59 A) to the para-hydrogen of the
RR-1 phenyl group of the faced sheet. This distance is
smaller than the sum of van der Waals radii of the hydrogen
˚
and fluorine atoms (1.20 and 1.47 A, respectively). These
interactions seem to contribute to the stability of the
RR-1$G1-F crystals.13
˚
Here, we wish to define the direction of the pleated sheet by
the direction of the arranged RR-1 molecules from their
N-terminal to C-teminal. Interestingly, the sheets in
RR-1$G1-Br and RR-1$G1-I are arranged in a parallel
fashion, while those of RR-1$G1-F are in anti-parallel
(Fig. 6). These sheet arrangements are reflected in the space
groups (P21 and P212121, respectively) of the crystals. The
anti-parallel arrangement of the sheets in RR-1$G1-F
In contrast, RR-1$G1-Br and RR-1$G1-I inclusion crystals
do not exhibit so intimate C–H/halogen interaction; the

M. Akazome et al. / Tetrahedron 60 (2004) 12085–12093
12089
˚
˚
(1.85C1.80) A and 3.78 (1.98C1.80) A, respectively.
Although the S–O bond of a sulfinyl group is so polar that
the electron-deficient sulfinyl sulfur atom is known to serve
as a counter for a halogen substituent,14 this is not the case.
Thus, these findings seem to show that the kind of halogen
of the guest plays an important role in the formation of the
inclusion crystals.
2.3. Guest exchange in inclusion crystals of RR-1
With several inclusion crystals of RR-1 and p-halobenzyl
methyl sulfoxides in hand, we were interested in the guest
exchange in these crystals, which would reveal how strong
the host framework interacts with the guest molecules.
Fischer’s lock-and-key model shows that polypeptides as
enzymatic proteins catch their own substrate selectively and
the product was easily exchanged with the upcoming
substrate after the catalytic reaction in the cavity. Similarly,
guest exchange processes of inclusion compounds are
important for sensing and catalytic process of inclusion
crystals in the solid phase. In such a crystal lattice inclusion
by solid hosts, the guest exchange in solid inclusion
compounds is usually examined using gaseous guest
molecules, because reconstruction of dissolved host-guest
complex in solution would be ruled out as a mechanistic
problem.15 However, there is a few reports which deal with
guest exchange in inclusion crystals in solid-solution
biphase.16 Now, we discuss the guest exchange in these
inclusion compounds from a standpoint of their crystal
structures and host-guest interaction, using RR-1$G1-H and
RR-1$G1-Br that have the parallel-arranged sheets therein.
At first, we performed a control experiment: when the
inclusion crystals are suspended in chloroform and the
resultant suspension was stirred for 1d, the guest was slowly
released (the second column of Table 2). Next, solid RR-1
was immersed in chloroform containing the guest
molecules, but the inclusion phenomenon was not observed
at all. This suggests that the once-dissolved RR-1 molecules
cannot form the inclusion crystals with the second guest
(G2-X) in the solution phase. Hence, the exchange
experiments were performed as follows: the inclusion
compound (0.077 mmol, RR-1$G1-X) was stirred with
5 equiv of second racemic sulfoxide guest (0.385 mmol,
G2-X) in CHCl3 (1 mL) for 24 h. It should be noted that the
Table 2. Guest exchange experiment
Figure 6. Layer structure of inclusion crystals. (a) RR-1$G1-F. (b) RR-
1$G1-Br. (c) RR-1$G1-I.
closest distances of H/halogen in these crystals are 3.10
˚
RR-1$G1-X
RR-1$G1-H
RR-1$G1-Br
Guest ratiosa in RR-1$G1-X$G2-X
and 3.28 A, respectively, which are somewhat larger than
the sum of van der Waals radii7 of hydrogen and halogen
Blank
G2-H
G2-Br
˚
˚
(Br or I) [3.05 (1.20C1.85) A, and 3.18 (1.20C1.98) A].
The bromine atom and iodine atom in these inclusion
crystals are surrounded not only by the phenyl group, but
also by the sulfur atom of the adjacent guest sulfoxide. Since
G1-H
0.0
G1-H:G2-H-d3
0.59:0.04
Rac.b
G1-H:G2-Br
0.0:0.0
G1-Br
0.81
G1-Br:G2-H
0.02:0.80
Rac.b
G1-Br:G2-Br-d3
0.93:0.03
˚
the closest distances of Br/S and I/S are 3.88 and 4.10 A,
respectively, it is likely that strong van der Waals
interactions between these atoms do not work, comparing
these values with the sum of their van der Waals radii,7 3.65
a Guest ratios based on RR-1 in the inclusion compound.
b Rac. means enantioselectivity within 10%.

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M. Akazome et al. / Tetrahedron 60 (2004) 12085–12093
inclusion compounds of RR-1 are insoluble. The results are
summarized in Table 2.
in parallel and zigzags to construct a pleated sheet. We
demonstrated the first example of guest exchange process in
the layered dipeptide inclusion compounds. These findings
show that dipeptides are able to capture their own substrate
(guest) selectively and exchange easily with the upcoming
substrate as if enzymatic polypeptides do.
In order to examine the guest exchange between the
same sulfoxides of RR-1$G1-X, we used (p-halo)benzyl
d3-methyl sulfoxides (G2-X-d3) as the second guest. In the
presence of G2-Br-d3 (5 equiv), the release of the guest
molecules from RR-1$G1-Br was retarded. Apparently, this
result can be explained by considering that the high
concentration of the guest (G2-Br-d3) in solution phase
slows down the release of the G1-Br, because adsorption of
the guest (G2-Br-d3) on the crystal of RR-1$G1-Br is
promoted. However, the remained guest in crystals did not
contain G2-Br-d3. This means that the guest exchange was
not induced so easily by the same guest. Recently, Aida and
his coworkers reported the similar behavior for the guest
exchange by porphyrinogen host molecules: the exchange
of CH3OH with CD3OH, which should require no structural
change of the crystal lattice, took place extremely slow.15a
These cases have no driving force for guest exchange
because these crystals are also isostructural. Next, we
treated the inclusion crystal RR-1$G1-Br with benzyl
methyl sulfoxide (G2-H). As soon as RR-1$G1-Br was
stirred together with G2-H (5 equiv), the guest exchange
started and occurred smoothly within 5 min, as shown in
Figure 7. The stereochemistry of included G2-H was
racemic, which agrees with the selectivity shown in
Table 1. On the other hand, RR-1$G1-H did not allow the
guest exchange with G2-Br. In this case, the release of
G1-H occurred exclusively to give insoluble RR-1 solid.
Thus, we found that the guest exchange takes place in the
case that the backbone sheets are extended from a pleated
form into a flat form. Since these are preliminary results, we
are going to continue our investigation on the guest
exchange in the various inclusion crystals using various
guest molecules.
4. Experimental
4.1. General methods
1H NMR spectra were recorded at 300 MHz using a Varian
Gemini-2000NMR spectrometer and chemical shifts were
referenced to TMS as an internal standard. Decomposition
points (Dec.) were measured on a TG-DTA (MAC Science
TG-DTA2000S). X-ray powder diffractions (PXRD) were
obtained with a MAC Science MXP18 diffractometer using
graphite-monochromated Cu Ka radiation (30 kV,
200 mA). The spectra were measured at room temperature
between 2 and 508 in the 2q/q-scan mode with steps of 0.018
in 2q and 4 deg minK1. Elemental analyses were performed
at the Chemical Analysis Center, Chiba University, Japan.
4.2. Materials
Chiral compounds, (R)-phenylglycine (99% ee) and (S)-a-
methoxyphenyl acetic acid [(S)-MPAA] as a chiral shift
reagent, were purchased from Tokyo Chemical Industry and
Aldrich Chemical Co., respectively. Iodomethane-d3
(99.5Catom%D) was purchased from C/D/N isotopes.
(R)-phenylglycyl-(R)-phenylglycine (RR-1) was prepared
according to our procedures previously reported.6b p-
Halophenylmethanethiols were prepared from correspond-
ing p-halobenzyl bromides and thiourea according to the
literature.17 By Williamson-type sulfide synthesis, sulfides
were obtained from the p-halophenylmethanethiols and
methyl iodide (or D-labeled methyl iodide).18 Sulfides were
oxidized to sulfoxides (G1-X, XZH, F, Cl, Br, or I) by
hydrogen peroxide and acetic acid.19
3. Conclusion
Substitution by halogen atoms on para-position of benzyl
methyl sulfoxide, a guest molecule, disrupted original
benzene–benzene interaction of the host-guest inclusion
system with RR-1 as the host so as to generate a new
structure of inclusion compounds. The guest molecules
induced the conformational change of RR-1 to give the
novel rhombic cavity suitable for the shape of
(R)-halobenzyl methyl sulfoxides, where RR-1 aggregates
4.3. Preparation of inclusion compounds of RR-1 and
benzyl methyl sulfoxides
RR-1 was dissolved in 0.1 M aqueous HCl, then the pH was
adjusted to about 6.5 by addition of 0.1 M aqueous NaOH.
After the addition of a racemic sulfoxide (G1-X, XZH, F,
Cl, Br, or I, 2.2 equiv) to the aqueous solution of RR-1, the
resulting mixture was allowed to stand at an ambient
temperature. Then the deposited inclusion compound was
collected by filtration and washed with chloroform and
water.
4.4. Determination of efficiency, stereochemistry, and
enantiomeric excess in the inclusion
After decomposition of the inclusion compound with
diluted DCl in D2O, inclusion efficiency was determined
by NMR measurement. The included sulfoxide was isolated
by dissolution of the inclusion compound in 0.1 M aqueous
HCl and extraction with CHCl3. Absolute stereochemistry
of recognized sulfoxides was determined by a chiral shift
reagent, (S)-a-methoxyphenyl acetic acid20[(S)-a-MPAA:
Figure 7. Time-course of guest exchange. Exposure of RR-1$G1-Br to G2-
H in CHCl3.

M. Akazome et al. / Tetrahedron 60 (2004) 12085–12093
12091
3 equiv for the sulfoxide]. Enantiomeric excess of the
sulfoxide was determined by a chiral HPLC (Daicel
Chiralcel OB).
1H, JZ13.2 Hz), 2.62 (s, 3H); IR (KBr) 3377, 3238, 1676,
1626, 1591, 1527, 1012 cmK1; powder X-ray diffraction
˚
[A(I/I0)] 6.71 (0.28), 6.21 (0.26), 5.10 (0.37), 4.53 (0.52),
4.15 (1.00), 3.95 (0.83). Anal. Calcd for C16H16N2O3$
1.00C8H9IOS: C, 51.07; H, 4.46; N, 4.96. Found: C, 51.26;
H, 4.48; N, 5.00. Included G1-I: [a]2D5ZK61.6 (cZ1.02,
acetone); 95% ee R by HPLC; Chiralcel OB, HPLC eluent,
hexane/2-propanolZ9/1, flow rateZ0.7 mL/min, tR(S)Z
35 min, tR(R)Z55 min; 1H NMR (with (S)-MPAA in
CDCl3, 93% ee R) d 4.04 (d, 1.0H, JZ12.9 Hz, R major
and S minor), 3.94 (d, 0.03H, JZ12.9 Hz, S minor), 3.93
(d, 0.97H, JZ12.9 Hz, R major), 2.51 (s, 2.91H, R major),
2.50 (s, 0.09H, S minor). Aromatic 4H could be not
identified because of (S)-MPAA.
4.4.1. Compound RR-1$G1-F. Colorless crystals; dec.
190 8C; H NMR (D2O-DCl) d 7.56–7.39 (m, 10H), 7.40
1
(dd, 2H, JZ8.72, 5.43 Hz), 7.22 (dd, 2H, JZ8.86 Hz), 5.50
(s, 1H), 5.22 (s, 1H), 4.28 (d, 1H, JZ13.5 Hz), 4.07 (d, 1H,
JZ13.5 Hz), 2.64 (s, 3H); IR (KBr) 3242, 1674, 1626, 1593,
1523, 1009 cmK1; powder X-ray diffraction [A(I/I0)] 13.4
˚
(0.12), 12.1 (0.13), 4.44 (1.0), 4.15 (0.43), 3.88 (0.39). Anal.
Calcd for C16H16N2O3$1.00C8H9FOS: C, 63.14; H, 5.52; N,
6.14. Found: C, 62.84; H, 5.44; N, 6.12. Included G1-F:
[a]2D5ZK90.8 (cZ1.0, acetone); 99% ee R by HPLC;
chiralcel OB, eluent, hexane/2-propanolZ9/1, flow rateZ
1
0.7 mL/min, tR(R)Z33 min; H NMR (with (S)-MPAA in
4.5. Typical guest exchange experiment
CDCl3, 98% ee R) d 4.08 (d, 1.0H, JZ13.1 Hz, R major and
S minor), 3.98 (d, 0.01H, JZ13.1 Hz, S minor), 3.97
(d, 0.99H, JZ13.1 Hz, R major), 2.52 (s, 2.97H, R major),
2.49 (s, 0.03H, S minor). Aromatic 4H could be not
identified because of (S)-MPAA.
Starting inclusion compounds (RR-1$G1-X) were prepared
by crystallization of RR-1 with first sulfoxide guest (G1-X)
as mentioned above. The finely pulverized inclusion crystals
(RR-1$G1-X, 0.077 mmol) was stirred with 5 equiv of
second racemic sulfoxide guest (G2-X, 0.385 mmol) in
CHCl3 (1 mL) for 24 h at room temperature. Then resulting
solid was collected by filtration and washed with chloroform
(3 mL). The obtained crystal (RR-1$G1-X$G2-X) were
analyzed by X-ray powder diffractions and infrared
spectroscopy. The inclusion efficiency of the included
G1-X and G2-X was determined by 1H NMR. The absolute
stereochemistry and enantiomeric excess of the included
sulfoxide were determined by a chiral HPLC (Daicel
Chiralcel OB-H).
4.4.2. Compound RR-1$G1-Cl. Colorless crystals; dec.
173 8C; H NMR (300 MHz, D2O-DCl) d 7.56–7.39 (m,
1
10H), 7.48 (d, 2H, JZ8.38 Hz), 7.35 (d, 2H, JZ8.67 Hz),
5.50 (s, 1H), 5.22 (s, 1H), 4.27 (d, 1H, JZ13.5 Hz), 4.05 (d,
1H, JZ13.5 Hz), 2.63 (s, 3H); IR (KBr) 3240, 1674, 1624,
1591, 1523, 1009 cmK1; powder X-ray diffraction [A(I/I0)]
˚
14.2 (0.29), 12.1 (0.11), 4.49 (1.0), 4.20 (0.37), 3.93 (0.28).
Anal. Calcd for C16H16N2O3$1.00C8H9ClOS: C, 60.94; H,
5.33; N, 5.92. Found: C, 60.77; H, 5.24; N, 5.94. Included
G1-Cl: [a]2D5ZK73.5 (cZ1.0, acetone); 86% ee R by
HPLC; chiralcel OB, HPLC eluent, hexane/2-propanolZ9/
1, flow rateZ0.7 mL/min, tR(S)Z29 min, tR(R)Z44 min;
1H NMR (with (S)-MPAA in CDCl3, 83% ee R) d 4.09 (d,
1.0H, JZ12.9 Hz, R major and S minor), 3.98 (d, 0.08H,
JZ12.9 Hz, S minor), 3.97 (d, 0.92H, JZ12.9 Hz, R major),
2.52 (s, 2.76H, R major), 2.50 (s, 0.24H, S minor). Aromatic
4H could be not identified because of (S)-MPAA.
˚
RR-1$G1-Br$G2-H; Powder X-ray diffraction [A(I/I0)] 12.7
(0.89), 5.29 (0.11), 5.14 (0.19), 4.26 (1.00), 4.11 (0.23), 4.02
(0.34); IR (KBr) 3359, 1672, 1579, 1508, 1022 cmK1. G2-H
in RR-1$G1-Br$G2-H; racemic by HPLC; Chiralcel OB-H,
HPLC eluent, hexane/2-propanolZ5/1, flow rateZ1.0 mL/
min, tR(S)Z17 min, tR(R)Z21 min.
4.6. Crystallographic data for the inclusion compounds
4.4.3. Compound RR-1$G1-Br. Colorless crystals; dec.
1
179 8C; H NMR (300 MHz, D2O-DCl) d 7.63 (d, 2H, JZ
To the solution of RR-1 was added the sulfoxide guest
directly in a vial, then a lid of the vial was loosely closed for
evaporation of the solvent. The samples were allowed to
stand for several days to form the desirable single crystals.
Data collection was performed on a Mac Science MXC18
four-circle diffractometer with graphite-monochromated
Cu Ka (lZ1.54178) radiation using the 2qKu scan
technique, and the X-ray intensities were measured up to
2qZ1408 at 298 K. The structures were solved by a direct
method SIR9721 and DIRDIF9622 and refined by a computer
program package; maXus ver. 1.1 from MAC Science Co.
Ltd. Hydrogen atoms were placed in calculated position
8.52 Hz), 7.56–7.39 (m, 10H), 7.28 (d, 2H, JZ8.38 Hz),
5.50 (s, 1H), 5.22 (s, 1H), 4.25 (d, 1H, JZ13.3 Hz), 4.04 (d,
1H, JZ13.3 Hz), 2.62 (s, 3H); IR (KBr) 3240, 1676, 1626,
1591, 1527, 1011 cmK1; powder X-ray diffraction [A(I/I0)]
˚
14.8 (0.053), 10.1 (0.052), 5.12 (0.61), 4.58 (0.83), 4.20
(0.82), 3.96 (1.0). Anal. Calcd for C16H16N2O3$1.00C8H9-
BrOS: C, 55.71; H, 4.87; N, 5.41. Found: C, 55.58; H, 4.87;
N, 5.36. Included G1-Br: [a]2D5ZK77.4 (cZ0.99, acetone);
96% ee R by HPLC; chiralcel OB, HPLC eluent, hexane/
2-propanolZ9/1, flow rateZ0.7 mL/min, tR(S)Z31 min,
1
tR(R)Z46 min; H NMR (with (S)-MPAA in CDCl3, 96%
˚
ee R) d 4.06 (d, 1.0H, JZ12.9 Hz, R major and S minor),
3.96 (d, 0.02H, JZ12.9 Hz, S minor), 3.95 (d, 0.98H, JZ
12.9 Hz, R major), 2.52 (s, 2.94H, R major), 2.50 (s, 0.06H,
S minor). Aromatic 4H could be not identified because of
(S)-MPAA.
with C–HZ0.96 A. Crystallographic data (excluding struc-
ture factors) for the structure in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication number CCDC 249240–
249242. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: C44 1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk].
4.4.4. Compound RR-1$G1-I. Colorless crystals; dec.
1
188 8C; H NMR (300 MHz, D2O-DCl) d 7.84 (d, 2H, JZ
8.38 Hz), 7.56–7.39 (m, 10H), 7.15 (d, 2H, JZ8.38 Hz),
5.50 (s, 1H), 5.22 (s, 1H), 4.24 (d, 1H, JZ13.2 Hz), 4.02 (d,
4.6.1. Compound RR-1$G1-F. C24H25FN2O4S, MZ

12092
M. Akazome et al. / Tetrahedron 60 (2004) 12085–12093
Uchida, T.; Ogura, K. Tetrahedron 1997, 53, 8315–8322.
(b) Akazome, M.; Ueno, Y.; Ooiso, H.; Ogura, K. J. Org.
Chem. 2000, 65, 68–76.
456.54, crystal dimensions 0.30!0.10!0.02 mm, ortho-
˚
˚
rhombic, P212121, aZ14.037 (7) A, bZ27.903 (3) A, cZ
5.513 (7) A, VZ2159 (2) A , ZZ4, rcalcldZ1.404 g cmK3
,
3
˚
˚
7. Bondi, A. J. Phys. Chem. 1964, 68, 441–451.
TZ173 K, 2432 reflections measured, 2403 independent,
refinement on F2, RZ0.057 (1476 reflections with
IO1.00s(I)), wR(F2)Z0.160, SZ1.036, 289 parameters,
with heavy atoms refined anisotropically, residual electron
density 1.03/K1.93.
8. (a) Akazome, M.; Takahashi, T.; Sonobe, R.; Ogura, K.
Supramol. Chem. 2001, 13, 109–136. (b) Akazome, M.;
Takahashi, T.; Ogura, K. J. Org. Chem. 1999, 64, 2293–2300.
(c) Akazome, M.; Yanagita, Y.; Sonobe, R.; Ogura, K. Bull.
Chem. Soc. Jpn 1997, 70, 2823–2827. (d) Akazome, M.;
Sumikawa, A.; Sonobe, R.; Ogura, K. Chem. Lett. 1996,
995–996.
4.6.2. Compound RR-1$G1-Br. C24H25BrN2O4S, MZ
517.45, crystal dimensions 0.20!0.15!0.02 mm, mono-
˚
˚
9. (a) Taylor, R.; Kennard, O.; Versichel, W. J. Am. Chem. Soc.
1983, 105, 5761–5766. (b) Taylor, R.; Kennard, O.; Versichel,
W. J. Am. Chem. Soc. 1984, 106, 244–248.
clinic, P21, aZ5.451 (4) A, bZ13.802 (8) A, cZ15.368
3
˚
˚
(7) A, bZ96.87 (5), VZ1148.0 (12) A , ZZ2, rcalcld
Z
1.497 g cmK3, TZ173 K, 4862 reflections measured, 2394
independent, refinement on F2, RZ0.078 (1848 reflections
with IO1.00s(I)), wR(F2)Z0.181, SZ1.047, 289 para-
meters, with heavy atoms refined anisotropically, residual
electron density 0.52/K1.14.
10. (a) Jeffrey, G. A.; Maluszynska, H. Int. J. Biol. Macromol.
1982, 4, 173–185. (b) Taylor, R.; Kennard, O. J. Am. Chem.
Soc. 1982, 104, 5063–5070.
11. In proteins, p–p interactions on their side chains have already
been investigated to reveal the edge-to-face interaction
between benzene rings to be important: (a) Burley, S. K.;
Petsko, G. A. Science 1985, 229, 23–28. (b) Gould, R. O.;
Gray, A. M.; Taylor, P.; Walkinshaw, M. D. J. Am. Chem. Soc.
1985, 107, 5921–5927. (c) Burley, S. K.; Petsko, G. A. J. Am.
Chem. Soc. 1986, 108, 7995–8001.
4.6.3. Compound RR-1$G1-I. C24H25IN2O4S, MZ564.44,
crystal dimensions 0.30!0.20!0.10 mm, monoclinic, P21
˚
˚
˚
aZ15.851 (6) A, bZ13.940 (9) A, cZ5.443 (2) A, bZ
82.08 (3), VZ1191.3 (10) A , ZZ2, rcalcldZ1.574 g cmK3
,
3
˚
TZ298 K, 2629 reflections measured, 2492 independent,
refinement on F2, RZ0.069 (2063 reflections with
IO1.00s(I)), wR(F2)Z0.156, SZ1.043, 290 parameters,
with heavy atoms refined anisotropically, residual electron
density 0.77/K1.45.
12. (a) Hunter, C. A.; Lawson, K. R.; Perkins, J.; Urch, C. J.
J. Chem. Soc., Perkin Trans. 2 2001, 651–668. (b) Swift, J. A.;
Pal, R.; McBride, J. M. J. Am. Chem. Soc. 1998, 120, 96–104.
(c) Lewis, F. D.; Yang, J.-S.; Stern, C. L. J. Am. Chem. Soc.
1996, 118, 12029–12037. (d) Hunter, C. A.; Sanders, J. K. M.
J. Am. Chem. Soc. 1990, 112, 5525–5534. (e) Desiraju, G. R.;
Gavezzotti, A. J. Chem. Soc., Chem. Commun. 1989, 621–623.
13. The C–H/F interactions are often found in the crystals to
contribute the stability: (a) Thalladi, V. R.; Weiss, H.-C.;
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research (C) (No. 16550120) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
¨
Blaser, D.; Boese, R.; Nangia, A.; Desiraju, G. R. J. Am. Chem.
Soc. 1998, 120, 8702–8710. (b) Howard, J. A. K.; Hoy, V. J.;
O’Hagan, D.; Smith, G. T. Tertahedron 1996, 52,
12613–12622. (c) Shimoni, L.; Glusker, J. P. Struct. Chem.
1994, 5, 383–397. (d) Shimoni, L.; Carrell, H. L.; Glusker, J. P.;
Coombs, M. M. J. Am. Chem. Soc. 1994, 116, 8162–8168.
14. Patai, S., Rappoport, Z., Stirling, C., Eds.; The Chemistry of
Sulphones and Sulphoxides; Wiley: Chichester, 1988.
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