A simple preparation of d-alloisoleucine from l-isoleucine via acetylation and separation of the ammonium salts

Article abstract of DOI:10.1016/j.tetasy.2008.05.004

d-Alloisoleucine was obtained from l-isoleucine by acetylation and epimerization by acetic anhydride followed by separation of the diastereoisomeric ammonium salts using the solubility difference. The structure-solubility relationship of diastereoisomeric salts was explained by X-ray crystal structure analysis.

Full text of DOI:10.1016/j.tetasy.2008.05.004

Tetrahedron: Asymmetry 19 (2008) 1285–1287
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A simple preparation of D-alloisoleucine from L-isoleucine via acetylation
and separation of the ammonium salts
Tatsuo Yajima a, , Takao Horikawa , Nobuhiro Takeda , Eri Takemura , Hiroaki Hattori , Yuichi Shimazaki ,
a
a
a
a
b
*
a
Tadashi Shiraiwa
a
Faculty of Chemistry, Materials and Bioengineering, Kansai University, Yamate-cho, Suita 564-8680, Japan
College of Science, Ibaraki University, Mito, Ibaraki 310-8512, Japan
b
a r t i c l e i n f o
a b s t r a c t
Article history:
D-Alloisoleucine was obtained from L-isoleucine by acetylation and epimerization by acetic anhydride fol-
Received 22 March 2008
Accepted 2 May 2008
Available online 10 June 2008
lowed by separation of the diastereoisomeric ammonium salts using the solubility difference. The struc-
ture–solubility relationship of diastereoisomeric salts was explained by X-ray crystal structure analysis.
Ó 2008 Elsevier Ltd. All rights reserved.
1
. Introduction
2. Results and discussion
D
-Alloisoleucine ((2R,3S)-2-amino-3-methylpentanoic acid;
is a diastereoisomer of -isoleucine ((2S,3S)-2-amino-3-methyl-
pentanoic acid; -Ile) and is known to be contained in
biologically active peptides such as theonellapeptolides.
D
-aIle)
2.1. Epimerization of L-Ile
L
L
Among several methods of racemization (or epimerization) at
a-position of a-amino acids, we examined two methods to epimer-
ize L-Ile: one using acetic anhydride, which causes N-acetylation,
1
–3
It is a
starting material for the synthesis of isostatine, which is a compo-
nent of potent antitumor peptides, tamandarins, and didemnins.
Considering that compounds containing nonprotein amino acids
such as -aIle could be less biodegradable, -aIle may be expected
4
12
5
,6
13
and one using a catalytic amount of salicylaldehyde in glacial
acetic acid. By the latter method about 50% of -Ile was converted
to -aIle at 80 °C within 1 h, and an additional reaction time made
little change to the ratio of epimers. Acetic anhydride in glacial ace-
tic acid reacted with -Ile to acetylate and epimerized it simulta-
neously at 80 °C, giving mixture of approximately equal
amounts of N-acetyl- -isoleucine (Ac- -Ile) and N-acetyl- -alloiso-
leucine (Ac- -aIle) within 15 min. Although these two types of epi-
merizations take place through different reaction mechanisms, the
ratios of the acetylated epimers, Ac- -Ile: Ac- -aIle, were very sim-
ilar (ca. 1:1). However, Ac- -aIle and Ac- -Ile have similar solubil-
L
D
D
D
to be important for potential medical use.
L
a
COOH
NH2
L
L
D
D
(
2R,3S)-2-Amino-3-methylpentanoic acid
L
D
D-Alloisoleucine (D-aIle)
D
L
ities in various solvents, so that it is difficult to separate Ac-
from the mixture by recrystallization.
D-aIle
D
-AIle has been prepared by various methods: a total synthesis
7
from (S)-2-methyl-1-butanol by the Strecker method, a chemo-
2.2. Solubilities of the ammonium salts of N-acetylated
derivatives
8
enzymatic method using alcalase, and some resolution methods
using resolving reagents.9
,10
Noda et al. prepared D-aIle via an
11
insoluble salt with a chiral tartaric acid derivative. These meth-
ods are rather complicated and expensive, and there is a strong de-
An approximately 1:1 mixture of Ac-
aIleꢀNH , obtained by treating the N-acetylated mixture with
1 mol/dm aq NH
OH in 94% yield. We found that the solubilities in C
these N-acetylated derivatives are drastically reduced by conver-
sion to ammonium salts: while the solubilities of Ac- -aIle and
OH at 20 °C are 85.9 and 89.6 g,
respectively, those of the corresponding ammonium salts, Ac-
aIleꢀNH 1 and Ac- -IleꢀNH 2, are 0.25 and 2.29 g, respectively,
L
-IleꢀNH
3
and Ac-D-
3
3
mand for a facile and low-cost method of preparation of
D
-aIle. We
3
, gave Ac-
D
-aIleꢀNH
4
by recrystallization from
report herein a simple method for preparation of -aIle from
D
L-Ile
C H
2 5
2 5
H OH of
in several steps via acetylation and recrystallization of the ammo-
nium salts.
D
3
2 5
Ac-L-Ile in 100 cm of 95% C H
D
-
*
Corresponding author. Tel.: +81 6 6368 1286; fax: +81 6 6330 3770.
E-mail address: t.yajima@ipcku.kansai-u.ac.jp (T. Yajima).
4
L
4
0
957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.05.004

1
286
T. Yajima et al. / Tetrahedron: Asymmetry 19 (2008) 1285–1287
which indicates that compound 2 is about 9 times more soluble
than 1. Compound 1 could be isolated from the mixture of the
Table 1
Hydrogen bond distances around an ammonium ion of 1
14
ammonium salts and converted to
exhibited [a]
D
-aIle in 89.0% yield, which
Atoms
Distance (Å)
3
15
D
3
= ꢁ38.3 (c 2, 5 mol/dm HCl) {lit. [a] = ꢁ38.4 (c
D
O(1)ꢀ ꢀ ꢀH(15)
1.88(1)
1.85(2)
1.87(2)
1.88(1)
4
, 6 mol/dm HCl)}.
O(1
O(2 )ꢀ ꢀ ꢀH(17)
0
0
0
)ꢀ ꢀ ꢀH(16)
0
00
O(3 )ꢀ ꢀ ꢀH(18)
2
.3. Relationship between solubilities and structures in crystals
In order to reveal the observed large solubility difference
between the ammonium salts 1 and 2, we determined their struc-
tures by X-ray crystal structure analysis.16 The molecular structures
of 1 and 2 are shown in Figures 1 and 2, respectively, and the dis-
tances of the hydrogen bonds in these structures are summarized
Table 2
Hydrogen bond distances around an ammonium ion of 2
Atoms
Distance (Å)
O(1)ꢀ ꢀ ꢀH(15)
1.81(3)
1.91(2)
1.82(2)
1.97(2)
in Tables 1 and 2, respectively. Because Ac-
epimers regarding the C carbon, they have different conformations
at the C –C bond. Considering that the C(2)–C(3)–C(5)–N(1) tor-
sion angles for 1 and 2 are 56.88(11)° and ꢁ167.14(16)°, respec-
tively, the conformations of the acetylamino group on C (C(5))
and the ethyl group on C (C(3)) in the Ac- -aIle anion are gauche
in order to make the molecule compact, while those for the Ac-
D-aIle and Ac-L-Ile are
0
O(1 )ꢀ ꢀ ꢀH(16)
a
0
0
O(2 )ꢀ ꢀ ꢀH(17)
a
b
000
O(3 )ꢀ ꢀ ꢀH(18)
a
b
L
hydrogen bonds between the ammonium ions and carboxylates
or amides, giving a more densely packed crystal structure. The ethyl
group of 2 gives rise to a steric hindrance for packing the Ac-L-Ile
anions, and thus vacant sites in hydrophobic layers. The interac-
tions between the side chains of the anions have strong effects on
crystal packing and the other interactions in crystals. The crystal
of 1 belongs to the orthorhombic system, which is of higher sym-
metry than the monoclinic system, to which the crystal of 2
belongs. The ammonium ion interacts with the oxygens of three
L-
Ile anion are equatorial to make the molecule linear. The difference
of the molecular shapes might have influences on molecular pack-
ing (Fig. 3). The ethyl group of 1 is stretched in a direction perpen-
dicular to the ab plane, which is parallel to the layer formed by
carboxylate groups and one oxygen of the amide group. The Ac-D-
aIle anion forms four similar hydrogen bonds with the ammonium
ion with the Hꢀ ꢀ ꢀO distances of 1.85–1.88 Å (Table 1). On the other
hand, because of the steric hindrance between the side chains, the
Ac-L-Ile anion interacts with the ammonium ions with two strong
hydrogen bonds (d(Hꢀ ꢀ ꢀO) = 1.81 and 1.82 Å) and two weak hydro-
gen bonds (d(Hꢀ ꢀ ꢀO) = 1.91 and 1.97 Å) (Table 2), differences be-
tween the bond distances being over 0.1 Å. Since the stability of
the crystal structure is considered to largely depend on the strength
of the intermolecular interactions, the difference in the hydrogen
bonding modes between 1 and 2 may explain the difference in
the solubility.
Figure 1. Structure of Ac-
D-aIleꢀNH
4
(1).
Figure 2. Structure of Ac-
L-IleꢀNH
4
(2).
Figure 3. Schematic views of packing in 1 and 2: (a) Ac-
D-aIleꢀNH
4
; (b) Ac-
L
-IleꢀNH
4
.

T. Yajima et al. / Tetrahedron: Asymmetry 19 (2008) 1285–1287
1287
(
1H, d, 2-CH), 2.06 (3H, s, –NHCOCH
3
), 2.00 (1H, sep, 3-CH), 1.33 (2H, quin, 4-
3
. Conclusion
CH
Ac-
2
), 0.92 (3H, d, 3-CHCH
-aIle 3.01 g (17.4 mmol) dissolved in 2 mol/dm aq HCl (20 cm ) was
refluxed for 2 h at 80 °C, and the resulting solution was evaporated to dryness.
3 3
), 0.89 (2H, t, 5-CH ).
3
3
D
In conclusion, we established a facile method of preparation of
3
D
-aIle via acetylation and separation of Ac-
D
-aIle in the form of the
The residue was dissolved in
triethylamine. -AIle was obtained by filtration1 as
recrystallized from hot water. Yield 2.12 g (93.0%). H NMR(400 MHz, 0.1 mol/
dm DCl, DSS) d
CH ), 1.00 (3H, d, 3-CHCH
C
2
H
5
OH (20 cm ) and neutralized by
D
a
white powder and
ammonium salt. We revealed that the ammonium salts of (RS)-N-
acetyl-aminobutanoic acid, N-acetyl-DL-norvaline, N-acetyl-DL-nor-
leucine, and N-benzoyl-DL-alanine are conglomerates, which
are optically resolved by preferential or replacing crystallization.
The procedure which makes use of the hydrogen bonds involving
the ammonium ion will be applicable to similar systems.
3
H
: 4.11 (1H, d, 2-CH), 2.17 (1H, sep, 3-CH), 1.40 (2H, quin, 4-
), 0.96 (2H, t, 5-CH ).
1
7
18
2
3
3
1
1
5. Davies, J. S. Amino Acids and Peptides; Chapman and Hall: NY, London, 1985.
6. Crystals for X-ray crystal structure analysis were obtained by recrystallization
from 95% C
Saturn CCD system with graphite-monochromated Mo Ka radiation
k = 0.71070 Å). The crystal was mounted on a nylon loop at ꢁ100 °C. For
2 5
H OH. The X-ray experiments for 1 were carried out on a Rigaku
(
determination of the cell constant and orientation matrix, six oscillation
photographs were taken for each frame with the oscillation angle of 0.5° and
the exposure time of 5 s. The X-ray experiments for 2 were carried out on a
Rigaku RAXIS imaging plate area detector with graphite-monochromated Mo
Ka radiation. The crystal was mounted on a nylon loop at ꢁ100 °C. For
determination of the cell constant and orientation matrix, three oscillation
photographs were taken for each frame with the oscillation angle of 3° and the
exposure time of 3 s. Intensity data were collected by taking oscillation
photographs, and the reflection data were corrected Lorentz and polarization
effects. The structures were solved by the direct method and expanded by
Fourier techniques. The non-hydrogen atoms were refined anisotropically by
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4
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= ꢁ21.5 (c 2, C OH) (lit.
OH)). H NMR(400 MHz, 0.1 mol/dm DCl, DSS) d : 4.44
D
2 5
H
1
1
3
[a]
D
= ꢁ21.5 (c 2, C
2
H
5
H