Facile synthesis of optically active homocysteine from methionine

Article abstract of DOI:10.1246/cl.2000.468

L-Methionine (L-Met) reacted with dichloroacetic acid in concentrated hydrochloric acid under refluxing to give (45)-1,3-thiazane-2,4-dicarboxylic acid hydrochloride [(4S)-TDC· HCl]. L-Homocysteine (L-Hcy) was obtained in an optically pure form by treatme

Full text of DOI:10.1246/cl.2000.468

4
68
Chemistry Letters 2000
Facile Synthesis of Optically Active Homocysteine from Methionine
Tadashi Shiraiwa,* Kazuo Nakagawa, and Norito Kanemoto
Unit of Chemistry, Faculty of Engineering and High Technology Research Center, Kansai University,
3-3-35 Yamate-cho, Suita, Osaka 564-8680
(Received February 1, 2000; CL-000107)
L-Methionine (L-Met) reacted with dichloroacetic acid in
concentrated hydrochloric acid under refluxing to give (4S)-
,3-thiazane-2,4-dicarboxylic acid hydrochloride [(4S)-TDC·
1
HCl]. L-Homocysteine (L-Hcy) was obtained in an optically
pure form by treatment of (4S)-TDC·HCl with hydroxylamine
hydrochloride. D-Hcy was also synthesized starting from D-Met
via (4R)-TDC·HCl intermediate.
L- And D-homocysteines (L- and D-Hcy), non-proteinogenic
α-amino acids, are useful as key intermediates for syntheses of
pharmaceutical chemicals. For example, L-Hcy has been used
as a chiral building block for syntheses of benzo-fused
azepinone and piperidinone compounds, which are selective
further precipitate was collected by filtration. However, its ele-
1
angiotensin-converting enzyme inhibitors. Therefore, Hcy is
1
mental analysis and H NMR spectrum indicated that the
required to be used as a single enantiomer. Hcy has been syn-
thesized from methionine (Met) as derivatives, such as homo-
cystine, which is reduced with sodium in liquid ammonia to
Hcy, and homocysteine thiolactone, which generates Hcy under
alkaline conditions. Although L-Met has been reported to
afford homocystine by refluxing in sulfuric acid, the obtained
8
obtained compound was not (2S)-ACM·HCl. The compound
was determined to be (4S)-TDC hydrochloride [(4S)-
1
13
TDC·HCl], because its H and C NMR and IR spectra were
identical to those of (4S)-TDC·HCl, which was obtained by
8,9
reacting L-Hcy with glyoxylic acid monohydrate.
Therefore,
the (2S)-ACM·HCl that was formed by the reacting L-Met with
dichloroacetic acid was estimated to immediately undergo
intramolecular condensation to give (4S)-TDC·HCl. As shown
in Figure 1, the reaction of L-Met (50.0 mmol) with
dichloroacetic acid (200 mmol) afforded (4S)-TDC·HCl in the
highest yield (40.7%). (4S)-TDC·HCl should be obtained as a
mixture of two diastereoisomers because of formation of a chi-
2
homocystine undergoes partial racemization. In addition, L-
Met is refluxed in hydroiodic acid to give racemic homocys-
3
teine thiolactone hydroiodide. Optically active Hcy is
obtained via asymmetric transformation of (RS)-1,3-thiazane-4-
4
carboxylic acid and as N-acyl homocysteine thiolactone by
optical resolution.5 We designed a method to synthesize D- and
L-Hcy in optically pure forms from optically active Met by a
more facile procedure.
We attempted synthesis of a 1,3-thiazane derivative from
Met because the derivative was easily ring-opened by treatment
4
with hydroxylamine to give Hcy. L-Met reacts with benzyl
chloride and chloroacetic acid in concentrated hydrochloric acid
6
under refluxing to afford S-benzyl-l-homocysteine and (S)-2-
7
amino-4-[(carboxymethyl)sulfanyl]butanoic acid, respectively.
Therefore, we first attempted to synthesize (2S)-2-amino-4-
[
[
(carboxychloromethyl)sulfanyl]butanoic acid hydrochloride
(2S)-ACM·HCl] by reacting L-Met with dichloroacetic acid in
concentrated hydrochloric acid under refluxing and then to
obtain (4S)-1,3-thiazane-2,4-dicarboxylic acid [(4S)-TDC],
which seemed to be a precursor of L-Hcy, by intramolecular
condensation of (2S)-ACM·HCl (Scheme 1).
After refluxing (105 ˚C) the mixture of L-Met (50.0 mmol,
7
.46 g) and dichloroacetic acid (50.0−300 mmol) in concentrat-
3
ed hydrochloric acid (100 cm ) for 6 h, followed by concentrat-
ing to 30 cm in vacuo at 60 °C, the mixture was allowed to
3
stand overnight at 5 °C. The precipitated compound was col-
lected by filtration, washed thoroughly with tetrahydrofuran,
and dried. The filtrate was evaporated to dryness in vacuo to
3
give oily matter, and then ethanol (10 cm ) was added to the
residue. After allowing the mixture to stand overnight at 5 °C,
Copyright © 2000 The Chemical Society of Japan

Chemistry Letters 2000
469
1
ral center at the C-2 position. In the H NMR spectrum of (4S)-
TDC·HCl, which was synthesized from L-Hcy, methine protons
at the C-2 positions appeared at 5.39 and 5.23 ppm in the inten-
(1951).
8
The (4S)-TDC·HCl obtained by the reaction of L-Met (50.0
mmol) with dichloroacetic acid (200 mmol): Yield 4.63 g
1
0
20
sity ratio of 1:66.5 as singlet signals. Therefore, the intensity
ratio suggested that one of (4S)-TDC·HCl diastereomers was
obtained in 97% de. On the other hand, the reaction of L-Met
with dichloroacetic acid yielded (4S)-TDC·HCl as a single
diastereoisomer because the obtained (4S)-TDC·HCl did not
show any proton signals due to another diastereoisomer.
(40.6%); mp 178−179 ˚C (decomp); [α]
+6.6˚ (c 1.00,
D
−
1 1
water); IR (KBr) νC=O 1763, 1742 cm ; H NMR (270
+
MHz, D O) δ = 5.23 (1H, s, -SCH(COOH)N H -), 4.11
2
2
+
(1H, dd, J = 2.8, 12.8 Hz, -H N CH(COOH)CH -), 3.26−
2
2
3.15 (1H, m), 3.05−2.97 (1H, m), 2.73−2.64 (1H, m),
1
3
2.13−1.97 (1H, m); C NMR (67.5 MHz, D O) δ = 152.9,
2
The obtained (4S)-TDC·HCl was treated with hydroxyl-
amine hydrochloride without purification to give L-Hcy. Thus,
a suspension of (4S)-TDC·HCl (20.0 mmol, 4.55 g) in 100 cm
150.4, 41.4, 40.1, 9.5, 9.2. Found: C, 31.43; H, 4.25; N,
6.14%. Calcd for C H ClNO S: C, 31.65; H, 4.43; N,
6
10
4
3
6.15%.
of ethanol was adjusted with triethylamine to pH 7; (4S)-
TDC·HCl was completely dissolved in ethanol. To the solution
9
L-Hcy was obtained via asymmetric transformation of
(RS)-THA by using (2R,3R)-tartaric acid as the resolving
agent and salicylaldehyde as the epimerization catalyst in
propanoic acid; (RS)-THA was prepared from (RS)-homo-
cysteine thiolactone hydrochloride. The obtained (S)-1,3-
thiazane-4-carboxylic acid was treated with hydroxylamine
3
−3
was gradually added 40 cm of 0.5 mol dm ethanolic hydrox-
3
ylamine hydrochloride at 10 min intervals (8 cm × 5) under
refluxing. After adding the ethanol solution of hydroxylamine
3
hydrochloride (8 cm ), the mixture was immediately maintained
4
at pH 7 to 8 with triethylamine. After further refluxing the mix-
ture for 1 h, followed by cooling to room temperature, the pre-
cipitated L-Hcy was collected by filtration, washed with
hydrochloride in ethanol to give L-Hcy.
10 (2S)-TDC·HCl from L-Hcy: Mp 181−183 ˚C (decomp);
2
0
1
[α]D +5.8˚ (c 1.00, water); H NMR (270 MHz, D O) δ =
2
1
1
+
methanol, and dried; the yield was 2.02 g (74.8%). In addi-
tion, D-Hcy was synthesized from D-Met by the method similar
5.89 (s, -SCH(COOH)N H -), 5.23 (1H, s, -SCH(COOH)-
2
+
+
N H -), 4.7−4.6 (m, -H N CH(COOH)CH -), 4.11 (1H, dd,
2
2
2
1
2,13
+
to that described for L-Hcy; the yield was 2.00 g (74.1%).
J = 2.8, 12.8 Hz, -H N CH(COOH)CH -), 3.26−3.15 (1H,
2 2
As described above, L- and D-Hcys were easily obtained in
optically pure forms by synthesizing from L- and D-Mets via
m), 3.05−2.97 (1H, m), 2.73−2.64 (1H, m), 2.6−2.5 (m),
2.3−2.4 (m), 2.13−1.97 (1H, m). The IR spectrum was
idential to that of (2S)-TDC·HCl from L-Met.
(4S)- and (4R)-TDC·HCl as the intermediates, respectively.
2
0
11
L-Hcy: Mp 247−249 ˚C (decomp); [α]
+27.2˚ (c 1.00, 1
D
−
3
4
20
−3
References and Notes
mol dm HCl) (ref. [α]
+26.8˚ (c 1.00, 1 mol dm
D
−
1 1
1
2
J. A. Robl and C.-Q. Sun, Eur. Pat. 0743319 (1996); Chem.
Abstr., 126, 74877h (1997).
V. du Vigneaud and W. I. Patterson, J. Biol. Chem., 109,
HCl)); IR (KBr) νC=O 1586 cm ; H NMR (270 MHz,
D O) δ = 3.89 (1H, dd, J = 5.9, 7.0 Hz, -CH(NH )COOH),
2
2
2.73−2.56 (2H, m, -CH SH), 2.25−2.07 (2H, m, -CH -);
2
2
1
3
97 (1935).
C NMR (67.5 MHz, D O) δ = 176.7, 56.1, 37.2, 22.4.
2
Found: C, 35.56; H, 6.41; N, 10.29%. Calcd for
C H NO S: C, 35.54; H, 6.71; N, 10.36%.
3
4
H. D. Baernstein, J. Biol. Chem., 106, 451 (1934).
H. Miyazaki, A. Ohta, N. Kawakatsu, Y. Waki, Y. Gogun,
4
9
2
T. Shiraiwa, and H. Kurokawa, Bull. Chem. Soc. Jpn., 66,
12 (4R)-TDC·HCl: Yield 4.73 g (41.5%); mp 176−179 ˚C
2
0
1
13
5
36 (1993).
(decomp); [α]D −6.5˚ (c 1.00, water). The H and
C
5
Y. Akiyama, Y. Aoki, and H. Nohira, Symposium on
Molecular Chirality '99, Sendai, May 1999, Abstr., No. PS-
NMR and IR spectra were virtually identical to those of
(4S)-TDC·HCl.
2
0
2
8.
C. A. Dekker and J. S. Fruton, J. Biol. Chem., 173, 471
1948).
M. D. Armstrong and J. D. Lewis, J. Org. Chem., 16, 74
13 D-Hcy: Mp 248−250 ˚C (decomp); [α] −27.2˚ (c 1.00, 1
D
−
3
4
20
−3
6
7
mol dm HCl) (ref. [α]
−26.8˚ (c 1.00, 1 mol dm
D
1
13
(
HCl)). The H and C NMR and IR spectra were virtually
identical to those of L-Hcy.