A new simple preparation of D-alloisoleucine suitable for large-scale manufacture

Article abstract of DOI:10.1016/S0957-4166(02)00719-X

D-Alloisoleucine (D-aIle) was obtained by the resolution of the epimer mixture of L-isoleucine (L-Ile) and D-aIle, which was formed by epimerization of L-Ile, with a resolving agent such as (2S,3S)-dibenzoyltartaric acid ((2S,3S)-DBTA) or (2S,3S)-di-4-toluoyl-tartaric acid ((2S,3S)-DTTA).

Full text of DOI:10.1016/S0957-4166(02)00719-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2649–2652
A new simple preparation of
D
-alloisoleucine suitable for
large-scale manufacture
Hirofumi Noda, Kenichi Sakai* and Hisamichi Murakami
R&D Division, Yamakawa Chemical Industry Co. Ltd., 1180-1 Isohara, Kitaibaraki, Ibaraki 319-1541, Japan
Received 9 September 2002; accepted 31 October 2002
Abstract—
D
-Alloisoleucine (
D
-aIle) was obtained by the resolution of the epimer mixture of
-Ile, with a resolving agent such as (2S,3S)-dibenzoyltartaric acid ((2S,3S)-DBTA) or
2S,3S)-di-4-toluoyl tartaric acid ((2S,3S)-DTTA). © 2002 Elsevier Science Ltd. All rights reserved.
L-isoleucine (L-Ile) and D-aIle, which
was formed by epimerization of
L
(
1
. Introduction
consequence this amino acid is very expensive and only
available in sub-gram units on the market.
†
D
-Alloisoleucine (
D-aIle) is a well-known stereoisomer
of
L
-isoleucine ( -Ile) and seems to have a potentially
L
To obtain this unnatural amino acid, much effort has
wide usage as a component of unnatural peptides or
medicines. It is a precursor of (3S,4R,5S)-isostatine
been expended and several methods have been pro-
4
posed. Although the epimer mixture of
L
-Ile and
D
-aIle
(
Ist), which is the characteristic component of cyclic
5–8
is known to be obtained by epimerization of L-Ile or
1,2
peptide didemnins isolated from a Caribbean tunicate
by synthesis from (S)-2-methylbutanol (optically active
and known to have a potent antitumor activity as wel3l
as a potential immunosuppressive activity. A patent
describes the syntheses of drugs for cardiovascular dis-
4
isoamylalcohol), no efficient method to separate the
epimer mixture has been reported. The epimer mixture
9
has to be protected by an acetyl or benzyloxy-
ease starting from
D-aIle.
10,11
carbonyl
group and separated as the salts with
optically active amines. Inversion of 2-amino group of
12
L
-Ile is also devised by Schmidt et al., but this method
requires five steps and is very laborious. Several
stereoselective syntheses of -,a1I3le being also described,
all remain of laboratory use.
D
2
We report here a new simple method for the prepara-
tion of -aIle. It starts from -Ile, which is manufac-
D
L
tured in an industrial scale and inexpensive, and
comprises a very efficient resolution method of the
epimer mixture with a resolving agent and the
improved procedure for epimerizing
L-Ile, which is
applicable for other amino acids. Final liberation of the
amino acid from the resulting complex or salt is very
simple and the enantiomerically pure amino acid is
obtained in a high yield.
Unfortunately, there was no efficient method to obtain
this unnatural amino acid in large quantities. As a
†
D
-Alloisoleucine is available only as reagents in 100 mg to 1 g
*
0
Corresponding author. E-mail: sakai@yamakawa-chemical.co.jp
packages.
957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00719-X

2
650
H. Noda et al. / Tetrahedron: Asymmetry 13 (2002) 2649–2652
2
. Results and discussion
The epimer mixture has been found to be efficiently
separated as the salt or complex with a resolving agent
such as (2S,3S)-dibenzoyltartaric acid ((2S,3S)-DBTA)
or (2S,3S)-di-4-toluoyl tartaric acid ((2S,3S)-DTTA).
The most favorable separation is achieved when 0.5
equiv. of the resolving agent and hydrochloric acid are
mixed with the epimer mixture as shown in Table 2.
Various methods for the isomerization (racemization or
epimerization) of amino acids have been proposed and
well documented. Of these, the method found by Chi-
8
6
,14
bata et al.,
in which amino acids are heated with a
catalytic amount of salicylaldehyde in glacial acetic
acid, is most favourable for Ile, because no protection
of the amino group is required. However, this method
imposes a severe difficulty of evaporating a large
amount of glacial acetic acid from the reaction mass to
isolate racemized amino acids. We have found that the
isomerization of amino acids can be performed in aro-
matic solvents and the isomerized acid separates as a
solid and is easily recovered in a high recovery after
L
-Ile in the mother liquor is also recovered and recycled
to the epimerization step. From elemental analysis, and
1
the H NMR spectrum,
D-aIle is estimated to form a
less soluble 1:1 complex with (2S,3S)-DBTA (anhy-
drous) or with (2S,3S)-DTTA (mono- or dihydrate).
cooling the reaction mass. Thus,
L-Ile is refluxed in
toluene with 4 equiv. of glacial acetic acid and a
catalytic amount of salicylaldehyde. Epimerization is
completed within about 3 h. After cooling the reaction
mixture, the precipitated epimer mixture is isolated by
filtration to give a highly pure product in ca. 90% yield.
The mother liquor containing acetic acid and salicyl-
aldehyde can be reused in next batches by supplement-
ing some loss of acid and aldehyde. This isomerization
procedure in an aromatic solvent is generally applicable
for other amino acids very efficiently (Table 1). The
degree of isomerization is defined by the following
equation:
The complex or salt formed from D-Ile and tartaric acid
derivative (2S,3S)-DBTA or (2S,3S)-DTTA easily
decomposes in alcoholic solvents to give diastereomeri-
cally pure
D-aIle as a solid by filtration. Better results
are obtained by decomposing the complex or salt in
polar solvents such as lower alcohols or acetic acid
ester containing 5–10% of water. These facts suggest
Degree of isomerization (%)={(P −P )/P }×100
0
I
0
that
D-Ile is interacted with (2S,3S)-DBTA or (2S,3S)-
where P is the enantiomeric or diastereomeric purity of
DTTA mainly by weak bonds such as a hydrogen bond
or a van der Waals force; it seems appropriate to regard
the solid as a complex, but not a salt.
0
the amino acid before the isomerization, and P , is that
I
15
after the isomerization.
Table 1. Racemization of L-amino acids
Entry
Amino acid
Time (h)
Degree of racemization (%)
Yield (%)
1
2
3
4
5
6
7
8
9
Alanine
Valine
Leucine
Isoleucine
Phenylalanine
Tryptophan
Methionine
3
2
2
3
3
2
2
2
2
97
48
98
92
90
88
90
82
87
86
92
85
a
100
87
82
86
81
96
Serine
Aminobutanoic acid
Amino acid 5.0 g; PhCH 25 ml; AcOH 4.0 equiv.; salicylaldehyde 0.2 equiv.
3
a
Epimer mixture of
L-isoleucine and D-alloisoleucine.
Table 2. Diastereomeric resolution of epimer mixture
Entry
Resolving agent (mol equiv.)
HCl (equiv.)
Yield (%)
DPa (% de)
Eb (%)
1
2
3
4
(2S,3S)-DBTA/0.50
(2S,3S)-DBTA/0.50
(2S,3S)-DBTA/0.50
(2S,3S)-DTTA/0.50
None
0.50
0.50
0.50
42
44
45
96
96
95
95
81
85
86
84
c
44
Solvent: entries 1, 2 and 4, H O; entry 3, H O/MeOH=5/1.
2
2
DBTA, dibenzoyltartaric acid; DTTA, di-4-toluoyltartaric acid.
a
Diastereomeric purity.
Resolution efficiency (E, %)=yield (%)×diastereomeric purity (%)/100.
Monohydrate.
b
c

H. Noda et al. / Tetrahedron: Asymmetry 13 (2002) 2649–2652
2651
1
−
1
The complex having a diastereomeric purity higher
than 95% de gives diastereomerically pure -aIle (100%
1528 (m), 1320, 1266 (s), 1118 (s), 719 (s) cm ; H
D
NMR (CD OD): l 0.97 (3H, t, J=4.0 Hz,
D
-aIle-5
3
de) in a yield of up to 90%. The resolving agent in the
mother liquor can be recovered and reused. This simple
and efficient process could be successfully scaled up
with no trouble to give multi-kilograms of highly pure
CH ), 1.00 (3H, t, J=4.0 Hz, CH ), 1.24–1.40, 1.43–
3
3
1.59 (1H×2, each m, CH ), 2.01–2.14 (1H, m,
D
-aIle-3
D-aIle-2 CH), 4.90 (7.5H,
2
CH), 3.71 (1H, d, J=3.5 Hz,
s, CD OH), 5.94 (2H, s, DBTA CH×2), 7.50 (4H, t,
3
1
6
D
-aIle in our pilot plant.
Bz-3,5×2), 7.64 (2H, tt, Bz-4×2), 8.11 (4H, dd, Bz-2,6×
2
).
3. Experimental
Other experimental results are summarized in Table 2
entries 2 and 3).
(
3
.1. General
3
.4. Preparation of D-aIle
1
H NMR spectra were measured on a JEOL GSX 270
spectrometer. IR spectra were measured on a Jasco IR
To a suspension of the epimer mixture of
L-Ile and
700 spectrometer. Enantiomeric or diastereomeric puri-
D-aIle (50.0 g, 381 mmol) in water (490 ml) was added
ties of amino acids were determined by HPLC analysis
with a Jasco UV-975 detector (wavelength 254 nm)
under the following conditions. Column: Sumichiral
OA-5000 4.6 mm I.D.×150 mm for isoleucine, alanine,
valine, leucine, phenylalanine, methionine, serine, and
35% hydrochloric acid (7.94 g, 76.2 mmol) under stir-
ring. A suspension was added dropwise to a mixture of
(2S,3S)-DBTA monohydrate (71.7 g, 190.5 mmol) in
methanol (100 mL) under stirring. A further 11.9 g (114
mmol) 35% hydrochloric acid was added to the slurry,
and the mixture was heated at 70°C for 1 h. The slurry
formed by reaction of the amino acids and the DBTA
was then cooled to 25°C. The precipitated crystals were
filtered, rinsed with water and dried to give a 1:1
2
-aminobutanoic, Daicel Chiralpak MA (+) 4.6 mm
I.D.×50 mm for tryptophan. Mobile phase: 2 mmol
CuSO +isopropnol (IPA) (98:2) for isoleucine, 2 mmol
4
CuSO for alanine, valine, serine, and 2-aminobutanoic
4
acid, 2 mmol CuSO +IPA (90:10) for phenylalanine, 2
complex of D-aIle and (2S,3S)-DBTA (84.7 g, yield
4
mmol CuSO +methanol (85:15) for tryptophan.
(based on the epimer mixture) 45.5%) as a white crys-
talline powder of 94.8% de. This complex (80.0 g, 163
mmol), obtained by the above procedures, was placed
in a mixture of 2-propanol (720 ml) and water (80 ml).
The mixture was heated under reflux for 1 h and, after
cooling, the solid was filtered from the mixture at 25°C.
The solid was rinsed three times with 2-propanol and
4
3.2. Epimerization of L-Ile
A suspension of
acid (109.8 g, 1.83 mol) and salicylaldehyde (11.2 g,
1.4 mol) in toluene (300 ml) was heated under reflux
L-Ile (60 g, 0.457 mol), glacial acetic
9
for 3 h and then cooled to room temperature. The
precipitated crystals were filtered, rinsed with toluene
dried to give
D-aIle (19.0 g, yield (based on the com-
plex) 89.0%) as a white crystalline powder of 99.9% de.
and dried to give the epimeric mixture of
-aIle (54.0 g, yield 90%) as a white crystalline powder.
L-Ile and
D
3.5. Separation of epimer mixture of L-Ile and D-aIle
by (2S,3S)-DTTA
As for other amino acids, the typical epimerization
procedure is as follows: a suspension of -amino acid (5
g), glacial acetic acid (4 mol equiv.) and salicylaldehyde
0.2 mol equiv.) in toluene (25 ml) was heated under
reflux for 2 h. Subsequent treatment was similarly
carried out for -Ile. The results of the racemization of
the various amino acids are shown in Table 2.
L
To a suspension of the epimer mixture of
-aIle (5.0 g, 38.1 mmol) in water (90 ml) was added
(2S,3S)-DTTA monohydrate (7.72 g, 19.1 mmol) under
stirring, and the mixture was heated at 70°C for 1 h.
The slurry formed by reaction of the amino acids with
the DTTA was then cooled to 25°C. The precipitated
crystals were filtered, rinsed with water and dried to
L-Ile and
D
(
L
3
.3. Separation of epimer mixture of
L
-Ile and
D
-aIle
give a complex of
of 1:1:1–2 (9.2 g, yield (based on the epimer mixture)
4.3%). The diastereomeric purity of this complex was
D-aIle:(2S,3S)-DTTA:water in a ratio
by (2S,3S)-DBTA
4
To a suspension of the epimer mixture of
-aIle (5.0 g, 38.1 mmol) in water (90 ml) was added
2S,3S)-DBTA monohydrate (7.19 g, 19.1 mmol) under
L
-Ile and
94.8% de (Table 2, entry 4); mp 157–161°C; water
(Karl–Fischer) found: 5.64% (dihydrate calcd 6.51%);
Elemental analysis found: C, 58.9; H, 6.1; N, 2.8%.
Calcd for (C H NO ·H O): C, 58.3; H, 6.2; N, 2.6%;
D
(
stirring, and the mixture was heated at 70°C for 1 h.
The slurry formed by reaction of the amino acids with
the DBTA was then cooled to 25°C. The precipitated
crystals were filtered, rinsed with water and dried to
26
31
10
2
(C H NO ·2H O): C, 56.4; H, 6.4; N, 2.5%; IR
26
31
10
2
(KBr): 3526, 2966, 2924, 1717 (s), 1609 (s), 1546 (m),
−
1 1
1259 (s), 1176, 1123, 1108 (s), 755 (s) cm ; H NMR
(CD OD): l 0.97 (3H, t, J=4.0 Hz, -aIle-5 CH ), 1.00
give a 1:1 complex of
D
-aIle and (2S,3S)-DBTA (7.77
D
3
3
g, yield (based on the epimer mixture) 41.7%) as a white
crystalline powder of 95.6% de (Table 2, entry 1); mp
(3H, t, J=4.0 Hz, CH ), 1.26–1.40, 1.43–1.58 (1H×2,
3
each m, CH ), 2.03–2.13 (1H, m,
D
-aIle-3 CH), 2.42
2
175.5–176.5°C; water (Karl–Fisher) found: 0.08%; Ele-
(6H, s, toluoyl CH ), 3.70 (1H, d, J=3.5 Hz, -aIle-2
D
3
mental analysis found: C, 59.0; H, 5.6; N, 3.1%. Calcd
for (C H NO ): C, 58.9; H, 5.6; N, 2.9%; IR (KBr):
CH), 4.89 (11H, s, CD OH), 5.91 (2H, s, DTTA CH×
2), 7.31 (4H, d, toluoyl 3,5×2), 8.03 (4H, d, toluoyl
2,6×2).
3
2
4
27
10
3156, 2972, 2942, 2882, 1733 (s), 1692 (s), 1601 (m),

2
652
H. Noda et al. / Tetrahedron: Asymmetry 13 (2002) 2649–2652
Giralt, E. J. Chem. Soc., Perkin Trans. 1 1994, 1969.
References
8. Ebbers, E. J.; Ariaans, G. J. A.; Houbiers, J. P. M.;
1
. Rinehart, K. L.; Kishore, V.; Nagarajan, S.; Gloer, R. J.;
Bozich, F. A.; Li, K.-M.; Maleczka, R. E.; Todsen, W. L.;
Munro, M. H. G.; Sullins, D. W.; Sakai, R. J. Am. Chem.
Soc. 1987, 109, 6846.
Bruggink, A.; Zwanenburg, B. Tetrahedron 1997, 53, 9417.
9. Huffmann, W. A.; Ingersoll, A. W. J. Am. Chem. Soc.
1951, 73, 3366.
10. Volger, K.; Lans, P. Helv. Chim. Acta 1966, 49, 1348.
11. Oki, K.; Suzuki, K.; Tuchida, S.; Saito, T.; Kotake, H. Bull.
Chem. Soc. Jpn. 1970, 43, 2554.
2. Portonovo, P.; Liang, B.; Joulli e´ , M. M. Tetrahedron:
Asymmetry 1999, 10, 1451.
3
. Oinuma, H.; Suda, S.; Yoneda, N.; Kotake, M.; Hayashi,
K.; Miyake, K.; Mori, N.; Saito, M.; Matsuoka, T.;
Namiki, M.; Sudo, T.; Souda, S. WO 94/28901, 1994; Eur.
Pat. 671,172, 1995; Chem. Abstr. 1995, 123, 170180.
. See references cited in Ref. 2.
12. Schmidt, U.; Kroner, M.; Griesser, H. Synthesis 1989, 832.
13. Tsunoda, T.; Tatsuki, S.; Shiraishi, Y.; Akasaka, M.; It oˆ ,
S. Tetrahedron Lett. 1993, 34, 3297.
14. Yamada, S.; Hongo, C.; Yoshioka, R.; Chibata, I. J. Org.
4
5
6
Chem. 1983, 48, 843.
15. Nemak, K.; Acs, M.; Jaszay, Z. M.; Kozma, D.; Fogassy,
E. Tetrahedron 1996, 52, 1637.
16. Noda, H.; Ohsaka, K.; Sakai, K.; Murakami, H. Jpn. Pat.
11 228512, 1999; Eur. Pat. 9,377,058, 1999; US Pat.
6,310,242, 1999.
. Flouret, G.; Nakagawa, S. H. J. Org. Chem. 1975, 40, 2635.
. Yamada, S.; Hongo, C.; Yoshioka, R.; Chibata, I. Jan.
Kokai Tokkyo Koho Jpn. Pat. 57 123150, 1982; Chem.
Abstr. 1982, 98, 54479.
7. Lloyd-Williams, P.; Monerris, P.; Gonzalez, I.; Jon, G.;