Biocatalytic Synthesis of Enantiopure β-Methoxy-β-arylalanine Derivatives

Article abstract of DOI:10.1002/ejoc.201402470

Chiral β-hydroxy-β-arylalanine and β-methoxy-β-arylalanine derivatives, which occur widely in marine nature products, were stereoselectively synthesized with 99 % ee values. The two erythro isomers were prepared by L- or D-aminoacylase-catalyzed resolution of the corresponding N-acetyl derivatives, whereas the two threo isomers were obtained only by D-aminoacylase-catalyzed resolution of the derivatives. erythro-β-Hydroxy-β-arylalanine derivatives were prepared by diastereoselective hydrogenation of ethyl 2-(hydroxyimino)-3-oxo-3-arylpropanoates, which were in turn acquired by the oximation of ethyl 3-oxo-3-arylpropanoates with ethyl nitrite in the presence of nano-K₂CO₃ with yields of 72 % to 80 %. β-Methoxy-β-arylalanine derivatives were synthesized through Williamson reactions between the corresponding β-hydroxy-β-arylalanines and iodomethane with silver oxide as base.

Full text of DOI:10.1002/ejoc.201402470

FULL PAPER
DOI: 10.1002/ejoc.201402470
Biocatalytic Synthesis of Enantiopure β-Methoxy-β-arylalanine Derivatives
Shiming Fan,[a] Shouxin Liu,*[a,b] Hubo Zhang,[b] Ying Liu,[b] Yihuang Yang,[b] and
Longyi Jin*[a]
Keywords: Asymmetric synthesis / Enzyme catalysis / Nanoparticles / Amino acids / Nonnatural amino acids
Chiral β-hydroxy-β-arylalanine and β-methoxy-β-arylalanine
derivatives, which occur widely in marine nature products,
were stereoselectively synthesized with Ն99% ee values.
The two erythro isomers were prepared by L- or D-amino-
acylase-catalyzed resolution of the corresponding N-acetyl
derivatives, whereas the two threo isomers were obtained
pared by diastereoselective hydrogenation of ethyl 2-
(hydroxyimino)-3-oxo-3-arylpropanoates, which were in turn
acquired by the oximation of ethyl 3-oxo-3-arylpropanoates
with ethyl nitrite in the presence of nano-K2CO3 with yields
of 72% to 80%. β-Methoxy-β-arylalanine derivatives were
synthesized through Williamson reactions between the corre-
sponding β-hydroxy-β-arylalanines and iodomethane with
only by
D-aminoacylase-catalyzed resolution of the deriva-
tives. erythro-β-Hydroxy-β-arylalanine derivatives were pre- silver oxide as base.
Introduction
Chiral β-hydroxy-β-arylalanine and β-methoxy-β-aryl-
alanine derivatives, as nonproteinogenic amino acids, are
found in numerous natural products and perform key func-
tions in biological activity.[1] For example, scutianine E,
which contains β-phenylserine, exhibits wide-spectrum anti-
microbial activity,[1f] and callipeltin B, which contains β-
methoxytyrosine, is cytotoxic against various human carci-
noma cells in vitro[1c] (Figure 1). Additionally, these non-
proteinogenic amino acids can serve as useful synthetic
building blocks and chiral auxiliaries in organic synthesis.[2]
Extensive studies on the preparation of these amino acids
have been performed because of their importance in bio-
logical systems and organic synthesis. Recently, several stra-
tegies such as asymmetric metal-catalyzed syntheses,[3] chi-
ral-auxiliary-induced syntheses,[4] and chiral pool syntheses
have been formulated.[5] However, the main difficulties en-
countered in the current protocols involve the control of the
stereochemistry at the α- and β-positions and the low yields
caused by the long reaction routes.
Thanks to the specificity and efficiency of enzymes,
biocatalysis provides an interesting alternative way. We
therefore envisaged using aminoacylase-catalyzed resolu-
Figure 1. Structures of scutianine E and callipeltin B.
[a] Department of Chemistry, College of Science, Yanbian
University,
tion to furnish enantiopure β-hydroxy (or β-methoxy) β-
arylalanine derivatives. Aminoacylases, including l- and d-
aminoacylase, have been used in the production of enantio-
pure l-amino and d-amino compounds from the corre-
sponding N-acetyl derivatives,[6] almost invariably to pre-
pare amino compounds containing single chiral centers.[7]
However, the aminoacylase-catalyzed resolution of amino
acids containing two consecutive chiral centers has only
rarely been reported. Inoue et al. accomplished the total
Yanji 133002, China
E-mail: lyjin@ybu.edu.cn
http://science.ybu.cn/
[b] State Key Laboratory Breeding Base, Hebei Laboratory of
Molecular Chemistry for Drug Research, Hebei University of
Science and Technology,
Shijiazhuang 050018, China
E-mail: chlsx@hebust.edu.cn
http://hgxy.web.hebust.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402470.
Eur. J. Org. Chem. 2014, 5591–5597
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
synthesis of (2R,3S)-3-(4-methoxyphenyl)glycidic ester by pound 8a was also hydrolyzed with 1% hydrochloric acid
using (2S,3S)-β-hydroxy-β-(4-methoxyphenyl)alanine as solution to yield the product 5a. (2R,3R)-β-Hydroxy-β-phe-
starting material.[8] In this paper we report a general, expe- nylalanine (7a) was obtained by d-aminoacylase-catalyzed
ditious, and practical synthesis of enantiopure β-hydroxy- hydrolysis either of (Ϯ)-erythro-4a or of 6a under similar
β-arylalanine and β-methoxy-β-arylalanine derivatives con- conditions. The result was similar to that above, with ee Ͼ
taining two chiral centers, by l- or d-aminoacylase-cata- 99% and conversion Ͼ 99% (Table 1, Entry 2). The
lyzed hydrolysis of N-acetylamino acids. Here we report for enantioselectivity and conversion were confirmed by
1
the first time the reaction behavior of aminoacylases with HPLC, specific rotation, and H NMR spectroscopy.
the substrates (Ϯ)-threo-N-acetyl-β-hydroxy-β-phenyl-
alanine and (Ϯ)-erythro-N-acetyl-β-methoxy-β-arylalanine
derivatives.
Results and Discussion
Synthesis of the Four Optically Pure Isomers of β-
Hydroxy-β-phenylalanine
Scheme 2. Aminoacylase-catalyzed synthesis of (2S,3S)- and
(2R,3R)-β-hydroxy-β-phenylalanine.
The four optically pure isomers of β-hydroxy-β-phenyl-
alanine were obtained by aminoacylase-catalyzed hydrolysis
of (Ϯ)-erythro- and (Ϯ)-threo-N-acetyl-β-hydroxy-β-phenyl-
alanine. A convenient synthetic method for (Ϯ)-erythro-3a
was initially examined (Scheme 1). The intermediate oxime N-acetyl-β-hydroxy-β-phenylalanine.
Table 1. Aminoacylase-catalyzed hydrolysis of erythro- and threo-
2a was successfully produced by the oximation of 1a with
ethyl nitrite in the presence of the new, efficient, and safe
base nano-K2CO3, developed by the authors.[9] Sub-
sequently, a convenient approach to converting compound
2a into erythro-3a in one-pot fashion was developed. The
process involved two reaction steps. Diastereoselective hy-
drogenation of oxime 2a in the presence of Pd/C and AcOH
yielded ethyl erythro-β-hydroxy-β-phenylalanine with 98%
selectivity, and N-acetylation occurred in Ac2O/AcONa.
The method resulted in a 90% yield, higher than that in the
literature.[10]
Entry Substrate
Acylase
Conversion [%][a]
ee [%][b]
1
2
3
4
erythro
erythro
threo
l
d
l
Ͼ99
Ͼ99
Ͼ99
Ͼ99
[c]
[c]
–
–
threo
d
Ͼ99
Ͼ99
[a] The conversion was calculated as 0.5 molar quantity of rac-sub-
strate. [b] Determined by HPLC on a chiral stationary phase. [c] No
reaction was observed.
Compound 10, (Ϯ)-threo-N-acetyl-β-hydroxy-β-phenyl-
alanine, was prepared selectively through the thermody-
namically controlled aldol reaction between glycine and
benzaldehyde under alkaline conditions,[11] followed by N-
acetylation (Scheme 3). Use of the same approach to hy-
drolyze the (Ϯ)-threo isomer 10 to prepare compound 13
was unexpectedly unsuccessful. l-Aminoacylase does not
work with the substrate (2S,3R)-N-acetyl-β-hydroxy-β-
phenylalanine. However, d-aminoacylase can work
well with (2R,3S)-N-acetyl-β-hydroxy-β-phenylalanine
(Scheme 3). Therefore, the hydrolysis of (Ϯ)-threo-N-acetyl-
β-hydroxy-β-phenylalanine was catalyzed selectively by d-
aminoacylase to achieve the resolution of the (Ϯ)-threo iso-
mer to yield the optical pure product (2R,3S)-β-hydroxy-β-
phenylalanine with excellent conversion (Ͼ99%), whereas
Scheme 1. Synthesis of (Ϯ)-erythro-β-hydroxy-β-phenylalanine.
To obtain enantiopure β-hydroxy-β-phenylalanine, the (2S,3R)-amino acid 13 was obtained by hydrolysis of
selective hydrolysis of (Ϯ)-erythro-4a in the presence of (2S,3R)-N-acetyl-β-hydroxy-β-phenylalanine with 1% HCl.
aminoacylase as catalyst was investigated. Enantiopure
In summary, the resolution of N-acetyl-β-hydroxy-β-
(2S,3S)-β-hydroxy-β-phenylalanine (5a) was obtained suc- phenylalanine can be performed by enzyme-catalyzed hy-
cessfully by l-aminoacylase-catalyzed hydrolysis either of drolysis to yield the corresponding optically pure products.
(Ϯ)-erythro-4a or of 8a in the presence of Co2+ at pH 7.5 However, both l- and d-aminoacylase showed good activity
(Scheme 2). The resolution process can be performed on a towards (Ϯ)-erythro-N-acetyl-β-hydroxy-β-phenylalanine as
gram scale, and a high ee (Ͼ99%) and excellent conversion substrate, whereas only d-aminoacylase worked well with
(Ͼ99%) were achieved (Table 1, Entry 1). Meanwhile, com- the (Ϯ)-threo isomers as substrate.
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Enantiopure β-Methoxy-β-arylalanine Derivatives
no noticeable influence on the molecular recognition by the
aminoacylase. Notably, however, when a 4-hydroxy sub-
stituent was present – in compound 4d – the enzyme-cata-
lyzed hydrolysis did not yield the predicted products
(Table 2, Entries 5 and 6). p-Hydroxybenzaldehyde and
glycine, the products of the retro-aldol reaction of 4d, were
formed, which might be due to the more strongly electron-
donating effect of the phenol hydroxy group enhancing the
by-reaction.
Synthesis of (2S,3S)-β-Methoxy-β-phenylalanine
To obtain enantiopure β-methoxy-β-phenylalanine, the
β-hydroxy group in N-Boc-β-hydroxy-β-phenylalanine was
methylated. A series of different bases, including Na2CO3,
K2CO3, and NaH, was tried, but dehydration and retro-
aldol reactions were the main results (Scheme 4).
Scheme 3. Aminoacylase-catalyzed hydrolysis of threo-N-acetyl-β-
hydroxy-β-phenylalanine.
Synthesis of (2S,3S)- and (2R,3R)-β-Hydroxy-β-arylalanine
Derivatives
In view of the good results exhibited by the aminoacyl-
ase-catalyzed enantioselective hydrolysis of the erythro sub-
strates, extension of the scope of erythro substrates was fur-
ther investigated. The erythro substrates were obtained by
the same preparation method as used for 4a, and the resolu-
tion results are shown in Table 2. As predicted, the sub-
strates, with p-chloro substitution and p-methoxy substitu-
tion on benzene (erythro-4b and -4c), could be enantioselec-
tively hydrolyzed by l- or d-aminoacylase catalysis with ex-
cellent ee values and good levels of conversion (Table 2, En-
tries 1 to 4). The results indicated that the different elec-
tronic effects of the substituents on the aromatic ring have
Scheme 4. Methylation of Boc-protected enantiopure β-hydroxy-β-
phenylalanine.
The unsuccessful results led us to revise our research
strategy; that is, we attempted to hydrolyze erythro-N-
acetyl-β-methoxyphenylalanine directly with aminoacylase
as catalyst. Initially, methylation of the β-hydroxy group in
(Ϯ)-erythro-N-acetyl-β-methoxyphenylalanine (7a) was in-
vestigated. Classical Williamson reactions were conducted
with MeI as methylation reagent in the presence of different
bases (Table 3, Entries 1 to 4), but the results were similar
to those of Scheme 3, with the dehydration and retro-aldol
products being obtained. In view of the fact that the by-
reaction occurred under basic conditions, diazomethane
was selected as methylation reagent to complete the reac-
tion, and the desired product 14a was obtained in a low
yield of 10% (Table 3, Entry 5). Although the yield of the
diazomethane method is considerably lower, the approach
may prevent the by-reaction. Finally, a heterogeneous meth-
ylation of 7a with iodomethane with use of silver oxide as
base in CH2Cl2 was selected. The result showed that the
methylation of hydroxy group was completed in good yield
(Table 3, Entry 6).
Table 2. Aminoacylase-catalyzed hydrolysis of erythro-N-acetyl-β-
hydroxy-β-arylalanine derivatives.
Furthermore, the enzyme-catalyzed hydrolysis of com-
pounds (Ϯ)-erythro-15 was investigated. (2S,3S)-N-Acetyl-
β-OMe-amino acids could be enantioselectively hydrolyzed
by l-aminoacylase to afford the corresponding (2S,3S)-β-
OMe-amino acid products with excellent ee values (Table 4,
Entries 1, 3, and 5). However, d-aminoacylase did not work
on the corresponding isomer substrates (Table 4, Entries 2,
4, and 6). The l-aminoacylase-catalyzed reaction of (Ϯ)-
erythro-15a was found to be more difficult than that of (Ϯ)-
erythro-4a, and the level of conversion of (Ϯ)-erythro-15a
into (2S,3S)-16a was only 49% under the same reaction
conditions (Table 4, Entry 1). The O-methylation products
Entry p-Substituent
Acylase Conversion [%][a]
ee [%][b]
1
2
3
4
5
6
Cl
Cl
OMe
OMe
OH
OH
l
d
l
d
l
Ͼ99
Ͼ99
Ͼ95
Ͼ93
Ͼ99
Ͼ99
Ͼ99
Ͼ99
–
[c]
–
[c]
d
–
–
[a] The conversion was calculated as 0.5 molar quantity of rac-sub-
strate. [b] Determined by HPLC on a chiral stationary phase. [c] De-
composition of the substrate under the enzyme catalysis conditions
was found.
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S. Fan, S. Liu, H. Zhang, Y. Liu, Y. Yang, L. Jin
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Table 3. Methylation conditions.
tives containing two consecutive asymmetric centers. l-
Aminoacylase was able to catalyze the hydrolysis of all
(2S,3S)-N-acetyl-amino acids examined, whereas d-amino-
acylase could only hydrolyze (2R,3R)-N-acetyl-β-hydroxy-
β-arylalanine derivatives. In contrast, d-aminoacylase func-
tioned well with (Ϯ)-threo-N-acetyl-β-hydroxy-β-phenyl-
alanine, but l-aminoacylase did not work with this sub-
strate. Additionally, large-scale aminoacylase-catalyzed
resolution of β-hydroxy/methoxy-β-arylalanine derivatives
is being developed in our laboratory.
Entry Reagent Catalyst Solvent
Conditions Yield [%][a]
1
2
3
4
5
6
MeI
MeI
MeI
MeI
Na
NaH
K2CO3
THF
THF
CH3CN
0 °C
r.t
reflux
reflux
0
0
0
Na2CO3 CH3CN
0
CH2N2 Et2O·BF3 (CH3)2CO r.t
MeI Ag2O CH2Cl2 reflux
10
75
Experimental Section
[a] Yield of the isolated product.
1
General Methods and Materials: H NMR and 13C NMR spectra
were recorded with a Bruker Advance II 500 instrument at 500 and
126 MHz, respectively. Chemical shifts are given as δ values (ppm)
with tetramethylsilane as the internal standard, and coupling con-
stants (J) are given in Hertz (Hz). Melting points were determined
with an X4 apparatus and are uncorrected. The optical rotations
were measured with a polarimeter at the sodium D line. HPLC was
performed with a Dionex UltiMate-3000 HPLC, with Daicel
Chem. Ind. Crownpak CR(+) as stationary phase and MeOH/H2O
1:7 at pH 1.0 (HClO4) as mobile phase. HPLC-MS was performed
with a Thermo Finnigan LCQ-Advantage mass spectrometer. Re-
actions were monitored by thin-layer chromatography on silica gel
plates (GF254). Flash chromatography was performed with silica
gel (200 mesh–400 mesh).
of erythro-N-acetyl-β-hydroxy-β-arylalanine derivatives ex-
hibited characteristics different from those of their non-
methylated counterparts in the presence of aminoacylases.
Specifically, d-aminoacylase was inactive with the sub-
strates (2R,3R)-N-acetyl-β-OMe-β-arylalanine. The dif-
ferent responses with aminoacylases probably reflect dif-
ferent hydrogen-bonding interactions of the aminoacylases
with the methylated and non-methylated. The correspond-
ing (2R,3R)-amino acid isomers, such as (2R,3R)-18b, were
readily obtained by chemical hydrolysis.
Table 4. Aminoacylase-catalyzed hydrolysis of erythro-N-acetyl-β-
methoxy-β-arylalanine derivatives.
l-Aminoacylase from Aspergillus oryzae (EC 3.5.1.4) and d-amino-
acylase (recombinant) from Escherichia coli (EC 3.5.1.81) were pur-
chased from Sigma–Aldrich (Shanghai). Most reagents were com-
mercially available reagent-grade chemicals and were used without
further purification, unless noted otherwise. The preparation of
nano-K2CO3: commercial anhydrous K2CO3 (200 g) and absolute
ethyl alcohol (200 mL) were placed in a high frequency resonance
grinding machine. The mixture was ground for 5 h. The nano-
K2CO3 was collected by centrifugation and then directly used for
the next reaction.
Ethyl 3-Oxo-3-phenylpropanoate (1a): Acetophenone (3.6 g,
30 mmol) was added at 0 °C to a suspension of NaH (3.6 g,
150 mmol) in DMF (20 mL), and the mixture was stirred for
30 min. Then, diethyl carbonate (17.7 g, 150 mmol, dissolved in
20 mL DMF) was added dropwise. The mixture was stirred at room
temperature for 12 h, and the reaction mixture was then quenched
with ice/water and extracted with Et2O (50 mLϫ3). The extracts
were combined, washed with water, dried with anhydrous MgSO4,
and distilled in vacuo after removal of ether to yield ethyl 3-oxo-3-
phenylpropanoate as a pale yellow oil with b.p. 140–142 °C
(4 Torr), yield (34.6 g, 60%). 1H NMR (CDCl3, 500 MHz): δ =
7.94–7.96 (m, 2 H), 7.59–7.60 (m, 1 H), 7.47–7.50 (m, 2 H), 4.22
(q, J = 7.0 Hz, 2 H), 3.99 (s, 2 H), 1.26 (t, J = 7.0 Hz, 3 H) ppm.
Entry p-Substituent
Acylase
Conversion [%][a]
49
ee [%][b]
Ͼ99[b]
–
Ͼ99
–
Ͼ99
–
1
2
3
4
5
6
H
H
Cl
Cl
OMe
OMe
l
d
l
d
l
[c]
–
Ͼ99
[c]
–
79
[c]
d
–
Compounds 1b, 1c, and 1d were prepared according to the pro-
cedure used for 2a.
Ethyl 3-(4-Chlorophenyl)-3-oxopropanoate (1b): Yield (65%). 1H
NMR (CDCl3, 500 MHz): δ = 7.88 (d, J = 10.5 Hz, 2 H), 7.45 (d,
J = 10.5 Hz, 2 H), 4.21 (q, J = 7.0 Hz), 3.96 (s, 2 H), 1.26 (t, J =
7.0 Hz, 3 H) ppm.
Ethyl 3-(4-Methoxyphenyl)-3-oxopropanoate (1c): Yield (63%). 1H
NMR (CDCl3, 500 MHz): δ = 7.93 (d, J = 9.0 Hz, 2 H), 6.95 (d,
J = 9.0 Hz, 2 H), 4.21 (q, J = 7.0 Hz), 3.94 (s, 2 H), 3.88 (s, 3 H),
[a] The conversion was calculated as 0.5 molar quantity of rac-sub-
strate. [b] Determined by HPLC on a chiral stationary phase. [c] No
reaction was observed.
Conclusions
In conclusion, we describe an expeditious and practical
route based on aminoacylase catalysis for the synthesis of
enantiopure β-hydroxy(or methoxy)-β-arylalanine deriva- 1.26 (t, J = 7.0 Hz, 3 H) ppm.
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Enantiopure β-Methoxy-β-arylalanine Derivatives
Methyl 3-[4-(Benzyloxy)phenyl]-3-oxopropanoate (1d): Yield (67%).
1H NMR (CDCl3, 500 MHz): δ = 7.84 (d, J = 9.0 Hz, 2 H), 7.40–
7.42 (m, 5 H), 7.05 (d, J = 9.0 Hz, 2 H), 5.15 (s, 2 H), 3.85 (s, 3
H) ppm.
6.5 Hz, 1 H), 4.70 (d, J = 6.0 Hz, 1 H), 4.22 (q, J = 7.0 Hz, 2 H),
2.04 (s, 3 H), 1.27 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 171.8, 169.2, 139.1, 133.7, 128.2, 125.9, 75.1, 62.0,
22.9, 14.0 ppm. HRMS: calcd. for C13H17ClNO4 [M + H]+
286.0846; found 286.0823.
Ethyl 2-(Hydroxyimino)-3-oxo-3-phenylpropanoate (2a): Nano-
K2CO3 (0.6 mol, 83.5 g) was added to a solution of ethyl 3-oxo-3-
phenylpropanoate (1a, 52 mmol, 10 g) in ethanol (52 mL). Then,
the mixture was cooled to 10 °C. Separately, a solution of sodium
nitrite (78 mmol, 5.4 g) in water (26 mL) and ethanol (4 mL) was
placed in a 100 mL one-port flask. Then, a solution of sulfuric acid
(31 mmol, 3.1 g) in water (52 mL) and ethanol (3 mL) was added
dropwise slowly to generate ethyl nitrite. Ethyl nitrite was intro-
duced into the reactor through a drying tube. Stirring was main-
tained for 3 h at a low temperature after the sulfuric acid solution
had been added. The reaction mixture was then concentrated to
remove ethanol. Cold water (30 mL) was then added to the residue,
and the pH of the solution was adjusted to 6 with hydrochloric
acid (0.5 m). The solution was extracted with ethyl acetate (3ϫ
50 mL), and the organic phase was dried with anhydrous MgSO4.
Ethyl acetate was removed under reduced pressure to yield solid
erythro-Ethyl 2-Acetamido-3-hydroxy-3-(4-methoxyphenyl)propano-
ate (3c): Yield (86%), m.p. 146–148 °C. 1H NMR (CDCl3,
500 MHz): δ = 7.15 (dd, J = 2.0, 7.0 Hz, 2 H), 6.85 (dd, J = 2.0,
7.0 Hz, 2 H), 6.25 (d, J = 7.0 Hz, 1 H), 5.22 (dd, J = 3.5, 5.5 Hz,
1 H), 4.96 (dd, J = 3.5, 6.5 Hz, 1 H), 4.44 (d, J = 5.5 Hz, 1 H),
4.20 (q, J = 7.5 Hz, 2 H), 2.04 (s, 3 H), 1.27 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 171.7, 169.5, 159.4,
131.2, 127.1, 113.7, 74.9, 62.0, 59.3, 55.2, 22.9, 14.1 ppm. HRMS:
calcd. for C14H20NO5 [M + H]+ 282.1341; found 282.1329.
erythro-Methyl 2-Acetamido-3-hydroxy-3-(4-hydroxyphenyl)prop-
1
anoate (3d): Yield (41%). H NMR (DMSO, 500 MHz): δ = 9.31
(s, 1 H), 8.15 (d, J = 9.0 Hz, 1 H), 7.14 (d, J = 8.5 Hz, 2 H), 6.88
(d, J = 8.5 Hz, 2 H), 5.60 (d, J = 5.0 Hz, 1 H), 4.61 (dd, J = 5.0,
8.5 Hz, 1 H), 4.40 (t, J = 8.5 Hz, 1 H), 3.61 (s, 3 H), 1.70 (s, 3
H) ppm.
1
product 2a (9.2 g, 80%). H NMR (CDCl3, 500 MHz): δ = 7.88–
(2S,3S)-2-Amino-3-hydroxy-3-phenylpropanoic Acid (5a): A solu-
tion of 7a (30 mmol, 7.6 g) in a mixture of ethanol (65 mL) and
NaOH (4 n, 10 mL) was stirred for 1.5 h and then concentrated
under reduced pressure until the volume was approximately 10 mL.
The residue was acidified with concentrated HCl and extracted
with ethyl acetate. The extracts were combined, dried with anhy-
drous MgSO4, and then concentrated to yield the product 8a as a
white solid (5.9 g, 90%). A suspension of 4a in water (250 mL) was
converted into a solution by adjusting its pH to 7.5 with NaOH
(2 m). Acylase (120 mg) and CoCl2 (0.05 m, 5 mL) were added at
37 °C to this magnetically stirred solution. The reaction pH was
adjusted to 7.0 by adding NaOH (0.5 m), and this pH was main-
tained for 36 h. The reaction mixture was concentrated under re-
duced pressure until the volume was approximately 30 mL, acidi-
fied with concentrated HCl until the pH was about 1, and extracted
with ethyl acetate (100 mLϫ3). The extracts were washed with HCl
(2%, 30 mLϫ2) and were then combined, dried with anhydrous
MgSO4, and concentrated to yield N-acetyl-β-phenylserine (6a,
2.5 g). The aqueous layer was adjusted to pH 6 with aq. NaOH
and concentrated until the volume was 5 mL. The precipitated crys-
tals were collected on a filter, washed with a small amount of water,
and dried to give 5a (2.1 g, 79%) as a tan solid, m.p. 173–175 °C
(dec.). [α]2D0 = 61.0 (c = 0.4, 6 n HCl). [lit[4b] [α]2D0 = 60.7 (c = 0.4,
6 n HCl).]. HPLC: column: Daicel Chem. Ind. Crownpak CR(+),
mobile phase: MeOH/H2O 1:7 at pH 1.0 (HClO4), 25 °C, flow rate:
7.89 (m, 2 H), 7.63–7.67 (m, 1 H), 7.51–7.54 (m, 2 H), 4.33 (q, J
= 7.0 Hz, 2 H), 1.29 (t, J = 7.0 Hz, 3 H) ppm.
Compounds 2b, 2c, and 2d were prepared similarly according to
the procedure used for 2a.
Ethyl 3-(4-Chlorophenyl)-2-(hydroxyimino)-3-oxopropanoate (2b):
Yield (72%). 1H NMR (CDCl3, 500 MHz): δ = 7.82 (d, J = 8.5 Hz,
2 H), 7.50 (d, J = 8.5 Hz, 2 H), 4.32 (q, J = 7.0 Hz, 2 H), 1.27 (t,
J = 7.0 Hz, 3 H) ppm.
Ethyl 2-(Hydroxyimino)-3-(4-methoxyphenyl)-3-oxopropanoate (2c):
Yield (77%). 1H NMR (CDCl3, 500 MHz): δ = 9.52 (br., 1 H), 7.85
(d, J = 8.5 Hz, 2 H), 6.98 (d, J = 8.5 Hz, 2 H), 4.31 (q, J = 7.0 Hz,
2 H), 1.27 (t, J = 7.0 Hz, 3 H) ppm.
Methyl 3-[4-(Benzyloxy)phenyl]-2-(hydroxyimino)-3-oxopropanoate
1
(2d): Yield (74%). H NMR (CDCl3, 500 MHz): δ = 7.85 (d, J =
9.0 Hz, 2 H), 7.35–7.43 (m, 5 H), 7.06 (d, J = 9.0 Hz, 2 H), 5.15
(s, 2 H), 3.86 (s, 3 H) ppm.
erythro-Ethyl 2-Acetamido-3-hydroxy-3-phenylpropanoate (3a): Pd/
C catalyst (10%, 1.0 g) was added to a solution of 2a (50.7 mmol,
11.2 g) in ethanol (91 mL) and acetic acid (3 mL), and the nitrogen
atmosphere was replaced by hydrogen. The reaction mixture was
stirred (atmospheric pressure) at room temperature for 24 h. The
pH of the reaction was adjusted to 7.0 by the addition of NaOH,
and then acetic anhydride (146.9 mmol, 15.0 g) was added. The re-
action mixture was stirred at room temperature overnight and then
filtered. The filtrate was concentrated, and then water was added.
Finally, the mixture was filtered to give 3a (11.5 g, 90%), m.p. 147–
148 °C. 1H NMR (CDCl3, 500 MHz): δ = 8.24 (d, J = 8.5 Hz, 1
H), 7.24–7.37 (m, 5 H), 5.79 (d, J = 3.0 Hz, 1 H), 4.73 (d, J =
4.5 Hz, 1 H), 4.46 (d, J = 4.5 Hz, 1 H), 4.04 (q, J = 6.0 Hz, 2 H),
1.72 (s, 3 H), 1.12 (t, J = 6.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 171.7, 169.4, 139.2, 128.3, 125.9, 75.3, 62.1, 59.3,
22.9, 14.0 ppm. HRMS: calcd. for C13H18NO4 [M + H]+ 252.1236;
found 252.1226.
1
0.4 mLmin–1, retention time: 6.7 min. H NMR (D2O, 500 MHz):
δ = 7.24–7.49 (m, 5 H), 5.38 (d, J = 4.0 Hz, 1 H), 4.11 (d, J =
4.0 Hz, 1 H) ppm. HRMS: calcd. for C9H12NO3 [M + H]+
182.0817; found 182.0810.
(2R,3R)-2-Amino-3-hydroxy-3-phenylpropanoic Acid (7a): Similarly,
11a was obtained by use of d-aminoacylase according to the pro-
cedure described above (yield 71%). [α]2D0 = –60.9 (c = 0.4, 6 n
HCl). [ref.[4b] [α]2D0 = –63.2 (c = 0.65, 6 n HCl)]. HPLC: column:
Daicel Chem. Ind. Crownpak CR(+), mobile phase: MeOH/H2O
1:7 at pH 1.0 (HClO4), 25 °C, flow rate: 0.4 mLmin–1, retention
time: 5.8 min.
Compounds 3b, 3c, and 3d were prepared similarly according to
the procedure used for 3a.
Compounds 5b and 5c were prepared similarly according to the
procedure used for 5a, whereas compounds 7b and 7c were pre-
pared similarly according to the procedure used for 7a.
erythro-Ethyl 2-Acetamido-3-(4-chlorophenyl)-3-hydroxypropanoate
1
(3b): Yield (85%), m.p. 113–115 °C. H NMR (CDCl3, 500 MHz):
δ = 7.31 (d, J = 8.0 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 6.25 (d, J (2S,3S)-2-Amino-3-(4-chlorophenyl)-3-hydroxypropanoic Acid (5b):
= 4.5 Hz, 1 H), 5.27 (dd, J = 3.0, 6.0 Hz, 1 H), 4.97 (dd, J = 3.0, Yield (68%), m.p. 175–177 °C. [α]2D0 = 32.5 (c = 0.2, H2O). HPLC:
Eur. J. Org. Chem. 2014, 5591–5597
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5595

S. Fan, S. Liu, H. Zhang, Y. Liu, Y. Yang, L. Jin
FULL PAPER
column: Daicel Chem. Ind. Crownpak CR(+), mobile phase:
76%), m.p. 182–184 °C (dec). [α]2D0 = –30.6 (c = 0.5, H2O). [ref.[4a]
[α]2D0 = –30.0 (c = 1.0, H2O).]. HPLC: column: Daicel Chem. Ind.
Crownpak CR(+), mobile phase: MeOH/H2O 1:7 at pH 1.0
MeOH/H2O 1:7 at pH 1.0(HClO4), 25 °C, flow rate: 0.3 mLmin–1,
1
retention time: 7.1 min. H NMR (D2O, 500 MHz): δ = 7.40 (d, J
= 8.5 Hz, 2 H), 7.32 (d, J = 8.5 Hz, 2 H), 5.29 (d, J = 4.0 Hz, 1 (HClO4), 25 °C, flow rate: 0.4 mLmin–1, retention time: 5.6 min.
H), 4.02 (d, J = 4.0 Hz, 1 H) ppm. HRMS: calcd. for C9H11ClNO3
erythro-Ethyl 2-Acetamido-3-methoxy-3-phenylpropanoate (14a):
[M + H]+ 216.0427; found 216.0421.
Ag2O (3.8 g, 16.4 mmol) was added to a solution of 7a (5.8 g,
(2R,3R)-2-Amino-3-(4-chlorophenyl)-3-hydroxypropanoic Acid (7b):
Yield (69%). [α]2D0 = –30.1 (c = 0.2, H2O). HPLC: column: Daicel
Chem. Ind. Crownpak CR(+), mobile phase: MeOH/H2O 1:7 at
pH 1.0 (HClO4), 25 °C, flow rate: 0.3 mLmin–1, retention time:
6.1 min.
23.3 mmol) and MeI (3.4 mL) in CH2Cl2 (50 mL). The reaction
mixture was heated at reflux for 24 h in darkness under nitrogen
and then filtered. The filtrate was concentrated in vacuo and puri-
fied by chromatography (hexane/EtOAc 2.7:1) to afford 12a as a
1
white solid (4.6 g, 75%). H NMR (CDCl3, 500 MHz): δ = 7.27–
7.38 (m, 5 H), 6.16 (d, J = 8.5 Hz, 1 H), 4.94 (dd, J = 4.5, 8.5 Hz,
1 H), 4.61 (d, J = 4.5 Hz, 1 H) 4.04–4.09 (m, 2 H), 3.35 (s, 3 H),
2.02 (s, 3 H), 1.11 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 169.8, 169.7, 137.0, 128.5, 126.8, 83.6, 61.4, 57.9,
57.1, 23.3, 13.9 ppm. HRMS: calcd. for C14H20NO4 [M + H]+
266.1392; found 266.1381.
(2S,3S)-2-Amino-3-hydroxy-3-(4-methoxyphenyl)propanoic
Acid
(5c): Yield (63%), m.p. 164–166 °C (dec). [α]2D0 = –2.76 (c = 0.4,
methanol/H2O 1:1). [ref.[8] [α]2D0 = –2.73 (c = 0.586, methanol/H2O
1:1)]. HPLC: column: Daicel Chem. Ind. Crownpak CR(+), mobile
phase: MeOH/H2O 1:7 at pH 1.0 (HClO4), 6 °C, flow rate:
1
0.3 mLmin–1, retention time: 9.5 min. H NMR (D2O, 500 MHz):
δ = 7.36 (d, J = 8.5 Hz, 2 H), 7.32 (d, J = 8.5 Hz, 2 H), 5.33 (d, J
= 4.0 Hz, 1 H), 4.07 (d, J = 4.0 Hz, 1 H) 3.87 (s, 3 H) ppm. HRMS:
calcd. for C10H14NO4 [M + H]+ 212.0923; found 212.0921.
Compounds 14b and 14c were prepared similarly according to the
procedure used for 14a.
erythro-Ethyl 2-Acetamido-3-(4-chlorophenyl)-3-methoxypropanoate
(14b): Yield (71%). 1H NMR (CDCl3, 500 MHz): δ = 7.28–7.38
(m, 5 H), 6.13 (d, J = 8.0 Hz, 1 H), 4.94 (dd, J = 4.0, 9.0 Hz, 1 H),
4.60 (d, J = 4.0 Hz, 1 H), 4.06 (q, J = 7.0 Hz, 2 H), 3.35 (s, 3 H),
2.02 (s, 3 H), 1.11 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 169.8, 169.7, 137.0, 128.5, 128.3, 126.8, 83.5, 61.4,
57.9, 57.1, 23.3, 13.9 ppm. HRMS: calcd. for C14H19ClNO4 [M +
H]+ 300.1003; found 300.0989.
(2R,3R)-2-Amino-3-hydroxy-3-(4-methoxyphenyl)propanoic
Acid
(7c): Yield (60%), m.p. 164–166 °C (dec). [α]2D0 = +2.65 (c = 0.4,
MeOH/H2O 1:1). HPLC: column: Daicel Chem. Ind. Crownpak
CR(+), mobile phase: MeOH/H2O 1:7 at pH 1.0 (HClO4), 6 °C,
flow rate: 0.3 mLmin–1, retention time: 11.8 min.
Compounds 7a, 7b, 5a, and 5b were also obtained by hydrolysis of
the corresponding N-acetyl-enantiomers with HCl (1%).
A suspension of 8a (0.9 g, 4 mmol) in HCl (1%, 80 mL) was heated
at reflux for 4 h. The reaction mixture was cooled and washed with
ethyl acetate, and then concentrated under reduced pressure until
the volume was 2 mL. The aqueous layer was adjusted to pH 6
with aqueous NaOH. The precipitated crystals were collected on a
filter, washed with a small amount of water, and dried to give 5a
(yield 0.55 g, 76%) as a tan solid.
erythro-Ethyl
2-Acetamido-3-methoxy-3-(4-methoxyphenyl)prop-
1
anoate (14c): Yield (73%). H NMR (CDCl3, 500 MHz): δ = 7.20
(d, J = 8.5 Hz, 2 H), 6.89 (d, J = 8.5 Hz, 2 H), 4.91 (dd, J = 4.5,
9.0 Hz, 1 H), 4.54 (d, J = 4.5 Hz, 1 H), 4.08–4.13 (m, 2 H), 3.81
(s, 3 H), 3.31 (s, 3 H), 2.00 (s, 3 H), 1.16 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (CDCl3, 125 MHz): δ = 170.1, 169.7, 159.7, 128.9, 128.0,
113.9, 83.1, 61.4, 57.6, 57.1, 55.3, 23.3, 14.1 ppm. HRMS: calcd.
for C15H22NO5 [M + H]+ 296.1498; found 296.1486.
threo-2-Amino-3-hydroxy-3-phenylpropanoic Acid (9): Compound 9
was prepared as described in the literature.[10]
(2S,3S)-2-Amino-3-methoxy-3-phenylpropanoic Acid (16a): Simi-
larly, 16a was obtained by use of l-aminoacylase according to the
threo-2-Acetamido-3-hydroxy-3-phenylpropanoic Acid (10): Acetic
anhydride (45 mmol, 4.6 g) was added dropwise to a solution of 9
(15 mmol, 2.7 g) and sodium acetate (60 mmol, 4.9 g) in water
(66 mL) at 0 °C. The reaction mixture was stirred at room tempera-
ture overnight, and then concentrated until the volume was 5 mL.
The mixture was acidified with concentrated HCl until the pH was
approximately equal to 1 and was then filtered to give 16 (2.4 g,
77%), m.p. 164–167 °C. 1H NMR (MeOD, 500 MHz): δ = 7.38–
7.41 (m, 2 H), 7.29–7.32 (m, 2 H), 7.21–7.24 (m, 1 H), 5.29 (d, J
= 3.0 Hz, 1 H), 4.71 (d, J = 3.0 Hz, 1 H), 1.87 (s, 3 H) ppm.
procedure described above (yield 32%), m.p. 190–192 °C. [α]2D0
=
+36.3 (c = 0.6, H2O). [ref.[5c] [α]2D0 = +34.5 (c = 0.6, H2O)]. HPLC:
column: Daicel Chem. Ind. Crownpak CR(+), mobile phase: H2O
at pH 1.0 (HClO4), 25 °C, flow rate: 0.4 mLmin–1, retention time:
12.2 min. 1H NMR (D2O, 500 MHz): δ = 7.45–7.49 (m, 3 H), 7.36–
7.37 (m, 2 H), 4.93 (d, J = 2.5 Hz, 1 H), 4.11 (d, J = 2.5 Hz, 1 H),
3.41 (s, 3 H) ppm. 13C NMR (D2O, 125 MHz): δ = 171.0, 134.6,
129.1, 128.9, 127.1, 80.6, 58.9, 56.8 ppm. HRMS: calcd. for
C10H14NO3 [M + H]+ 196.0974; found 196.0966.
(2S,3S)-2-Amino-3-(4-chlorophenyl)-3-methoxypropanoic
Acid
(2R,3S)-2-Amino-3-hydroxy-3-phenylpropanoic Acid (11): Com-
pound 11 was obtained by use of d-aminoacylase according to the
(16b): Yield (70%), m.p. 198–202 °C. [α]2D0 = +29.0 (c = 0.4, H2O).
HPLC: column: Daicel Chem. Ind. Crownpak CR(+), mobile
phase: MeOH/H2O 1:7 at pH 1.0 (HClO4), 6 °C, flow rate:
procedure used for 7a (yield 72%), m.p. 182–185 °C (dec). [α]2D0
=
+31.4 (c = 0.5, H2O). [ref.[4a] [α]2D0 = +31.0 (c = 1.28, H2O).]. HPLC:
column: Daicel Chem. Ind. Crownpak CR(+), mobile phase:
MeOH/H2O 1:7 at pH 1.0 (HClO4), 25 °C, flow rate: 0.4 mLmin–1,
1
0.4 mLmin–1, retention time: 9.3 min. H NMR (D2O, 500 MHz):
δ = 7.47–7.49 (m, 3 H), 7.37–7.38 (m, 2 H), 4.92 (d, J = 4.0 Hz, 1
H), 4.18 (d, J = 4.0 Hz, 1 H), 3.42 (s, 3 H) ppm. 13C NMR (D2O,
125 MHz): δ = 170.9, 134.5, 128.9, 128.5, 127.0, 80.6, 58.8,
56.8 ppm. HRMS: calcd. for C10H13ClNO3 [M + H]+ 230.0584;
found 230.0575.
1
retention time: 5.2 min. H NMR (D2O, 500 MHz): δ = 7.43–7.48
(m, 5 H), 5.32 (d, J = 4.0 Hz, 1 H), 3.93 (d, J = 4.0 Hz, 1 H) ppm.
13C NMR (D2O, 125 MHz): δ = 171.9. 139.2. 128.9. 128.6. 125.9.
71.3. 60.9 ppm. HRMS: calcd. for C9H12NO3 [M + H]+ 182.0817;
found 182.0809.
(2R,3R)-2-Amino-3-(4-chlorophenyl)-3-methoxypropanoic
Acid
(2S,3R)-2-Amino-3-hydroxy-3-phenylpropanoic Acid (13): Com-
pound 13 was obtained by hydrolysis of the corresponding N-
acetyl-enantiomer 12 with HCl (1%) as in the case of 7a (yield
(18b): (Removal of acetyl group with 1% HCl), yield (72%), m.p.
198–202 °C. [α]2D0 = –26.9 (c = 0.4, H2O). HPLC: column: Daicel
Chem. Ind. Crownpak CR(+), mobile phase: MeOH/H2O 1:7 at
5596
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 5591–5597

Enantiopure β-Methoxy-β-arylalanine Derivatives
pH 1.0 (HClO4), 6 °C, flow rate: 0.4 mLmin–1, retention time:
8.3 min.
Morel, G. Maldaner, V. Ilha, F. Missau, U. F. Silva, I. I. Dalcol,
Phytochemistry 2005, 66, 2571–2576.
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47, 2844–2848; Angew. Chem. 2008, 120, 2886; b) S.-J. Wen, Z.-
J. Yao, Org. Lett. 2004, 6, 2721–2724; c) R. Krishnamoorthy,
L. D. Vazquez-Serrano, J. A. Turk, J. A. Kowalski, A. G.
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D. A. Evrard, J. C. Barrow, J. Am. Chem. Soc. 1997, 119, 3417–
3418.
[3] a) K. Makino, T. Goto, Y. Hiroki, Y. Hamada, Tetrahedron:
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saka, K. Akaji, Synthesis 2007, 3666–3672.
(2S,3S)-2-Amino-3-(4-methoxyphenyl)-3-methoxypropanoic
Acid
(16c): Yield 63%, m.p. 177–180 °C (dec). [α]2D0 = +55.7 (c = 0.4,
H2O). HPLC: column: Daicel Chem. Ind. Crownpak CR(+), mo-
bile phase: MeOH/H2O 1:7 at pH 1.0 (HClO4), 25 °C, flow rate:
0.4 mLmin–1, retention time: 18.6 min. 1H NMR (D2O, 500 MHz):
δ = 7.31 (d, J = 8.5 Hz, 2 H), 7.06 (d, J = 8.5 Hz, 2 H), 4.88 (d, J
= 4.0 Hz, 1 H), 4.16 (d, J = 4.0 Hz, 1 H), 3.87 (s, 3 H), 3.89 (s, 3
H) ppm. 13C NMR (D2O, 125 MHz): δ = 171.0, 159.3, 128.6, 126.9,
114.4, 80.1, 58.8, 56.7, 55.5 ppm. HRMS: calcd. for C11H16NO4
[M + H]+ 226.1079; found 226.1069.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra and HPLC chromatograms of prod-
ucts.
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Received: April 23, 2014
Acknowledgments
The authors are grateful for financial assistance received from the
National Natural Science Foundation of China (NSFC) (grant
numbers 30472074, 30873139, and 21272052), the National Basic
Research Program of China (grant numbers 2011CB512007 and
2012CB723501), and the Hebei Province Key Technology R&D
Program (grant number 10276406D6).
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Published Online: July 21, 2014
Eur. J. Org. Chem. 2014, 5591–5597
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5597