Molecular recognition of l-leucyl-l-alanine: Enantioselective inclusion of alkyl methyl sulfoxides

Article abstract of DOI:10.1016/j.tet.2004.11.058

A simple aliphatic dipeptide, l-leucyl-l-alanine (Leu-Ala), includes several alkyl methyl sulfoxides enantioselectively to form inclusion crystals. From single-crystal X-ray analyses of three inclusion compounds of dimethyl sulfoxide (DMSO), isobutyl methyl sulfoxide, and benzyl methyl sulfoxide, it was elucidated that Leu-Ala molecules self-assemble to form layer structures and the sulfoxides are included via hydrogen bonding in a cavity between these layers. The inclusion cavity has methyl group and isobutyl group at its each side, and the guest sulfoxide is placed in such a manner that its methyl group faces toward the methyl of the Leu-Ala cavity. When the alkyl group of the sulfoxide is comparably large, it is located in the residual space of the cavity to attain effective crystal packing. Thus, the sulfoxides having a comparably large group such as isobutyl, butyl, and benzyl are included with a high (R)-enantioselectivity in Leu-Ala crystals.

Full text of DOI:10.1016/j.tet.2004.11.058

Tetrahedron 61 (2005) 1107–1113
Molecular recognition of L-leucyl-L-alanine: enantioselective
inclusion of alkyl methyl sulfoxides
b
a
a
Motohiro Akazome,a, Atsushi Hirabayashi, Kousuke Takaoka, Satoru Nomura
*
and Katsuyuki Oguraa,b,
*
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 14 October 2004; accepted 19 November 2004
Available online 10 December 2004
Abstract—A simple aliphatic dipeptide, L-leucyl-L-alanine (Leu-Ala), includes several alkyl methyl sulfoxides enantioselectively to form
inclusion crystals. From single-crystal X-ray analyses of three inclusion compounds of dimethyl sulfoxide (DMSO), isobutyl methyl
sulfoxide, and benzyl methyl sulfoxide, it was elucidated that Leu-Ala molecules self-assemble to form layer structures and the sulfoxides are
included via hydrogen bonding in a cavity between these layers. The inclusion cavity has methyl group and isobutyl group at its each side,
and the guest sulfoxide is placed in such a manner that its methyl group faces toward the methyl of the Leu-Ala cavity. When the alkyl group
of the sulfoxide is comparably large, it is located in the residual space of the cavity to attain effective crystal packing. Thus, the sulfoxides
having a comparably large group such as isobutyl, butyl, and benzyl are included with a high (R)-enantioselectivity in Leu-Ala crystals.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
sulfoxides has been realized by NMR chiral shift reagents
such as binaphthol,7a,b a-methoxyphenylacetic acid,7c (R)-
(K)-N-(3,5-dinitrophenyl)-a-phenylethylamine.7d From the
facts mentioned above, the presence of benzene rings in the
hosts and/or the guest seems to be crucial to the chiral
recognition of the sulfoxides. Is this generally valid? With
this question in mind, we started our investigation to realize
that a host having no benzene ring can recognize the
chirality of aliphatic sulfoxides to form an inclusion
compound.
The chemistry of inclusion crystals has a long history, and
one important aspect of this chemistry is to recognize the
chirality of the included guest: for optical resolution of
racemic compounds, enantioselective inclusion has
emerged in the field of crystal engineering so that many
artificial hosts have been developed for molecular recog-
nition of organic guests.1,2 For example, several chiral hosts
were reported for asymmetric sulfoxides that have a chiral
center on their sulfur atom. Toda has reported a practical
separation of dialkyl sulfoxides using inclusion phenomena
with chiral binaphthol3a,b or TADDOL derivatives.3c These
host molecules have widely spread aromatic parts, which act
as the walls of the chiral cavities. We have also demon-
strated that a simple dipeptide host, (R)-phenylglycyl-(R)-
phenylglycine, effectively forms inclusion crystals with
various sulfoxides in a highly enantioselective manner.4 The
sulfoxides were included in the channel between the layers
that were constructed by dipeptide backbones. In addition to
hydrogen bonding, p–p interactions5 and CH/p inter-
actions6 between the sulfoxide and two phenyl groups of the
dipeptide play an essential role in recognizing the chirality
of the sulfoxide. In a solution phase, chiral discrimination of
First, our attention was focused on the dipeptides that
consisted of aliphatic amino acids. This is mainly because
their backbones can be considered from our previous
literatures4,8 to construct a layer structure via salt formation
and hydrogen bonding between their terminal amino and
carboxyl groups. It is also likely that the inclusion cavities
are produced by the alkyl side chains of the dipeptide that
stand perpendicular to the layer. We synthesized several
aliphatic dipeptides such as Leu-Gly, Leu-Ala, Ala-Leu, and
Leu-Leu, which were subjected to a preliminary experiment
to evaluate their recognition ability toward aliphatic
sulfoxides: the solid dipeptides were simply stirred together
with typical aliphatic sulfoxides such as methyl propyl
sulfoxide and butyl methyl sulfoxide in hexane for 24 h. The
formed inclusion compound was collected by filtration and
washed with diethyl ether. Except for Leu-Leu, the aliphatic
dipeptides examined here gave the expected inclusion
Keywords: Crystal engineering; Inclusion compounds; Peptides; Sulf-
oxides; Enantiomeric recognition.
* Corresponding authors. Tel.: C81 43 290 3388; fax: C81 43 290 3402;
e-mail: katsuyuki@faculty.chiba-u.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.058

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M. Akazome et al. / Tetrahedron 61 (2005) 1107–1113
compound that consists of the dipeptide and the sulfoxide in
a ratio of approximatly 1:1. Among them, the inclusion
compound of Leu-Ala and butyl methyl sulfoxide showed
the highest chiral recognition ability (the enantiomeric
excess of the included sulfoxide: 58%. Cf. Leu-Gly/
nPrSOMe 32%; Leu-Gly/nBuSOMe 15%; Leu-Ala/
nPrSOMe 17%; Ala-Leu/nPrSOMe 10%; Ala-Leu/
nBuSOMe 47%). Hence, we selected Leu-Ala as a host
aliphatic dipeptide for further detailed investigation. It is
noted that the crystal structure of Leu-Ala accompanied
with water9a or dimethyl sulfoxide (DMSO)9b as solvation
ligands have been reported from the standpoint of structural
interest and conformational information of the dipeptide.
lower 2q range. This assignment of the interlayer distance
was confirmed by the single-crystal structure (vide infra).
Clearly, these results showed the formation of a 1:1
complex. The included alkyl methyl sulfoxide was
recovered from the inclusion crystals and its enantiomeric
excess was estimated by its optical rotation and the
Kusumi’s NMR method that transforms the sulfoxide into
a diastereomeric mixture of its N-(methoxyphenylacetyl)-
sulfoximine derivatives in order to estimate the enantio-
meric excess.10 We also examined the inclusion of
benzyl methyl sulfoxide, a typical dialkyl sulfoxide having
one phenyl group, whose result is also shown in Table 1
(entry 6).
In all entries of Table 1, both methods A and B gave
comparable results for molecular recognition, though
method A is often superior to method B in terms of the
enantiomeric excess of the included sulfoxide. Small
sulfoxides such as dimethyl sulfoxide and ethyl methyl
sulfoxide formed the inclusion compounds with narrow
2. Results and discussion
Since the present Leu-Ala shows good solubility in water,
an inclusion compound was prepared by two methods: (a)
Leu-Ala was crystallized from water in the presence of an
alkyl methyl sulfoxide [method A: ‘crystallization’] and (b)
Leu-Ala and the sulfoxide were simply stirred in hexane for
24 h because Leu-Ala is insoluble in hexane [method B:
‘sorption’]
˚
interlayer distances (LDZ9.3 and 9.4 A). The stereo-
chemistry of the preferably included enantiomer of ethyl
methyl sulfoxide was S-form (8% ee by method A and 14%
ee by method B in entry 2). In contrast, (R)-enantiomer was
preferably recognized in the inclusion compound of methyl
propyl sulfoxide though its enantioselectivity was low (13%
ee by method A and 17% ee by method B in entry 3).
Interestingly, other (R)-alkyl methyl sulfoxides bearing
isobutyl, butyl, and benzyl groups were included with a high
enantioselectivity (94, 94, and 93% ee by method A,
respectively), and their interlayer distances were similar to
The results for enantioselective inclusion of several alkyl
methyl sulfoxides are summarized in Table 1. Efficiency
(Ef. in Tables 1 and 2) means ‘mol percentage’ of the guest
molecule based on Leu-Ala molecule in the inclusion
compound, which was determined by 1H NMR spectra and
elemental analyses. Interlayer distances (LD in Table 1)
were gained by powder X-ray diffraction (PXRD) of the
inclusion compounds, which showed diffraction peaks at
˚
each other within the range of 11.0–11.2 A (entries 4–6).
The efficient chiral recognition of benzyl methyl sulfoxide
Table 1. Enantioselective inclusion of alkyl methyl sulfoxides by Leu-Ala
a
LD /A
˚
Entry
Sulfoxide
A: crystallization
Ef.b/%
B: sorption
ee/%
—
ee/%
—
Ef.b/%
103
1
2
3
4
5
6
100
98
9.4
9.3
8(S)
14(S)
17(R)
60(R)
58(R)
44(R)
98
99
13(R)
94(R)
94(R)
93(R)
97
10.4
11.2
11.2
11.0
100
100
93
98
104
97
a LD is an interlayer distance measured by PXRD.
b Ef. means mol% of the guest based on the dipeptide in the inclusion complex.

M. Akazome et al. / Tetrahedron 61 (2005) 1107–1113
Table 2. Enantioselective inclusion of butyl methyl sulfoxide by Leu-Ala
1109
Entry
Solvent
Equiv of guest
ee/%
Ef.a/%
1
2
3
4
5
Hexane
Hexane
Hexane
Diethyl ether
Toluene
2.2
4.0
8.0
2.2
2.2
58 (R)
69 (R)
75 (R)
59 (R)
57 (R)
104
86
99
98
102
a Ef. means mol% of the guest based on the dipeptide in the inclusion complex.
by Leu-Ala is in marked contrast with that by (R)-
phenylglycyl-(R)-phenylglycine, which formed the
inclusion crystals containing both enantiomers of benzyl
methyl sulfoxide to result in the racemic recognition.4a
It is worthy to note that these dipeptide backbone
arrangements are quite similar to those of the inclusion
compounds of (R)-phenylglycyl-(R)-phenylglycine.4
Although the chiral cavity of Leu-Ala possesses no benzene
ring, isobutyl methyl sulfoxide is included with a high
enantioselectivity. Careful insight into the X-ray structure of
the inclusion cavity suggests the reason why the chiral
discrimination is achieved. Although the layer structure of
Leu-Ala is similar in all of the inclusion compounds
mentioned herein, these dipeptide sheets are arranged
As shown in Table 2, the replacement of hexane with diethyl
ether or toluene as a dispersion solvent in method B did not
affect the enantioselectivity and the Ef. significantly (entries
4 and 5). As the amount of the guest increased, the
enantioselectivity was raised up to 75% ee with 8 equiv of
sulfoxide (entries 2 and 3).
Fortunately, we obtained good-quality single crystals for the
inclusion compound of isobutyl methyl sulfoxide, DMSO,
and benzyl methyl sulfoxide, which could be analyzed by
single-crystal X-ray crystallography. Figure 1 shows the top
view of the sheet structure of the inclusion compound,
where the dipeptide backbones are colored in black, guest
sulfoxides in gray, and alkyl groups of Leu-Ala in white.
The space-filling models reveal that, in all of these inclusion
crystals, the guest molecules are similarly arranged in the
cavity of Leu-Ala, though dimethyl sulfoxide is disordered
(Fig. 1b). As mentioned previously, the inclusion crystal of
DMSO was reported in the literature.9b The result obtained
here is similar to the literature one: the guest DMSO has the
disordered structure of a trigonal-bipyramidal geometry
having the sulfur atom that occupies two coordination sites
(6:4). Our result is shown in Figure 1b: the ratio (S1/S2Z
62:38) is reproducible and the disordered site occupancy is
statistic.
In the present inclusion compounds, the dipeptide molecules
have a straight glycylglycine backbone to construct a two-
dimensional layer. In Figure 2, the intermolecular distances
of hydrogen bonding in crystals are summarized. A set of
the hydrogen bonding distances is similar to each other in all
of the Leu-Ala inclusion compounds. The Leu-Ala back-
bones are arranged into a parallel motif to construct a sheet
by ionic pairing of the carboxyl and amino groups via
hydrogen bonding network: one terminal COOK links two
CNH3 of adjacent dipeptides and the CNH3 also binds two
adjacent COOK groups. Here, two characteristic distances,
the repetition of glycylglycine backbone (L) and the
distance between dipeptides arranged side by side (W), are
introduced, and then the area occupied by glycylglycine
backbone is estimated by L!W. By comparison of three
crystal structures of Leu-Ala, it was found that the values of
L!W increased as the guest sulfoxides became larger.
Figure 1. Top views of sheet structure of inclusion crystals (CPK model).
(a) Leu-Ala with (R)-isobutyl methyl sulfoxide. (b) Leu-Ala with dimethyl
sulfoxide. Hydrogens of the sulfoxide were omitted for its disordered
structure. (c) Leu-Ala with (R)-benzyl methyl sulfoxide.

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M. Akazome et al. / Tetrahedron 61 (2005) 1107–1113
Figure 2. Atomic distances of intermolecular hydrogen bonds and
dipeptide backbones.
differently depending on the guest structure, as shown in
Figure 3.
Figure 3. Layer structure of inclusion crystals. The arrows indicate the
direction of the sheet from the C-terminal to the N-terminal. (a) Leu-Ala
with (R)-isobutyl methyl sulfoxide. (b) Leu-Ala with dimethyl sulfoxide.
(c) Leu-Ala with (R)-benzyl methyl sulfoxide.
The guest sulfoxide in Leu-Ala crystals is bound to the
dipeptide-backbone layer via hydrogen bonding between
the sulfoxide oxygen and the ammonio proton of Leu-Ala
˚
with a N/O(G) distance of 2.79–2.84 A. The inclusion
Ala (Fig. 3b), another DMSO molecule belonging to the
adjacent layer sticks the residual vacant space and, as a
result, the layers interdigitate each other so as to make
compound of (R)-isobutyl methyl sulfoxide has P212121
space group: the sheets piles up in the opposite direction
(arrows in Fig. 3a). In this inclusion compound, the sulfinyl
methyl group is faced toward the methyl group of Leu-Ala
in the cavity. The larger area in the Leu-Ala cavity is filled
with the isobutyl group. The such placement of isobutyl
methyl sulfoxide in the inclusion cavity can diminish the
space between the layers to make the host–guest packing
effective. Consequently, (R)-enantiomer of the sulfoxide is
recognized as the suitable guest. It should be noted that, in
the inclusion compound of benzyl methyl sulfoxide, the
sheets stacked in the same direction shown by the arrows to
become the space group P21 (see Fig. 3c). In this case, the
phenyl ring of the sulfoxide seems to contact with the Leu-
Ala in the neighboring layer. Thus, the terminal proton of
˚
the interlayer distance smaller (9.4 A). The PXRD pattern of
the inclusion crystals with ethyl methyl sulfoxide showed
˚
the interlayer distance of 9.3 A that is comparable with that
of the DMSO inclusion crystal. This suggests that these
crystals have the interdigitating structure similar to that of
the DMSO inclusion compound. If the C1 (methyl) group of
the disordered sulfoxide (Fig. 3b) is replaced with ethyl
group, the stereochemistry of the included ethyl methyl
sulfoxide would be S. Indeed, ethyl methyl sulfoxide was
recognized with an enantioselectivity of 8–14% ee (S).
While, methyl propyl sulfoxide and butyl methyl sulfoxide
˚
expanded the interlayer distance to 10.4 and 11.2 A,
respectively. From these facts, it seems to be suggested
that the sulfoxide molecule itself is large enough to fill the
cavity without the aid of another sulfoxide molecule. Since
the (R)-form of these sulfoxides was preferably recognized
by Leu-Ala crystal, it is likely that the structures of these
sulfoxide inclusion crystals are analogous to that of (R)-
isobutyl methyl sulfoxide inclusion crystal.
˚
the Leu part is located 2.9 A from the center of the benzene
ring. This is within the distance that is capable of CH/p
interaction.6 This interaction would compel the dipeptide
sheets to pile up in the same direction.
Since DMSO is too small to fill the inclusion cavity of Leu-

M. Akazome et al. / Tetrahedron 61 (2005) 1107–1113
1111
3. Conclusion
Method B. Crystals of Leu-Ala are essentially insoluble in
hexane. A suspension of Leu-Ala (1.0 mmol) in hexane
(2 mL) was stirred together with a racemic sulfoxide
(2.2 mmol) at an ambient temperature for 1 day. The
formed inclusion compound was collected by filtration and
washed with diethyl ether (20 mL).
L-Leucyl-L-alanine molecules self-assemble by inter-
molecular salt formation and hydrogen bonding to form a
layer structure. In the cavity between the layers, alkyl
methyl sulfoxides (alkylZmethyl, ethyl, propyl, isobutyl,
butyl, and benzyl) were included by the driving force of
hydrogen bonding between the oxygen atom of the sulfinyl
group and the ammonio proton of Leu-Ala. The included
sulfoxide is placed in such a manner that the sulfinyl methyl
group faces toward the methyl group of Ala part. When the
sulfoxide such as DMSO or ethyl methyl sulfoxide is too
small to fill the cavity, the layers are interdigitated to one
another and, as a result, the cavity is filled by two sulfoxide
molecules. In the case that the alkyl group is comparably
large, it is placed in the residual space and, as a result, one
molecule of the sulfoxide itself can fill the cavity. Thus, the
alkyl methyl sulfoxide having a comparably large group as
the alkyl was included with a high (R)-enantioselectivity.
4.2.1. Leu-Ala$ethyl methyl sulfoxide. A colorless solid;
.
dec 127.2 8C; IR (KBr) 3350, 1664, 1587, 1510, 1005 cmK1
˚
Powder X-ray diffraction [A(I/I0)] 9.33(0.34), 9.14(0.31),
6.99(0.33), 4.98(1.00), 4.90(0.77), 4.01(0.61). Anal. Calcd
for C9H18N2O3$0.98C3H8OS: C, 49.02; H, 8.90; N, 9.57.
Found: C, 48.92; H, 9.11; N, 9.53.
4.2.2. Leu-Ala$methyl n-propyl sulfoxide. A colorless
solid; dec 135.2 8C; IR (KBr) 3352, 1666, 1583, 1510,
1005 cmK1. Powder X-ray diffraction [A(I/I0)] 10.4(0.93),
˚
8.70(0.24), 5.27(0.90), 5.00(1.00), 3.73(0.69), 3.54(0.65).
Anal. Calcd for C9H18N2O3$0.97C3H8OS: C, 50.68; H,
9.15; N, 9.18. Found: C, 50.42; H, 9.14; N, 9.03.
4. Experimental
4.2.3. Leu-Ala$n-butyl methyl sulfoxide. A colorless
solid; dec 130.2 8C; IR (KBr) 3354, 1669, 1581, 1507,
1009 cmK1. Powder X-ray diffraction [A(I/I0)] 11.2(0.34),
˚
4.1. General methods
10.7(0.38), 7.80(1.00), 5.53(0.18), 4.50(0.23), 3.66(0.79).
Anal. Calcd for C9H18N2O3$1.0C5H12SO: C, 52.15; H,
9.38; N, 8.69. Found: C, 52.05; H, 9.44; N, 8.61.
NMR spectra were recorded at 300 MHz for 1H NMR.
Elemental analyses were performed at the Chemical
Analysis Center, Chiba University, Japan. Inclusion
efficiency was determined by NMR measurements and
elemental analyses. Melting points (decomposition) were
measured on a TG-DTA. As a chiral shift reagent, (S)-a-
methoxyphenyl acetic acid [(S)-MPAA] was purchased
from Aldrich Chemical Co.
4.2.4. Leu-Ala$isobutyl methyl sulfoxide. A colorless
solid; dec 130.5 8C; IR (KBr) 3353, 1666, 1584, 1508,
1009 cmK1. Powder X-ray diffraction [A(I/I0)] 11.2(0.65),
˚
10.3(0.84), 5.37(0.47), 4.46(0.34), 3.70(1.00), 3.62(0.81).
Anal. Calcd for C9H18N2O3$1.0C5H12SO: C, 52.15, H,
9.38; N, 8.69. Found: C, 51.78; H, 9.66; N, 8.59.
4.1.1. Synthesis of Leu-Ala. Protected amino acids,
N-(benzyloxycarbonyl)-L-leucine and L-alanine benzyl
ester p-toluenesulfonate, were prepared according to
literature procedure.11,12 These were coupled with DCC
and HOBt to form the corresponding protected dipeptide.13
Final deprotection was performed by hydrogenation with Pd
black under hydrogen atmosphere. The Leu-Ala was dried
over 3 h at 70 8C in vacuo. It contained 2.1 wt% water
detected by elemental analysis and TG-DTA.14 Leu-
Ala$0.24H2O: a colorless solid; dec 143.5 8C; [a]2D5Z
C21.7 (c 0.82, methanol); [a]2D5ZC22.9 (c 5, methanol);15
1H NMR (300 MHz, D2O) d (q, 1.0H, JZ7.28 Hz), 4.01 (t,
1.0H, JZ7.21 Hz), 1.84–1.68 (m, 3.0H), 1.38 (d, 3.0H, JZ
7.28 Hz), 0.99 (d, 3.0H, JZ6.32 Hz), 0.97 (d, 3.0H, JZ
6.32 Hz); IR (KBr) 3057, 1664, 1589 1510 cmK1. Powder
4.2.5. Leu-Ala$benzyl methyl sulfoxide. A colorless solid;
.
Powder X-ray diffraction [A(I/I0)] 11.0(0.10), 10.5(0.10),
8.53(0.33), 4.49(0.47), 4.40(1.00), 3.95(0.52). Anal. Calcd
for C9H18N2O3$0.93C8H10SO: C, 57.12; H, 7.96; N, 8.10.
Found: C, 56.85; H, 8.05; N, 7.81.
dec 167.2 8C; IR (KBr) 3354, 1671, 1578, 1508, 1018 cmK1
˚
4.3. Determination of stereochemistry and enantiomeric
excess in the inclusion
The included sulfoxide was isolated by dissolution of the
inclusion compound in water (5.0 mL) and extraction with
CHCl3. In addition to comparison of the optical rotation to
the value of the literature, absolute configuration and
enantiomeric excess of recognized sulfoxides were deter-
mined by a Kusumi’s NMR method (chiral sulfoximines),
another NMR method with a chiral shift reagent [(S)-
MPAA], or a chiral HPLC method. According to the
Kusumi’s methodology,10 N-(methoxyphenylacetyl)-
sulfoximines were obtained from sulfoxides by a one pot
reaction (alkyl methyl sulfoxide/O-(mesitylsulfony)-
hydroxylamine16/CHCl3 then (S)-MPAA/PyBOP/HOBt/
pyridine).
˚
X-ray diffraction [A(I/I0)] 12.8(1.00), 7.16(0.43),
5.80(0.28), 4.87(0.47), 4.14(0.64). Anal. Calcd for
C9H18N2O3$0.24H2O: C, 52.33; H, 9.02; N, 13.56. Found:
C, 52.31; H, 9.11; N, 13.40.
4.2. Preparation of inclusion compounds of Leu-Ala and
alkyl methyl sulfoxide
Method A. To a solution of Leu-Ala (1.0 mmol) in water
(2 mL) was added a racemic sulfoxide (2.2 mmol).
Inclusion compounds were formed by slow evaporation of
a solution of the complex at an ambient temperature, then it
was collected by filtration and washed with diethyl ether
(20 mL).
4.3.1. Ethyl methyl sulfoxide. [a]2D5ZC7.69 (c 1.26,
ethanol). 8.1% ee S by NMR;10 S-ethyl methyl N-[(S)-
methoxyphenylacetyl]sulfoximine: colorless oil; H NMR
1
(300 MHz, CDCl3) d 7.51–7.27 (m, 5.0H), 4.75 (s, 0.54H, S

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M. Akazome et al. / Tetrahedron 61 (2005) 1107–1113
major), 4.74 (s, 0.46H, R minor), 3.47–3.10 (m, 8.0H, S
major and R minor), 1.31 (t, 1.38H, JZ7.42 Hz, R minor),
1.18 (t, 1.62H, JZ7.49 Hz, S major).
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-mono-
chromated 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 SIR9718 and refined by a computer program
package; maXus ver. 4.3.p2 from BrukerAXS. Hydrogen
atoms were placed in calculated position with C–HZ
4.3.2. Methyl propyl sulfoxide. [a]2D5ZK17.8 (c 0.94,
ethanol); 13% ee R by [a]; (R)-(K)-methyl n-propyl
sulfoxide: [a]2D5ZK139.0 (c 0.83, EtOH).17a S-Methyl
n-propyl N-[(S)-methoxyphenylacetyl]sulfoximine: color-
less oil; 1H NMR (300 MHz, CDCl3, 17% ee R) d 7.51–7.27
(m, 5.0H), 4.75 (s, 0.42H, S minor), 4.73 (s, 0.58H, R
major), 3.41–3.12 (m, 8.0H, R major and S minor), 1.79–
1.55 (m, 2.0H, R major and S minor), 1.03 (t, 1.74H, JZ
7.42 Hz, R major), 0.94 (t, 1.26H, JZ7.42 Hz, S minor).
˚
0.96 A. Crystallographic data (excluding structure factors)
for the structure in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 250905-250907. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
C44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.3.3. Butyl methyl sulfoxide. [a]2D5ZK103.2 (c 1.12,
ethanol); 94% ee R by [a]; (S)-(C)-n-butyl methyl
sulfoxide: [a]D25ZC109.9 (c 1.53, ethanol).17a,b S-n-Butyl
methyl N-[(S)-methoxyphenylacetyl]sulfoximine: colorless
oil; 1H NMR (300 MHz, CDCl3, 90% ee R) d 7.51–7.27 (m,
5.0H), 4.75 (s, 0.05H, S minor), 4.73 (s, 0.95H, R major),
3.48–3.12 (m, 8.0H, R major and S minor), 1.71–1.60 (m,
2.0H, R major and S minor), 1.40 (sext, 1.90H, JZ7.42 Hz,
R major), 1.30 (sext, 0.10H, J Z7.57 Hz, S minor), 0.89 (t,
2.85H, JZ7.28 Hz, R major), 0.81 (t, 0.15H, JZ7.32 Hz, S
minor).
The inclusion compound of Leu-Ala and isobutyl methyl
sulfoxide: C14H30N2O4S, Mw 322.47, crystal dimensions
0.50!0.50!0.10 mm3, orthorhombic, P212121, aZ
˚
˚
˚
22.212(7) A, bZ15.943(5) A, cZ5.401(2) A, VZ
1912.7(11) A , ZZ4, dcalcdZ1.120 g cmK3, 2237 reflec-
3
˚
tions measured, 2157 independent, R1Z0.051 (1541
reflections with IO2.00s(I)), Rw2Z0.174, SZ1.018, 190
parameters, with heavy atoms refined anisotropically,
residual electron density 0.25/K0.32.
4.3.4. Isobutyl methyl sulfoxide. [a]2D5ZK129.2 (c 2.94,
ethanol); 94% ee R by [a]; (S)-(C)-isobutyl methyl
sulfoxide: [a]D25ZC138.0 (c 0.97, ethanol).17a,b S-Isobutyl
methyl N-[(S)-methoxyphenylacetyl]sulfoximine: colorless
oil; 1H NMR (300 MHz, CDCl3, 88% ee R) d 7.51–7.27 (m,
5.0H), 4.77 (s, 0.06H, S minor), 4.74 (s, 0.94H, R major),
3.47–3.00 (m, 8.0H, R major and S minor), 2.23 (sept,
0.96H, JZ6.71 Hz, R major), 1.99 (sept, 0.04H, JZ
6.53 Hz, S minor), 1.07 (d, 2.88H, JZ6.73 Hz, R major),
1.02 (d, 2.88H, JZ6.73 Hz, R major), 0.96 (d, 0.12H, JZ
6.73 Hz, S minor), 0.83 (d, 0.12H, JZ6.87 Hz, S minor).
The inclusion compound of Leu-Ala and benzyl methyl
sulfoxide: C17H28N2O4S, Mw 356.49, crystal dimensions
3
˚
0.40!0.35!0.10 mm , monoclinic, P21, aZ10.983(8) A,
˚
˚
bZ15.878 (12) A, cZ5.569(4) A, bZ96.22(6)8, VZ
965.5(12) A , ZZ2, dcalcdZ1.226 g cmK3, 2010 reflections
3
˚
measured, 1932 independent, R1Z0.044 (1746 reflections
with IO2.00s(I)), Rw2Z0.144, SZ1.030, 217 parameters,
with heavy atoms refined anisotropically, residual electron
density 0.28/K0.32.
4.3.5. Benzyl methyl sulfoxide. [a]2D5ZK97.4 (c 0.27,
ethanol); 93% ee R by [a], (R)-(C)-benzyl methyl
sulfoxide: [a]2D5ZK105 (c 6.0, ethanol).17c HPLC (Daicel
Chiralcel OB–H) eluent, hexane/2-propanalZ9:1, flow
rateZ0.9 mL/min, tR(S)Z31 min, tR(R)Z39 min, 97% ee
The inclusion compound of Leu-Ala and dimethyl
sulfoxide: C11H24N2O4S, Mw 280.39, crystal dimensions
0.45!0.08!0.08 mm3, orthorhombic, P212121, aZ
˚
˚
˚
5.208(3) A, bZ16.095(3) A, cZ18.7069(10) A, VZ
3
1568.1(9) A , ZZ4, dcalcdZ1.188 g cmK3, 1911 reflections
˚
1
measured, 1782 independent, R1Z0.058 (1120 reflections
with IO2.00s(I)); Rw2Z0.176, SZ1.032, 174 parameters,
with heavy atoms refined anisotropically, residual electron
density 0.31/K0.28.
R. H NMR (300 MHz, with (S)-MPAA (3 mol equiv) in
CDCl3, 94% ee R) d 4.17 (d, 1.00H, JZ12.8 Hz, R major
and S minor), 3.99 (d, 0.03H, JZ13.2 Hz, S minor), 3.98 (d,
0.97H, JZ12.9 Hz, R major), 2.51 (s, 2.91H, R major), 2.49
(s, 0.09H, S major). Aromatic H could not be identified
because of (S)-MPAA.
Acknowledgements
4.4. X-ray analyses
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.
X-ray powder diffractions were obtained with a MAC
Science MXP diffractometer using graphite-mono-
chromated Cu Ka radiation (30 kV, 200 mA). The spectra
were measured at room temperature between 2 and 508 in
the 2q scan mode with steps of 0.018 in 2q and 48/min.
References and notes
4.5. Crystallographic data for the inclusion compounds
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sulfoxide, isobutyl methyl sulfoxide and benzyl methyl
sulfoxide) directly in a vial, then a lid of the vial was loosely
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