Predominant (S)-enantioselective inclusion of aryl methyl sulfoxides by (S)-isoleucyl-(S)-phenylglycines

Article abstract of DOI:10.1021/jo902197k

(Figure Presented) In terms of chiral recognition for racemic aryl methyl sulfoxides in the solid state, three kinds of crystalline (S)-alkylglycyl-(S)- phenylglycines were examined as potential dipeptides host molecules. When (S)-alanyl-(S)-phenylglycines [(S,S)-Ala-Phg] crystallized with aryl methyl sulfoxides, the stereochemistry of preferentially included sulfoxides depended on the individual shapes of the sulfoxides and the enantiomeric excess was relatively low. Although (S)-leucyl-(S)-phenylglycines [(S,S)-Leu-Phg] and (S)-isoleucyl-(S)-phenylglycines [(S,S)-Ile-Phg] mainly included the S-form of aryl methyl sulfoxides, the enantiomeric recognition of (S,S)-Ile-Phg was superior to that of (S,S)-Leu-Phg. Single-crystal X-ray analysis of these inclusion compounds revealed that the dipeptide molecules self-assembled to form layer structures and included sulfoxides between these layers through hydrogen bonding between the proton of ⁺NH₃ and the oxygen of the sulfoxide. Besides these host-guest interactions, the phenyl groups of the sulfoxides interacted with each other through the phenyl-phenyl interaction. Two adjacent homochiral sulfoxides make a pair having a 2-fold screw axis along the channel cavity. Thus, the self-recognition of sulfoxides made 2₁ helical column structures and had high enantioselectivity.

Full text of DOI:10.1021/jo902197k

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Predominant (S)-Enantioselective Inclusion of Aryl Methyl Sulfoxides by
(S)-Isoleucyl-(S)-phenylglycines
Motohiro Akazome,* Ai Doba, Shoji Matsumoto, and Katsuyuki Ogura
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, Chiba University,
1-33 Yayoicho, Inageku, Chiba 263-8522, Japan
akazome@faculty.chiba-u.jp
Received October 12, 2009
In terms of chiral recognition for racemic aryl methyl sulfoxides in the solid state, three kinds of
crystalline (S)-alkylglycyl-(S)-phenylglycines were examined as potential dipeptides host mole-
cules. When (S)-alanyl-(S)-phenylglycines [(S,S)-Ala-Phg] crystallized with aryl methyl sulf-
oxides, the stereochemistry of preferentially included sulfoxides depended on the individual
shapes of the sulfoxides and the enantiomeric excess was relatively low. Although (S)-leucyl-(S)-
phenylglycines [(S,S)-Leu-Phg] and (S)-isoleucyl-(S)-phenylglycines [(S,S)-Ile-Phg] mainly in-
cluded the S-form of aryl methyl sulfoxides, the enantiomeric recognition of (S,S)-Ile-Phg was
superior to that of (S,S)-Leu-Phg. Single-crystal X-ray analysis of these inclusion compounds
revealed that the dipeptide molecules self-assembled to form layer structures and included
sulfoxides between these layers through hydrogen bonding between the proton of þNH3
and the oxygen of the sulfoxide. Besides these host-guest interactions, the phenyl groups
of the sulfoxides interacted with each other through the phenyl-phenyl interaction. Two
adjacent homochiral sulfoxides make a pair having a 2-fold screw axis along the channel cavity.
Thus, the self-recognition of sulfoxides made 21 helical column structures and had high
enantioselectivity.
Introduction
p-toluenesulfinates. For the preparation of chiral sulfoxides,
asymmetric oxidation is undoubtedly beneficial in the case of
high enantioselectivity. If the enantioselectivity of the sulfide
oxidation is quite low, optical resolution of the racemic
sulfoxides must be an alternative approach. Generally, acidic
or basic compounds are optically resolved by forming
diastereomeric salts with appropriate chiral resolving
agents, but the method is not acceptable for neutral
sulfoxides. Recently, the optical resolution of neutral
compounds by lattice inclusion compounds, namely, clath-
rates, attracts significant attention on account of its high
efficiency and simplicity.3 Some sulfoxides were optically
resolved by dipeptides4 as well as several artificial host
molecules.5
Chiral sulfoxides are now widely used not only as impor-
tant auxiliaries to bring about numerous asymmetric syn-
thesis but also as biologically significant molecules.1 Many
methods are presently available to obtain optically active
sulfoxides: asymmetric oxidation, optical resolution, and
nucleophilic addition of alkyl or aryl ligands to diastereo-
chemically pure chiral sulfinates, the so-called Andersen
procedure.2 However, the Andersen method requires the
separation of the diastereomeric sulfinates except for com-
mercially available chiral sulfinates, such as (S)-menthyl
ꢀ
(1) (a) Pellissier, H. Tetrahedron 2006, 6, 5559–5601. (b) Fernandez, I;
ꢀ
Khiar, N. Chem. Rev. 2003, 103, 3651–3705. (c) Carreno, M. C. Chem. Rev.
1995, 95, 1717-1760 and references therein.
(2) (a) Andersen, K. K. Tetrahedron Lett. 1962, 3, 93–95. (b) Andersen,
K. K.; Gaffield, W.; Papanikolau, N. E.; Foley, J. W.; Perkins, R. I. J. Am.
Chem. Soc. 1964, 86, 5637–5646.
(3) Separations and Reactions in Organic Supramolecular Chemistry;
Perspectives in Supramolecular Chemistry; Toda, F., Bishop, R., Eds.; John
Wiley & Sons: West Sussex U.K., 2004; Vol. 8.
660 J. Org. Chem. 2010, 75, 660–665
Published on Web 01/05/2010
DOI: 10.1021/jo902197k
r
2010 American Chemical Society

Akazome et al.
JOCArticle
FIGURE 1. Structure of(R)-phenylglycyl-(R)-phenylglycine[(R,R)-
Phg-Phg] and the stereochemistry of methyl tolyl sulfoxides included
in the cavity of (R,R)-Phg-Phg.
In this context, we demonstrated high enantioselective
inclusion of aryl methyl sulfoxides using (R)-phenyl-
glycyl-(R)-phenylglycine [(R,R)-Phg-Phg].4d-f The host
molecules self-assemble by intermolecular salt formation to
form layer structures, and the sulfoxide guests are accom-
modated between layers. Although the enaitoselectivity is
high, we face a crucial problem that the stereochemistry of
preferably included sulfoxides is dependent on the shape of
aryl methyl sulfoxides. For the isomers of methyl tolyl
sulfoxide, the enantioselectivities were as follows: 2-tolyl,
94% ee (R); 3-tolyl, 93% ee (S); 4-tolyl, racemic (Figure 1).4d
Similar enantioselectivities were obtained for isomers of
chlorophenyl methyl sulfoxide.
FIGURE 2. Inclusion compound of (R,R)-Phg-Phg (R)-2-chloro-
3
methyl phenyl sulfoxide. (a) Layer structure. (b) CPK model of
packing where sheet structures are colored in black, guest sulfoxides
in gray, and phenyl groups of dipeptides in white.
SCHEME 1
In addition, we elucidated that a slight difference in the
shape of the guest molecule induces a conformational change
in (R,R)-Phg-Phg, especially the phenyl group of the dipep-
tides. As can be seen from the crystal structure of (R,R)-Phg-
Phg with (R)-chlorophenyl methyl sulfoxide (Figure 2), the
phenyl-phenyl interaction between host and guest occurs
most frequently. Since the phenyl-phenyl interaction
controls the position of sulfoxides in the cavity of (R,R)-
Phg-Phg, it is difficult for us to predict whether the R- or
S-form of the sulfoxide is predominantly included.
SCHEME 2
To overcome the problem, the phenyl group of the
N-terminal amino acid was replaced by three alkyl groups.
It is just like enzyme proteins choose appropriate amino
acids to construct the specific recognition site. We try to
examine three kinds of (S)-alkylglycyl-(S)-phenylglycines,
(S)-alanyl-(S)-phenylglycines [(S,S)-Ala-Phg], (S)-leucyl-
(S)-phenylglycines [(S,S)-Leu-Phg], and (S)-isoleucyl-(S)-
phenylglycines [(S,S)-Ile-Phg] (Scheme 1).
In the course of the study, we found that (S)-alkylglycyl-(S)-
phenylglycines form inclusion compounds with aryl methyl
sulfoxides, where the homochiral guest molecules aggregate 21
helical columns by the phenyl-phenyl interaction to achieve
high enantioselectivity. It is noteworthy that (S)-form of all
aryl methyl sulfoxides that have phenyl, tolyl, and xylyl groups
are included in (S)-isoleucyl-(S)-phenylglycine. These inter-
actions between guest molecules in the cavity of (S)-alkyl-
glycyl-(S)-phenylglycines were different from what was ob-
served in the case of (R,R)-Phg-Phg. In other words, the
present work provided us a greater understanding of the role
of side chains of the N-terminal amino acid for chiral discrimi-
nation of aryl methyl sulfoxides.
(4) (a) Akazome, M.; Hirabayashi, A.; Senda, K.; Ogura, K. Tetrahedron
2007, 63, 9933–9938. (b) Akazome, M.; Hirabayashi, A.; Takaoka, K.;
Nomura, S.; Ogura, K. Tetrahedron 2005, 61, 1107–1113. (c) Akazome,
M.; Hirabayashi, A.; Ogura, K. Tetrahedron 2004, 60, 12085–12093. (d)
Akazome, M.; Ueno, Y.; Ooiso, H.; Ogura, K. J. Org. Chem. 2000, 65, 68–76.
(e) Akazome, M.; Noguchi, M.; Tanaka, O.; Sumikawa, A.; Uchida, T.;
Ogura, K. Tetrahedron 1997, 53, 8315–8322. (f) Ogura, K.; Uchida, T.;
Noguchi, M.; Minoguchi, M.; Murata, A.; Fujita, M.; Ogata, K. Tetrahedron
Lett. 1990, 31, 3331–3334.
(5) (a) Toda, F.; Tanaka, K.; Okuda, T. J. Chem. Soc., Chem. Commun.
1995, 639–640. (b) Weber, E.; Wimmer, C.; Liamas-Saiz, A. L.; Foces-Foces,
C. J. Chem. Soc., Chem. Commun. 1992, 733–735. (c) Toda, F.; Tanaka, K.;
Nagamatsu, S. Tetrahedron Lett. 1984, 25, 4929–4932. (d) Toda, F.; Tanaka,
K.; Mak, T. C. W. Chem. Lett. 1984, 2085–2088.
Results and Discussion
Enantioselective Inclusion of Alkyl Phenyl Sulfoxides.
(S,S)-Ala-Phg, (S,S)-Leu-Phg, and (S,S)-Ile-Phg were
easily prepared in accordance with the synthetic method of
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TABLE 1. Enantioselective Inclusion of Alkyl Phenyl Sulfoxides by Dipeptides
guest RSOPh
(S,S)-Ala-Phg
(S,S)-Leu-Phg
(S,S)-Ile-Phg
b
LD (A)
b
LD (A)
b
LD (A)
G/Ha ratio
ee (%)
G/Ha ratio
ee (%)
G/Ha ratio
˚
˚
˚
entry
R
ee (%)
1
2
3
4
Me
Et
i-Pr
n-Pr
1
racc
racc
15(S)
racc
1.00
0.87
0.63
0.90
11.5
11.8
12.3
11.5
73(S)
33(S)
15(S)
racc
0.97
0.63
0.51
0.54
11.7
12.7
12.5
11.7
80(S)
17(S)
racc
0.97
0.57
0.67
0.09
11.1
12.6
12.7
12.4
2a
3a
3b
aG/H ratio means the ratio of the sulfoxide (guest) to the dipeptide (host) in the inclusion compound. bLD is an interlayer distance measured by
PXRD. crac means enantioselectivity within 10%.
(R,R)-Phg-Phg,5 and their inclusion abilities were examined.
The inclusion compound was prepared by crystallization
of the dipeptide in the presence of a racemic sulfoxide
(Scheme 2).
Table 1 summarizes the results for the inclusion of alkyl
phenyl sulfoxides with (S,S)-Ala-Phg, (S,S)-Leu-Phg, or
(S,S)-Ile-Phg. Here, G/H ratio means the ratio of the sulf-
oxide (guest) to the dipeptide (host). After dissolving the
inclusion compound with appropriate deuterated solvents,
the ratios were determined by 1H NMR measurement. The
layer distances (LD in Tables) were determined by powder
X-ray diffraction (PXRD). All of these inclusion compounds
have strong diffraction peaks in the lower 2Θ range. The
layer distances were assigned by the strong peak of PXRD,
which corresponds to the diffraction plane of the peptide
backbones in the single crystal structure (vide infra). (S,S)-
Ala-Phg showed inclusion ability but less enantioselecti-
vity for these sulfoxides. (S,S)-Leu-Phg and (S,S)-Ile-Phg
showed a similar tendency in molecular recognition. Among
these alkyl phenyl sulfoxides, only methyl phenyl sulfoxide
was included in both (S,S)-Leu-Phg and (S,S)-Ile-Phg with
high enantioselectivity (entry 1).
Pairing of the Guests in the Chiral Cavities. The crystal
structure of the inclusion compound of (S,S)-Ile-Phg with
methyl phenyl sulfoxide was determined by performing
single-crystal X-ray diffraction analysis (Figure 3, space
group P212121). In the inclusion crystals, the dipeptide
molecules have a straight glycylglycine backbone forming a
FIGURE 3. Inclusion compound of (S,S)-Ile-Phg (S)-methylphenyl
sulfoxide 1. (a) Layer structure. (b) CPK model of packing where
sheet structures are colored in black, guest sulfoxides in gray, and
phenyl groups of dipeptides in white.
3
two-dimensional layer by means of intermolecular salt for-
mation and hydrogen bonding between COO- and þNH3
groups.3 The sheet structure of (S,S)-Ile-Phg was similar to
that of (R,R)-Phg-Phg. Methyl phenyl sulfoxide was accom-
modated in the channel between sec-butyl and phenyl groups
of the dipeptides. As mentioned above, the N-terminal
phenyl group of (R,R)-Phg-Phg interacted with the phenyl
group of (R)-2-chlorophenyl methyl sulfoxide (see in
Figure 2). However, the methyl phenyl sulfoxide in (S,S)-
Ile-Phg did not contact with the phenyl groups of (S,S)-Ile-
Phg but did interact with the phenyl group of the adjacent
sulfoxide belonging to the upper layer. These phenyl-phenyl
interactions contribute to the secondary structure in pro-
teins6 as well as to artificial supramolecular aggregate.7
The above results indicate that methyl phenyl sulfoxide
paired in the channel cavity to form symmetrical columns
with a 2-fold screw axis. In other words, this pairing of
sulfoxides with the same chirality involved the self-recogni-
tion process of the guest. Highly enantioselective inclusion
occurred and thereby aided pairing of the guests in the host
cavity.
Enantioselective Inclusion of Methyl Phenyl Sulfoxides.
Next, we investigated how the methyl substituent group on
the phenyl group of sulfoxides influences the stereoselective
inclusion. Table 2 summarizes the results for enantioselective
inclusion of the dipeptides [(S,S)-Ala-Phg, (S,S)-Leu-Phg,
and (S,S)-Ile-Phg] for both structural isomers of methyl tolyl
sulfoxides (2b-2d) and methyl xylyl sulfoxides (3c-3h).
Although (S,S)-Ala-Phg included these sulfoxides, the
enantioselectivity was low except for methyl 3,5-xylyl sulf-
oxide 3g (65% ee) and methyl 3,4-xylyl sulfoxide 3h (75% ee)
(entries 8 and 9). The absolute configuration of preferably
included sulfoxides depended on the individual shape of the
(6) In proteins, π-π interactions of their side chains have already been
investigated to reveal the edge-to-face interaction between two 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.
(7) (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.
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TABLE 2. Enantioselective Inclusion of Structural Isomers by Dipeptides
guest ArSOMe
(S,S)-Ala-Phg
(S,S)-Leu-Phg
(S,S)-Ile-Phg
b
LD (A)
b
LD (A)
b
LD (A)
˚
˚
˚
entry
Ar
ee (%)
G/Ha ratio
ee (%)
racc
G/Ha ratio
ee (%)
G/Ha ratio
1
2
3
4
5
6
7
8
9
2-MeC6H4
3-MeC6H4
4-MeC6H4
2,6-Me2C6H3
2,3-Me2C6H3
2,5-Me2C6H3
2,4-Me2C6H3
3,5-Me2C6H3
3,4-Me2C6H3
2b
2c
2d
3c
3d
3e
3f
11(R)
racc
0.64
0.73
0.95
0.56
0.51
0.55
0.76
0.95
0.55
11.8
11.4
12.5
12.9
13.2
12.3
13.0
12.4
12.3
0.57
0.67
0.51
0.89
0.63
0.52
0.68
0.59
0.99
11.7
11.7
12.8
11.4
11.7
11.8
12.4
11.7
12.1
83(S)
41(S)
79(S)
83(S)
93(S)
72(S)
91(S)
84(S)
79(S)
0.99
0.98
0.97
0.91
1.00
0.90
0.90
0.43
0.96
14.7
14.9
12.0
12.5
14.2
14.1
12.3
11.4
12.0
13(S)
49(S)
52(S)
racc
40(R)
28(R)
46(R)
16(R)
22(R)
65(S)
75(S)
racc
racc
3g
3h
53(S)
77(S)
aG/H ratio means the ratio of the sulfoxide (guest) to the dipeptide (host) in the inclusion compound. bLD is the interlayer distance measured by
PXRD. crac means enantioselectivity within 10%.
FIGURE 4. Inclusion compound of (S,S)-Leu-Phg (S)-methyl 3,
3
4-xylyl sulfoxide 3h. (a) Layer structure. (b) CPK model of packing
where sheet structures are colored in black, guest sulfoxides in gray,
and phenyl groups of dipeptides in white.
FIGURE 5. Inclusion compound of (S,S)-Ile-Phg (S)-methyl 2-tolyl
3
guest. Since alanine has only a methyl group as the side
chain, the cavity might not be enough for chiral discrimina-
sulfoxide 2b. (a) Layer structure. (b) CPK model of packing where
sheet structures are colored in black, guest sulfoxides in gray, and
phenyl groups of dipeptides in white.
tion of the sulfoxide. In the case of (S,S)-Leu-Phg, the
sulfoxides having the phenyl group with an o-methyl group
were included with no enantioselectivity (entries 1 and 5-7).
(S,S)-Leu-Phg included the (S)-form of other sulfoxides with-
out an o-methyl group, but the enantiomeric excess was not
enough (entries 2-4, and 8). Only methyl 3,4-xylyl sulfoxide
3h was included in (S,S)-Leu-Phg with high enantiomeric
excess (77% ee), and the inclusion compound could be
analyzed in single-crystal X-ray analysis (vide infra).
sulfoxides had a methyl group at the ortho position of the
phenyl group. Table 2 indicates that these layer distances of
˚
(S,S)-Ile-Phg are often over 14 A and generally longer than
that of (S,S)-Leu-Phg.
Crystal Structures of Inclusion Compounds. Among the
sulfoxides listed in Table 2, (S,S)-Leu-Phg with methyl
3,4-xylyl sulfoxide 3h and (S,S)-Ile-Phg with methyl 2-tolyl
sulfoxide 2b were single crystals suitable for X-ray analysis
(Figures 4 and 5). The space group of these crystals was
P212121. The figures clearly show the pairing of sulfoxide
In sharp contrast with (S,S)-Leu-Phg, (S,S)-Ile-Phg gen-
erally included both methyl tolyl sulfoxides and methyl xylyl
sulfoxides with high (S)- enantioselectivity, even though the
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Akazome et al.
JOCArticle
alignment of the dipeptide backbones. Like the hydrogen
bonds between the dipeptide hosts, the hydrogen-bonding
distances (H G) between the þNH3 group and the sulfinyl
oxygen are close to one another.
3 3 3
Conclusions
Three dipeptides [(S,S)-Ala-Phg, (S,S)-Leu-Phg, and
(S,S)-Ile-Phg] were prepared as a new series of (S)-
alkylglycyl-(S)-phenylglycines, and they were examined in
terms of enantiomeric recognition of sulfoxides. Although
(S,S)-Ala-Phg included sulfoxides, its enantioselectivity was
low and the stereochemistry of the preferably included
sulfoxides depended on their shape. (S,S)-Leu-Phg and (S,
S)-Ile-Phg included methyl phenyl sulfoxides. (S,S)-Ile-Phg
showed high enantiselectivity for the (S)-form of sulfoxides.
The dipeptide molecules self-assembled to form layer
structures and included the sulfoxides between these layers.
In particular, guest molecules with the same chirality aggre-
gate 21 screw symmetric columns and have high enantio-
selectivity.
Experimental Section
Synthesis of (S)-Alkylglycyl-(S)-phenylglycine. The general
preparation method of (R)-phenylglycyl-(R)-phenylglycine8
was applied for (S)-alkylglycyl-(S)-phenylglycine. (S)-Alkyl-
glycine and (S)-phenylglycine were protected with CbzCl (ben-
zyloxycarbonyl chloride) and benzyl alcohol, respectively.9,10
These protected amino acids were coupled with DCC (N,N0-
dicyclohexylcarbodiimide) and HOBt (1-hydroxybenzotriazole)
to form the corresponding protected dipeptide.11 Final depro-
tection was performed by hydrogenation with Pd black under a
hydrogen atmosphere to obtain (S)-alkylglycyl-(S)-phenylgly-
cine. All steps proceeded in excellent yields.
FIGURE 6. Sheet structures of dipeptide backbones and hydrogen-
bond distances in these inclusion compounds.
guests in the cavity of these inclusion crystals. Figure 4 shows
that methyl 3,4-xylyl sulfoxide 3h got together through an
edge-to-face interaction to form a 21 symmetrical guest
column along the channel cavity,
The inclusion compound of (S,S)-Ile-Phg with (S)-methyl
2-tolyl sulfoxide 2b has a pleated sheet, whose interlayer
(S,S)-Ala-Phg. Colorless crystals; mp 194.1 °C; [R]25
=
D
þ146.1 (c 0.10, H2O); 1H NMR (300 MHz, CD3OD) δ
7.47-7.44 (m, 2H), 7.31-7.22 (m, 3H), 5.26 (s, 1H), 3.99 (q,
1H, J=7.0 Hz), 1.53 (d, 3H, J=7.0 Hz); IR (KBr) 3334, 2976,
2127, 1655, 1527, 1392, 1356, 1196, 1157, 737, 700 cm-1; powder
X-ray diffraction (I/I0) 12.0 (0.89), 8.0 (0.25), 7.0 (0.15), 6.0
˚
distance was 14.7 A (Figure 5). The pleated sheet is why the
layer distances of (S,S)-Ile-Phg are longer than those of
(S,S)-Leu-Phg. The figures clearly show the pairing of guests
in the cavity and the forming a 21 screw symmetrical column
through the edge-to-face interaction along the channel cavity
of these inclusion crystals. Furthermore, isoleucine (Ile)
involves an additional chirality on the sec-butyl group
(S-configuration). The chiral side chain acts as the wall of
the narrow cavity so as to enrich the chiral circumstance for
enatioselective recognition, even though the sulfoxides have
an o-methyl group on the phenyl group.
Figure 6 shows the sheet structures of the dipeptide back-
bones and hydrogen-bonding distances in these inclusion
compounds. In two of the three inclusion crystals mentioned
above, the conformation of the dipeptide backbones is very
similar for forming the sheet structure from the hydrogen-
bonding network. The lengths of the hydrogen bonds be-
tween COO- and þNH3 groups are almost the same as the
reported distances for (R,R)-Phg-Phg with (R)-2-chloro-
phenyl methyl sulfoxide in Figure 2.5a However, the inclusion
compound of (S,S)-Ile-Phg with (S)-methyl 2-tolyl sulfoxide
has a dipeptide backbone with a zigzag arrangement and
another two hydrogen bonds. One hydrogen bond is an
additional linkage (bond C) between COO- and a hydrogen
atom of the amide group. The other bond (bond D) is
between þNH3 and an oxygen atom of the amide group. It
is these hydrogen bonds that are responsible for the zigzag
˚
(0.13), 5.1 (0.46), 4.8 (1.00), 4.2 (0.82), 3.7 (0.70), 3.2 A (0.42).
Anal. Calcd for C11H14N2O3: C, 59.45; H, 6.35; N, 12,61.
Found: C, 59.36; H, 6.32; N, 12.51.
(S,S)-Leu-Phg. Colorless crystals; mp 144 °C; [R]25D=þ136.3
(c 0.29, MeOH); 1H NMR (300 MHz, CD3OD) δ 7.48-7.45 (m,
2H), 7.32-7.22 (m, 3H), 5.27 (s, 1H), 3.97 (m, 1H), 1.82-1.65
(m, 3H), 1.00 (t, 6H J=6.4 Hz); IR (KBr) 3379, 3313, 2962, 1670,
1577, 1506,1375, 1232, 1074, 729, 696 cm-1; powder X-ray
diffraction (I/I0) 11.7 (1.51), 8.1 (0.64), 7.2 (0.3 3), 5.0 (1.00),
˚
4.4 (1.00), 4.0 (0.92), 3.8 A (0.55). Anal. Calcd for C14H20N2O3:
C, 63.62; H, 7.63; N, 10.60. Found: C, 63.27; H, 7.51; N, 10.23.
(S,S)-Ile-Phg. Colorless crystals; mp 171.0 °C; [R]25
=
D
þ139.1 (c 0.10, MeOH); 1H NMR (300 MHz, CD3OD) δ
7.48-7.45 (m, 2H), 7.28-7.22 (m, 3H), 5.27 (s, 1H), 3.83 (d,
1H, J = 5.6 Hz), 1.94-1.89 (m, 1H), 1.66-1.57 (m, 1H)
1.30-1.20 (m, 1H), 1.04 (d, 3H, J=6.7 Hz); 0.98 (t, 3H, J=
6.7 Hz); IR (KBr) 3373, 3240, 2970, 2696, 2586, 2044, 1666,
1606, 1514, 1381, 733 cm-1; powder X-ray diffraction (I/I0) 11.6
(0.27), 9.2 (0.12), 7.5 (0.52), 5.4 (1.00), 4.6 (0.33), 4.4 (0.29), 3.9
(8) Akazome, M.; Matsuno, H.; Ogura, K. Tetrahedron: Asymmetry
1997, 8, 2331–2336.
(9) Doyle, F. P.; Fosker, G. R.; Nayler, J. H. C.; Smith, H. J. Chem. Soc.
1962, 1440–1444.
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664 J. Org. Chem. Vol. 75, No. 3, 2010

Akazome et al.
JOCArticle
˚
(0.36), 3.7 (0.32), 3.0 (0.55), 3.0 (0.23), 2.9 A (0.29). Anal. Calcd
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 Bruker APEXII CCD diffracto-
meter with graphite-monochromated Mo KR (λ = 0.71073)
radiation. The structures were solved by a direct method
SHELXS-9717 and refined by SHELXL-9717 in a computer
program package from Bruker AXS. Hydrogen atoms are
calculated in appropriate position.
for C14H20N2O3 0.67H2O: C, 60.84; H, 7.78; N, 10.14. Found:
3
C, 60.83; H, 7.71; N, 10.06.
Synthesis of Sulfoxide 1, 2, and 3. Sulfides were prepared from
corresponding halides and thiols by Williamson-typed sulfide
synthesis except for methyl 2,3-xylyl sulfoxide 3d.12 Oxidation
of sulfide was proceeded by hydrogen peroxide in acetic acid or
sodium metaperiodate.13 Except for phenyl propyl sulfoxide
3b14 and methyl 2,3-xylyl sulfoxide 3d, all sulfoxides have
already reported by our previous literature.5a
Preparation of Racemic Methyl 2,3-Xylyl Sulfoxide 3d. Ac-
cording the literature,15 2,3-xylyl Grignard reagent was reacted
with dimethyl disulfide to afford methyl 2,3-xylyl sulfide in 96%
yield. The compound was oxidated with hydrogen peroxide in
acetic acid to form the corresponding racemic sulfoxide in 94%
yield: mp71.2 °C; 1H NMR (300 MHz, CDCl3) δ 7.82 (d, 1H,,
J=7.8 Hz), 7.37 (t, 1H,, J=7.8 Hz), 7.29 (d, 1H, J=7.6 Hz), 2.66
(s, 3H), 2.31 (s, 3H), 2.26 (s, 3H), IR (KBr) 2996, 1560, 1459,
1049, 804, 680 cm-1. Anal. Calcd for C9H12OS: C, 64.24; H,
7.19. Found: C, 64.32; H, 7.29.
Inclusion Compound of (S,S)-Ile-Phg with Methyl Phenyl
Sulfoxide [(S,S)-Ile-Phg 1]. Colorless crystals; dec 168.2 °C;
3
C21H28N2O4S MW 404.51, crystal dimensions 0.42 ꢀ 0.05 ꢀ
˚
˚
0.03 mm, orthorhombic P2121213a=5.683(2) A, b=16.352(6) A, c
˚
˚
=22.299(9) A, V=2072.3(14) A , Z=4, T=173 K, dcalcd=1.297
g cm-3, 7004 reflections measured, 2337 independent, R =
0.0464 (1848 reflections with I > 2.00σ(I)), wR2=0.0920, S=
1.052, 258 parameters, residual electron density 0.047/-0.26. IR
(KBr) 3381, 2964, 2549, 2098, 1674, 1597, 1496, 1362, 1016, 733,
690 cm-1; powder X-ray diffraction (I/I0) 13.1 (0.16), 11.1
(0.34), 9.2 (0.16), 6.8 (0.24), 5.3 (0.22), 4.9 (1.00), 4.7 (0.55),
4.0 (0.60), 3.7 (0.47), 3.6 (0.43), 3.5 (0.39), 2.8 A (0.32). Anal.
Calcd for C14H20N2O3 1.00(C7H8SO) 0.20H2O: C, 61.80; H,
7.01; N, 6.86. Found: C, 61.82; H, 7.06; N, 6.89.
Inclusion Compound of (S,S)-Leu-Phg with Methyl 3,4-Xylyl
˚
Preparation of Inclusion Compounds of Alkyl Phenyl Sulfoxide
and the Dipeptides. After dipeptide (0.15 mmol) and a racemic
sulfoxide (1, 2, or 3) (0.30 mmol) were dissolved in methanol
(2 mL), the resulting mixture was allowed to stand at an ambient
temperature for several days. In the case of (S,S)-Ala-Phg,
(S,S)-Ala-Phg (0.15 mmol) was previously dissolved in small
amount of water. The deposited inclusion compound was
collected by filtration and washed with water and CHCl3
Determination of G/H Ratio, Stereochemistry, and Enantio-
meric Excess in the Inclusion. G/H ratio means the ratio of the
sulfoxide (guest) to the dipeptide (host) in the inclusion com-
pound. After dissolving the sample with d4-MeOH, the ratios
were determined by 1H NMR measurement. In the case of (S,S)-
Ala-Phg, a drop of DCl/D2O was added for complete solution in
the NMR sample tube. The included sulfoxide was isolated by
dissolution of the inclusion compound in 0.1 M aqueous HCl
(4 mL) and extraction with CHCl3. Absolute stereochemistry of
recognized sulfoxides was determined by a chiral shift reagent
[(R)-(þ)-2,20-dihydroxy-1,10-binaphthyl ((R)-BINOL, 1 mol
equiv for the sulfoxide)].16 Enantiomeric excess of the sulfoxide
was determined by a chiral HPLC (Daicel Chiralcel OB-H).
Analytical conditions and properties of all sulfoxides except for
methyl 2,3-xylyl sulfoxide 3d have already reported in our
previous literature.5a Only the enantiomeric excess of methyl
2,5-xylyl sulfoxide 3e was determined by optical rotation,
because the HPLC peaks of enantiomers were overlapped.
Methyl 2,3-Xylyl Sulfoxide 3d. [R]25D=-229.1 (c 0.1 CHCl3
92% ee S), HPLC eluent, hexane/2-propanol (4:1), flow rate=
0.4 mL/min, tR (S)=23.1 min, tR (R)=35.3 min); 1H NMR (with
(R)-BINOL in CDCl3) δ 2.25 (s, 3H), 2.33 (s, 3H), 2.63 (s, 0.09H,
R minor), 2.65 (s, 2.91H, S major), 7.13-7.39 (m, 3H).
3
3
Sulfoxide [(S,S)-Leu-Phg 3h)]. Colorless crystals; dec 161.7 °C;
3
C23H32N2O4S MW 432.57, crystal dimensions 0.40 ꢀ 0.08 ꢀ
˚
0.05 mm, orthorhombic P212121 a=5.8273(10) A, b=15.945(3)
3
˚
˚
˚
A, c=24.097(4) A, V=2239.0(7) A , Z=4, T=173 K, dcalcd
=
1.283 g cm-3, 6387 reflections measured, 2008 independent, R=
0.0546 (1823 reflections with I > 2.00σ(I)); wR2 = 0.0992,
S = 1.046, 278 parameters, with heavy atoms refined aniso-
tropically, residual electron density 0.747/-0.363; IR (KBr)
3386, 2958, 2117, 1676, 1583, 1496, 1375, 1018, 731, 696 cm-1
;
powder X-ray diffraction (I/I0) 13.3 (0.37), 12.1 (0.49), 11.5
(0.63), 9.6 (0.32),7.2 (0.41), 5.0 (0.77), 4.6 (1.00), 4.0 (0.84), 3.7
˚
(0.46). Anal. Calcd for
(0.81), 3.6 (0.69), 3.4
A
C14H20N2O3 0.96(C9H12OS) 0.10H2O: C, 63.59; H, 7.48; N,
3
3
6.55. Found: C, 63.52; H, 7.48; N, 6.75.
Inclusion Compound of (S,S)-Ile-Phg with Methyl 2-Tolyl
Sulfoxide [(S,S)-Ile-Phg 2b]. Colorless crystals; dec 169.2 °C;
3
C22H30N2O4S MW 418.54, crystal dimensions 0.42 ꢀ 0.10 ꢀ
˚
0.06 mm, orthorhombic P212121 a=5.3975(5) A, b=13.4459(11)
3
˚
˚
˚
A, c=29.519(3) A, V=2142.3(3) A , Z=4, T=173 K, dcalcd
=
1.298 g cm-3, 11481 reflections measured, 4448 independent,
R=0.0339 (3960 reflections with I > 2.00σ(I)), wR2=0.0698,
S = 0.981, 268 parameters., residual electron density 0.212/
-0.220. IR (KBr) 3213, 3051, 2960, 2359, 1678, 1599, 1367,
1238, 1007, 731,696 cm-1; powder X-ray diffraction (I/I0) 14.7
(1.00), 10.1 (0.70), 8.0 (0.38), 5.6 (0.38), 5.6 (0.80), 5.1 (0.80), 4.5
(0.97), 4.2 (0.64), 4.0 (0.62), 3.7 (0.39), 3.5 (0.52), 3.3 (0.85), 3.0
(0.37). Anal. Calcd for C14H20N2O3 1.00(C8H10SO) 0.10H2O:
3
3
C, 62.86; H, 7.24; N, 6.66. Found: C, 62.61; H, 7.27; N, 6.66.
Methyl 2,5-Xylyl Sulfoxide 3e. [R]25 = -87.4 (c 0.285,
D
acetone 72% ee S).5a
Acknowledgment. This work was supported by Grant-
in-Aids for Scientific Reseacrh (C) (no. 21550129) from
The Japan Society for the Promotion of Science.
Crystallographic Data for the Inclusion Compounds. A metha-
nol solution of the dipeptide and the guest (1, 3h, or 2b) was
prepared in a vial, and then a lid of the vial was loosely closed for
Supporting Information Available: Experimental methods,
1H and 13C NMR spectra for new compounds, and crystal-
lographic data in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
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Gottingen: Gottingen, Germany, 1997.
€
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