Structures and properties of a diastereoisomeric molecular compound of (2S,3S)- and (2R,3S)-N-acetyl-2-amino-3-methylpentanoic acids

Article abstract of DOI:10.1271/bbb.90389

An X-ray crystal structural analysis revealed that (2S,3S)-N-acetyl-2- amino-3-methylpentanoic acid (N- acetyl-l-isoleucine; Ac-l-I1e) and (2R,3S)-N-acetyl-2- amino-3-methylpentanoic acid (N-acetyl-d-alloisoleucine; Ac-d-aIle) formed a molecular compound containing one Ac-l-Ile molecule and one Ac-d-aIle molecule as an unsymmetrical unit. This molecular compound is packed with strong hydrogen bonds forming homogeneous chains consisting of Ac-l-Ile molecules or Ac-d- aIle molecules and weak hydrogen bonds connecting these homogeneous chains in a fashion similar to that observed for Ac-l-Ile and Ac-d-aIle. Recrystallization of an approximately 1:1 mixture of Ac-l-Ile and Ac-d-aIle from water gave an equimolar molecular compound due to its lower solubility than that of Ac-d-aIle or especially Ac-l-Ile. The results suggest that the equimolar mixture of Ac-l-Ile and Ac-d-aIle could be obtained from an Ac-l-Ile-excess mixture by recystallization from water.

Full text of DOI:10.1271/bbb.90389

Biosci. Biotechnol. Biochem., 73 (10), 2293–2298, 2009
Structures and Properties of a Diastereoisomeric Molecular Compound
of (2S,3S)- and (2R,3S)-N-Acetyl-2-amino-3-methylpentanoic Acids
y
Tatsuo YAJIMA, Makiko KIMURA, Mami NAKAKOJI, Takao HORIKAWA,
Yurie TOKUYAMA, and Tadashi SHIRAIWA
Faculty of Chemistry, Materials and Bioengineering, Kansai University, Yamate-cho, Suita, Osaka 564-8680, Japan
Received June 2, 2009; Accepted June 25, 2009; Online Publication, October 7, 2009
[doi:10.1271/bbb.90389]
An X-ray crystal structural analysis revealed that
2S,3S)-N-acetyl-2-amino-3-methylpentanoic acid (N-
Since L-Ile can easily be obtained from proteins,
D-aIle has been mostly prepared from L-Ile by the usual
method of epimerization and various ways of separating
the derivatives of D-aIle from diastereoisomeric mix-
tures. Some chemoenzymatic methods made use of
(
acetyl-L-isoleucine; Ac-L-Ile) and (2R,3S)-N-acetyl-2-
amino-3-methylpentanoic acid (N-acetyl-D-alloisoleucine;
Ac-D-aIle) formed a molecular compound containing
one Ac-L-Ile molecule and one Ac-D-aIle molecule as
an unsymmetrical unit. This molecular compound is
packed with strong hydrogen bonds forming homoge-
neous chains consisting of Ac-L-Ile molecules or Ac-D-
aIle molecules and weak hydrogen bonds connecting
these homogeneous chains in a fashion similar to that
observed for Ac-L-Ile and Ac-D-aIle. Recrystallization of
an approximately 1:1 mixture of Ac-L-Ile and Ac-D-aIle
from water gave an equimolar molecular compound due
to its lower solubility than that of Ac-D-aIle or especially
Ac-L-Ile. The results suggest that the equimolar mixture
of Ac-L-Ile and Ac-D-aIle could be obtained from an
Ac-L-Ile-excess mixture by recystallization from water.
6
)
7)
hydrolase or alcalase with laborious procedures. On
the other hand, a diastereoisomeric mixture can be easily
9
)
separated by managing the chiral derivatives of amines
1
0)
or tartaric acid, but the diastereoisomers can be
separated without using chiral resolving reagents, as we
1
1)
have shown in the previous report.
In general, the solubility and crystal properties of a
single enantiomer and its racemates have strong influ-
ence on the separation and optical resolution into a single
enantiomer. A racemate existing as a conglomerate can
be separated into a single enantiomer by preferential
crystallization or replacing crystallization. On the other
hand, it is difficult to separate a single enantiomer when
the racemate is more stable or less soluble than the single
enantiomer without using a resolving agent. Under-
standing the factors related to these properties is
important for obtaining a single enantiomer from a
racemic mixture. We report in this paper structural and
solubility studies clarifying the reason why it is difficult
to separate the N-acetylated derivative of L-Ile, Ac-L-Ile
(1), and that of D-aIle, Ac-D-aIle (2), and why conversion
to ammonium salts facilitates this separation.
Key words: D-alloisoleucine; separation of diaster-
eoisomers by crystallization; molecular
compound of N-acetyl-2-amino-3-methyl-
pentanoic acid
D-Alloisoleucine ((2R,3S)-2-amino-3-methylpentano-
ic acid; D-aIle) is a nonprotein amino acid and a
diasteroisomer of L-isoleucine ((2S,3S)-2-amino-3-meth-
ylpentanoic acid; L-Ile), a normal constituent of proteins.
D-aIle may be important for potential medical use, as it
has been reported as a starting material for compounds
Materials and Methods
1
,2)
that could possibly be used as cardiovascular drugs
Preparation of the 1:1 molecular compound of Ac-L-Ile (1) and
and for isostatin, a component of potent antitumor
peptides.3 D-aIle is prepared by a variety of procedures,
e.g., asymmetric synthesis from (S)-2-methyl-1-buta-
Ac-D-aIle (2), Ac-L-Ile Ac-D-aIle (3). To a solution of L-Ile (13 g,
.
)
99 mmol) in acetic acid (80 ml) was added acetic anhydride (13 ml,
ꢀ
140 mmol) dropwise, before the resulting solution was stirred at 80 C
for 3 h and evaporated to dryness. The residue was recrystallized from
nol,4 chemoenzymatic methods, and some resolving
,5)
6,7)
2
5
methods.8–10)
water. Yield, 14.3 g (83.4%); ½ꢀꢁD ꢂ2:0 (c 1, water). Compound 3 was
obtained by recrystallization from the aqueous solution of an
equimolar mixture of 1 and 2.
6
Ac-L-Ile (1), Ac-D-aIle (2), and their ammonium salts, Ac-L-
1
5
.
.
Ile NH3 and Ac-D-aIle NH3, respectively, were prepared according to
11)
the literature.
4
2
COOH
3
7
8
Solubility. Solubility was calculated from the weight of the
precipitated crystals. In addition, for the mixtures of Ac-L-Ile and
Ac-D-aIle, the solubility of each compound was calculated from the
ratios of the integrated peaks for the ꢀ-protons of Ac-L-Ile and Ac-D-
NH
(
2S,3S)-form: Ac-L-Ile
2R,3S)-form: Ac-D-aIle
aIle in the 1H-NMR spectra of the precipitate at 20 C. Ac-L-Ile (1):
ꢀ
O
3.43 g/(100 g of water); Ac-D-aIle (2): 1.83 g/(100 g of water); Ac-L-
.
Ile Ac-D-aIle (3): 2.34 g/(100 g of water).
(
y
To whom correspondence should be addressed. Fax: +81-6-6330-3770; E-mail: t.yajima@ipcku.kansai-u.ac.jp

2294
T. YAJIMA et al.
Table 1. Crystallographic Data
1
2
3
Chemical formula
Formula weight
Cell system
C8H15O3N
173.21
C8H15O3N
173.21
C16H30O6N2
346.42
monoclinic
P21
orthorhombic
P212121
orthorhombic
P212121
Space group
˚
a (A)
˚
5.8379(3)
10.7604(6)
7.7308(4)
102.3031(14)
474.48(4)
2
7.8685(8)
9.9760(10)
12.3927(15)
11.4821(6)
12.6436(6)
13.7938(6)
b (A)
˚
c (A)
ꢀ
ꢁ
( )
˚
3
V (A )
Z
972.79(18)
4
1.183
2002.51(17)
4
1.149
ꢂ3
Dcalc (g cm
)
1.212
188
0.919
F000
376
0.897
752
0.871
ꢂ1
ꢂ (cm
Crystal size (mm )
)
3
0:22 ꢃ 0:10 ꢃ 0:02
colorless, plate
0.743–0.998
4604
0:21 ꢃ 0:15 ꢃ 0:03
colorless, plate
0.842–0.997
8973
0:21 ꢃ 0:12 ꢃ 0:08
colorless, plate
0.791–0.993
19842
Crystal colour, habit
Transfer factor
No. of measured reflections
No. of unique reflections
No. of variables
2126
169
2149
169
4581
337
Reflections/parameters ratio
Rint
12.58
0.055
12.72
0.032
13.59
0.033
ꢀ
2
ꢃmax ( )
54.9
0.0361
54.9
0.0297
54.9
0.0332
a
R1 value
R valueb
0.0387
0.0882
0.0337
0.0597
0.0455
0.0348
wR2 valuec
Goodness of fit
˚
Min./max. peak in final difference Fourier map (e A
1.051
ꢂ0:36=0:40
1.063
ꢂ0:22=0:35
1.107
ꢂ0:32=0:48
ꢂ3
)
a
R1 ¼ ꢀjjFoj ꢂ jFcjj=ꢀjFoj ðfor I > 2ꢄðIÞÞ
R ¼ ꢀjjFoj ꢂ jFcjj=ꢀjFoj (for all reflections)
b
c
2
2
2
2
2
1=2
ꢂ1
2
2
wR2 ¼ ½ꢀðwðFo ꢂ Fc Þ Þ=ꢀwðFo Þ ꢁ ; w ¼ ꢄðFo Þð4Fo Þ (for all reflections)
Table 2. Hydrogen Bond Distances of 1, 2 and 3
a
H(1)
O(1)
˚
Distance (A)
Compound
1
Atoms
O(2)
C(1)
a
H(1)ꢄ ꢄ ꢄO(3)
1.72(2)
2.14(2)
1.70(2)
2.08(1)
1.59(2)
1.62(2)
2.05(1)
2.16(1)
b
d
H(12)ꢄ ꢄ ꢄO(2)
c
2
3
H(1)ꢄ ꢄ ꢄO(3)
H(12)ꢄ ꢄ ꢄO(2)
O(3)
C(2)
e
H(1A)ꢄ ꢄ ꢄO(3A)
f
H(1B)ꢄ ꢄ ꢄO(3B)
H(12A)ꢄ ꢄ ꢄO(2B)
H(12B)ꢄ ꢄ ꢄO(2A)
H(12)
N(1)
a
b
c
d
e
f
Symmetry operation: ꢂx þ 1, y þ 1=2, ꢂz þ 1
Symmetry operation: x ꢂ 1, y, z
C(5)
C(3)
C(4)
Symmetry operation: ꢂx þ 1=2, ꢂy þ 2, z ꢂ 1=2
Symmetry operation: ꢂx þ 1, y þ 1=2, ꢂz þ 3=2
Symmetry operation: ꢂx ꢂ 1=2, ꢂy, z ꢂ 1=2
Symmetry operation: ꢂx þ 1=2, ꢂy, z þ 1=2
C(6)
X-Ray crystal structure analyses. Crystals for the X-ray crystal
b
H
structure analyses were obtained by recrystallization from water. The
X-ray experiments for 1, 2, and 3 were carried out with a Rigaku
RAXIS imaging plate area detector with graphite-monochromated Mo
CH CONH
H
3
ꢀ
Kꢀ radiation. The crystals were mounted on nylon loops at ꢂ150 C.
H C
3
C H
2 5
To determine the cell constants and orientation matrix, three oscillation
ꢀ
COOH
photographs were taken for each frame with an oscillation angle of 3
and exposure time of 15 s. Intensity data were collected by taking
oscillation photographs, and the reflection data were corrected for
Lorentz and polarization effects. The structures were solved by the
direct method12) and expanded by the Fourier technique.13) Non-
hydrogen atoms were refined anisotropically by full-matrix least-
squares calculation. Hydrogen atoms were found on the difference
Fourier map and isotropically refined. All calculations were performed
by using the CrystalStructure14) and Crystals15) crystallographic
software packages. Crystallographic data for 1, 2, and 3 are summa-
rized in Table 1 and have been deposited with the Cambridge
Fig. 1. Structure of Ac-L-Ile (1): a, ORTEP View; b, Newman
Projection of the C(2)–C(3) Bond.
Crystallographic Data Centre (CCDC) as supplementary publication
numbers CCDC-733540, -733541, and -733539, respectively. Copies
of the data can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (Fax: +44-1223-336-003; E-
mail: deposit@ccdc.cam.ac.uk).

Properties of N-Acetyl-2-amino-3-methylpentanoic Acids
2295
Hydrophilic layer
Hydrophobic layer
Hydrophilic layer
Hydrophobic layer
Fig. 2. Schematic View of Crystal Packing for 1 along the bc Plane.
Table 3. Torsion Angles of 1, 2 and 3
a
Molecule Bb of 3
1
2
Molecule A of 3
C(2)–N(1)–C(7)–O(3)
O(1)–C(1)–C(2)–N(1)
O(2)–C(1)–C(2)–N(1)
N(1)–C(2)–C(3)–C(4)
N(1)–C(2)–C(3)–C(6)
C(1)–C(2)–C(3)–C(4)
C(2)–C(3)–C(4)–C(5)
C(6)–C(3)–C(4)–C(5)
ꢂ4.4(2)
ꢂ31.2(2)
149.5(2)
ꢂ170.4(2)
64.2(2)
ꢂ2.1(2)
2.3(1)
ꢂ3.2(2)
173.3(1)
ꢂ7.7(2)
57.6(1)
3.4(2)
ꢂ176.8(1)
3.8(2)
ꢂ178.3(1)
62.2(1)
61.6(2)
ꢂ64.4(1)
ꢂ172.8(1)
175.3(1)
ꢂ60.1(2)
ꢂ68.5(2)
ꢂ65.6(2)
166.0(1)
ꢂ69.6(2)
ꢂ63.2(1)
ꢂ175.1(1)
64.8(2)
64.0(2)
53.7(2)
ꢂ179.3(1)
ꢂ170.8(1)
aA denotes Ac-L-Ile molecule.
bB denotes Ac-D-aIle molecule.
Results and Discussion
along the b axis. Parallel zigzag chains formed a layered
structure aligned in the ab plane consisting of the
hydrophilic layers with the acetylamino and carboxylic
acid moieties and the hydrophobic layers with the
1-methylpropyl groups (Fig. 2).
Crystal and molecular structures of diasteroisomeric
compounds of N-acetyl-2-amino-3-methylpentanoic acid
N-Acetyl-2-amino-3-methylpentanoic acid has two
hydrogen bond donors (the OH group of carboxylic
acid and the NH group of the acetylamino moiety) and
two hydrogen acceptors (the CO groups of the carbox-
ylic acid and acetylamino moieties). The structures of 1,
.
Compound 2 collected as colorless crystals from an
.
acidified solution of Ac-D-aIle NH was analyzed to
give the structure shown in Fig. 3. While the COOH
3
groups of Ac-L-Ile in 1 and all of the nonacetylated
1
6)
2
, and molecular compound Ac-L-Ile Ac-D-aIle (3) have
2-amino-3-methylpentanoic acids
were anti to the
similar intermolecular hydrogen bonds which are pres-
ent between the OH group of carboxylic acid and the CO
group of acetylamino moiety and between the NH group
of the acetylamino moiety and the CO group of the
carboxylic acid (Table 2). The OHꢄ ꢄ ꢄOC hydrogen
ꢁ-hydrogen atom around the Cꢀ–Cꢁ bond, the COOH
group of Ac-D-aIle in 2 was found to be located in the
anti position of the ethyl group on Cꢁ, so that the Ac-D-
aIle molecule had a structure bent at the Cꢀ position.
The crystal packing did not exhibit clear alternate
hydrophilic-hydrophobic layers due to the extended
directions of the intermolecular hydrogen bonds and
1-methylpropyl groups. The intermolecular hydrogen
bonds appear to have been protected by the 1-methyl-
propyl groups sandwiching them.
˚
bonds (Oꢄ ꢄ ꢄO distances of 2.54–2.58 A) were shorter
than the NHꢄ ꢄ ꢄOC hydrogen bonds (Nꢄ ꢄ ꢄO distances of
˚
.90–2.97 A), indicating that, in forming the crystal
2
structures, the hydrogen bond between the two electro-
negative oxygen atoms was stronger and more predom-
inant than that involving a less electronegative nitrogen
atom and an oxygen atom, this being in line with the
difference in polarization of the O–H bond in carboxylic
acid and the N–H bond of the acetylamino moiety.
Compound 1 recrystallized from water as colorless
crystals had an anti conformation of the ethyl group on
Cꢁ to the acetylamino group on Cꢀ when viewed along
the C(2)–C(3) bond (Fig. 1), this being similar to the
conformation of the anionic form of 1 in Ac-L-
.
Molecular compound Ac-L-Ile Ac-D-aIle (3) was
obtained as colorless crystals by recrystallization of an
approximately 1:1 mixture of Ac-L-Ile and Ac-D-aIle
from water. An unsymmetric unit in the crystal structure
contained one molecule of 1, denoted as molecule A,
and one molecule of 2, denoted as molecule B, as shown
in Fig. 4. The two diastereoisomeric molecules were
connected by two weak intermolecular hydrogen bonds
between the acetylamino NH moiety and the CO moiety
of the carboxylic acids (Table 2). Both 1 and 2 formed
chains consisting of the same diastereoisomers and
grown toward the c axis by hydrogen bonds between the
OH group of the carboxylic acid moiety rotated around
11)
.
Ile NH
(
and resulting in an extended structure
Table 3). The stronger intermolecular hydrogen bond,
3
OHꢄ ꢄ ꢄOC, and the P2 symmetry of crystal packing
1
arranged the Ac-L-Ile molecules in a zigzag fashion

2296
T. YAJIMA et al.
the Cꢀ–CCOOH bond (Table 3) and the CO group of the
acetylamino moiety. A layer structure was formed by
hydrophilic and hydrophobic chains in the ac plane like
that in 1 (Fig. 5). With respect to the conformations of
the molecules, the conformation of the ꢅ-position methyl
group around the C –C bond and the direction of OH
group of the carboxylic acid of the Ac-D-aIle molecule
in 3 were only slightly different from those in 2, but the
conformation of the Ac-L-Ile molecule in 3 (Fig. 4b)
was very different from those in 1 (Fig. 1b), its
conformation being more like that of the Ac-D-aIle
molecule in 2 (Fig. 3b) and in 3 (Fig. 4c). The similarity
in conformation of the Ac-L-Ile and Ac-D-aIle molecules
in 3 was favorable for forming the molecular compound,
which may have had a crystal packing similar to that in
the racemic compound, Ac-DL-Ile or Ac-DL-aIle (data
not shown), as seen in the crystals of 2-amino-3-
methylpentanoic acids (vide infra). The methyl and
ethyl groups of Ac-L-Ile were in a rotational isomer
regarding the Cꢀ–Cꢁ bond that was different from that
observed for Ac-D-aIle, but this may not have caused
any significant difference in size.
ꢁ
ꢆ
1
6)
a
Effect of ammonium ions on hydrogen bonds in the
crystals
O(3)
Conversion of a carboxylic acid to an ammonium
carboxylate may influence on the intermolecular inter-
actions in crystals in the following respects: i) loss of
hydrogen bonds involving the OH group of the
carboxylic acid, and ii) formation of hydrogen bonds
involving the ammonium ion. Crystals of N-acetyl-2-
amino-3-methylpentanioc acids, 1, 2, and 3, maintained
crystal packing by homogeneous chains formed by a
hydrogen bonding network involving the carboxylic acid
and acetylamino moieties of Ac-L-Ile or Ac-D-aIle.
Deprotonation of the carboxylic acid destroyed this
H(12)
O(1)
O(2)
N(1)
C(2)
H(1)
C(1)
C(3)
C(4)
C(6)
C(5)
.
network, but the ammonium ion in Ac-L-Ile NH and
3
b
C H
2
5
.
Ac-D-aIle NH replaced the proton and interacted with
3
H
H
NHCOCH3
the deprotonated carboxylate and the CO moiety of the
acetylamino group and, in addition, two more carbox-
ylate oxygens gathered around the ammonium ion by
CH3
COOH
11)
strong hydrogen bonds with an electrostatic nature.
Various solid-state structures of the compounds and
molecular compounds of 2-amino-3-metylpentanoic
acids, Ile and aIle, suggest that the 1-methylpropyl side
chain is not suitable for crystal packing because of its
Fig. 3. Structure of Ac-D-AIle (2): a, ORTEP View; b, Newman
Projection of the C(2)–C(3) Bond.
a
O(3B)
O(1A)
H(1A)
N(1B)
O(2A)
H(12B)
H(12A)
N(1A)
O(2B)
O(1B)
O(3A)
H(1B)
Ac-D-aIle (B)
Ac-L-Ile (A)
b
CH3
H
c
C H
2 5
CH CONH
H
H
NHCOCH3
3
C H
H
CH3
COOH
2
5
COOH
.
Fig. 4. Structure of Molecular Compound Ac-L-Ile Ac-D-aIle (3): a, ORTEP View; b, Newman Projection of the C(2A)–C(3A) Bond of Molecule A
Ac-L-Ile); c, Newman Projection of the C(2B)–C(3B) Bond of Molecule B (Ac-D-aIle).
(

Properties of N-Acetyl-2-amino-3-methylpentanoic Acids
2297
a
Ac-L-Ile chain
Ac-D-aIle chain
b
Hydrophilic layer
Hydrophobic layer
Hydrophilic layer
Hydrophobic layer
Hydrophilic layer
Fig. 5. Crystal Packing of 3: a, Schematic View along the ac Plane; b, Schematic View along the bc Plane.
1
00
100
9
9
99
+
+
9
8
98
+
+
+
+
+
++
+
+
9
7
97
+
+
+
+
+
+
9
6
96
+
+
+
+
+
9
5
95
Ac-D-aIle (%)
Ac-D-aIle·NH (%)
3
.
Fig. 7. Ternary Phase Solubility Diagram of the Ac-L-Ile NH3—Ac-
Fig. 6. Ternary Phase Solubility Diagram of the Ac-L-Ile—Ac-D-
aIle—H2O System.
.
D-aIle NH3—95% C2H5OH System.
asymmetric property.16) Enantiomeric or diasereoiso-
meric mixtures of 2-amino-3-methylpentanoic acids
form racemic compounds or molecular compounds,
and the crystal structure of a stereochemically pure
compound of L-Ile or D-aIle contains two molecules with
different conformations in an unsymmetric unit. This
may result from an open space in the crystal structure to
which the unsymmetric side chain group is adapted with
conformational changes.
There may be no question about the crystal packing of
N-acetyl derivatives and their ammonium salts which
are strongly influenced by the asymmetric side chain
groups and the hydrogen bonds containing the OH
moieties of carboxylic acids or the ammonium ions. In
crystals of the N-acetyl derivatives, these two factors
work to form molecular compound 3. The four strong
hydrogen bonds around the ammonium ion, which
attract the carboxylate groups of two extra molecules
of Ac-L-Ile or Ac-D-aIle, may be considered to form the
asymmetric 1-methylpropyl side chain to discriminate
1
1)
themselves in crystals of the ammonium salts.
Solubility of the mixtures of Ac-L-Ile and Ac-D-aIle
and their ammonium salts
Recrystallization of an approximately 1:1 mixture of
Ac-L-Ile and Ac-D-aIle gave molecular compound 3,
suggesting that 3 would be less soluble in water than
stereochemically pure 1 and 2. Compound 1 was about 2
times more soluble in water than 2, but the addition of 2
to an aqueous solution of 1 decreased the solubility of
the latter. The solubility in water of mixtures of 1 and 2
at various ratios is shown in the ternary phase solubility
diagram (Fig. 6) which indicates that a mixture with a
molar ratio around 0.5 may give molecular compound 3

2
298
T. YAJIMA et al.
2) Simmons WH, US Patent, 20070060525 (Mar. 15, 2007).
and that, in particular, an Ac-L-Ile-excess mixture would
easily give crystals of 3. On the other hand, the
solubility diagram for the Ac-L-Ile NH3—Ac-D-
.
aIle NH —95% C H OH system exhibited no local
minimum (Fig. 7), showing that Ac-L-Ile NH and Ac-
D-aIle NH formed a simple mixture. Recrystallization
3
from 95% C H OH of an approximately 1:1 mixture of
2
Ac-L-Ile NH3 and Ac-D-aIle NH3 gave pure crystals of
Ac-D-aIle NH3 and an Ac-L-Ile NH3-excess solution,
this giving crystals of 3 and an Ac-L-Ile-excess solution
by acidification in water (vide supra).
3
)
Liang B, Portonovo P, Vera MD, Xiao D, and Joulli e´ MM, Org.
Lett., 1, 1319–1322 (1999) and references cited therein.
Lloyd-Williams P, Monerris P, Gonzalez G, Jou G, and Giralt E,
J. Chem. Soc., Perkin Trans. 1, 1969–1975 (1994).
.
4
)
3
2
5
.
3
5) Portonovo P, Liang B, and Joulli e´ MM, Tetrahedron: Asymme-
try, 10, 1451–1455 (1999).
.
6) Murayama S, Kira I, and Takemoto T, US Patent, 20050202542
(Sep. 15, 2005).
5
.
.
1
1)
7) Cambi e` M, D’Arrigo P, Fasoli E, Servi S, Tessaro D, Canevotti
F, and Corona LD, Tetrahedron: Asymmetry, 14, 3189–3196
.
.
(
2003).
Huffman WAH and Ingersoll AW, J. Am. Chem. Soc., 73, 3366–
369 (1951).
8
)
3
Concluding remarks
9) Flouret G and Nakagawa SH, J. Org. Chem., 40, 2635–2637
(1975).
X-Ray crystal structure analyses and solubility studies
revealed that Ac-L-Ile (1) and Ac-D-aIle (2) formed
molecular compound 3 upon recrystallization of a nearly
1:1 or Ac-L-Ile-excess mixture. We have already
reported that an approximately 1:1 mixture of Ac-L-
1
0) Noda H, Sakai K, and Murakami H, Tetrahedron: Asymmetry,
13, 2649–2652 (2002).
1) Yajima T, Horikawa T, Takeda N, Takemura E, Hattori H,
1
Shimazaki Y, and Shiraiwa T, Tetrahedron: Asymmetry, 19,
1
285–1287 (2008).
.
.
Ile NH3 and Ac-D-aIle NH3, including an ammonium
12) Altomare A, Cascarano G, Giacovazzo C, Guagliardi A, Burla
M, Polidori G, and Camalli M, J. Appl. Cryst., 27, 435
(1994).
.
salt of 3, was separated to pure Ac-D-aIle NH3 and an
.
Ac-L-Ile NH3-excess mixture by recrystallization from
11)
13) Beurskens PT, Admiraa G, Beurskens G, Bosma WP, de Gelder
R, Israel R, and Smits JMM, The DIRDIF-99 program system,
Technical Report of the Crystallography Laboratory, University
of Nijmegen, The Netherlands (1999).
.
9
5% C2H5OH.
Acidification of the Ac-L-Ile NH3-
excess mixture gave molecular compound 3 and a higher
diastereoisomeric excess mixture of Ac-L-Ile. The fore-
going procedure for obtaining D-aIle derivatives can
contribute to cutting the cost of preparing D-aIle.
1
4) Crystal Structure Analysis Package, Rigaku and Rigaku
Americas, 9009 New Trails DR, The Woodlands TX 77381
USA (2000–2007).
1
5) Carruthers JR, Rollett JS, Betteridge PW, Kinna D, Pearce L,
Larsen A, and Gabe E, Chemical Crystallography Laboratory,
Oxford, UK (1999).
References
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Oinuma H, Suda S, Yoneda N, Kotake M, Hayashi K, Miyake
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16) Dalhus B and G o¨ rbitz CH, Acta Cryst. B, B56, 720–727 (2000)
and references cited therein.