Asymmetric synthesis of nonproteinogenic amino acids with l-amino acid transaminase: synthesis of (2S)-2-amino-4-oxo-4-phenylbutyric and (3E,2S)-2-amino-4-phenylbutenoic acids

Article abstract of DOI:10.1016/j.tetasy.2006.07.034

2,4-Dioxo-4-phenylbutyric acid and 2-oxo-4-phenylbut-3-enoic acid are converted to the corresponding (S)-2-amino acids by recombinant Escherichia coli whole cells over-expressing aromatic transaminase from Enterobacter sp. BK2K-1 (AroATEs) in high yields (68-78%) and high enantiomeric purity (>99%) using l-aspartic acid as an amino donor.

Full text of DOI:10.1016/j.tetasy.2006.07.034

Tetrahedron: Asymmetry 17 (2006) 2199–2202
Asymmetric synthesis of nonproteinogenic amino acids
with L-amino acid transaminase: synthesis
of (2S)-2-amino-4-oxo-4-phenylbutyric
and (3E,2S)-2-amino-4-phenylbutenoic acids
Nitin W. Fadnavis, Su-Hyun Seo, Joo-Hyun Seo and Byung-Gee Kim*
School of Chemical and Biological Engineering and Institute of Molecular Biology and Genetics, Seoul National University,
Seoul, Republic of Korea
Received 3 November 2005; revised 15 July 2006; accepted 18 July 2006
Abstract—2,4-Dioxo-4-phenylbutyric acid and 2-oxo-4-phenylbut-3-enoic acid are converted to the corresponding (S)-2-amino acids by
recombinant Escherichia coli whole cells over-expressing aromatic transaminase from Enterobacter sp. BK2K-1 (AroATEs) in high yields
(68–78%) and high enantiomeric purity (>99%) using L-aspartic acid as an amino donor.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
reaction requires participation of pyridoxal 50-phosphate
(PLP) as a co-factor, it is usually tightly bound to the en-
zyme and does not require an external co-factor regenera-
Enantiomerically pure nonproteinogenic amino acids are
of considerable synthetic interest since they serve as build-
ing blocks in asymmetric synthesis and for the preparation
of anticancer and antiviral compounds.1 Also, by incorpo-
rating unnatural amino acids into biologically active pep-
tides and proteins, their activity, stability, bioavailability,
and binding specificity may be improved.2 A large number
of chemical1–3 and enzymatic4 methods for their synthesis
have been reported in the literature. While the chemical
methods involving asymmetric synthesis require several
steps to obtain the final product, the chemo-enzymatic
approach is much simpler. Most enzymatic methods are
based on reductive amination,5 transamination,6 and
kinetic resolution with lipase,7 pronase,8 penicillin acylase,9
and hydantoinase coupled with decarbamoylase.10 Among
these, the methodology of using transaminase is by far the
most simple and high yielding. It constitutes the transfer of
an amino group from a donor molecule (usually a natural
amino acid such as L-aspartic or L-glutamic acid) to an
accepter possessing a prochiral keto group. Although the
tion system.4 We have earlier reported
a putative
aromatic aminotransferase from Enterobacter sp. BK2K-
1 over-expressed in recombinant E. coli BL21 and its use
in the synthesis of L-homophenylalanine.6a Continuing
with our efforts to broaden the scope of its application in
the synthesis of nonproteinogenic amino acids, herein, we
report the synthesis of (2S)-2-amino-4-oxo-4-phenylbutyric
acid 2a and (3E,2S)-2-amino-4-phenylbutenoic acid 2b in
high isolated yields (>68–78%) and with high enantiomeric
purity (ee >99%) (Scheme 1). The unnatural amino acid 2a
and its derivatives are inhibitors of kynurenine-3-hydroxy-
lase11–14 and have a potential to be useful as neuroprotec-
tive agents; while b,c-unsaturated a-amino acids have been
Recombinant Aromatic
transaminase from
NH2
O
Enterobacter sp.
+
L-Asp
Ar
COOH
Ar
COOH
pH 7.2, 37 ºC
2
1
2a. Ar = Ph-CO-CH2
2b. Ar = Ph-CH=CH
1a. Ar = Ph-CO-CH2
1b. Ar = Ph-CH=CH
*
Corresponding author. Tel.: +82 2 880 6774; fax: +82 2 876 8945; e-mail:
byungkim@snu.ac.kr
e.e.>99%, yield 68-78%
Present address: Biotransformations Laboratory, Indian Institute of
Chemical Technology, Hyderabad 500007, India.
Scheme 1.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.07.034

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N. W. Fadnavis et al. / Tetrahedron: Asymmetry 17 (2006) 2199–2202
L-aspartate is better suited since the oxaloacetate produced
during the deamination of aspartate undergoes subsequent
spontaneous and/or enzymatic decarboxylation to pyru-
vate which is further metabolized to carbon dioxide. This
drives the equilibrium to the formation of the desired prod-
uct and inhibition due to oxaloacetate is minimized. We
have thus used L-aspartic acid as an amino donor for the
synthesis of 2. In order to examine the substrate inhibition,
the AroATEs activity of the cell extract (75 U/mL) ob-
tained from the recombinant E. coli expressing AroATEs
was measured at various substrate and aspartate concen-
trations. We observed that aspartate did not seriously inhi-
bit the reaction up to a concentration of 200 mM.
However, the reaction was inhibited by substrate 1a be-
yond 50 mM and by substrate 1b beyond 20 mM. The ef-
fect of aspartate and substrate concentration on the
reaction was found to be similar in case of both whole cells
and cell extract. However, the reaction with whole cells was
easier to perform. Thus, the synthesis of amino acids 2 was
carried out with whole cells of recombinant E. coli
BL21(DE3) over-expressing AroATEs from Enterobacter
sp. BK2K-1 in 0.05 M phosphate buffer (pH 7.2) contain-
ing 2 equiv of L-aspartic acid at 37 ꢁC. The optimum sub-
strate concentrations were 50 and 20 mM, respectively,
for 1a and 1b. The reaction was easily followed by UV–
vis spectrophotometry since the keto acids have a strong
peak around 310 nm, which decreases as the a-keto group
is converted to an amino group, and a new peak around
254 nm appears. When the reaction mixture, after comple-
tion of the reaction, was supplemented with more substrate
and fresh cells, very little conversion of freshly added sub-
strate took place indicating that the reaction is susceptible
to inhibition by both substrate and the product. The inhi-
bition of reaction with 1b at a lower concentration
(>20 mM) than that with 1a (>50 mM) is not surprising
in view of the observations that the b,c-unsaturated a-ami-
no acids act as inhibitors of PLP-dependent aminotransfer-
ases.15–18
found to be reversible or irreversible inhibitors of a number
of enzymes.15–18
The synthesis of 4-oxo-amino acid 2a in its racemic form
has been carried out in a variety of ways. Some of the nota-
ble routes are (a) condensation of a-oxo monohalides with
acetamidomalonate followed by hydrolysis and decarbox-
ylation;19–21 (b) addition of b-benzoylacrylic acid and its
ethyl ester to ethanolamine;22 (c) reduction of the isonitr-
oso derivative of b-benzoyl propinic acid;23 (d) reaction
of an electrophilic glycine cation equivalent with neutral
carbon nucleophiles;24 and (e) reaction of N-acylamino-2-
bromoacetates, via N-acylimino acetates, with higher order
mixed cuprates, trimethylsilyl enol ethers, and b-dicarbonyl
compounds.25 Enantiomerically pure 2a has been prepared
by classical resolution of N-acetyl derivative of the racemic
amino acid with a-methyl benzylamine21 or by enzymatic
resolution with hog renal acylase.25 The N-trifluoroacetyl
derivative has been resolved by enantioselective hydrolysis
with carboxypeptidase A.26 Asymmetric synthesis via Fri-
edel–Craft reaction with aspartic acid derivatives,14,28,29
Mannich type reactions of N-carbamate-protected a-imino
esters using a chiral copper(II)–diamine complex,30 and
catalytic enantioselective alkylation of N,O-acetals31 have
also been reported. In comparison, very few syntheses of
b,c-unsaturated a-amino acids such as 2b have been re-
ported, probably because of the tendency of the double
bond to migrate into conjugation with the carboxyl group
under basic conditions.27,32 Racemic 2b can be prepared in
relatively low yields by the classical Strecker synthesis from
cinnamaldehyde33 or by condensation of phosphorane syn-
thons.34 The resolution of the racemic form has been car-
ried out by enantioselective hydrolysis of its N-acetyl
derivative with biodiastase35 while asymmetric synthesis
has been achieved by condensation of benzaldehyde with
the dianion of L-aspartic acid followed by decarboxylative
dehydration36 to generate 2 as a mixture of (E) and (Z) iso-
mers. An interesting approach based on a three-component
Mannich type reaction involving the condensation of an
organoboronic acid with amine and a-keto acid has been
described by Petasis and Zavialov.37 All the approaches de-
scribed above suffer from disadvantages such as multi-step
synthesis and low yields. Our present methodology involv-
ing the aminotransferase catalyzed stereospecific transfer of
an amino group from L-aspartic acid to a-keto acids 1 is
very simple and provides products with excellent enantio-
meric purity in high yields.
At the end of the reaction, the reaction mixture contains
1 equiv of unreacted aspartic acid along with the product
2. The separation was achieved by crystallization from
HCl in case of 2a (yield 78%) and by boiling with 0.05 M
phosphate buffer at pH 7.2 in case of 2b (yield 69%). Enan-
tiomeric purity of both the products was >99% as deter-
mined by HPLC analysis on a chiral stationary phase
after hydrogenation over 10% Pd–C to obtain (S)-homo-
phenylalanine and then conversion to its N-benzoyl
derivative.
2. Results and discussion
3. Conclusion
2.1. Asymmetric synthesis of 2a and 2b by enzymatic
transamination
In this study, we have successfully demonstrated the asym-
metric synthesis of two nonproteinogenic amino acids with
excellent enantiomeric purity using a recombinant E. coli
expressing an aromatic aminotransferase. The starting
materials can be synthesized in >90% overall yield in only
one or two steps with cheap raw materials and the final
product is obtained directly in a single step. The reaction
can be conveniently performed with an approximately 4:1
(w/w) substrate to biomass ratio in 24 h and substrate load-
The transaminase reaction involves transfer of the amino
group from the amino donor to the amino acceptor via
an intermediate Schiff’s base formation with PLP, and is
prone to inhibition by concentrations of both donor and
the acceptor as well as the products.6 In our previous stud-
ies,6a we had observed that both L-aspartic acid and L-glu-
tamic acid can be used as amino donors for AroATEs.
Although L-glutamate is preferable due to its low cost,

N. W. Fadnavis et al. / Tetrahedron: Asymmetry 17 (2006) 2199–2202
2201
ing of 5–10 g/L. In case of substrate 1a, the enzymatic reac-
tion is completely stereo and regiospecific, converting only
the a-carbonyl group to an amino group. In case of sub-
strate 1b, the reaction is carried out under very mild condi-
tions and hence no migration of the double bond is
observed (NMR data). The methodology is very much sim-
pler and gives higher yields than the previously known
techniques.
tate (2 · 10 mL). The aqueous phase was again brought
to pH 7.2 with NaOH and lyophilized. The residual pow-
der was suspended in distilled water (10 mL), heated in a
boiling water bath for 5 min, and cooled in ice. The precip-
itated amino acid was filtered, suspended in 6 M HCl
(5 mL), and heated on a water bath until all the product
dissolved. The solution was then cooled in ice to obtain
white crystals of the hydrochloride salt (740 mg, 78%).
25
22
½aꢁD ¼ þ40:5 (c 0.1, 6 M HCl). Lit.29 ½aꢁD ¼ þ44:3 (c 0.1,
6 M HCl for amino acid). IR (KBr): 3320, 3150, 3050,
2910, 2530, 2080, 1680, 1640, 1590, 1530, 1485, 1400,
4. Experimental
1
1210, 745, 680 cmꢀ1. H NMR (D2O, 300 MHz): d 3.79
2,4-Dioxo-4-phenylbutyric acid was prepared by condensa-
tion of acetophenone with diethyl oxalate and subsequent
acidic hydrolysis as described in the literature.38 (E)-2-
oxo-4-phenylbut-3-enoic acid 1a was prepared as a potas-
sium salt by condensation of benzaldehyde with pyruvic
acid in methanolic KOH as per the literature procedure.39
Isopropyl b-D-thiogalactopyranoside (IPTG), pyridoxal 50-
phosphate (PLP), and kanamycin were obtained from Sig-
ma–Aldrich (MO, USA). UV–vis spectra were recorded on
a Hewlett Packard 845· spectrophotometer. NMR spectra
were recorded on Brucker Spectrospin 300 spectrometer.
Optical rotation was measured on Jasco 1030 polarimeter.
HPLC analyses were performed using a Waters HPLC sys-
tem. MALDI-Mass was determined on Brucker MALDI-
TOF MS. IR spectra were recorded on Thermo Nicolet
Nexus 670 spectrometer.
(2H, m), 4.22 (1H, m), 7.4–7.8 (3H, m), 8.0–8.2 (2H, m).
MALDI-TOF MS, m/z 193.32 ([M+], exact mass calcd
for C10H11NO3 193.07), 215.3 [M+Na+] calcd for
C10H10NNaO3 215.06.
4.2. Asymmetric synthesis of (3E,2S)-2-amino-4-phenyl-3-
butenoic acid 2b
The reaction was carried out with potassium salt of 1b
(428 mg, 2 mmol) and aspartic acid (532 mg, 4 mmol) in
phosphate buffer (0.05 M, pH 7.2, 100 mL) and the bio-
catalyst (100 mg dry cell wt) essentially as described
above. The reaction was followed by monitoring the dis-
appearance of the peak at 302 nm. The reaction was com-
plete in 24 h. The recovered crude amino acid was
dissolved in 0.1 M HCl (25 mL). The solution was centri-
fuged to remove small amounts of protein and then sol-
vent was removed on a rotavapor to obtain 2b as a
hydrochloride salt. The residue was boiled with 10 mL
of 0.05 M phosphate buffer (pH 7.2), cooled and filtered
to obtain the amino acid 2b (245 mg, 69% isolated yield,
ee >99%). IR (KBr): 3446, 1636, 1523, 1452, 1408, 1353,
4.1. Asymmetric synthesis of (2S)-2-amino-4-oxo-4-phenyl-
butyric acid 2a
The construction of recombinant E. coli BL21(DE3) har-
boring the plasmid pET24ma-AroATEs has been described
earlier.6a The recombinant E. coli was grown at 37 ꢁC in
1 L of Luria–Bertani (LB) medium containing 25 lg/mL
of kanamycin. At OD600 nm value of 0.6, the expression
of the enzyme was induced with 1 mM IPTG. After
6 h of induction, the cell pellet was harvested from the cul-
ture broth, washed once with cold 50 mM Tris–HCl buffer
(pH 7.2), and stored at ꢀ70 ꢁC. The biocatalytic reaction
was carried out in shake flask on an orbital shaker at
37 ꢁC. The wet cells were added to 100 mL reaction mixture
consisting of substrate 1a (960 mg, 5 mmol) and L-aspartic
acid (1.33 g, 10 mmol) in phosphate buffer (0.05 M,
pH 7.2). The weight of biocatalyst was estimated to be
380 mg dry cell weight based on the optical density of the
reaction mixture at 600 nm (0.3 mg/mL dry cell weight
gives absorbance 1.0). The reaction was followed on a
Hewlett Packard 845· UV–vis spectrophotometer. At
intervals of 2 h, an aliquot (100 lL) was centrifuged in an
Eppendorf tube and the supernatant was serially diluted
to 10 lM with 80% acetonitrile–water solution containing
0.1% formic acid, and its UV spectrum was recorded.
The starting substrate shows a strong peak at 316 nm
which disappears as the reaction proceeds and a new peak
appears at 254 nm. The reaction was generally complete in
24 h. The pH of the medium was adjusted to 8.5 to dissolve
any precipitated amino acid and the cells were then centri-
fuged in cold. The cold supernatant was transferred to a
conical flask, acidified with HCl to pH 2.0, centrifuged to
remove precipitated protein, and extracted with ethylace-
1321, 1085, 991, 870, 697, 529 cmꢀ1 1H NMR (D2O,
.
300 MHz): d 6.6–6.8 (m, 5H), 6.26 (d, 1H, J = 15.9 Hz),
5.61 (dd, 1H, J = 15.9 and 8.5 Hz), 4.15 (d, 1H,
J = 8.5 Hz). 13C NMR (300 MHz, D2O): d 170.2, 138.6,
134.8, 129.2, 128.9, 127.0, 118.0, 54.7. MALDI-TOF
MS, m/z 177.10 ([M+H+]), exact mass calcd for
C10H11NO2 177.08; 199.1 [{M+Na}+] exact mass calcd
25
for C10H10NaNO2 199.06. ½aꢁD ¼ þ38:4 (c 1, 0.1 M
20
HCl); lit.34 ½aꢁD ¼ ꢀ20 (c 1, 0.1 M HCl) for (R)-enantio-
mer of the amino acid.
4.3. Transformation of 2a and 2b to (S)-N-benzoyl
homophenylalanine
The hydrochloride of 2a or2b (100 mg, 0.5 mmol) was dis-
solved in 10% acetic acid in water (25 mL), 10% Pd–C
(50 mg) was added and the solution was hydrogenated for
6 h at room temperature with a hydrogen filled balloon.
The catalyst was then filtered off, the solution was evapo-
rated to dryness on a rotavapor, the residue was suspended
in ice cold 1 M NaOH (5 mL) and treated with benzoyl
chloride (60 lL, 0.5 mmol) under vigorous stirring for
30 min. The solution was then extracted with ethylacetate
(1 · 5 mL) to remove unreacted benzoyl chloride, acidified
with HCl, and the product was extracted with ethylacetate.
The solvent was then evaporated to dryness to obtain crude
N-benzoyl derivative which was directly analyzed by HPLC

2202
N. W. Fadnavis et al. / Tetrahedron: Asymmetry 17 (2006) 2199–2202
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on chiral stationary phase. The racemic sample was pre-
pared from commercially available homophenylalanine.
4.4. Analysis of enantiomeric purity
Enantiomeric purity of 2a and 2b was determined (after
hydrogenation to homophenylalanine and conversion to
N-benzoyl derivative) by HPLC analysis on Chiralpakꢂ
AD-H column (250 · 5 mm), Daicel Chemical Industries,
Japan. Mobile phase 10% isopropyl alcohol in hexane con-
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