Burkholderia cepacia lipase is an excellent enzyme for the enantioselective hydrolysis of β-heteroaryl-β-amino esters

Article abstract of DOI:10.1016/j.tetasy.2009.06.019

The enantioselective (E >200) lipase PS-catalysed hydrolysis of β-heteroaryl-β-amino esters is described. The reactions were performed with H₂O (0.5 equiv) in either diisopropyl ether or tert-butyl methyl ether at 25 °C. The resulting β-heteroaryl-substituted β-amino acid enantiomers were formed in high enantiomeric excess (ee ≥ 97%) and in good yield (≥40%).

Full text of DOI:10.1016/j.tetasy.2009.06.019

Tetrahedron: Asymmetry 20 (2009) 1771–1777
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Burkholderia cepacia lipase is an excellent enzyme for the enantioselective
hydrolysis of b-heteroaryl-b-amino esters
a
a,
a,b,
*
*
}
Gábor Tasnádi , Eniko Forró , Ferenc Fülöp
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
b Research Group for Stereochemistry, Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective (E >200) lipase PS-catalysed hydrolysis of b-heteroaryl-b-amino esters is described.
The reactions were performed with H2O (0.5 equiv) in either diisopropyl ether or tert-butyl methyl ether
at 25 °C. The resulting b-heteroaryl-substituted b-amino acid enantiomers were formed in high enantio-
meric excess (ee P 97%) and in good yield (P40%).
Received 21 May 2009
Accepted 25 June 2009
Available online 28 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
been described, for example, (i) asymmetric Mannich reactions;9
(ii) stereoselective reductions of an enamine;10 (iii) preparation
In view of their successful applications in peptidomimetics and
as valuable building blocks, b-amino acids are currently a focus of
pharmaceutical research.1 b-Heteroaryl-substituted b-amino acids
have wide-ranging potential applications as indicated by the follow-
ing examples. A substituted (R)-3-amino-3-(2-pyridyl)propionic
acid 6f moiety has been identified as the b-amino acid component
of kedarcidin, a potent antitumour antibiotic.2 Additionally, the
of a diastereomeric salt with (1R,2S)-ephedrine or quinine;11 (iv)
enolate additions to a chiral imine;12 (v) addition of a Reformatsky
reagent to a chiral imine;13 (vi) Michael addition to an
a,b-unsatu-
rated ester;14 or (vii) ozonolysis of a chiral N-acylated allylamine.15
In addition to the asymmetric methods,9–15 a number of enzy-
matic studies have been reported for the preparation of b-aryl- and
b-heteroaryl-b-amino acid enantiomers. As an example, we initially
performed the indirect enantioselective resolution of acyclic b-lac-
tams through the acylation of N-hydroxymethyl-b-lactams and
hydrolysis of the corresponding N-hydroxymethyl esters,16 fol-
lowed by ring opening of the enantiomeric lactams with aqueous
HCl. Next, we devised a direct enzymatic method for the enantiose-
lective ring cleavage of b-lactams.17a Later, we extended the method
to 4-aryl- and 4-arylalkyl-substituted b-lactams.17b,c Recently, on
the basis of a newly patented direct enzymatic method,18 we re-
ported the synthesis of carbocyclic cis- and trans-b-amino acid enan-
tiomers through enantioselective hydrolysis of b-amino esters in
organic media, enantioselective hydrolysis of b-aryl-substituted b-
amino esters resulting in biologically valuable enantiomers has also
been achieved.19 Some other methods relate to (i) hydrolysis of N-
acylated b-amino esters,4a,20 (ii) N-acylation of b-amino esters,21
(iii) hydrolysis of b-amino esters in an aqueous medium22 or (iv)
b-aminotransferase-catalysed amination of b-keto esters.23
synthetic L-azatyrosine analogue methyl (R)-3-amino-3-(5-hydro-
xy-2-pyridyl)propanoate is an important compound in anticancer
research.3 Several promising antithrombotic fibrinogen receptor
antagonists contain a b-heteroaryl-b-amino acid unit. A valuable
member of this family is elarofiban (RWJ-53308), which contains
(S)-3-amino-3-(3-pyridyl)propionic acid 7a.4 Elarofiban has pro-
gressed successfully through human phase II clinical trials involving
oral or intravenous administration.4d Compound 7a has also been
used in the synthesis of a peptidomimetic avb3-receptor antagonist
which could be a valuable agent in the treatment of osteoporosis.5
(R)-3-Amino-3-(3-pyridyl)propionic acid 6a has been tested as a
component of an inhibitor of hepatitis C virus (HCV) NS5B polymer-
ase, a valid target for antiviral therapy against HCV.6 Acylated (R)-3-
amino-3-(4-methoxy-3-pyridyl)propionic acid has been described
as a potent, specific and orally bioavailable antagonist of VLA-4.7
Therapeutic targets for this receptor include asthma, rheumatoid
arthritis, multiple sclerosis and inflammatory bowel disease. More-
over, several heteroaromatic taxanes have been prepared and dis-
play good to excellent activity in a microtubule assembly assay in
comparison with paclitaxel.8
Herein, we turned our attention to b-heteroaryl-substituted b-
amino esters and planned to carry out the lipase-catalysed hydro-
lysis of the pharmaceutically important substrates 3a–g.
The development of new enantioselective approaches for the
preparation of heteroaryl-substituted b-amino acid enantiomers
is of high priority, even if numerous asymmetric strategies have
2. Results and discussion
2.1. Syntheses of ethyl 3-amino-3-heteroaryl-propanoates 3a–g
* Corresponding authors. Tel.: +36 62 545564; fax: +36 62 545705 (F.F.).
E-mail addresses: Forro.Eniko@pharm.u-szeged.hu (E. Forró), fulop@pharm.u-sz
eged.hu (F. Fülöp).
Racemic compounds 2a–e were synthesized by a modified
Rodionov synthesis19 through the reactions of 1a–e with malonic
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.06.019

1772
G. Tasnádi et al. / Tetrahedron: Asymmetry 20 (2009) 1771–1777
COOH
COOEt
NH2
NH4OAc
CH2(COOH)2
O
1. SOCl2, EtOH
2. aq. K2CO3
EtOH, reflux
Ar
H
Ar
NH2
Ar
1a-e
2a-e
3a-e
O
S
N
O
S
Ar:
a
b
c
d
e
Scheme 1. Synthesis of 3a–e.
Table 1
acid in the presence of NH4OAc in EtOH at reflux (Scheme 1). Com-
pounds 3a–eꢀHCl were prepared by the esterification of 2a–e in the
presence of SOCl2 in EtOH. The free bases 3a–e were liberated by
treatment of 3a–eꢀHCl with aqueous K2CO3 (Scheme 1).
Racemic 3f and 3g were prepared by the decarboxylative Blaise
reaction24 of 1f and 1g following Pd(OH)2-catalysed reduction of
enamines 2f and 2g (Scheme 2).
Conversion and enantioselectivity of the hydrolysis of 3aa
Enzymec
T (°C)
t (h)
Conv. (%)
ees (%)
eep (%)
E
b
b
Entry
1
2
3
4
5
PPL
45
45
45
25
3
17
17
17
17
72
37
90
52
50
50
43
70
>99
>99
>99
74
8
10
2
Lipase AK
Lipase PS
Lipase PS
Lipase PS
90
98
98
99
>200
>200
a
0.05 M substrate, 1 mL i-Pr2O, 30 mg mLꢁ1 enzyme, 0.5 equiv of H2O.
According to HPLC (Section 4).
Contains 20% (w/w) lipase adsorbed on Celite in the presence of sucrose.
2.2. Lipase-catalysed enantioselective hydrolysis of 3a–g
b
c
The preliminary experiments were started with enzyme screen-
ing, using 3a as the model compound (Scheme 3). Among the li-
pases tested (Table 1), Chyrazyme L-5 (lipase A from Candida
antarctica) and Lipolase (lipase B from C. antarctica) did not exhibit
any selectivity towards 3a at 45 °C in i-Pr2O with 0.5 equiv of H2O,
while PPL (porcine pancreas lipase) and lipase AK (Pseudomonas
fluorescens) catalysed the reaction with moderate enantioselectivi-
ty (E 6 6) (entries 1 and 2). As lipase PS (Burkholderia cepacia) affor-
ded high enantioselectivity (E = 99) (entry 3), we chose this lipase
for further investigation.
When we increased the amount of added water (1–5 equiv), the
enantioselectivities decreased, while the reaction rates slightly in-
creased (Table 3). We observed that the enantioselectivities were
low (E 6 3) in a 1/1 (v/v) mixture of H2O and i-Pr2O, and also in
neat H2O. In a small-scale experiment, we could perform the
When we decreased the temperature, the enantioselectivity in-
creased to an excellent value (E >200) (Table 1, entries 4 and 5).
Moreover, as the reaction did not slow down at 25 °C (entry 4)
when compared with 45 °C (entry 3), we continued further exper-
iments at 25 °C.
Next, we analysed the effects of solvents (Table 2). The reaction
rates were highest in i-Pr2O, t-BuOMe and n-hexane (entries 1, 2
and 3) and lowest in Me2CO (entry 9). The enantioselectivities
were high (E >100) in all cases except in tert-amyl alcohol (entry
5). On the basis of our previous results,25 we developed a fully
green method for the resolution of 3a in a solvent-free system:
we achieved high enantioselectivity (E = 116), but a low reaction
rate (entry 10), when the reaction was performed with 0.5 equiv
of H2O using 30 mg mLꢁ1 of lipase PS at 25 °C. Further experiments
were carried out in i-Pr2O.
Table 2
Effects of solvents on the hydrolysis of 3aa
b
b
Entry
Solvent (1 mL)
Conv. (%)
ees (%)
eep (%)
E
1
2
3
4
5
6
7
8
9
i-Pr2O
48
50
52
40
31
17
13
6
>99
>99
>99
66
38
20
14
6
98
98
92
98
83
98
98
98
98
98
>200
>200
126
197
16
120
114
105
101
116
t-BuOMe
n-hexane
Toluene
t-amyl alcohol
THF
1,4-dioxane
CHCl3
Me2CO
—
2
14
2
16
c
10
a
0.05 M substrate, 30 mg mLꢁ1 lipase PS, 0.5 equiv of H2O at 25 °C after 18 h.
According to HPLC (Section 4).
Without solvent.
b
c
COOEt
NH2
COOEt
NH2
ZnCl2
Ar
KOOCCH2COOEt
Pd(OH)2/C
N
Ar
Ar
2 equiv. AcOH
0.1 equiv. Hünig's base
CH2Cl2, reflux, N2-atm.
1f and 1g
2f and 2g
3f and 3g
N
Ar:
N
f
g
Scheme 2. Syntheses of 3f and 3g.

G. Tasnádi et al. / Tetrahedron: Asymmetry 20 (2009) 1771–1777
1773
Table 3
5a–g with 22% HCl/EtOH resulted in the corresponding enantio-
pure 7a–g (ee P 98%).
Effect of added water on the hydrolysis of 3aa
b
b
Entry
H2O (equiv)
Conv. (%)
ees (%)
eep (%)
E
2.4. Absolute configurations
1
2
3
4
0
0.5
1
46
48
53
55
80
90
94
98
98
83
81
>200
>200
38
The absolute configurations and selectivities were proven by
comparing the specific rotation values with the literature data
(Section 4). The absolute configurations of 3f and 3g were given
on the basis of comparative specific rotations (5a–g negative, 6a–
g positive), assuming the same selectivity of lipase PS towards
3a–g. Thus, the absolute configurations indicated the (S)-selective
hydrolysis of 3a–g.
5
>99
49
0.05 M substrate, 1 mL i-Pr2O, 30 mg mLꢁ1 lipase PS at 25 °C after 7 h.
According to HPLC (Section 4).
a
b
hydrolysis without the addition of any added H2O with excellent
enantioselectivity (entry 1). As a conclusion, H2O in the reaction
medium (<0.1%) or at the surface of the enzyme preparation (<5%
w/w H2O) was responsible for the hydrolysis of 3a.
3. Conclusions
When more enzyme was added to the reaction mixture, higher
reaction rates were observed (Table 4). 75 mg mLꢁ1 of lipase PS re-
sulted in the highest rates with excellent enantioselectivity (entry
6). For economic reasons, preparative-scale resolutions were per-
formed with 30 mg mLꢁ1 of enzyme.
An efficient, direct enzymatic hydrolysis of the desired pharma-
cologically valuable b-heteroaryl-substituted b-amino acid enanti-
omers has been devised. The lipase PS-catalysed (S)-selective
hydrolysis of 3a–g with H2O (0.5 equiv) as a nucleophile in i-
Pr2O or in t-BuOMe at 25 °C (E >200) resulted in the enantiomers
of 4a–g (ee P 97%) and 5a–g (ee P 98%) in good yields (P40%).
The products could be easily separated. Ester enantiomers 4a–g
were readily hydrolysed with 18% aqueous HCl, resulting in acids
6a–g (ee P 97%).
Table 4
Effect of the quantity of lipase PS on the hydrolysis of 3aa
b
b
Entry
Lipase PSc (mg mLꢁ1
)
Conv. (%)
ees (%)
eep (%)
E
1
2
3
4
5
6
10
20
30
40
50
75
16 (49% after 22 h)
18
31
47
58
72
93
98
98
98
98
98
98
118
134
158
179
>200
>200
24
32
37
42
49
4. Experimental
4.1. Materials and methods
a
Lipase PS and lipase AK were from Amano Pharmaceuticals,
Lipolase (lipase B from C. antarctica, produced by submerged fer-
mentation of a genetically modified Aspergillus oryzae microorgan-
ism and adsorbed on a macroporous resin) and PPL (type II) were
from Sigma, and Chyrazyme L-5 was from Novo Nordisk. Before
use, lipase PS, lipase AK, CAL-A and PPL (5 g) were dissolved in
Tris–HCl buffer (0.02 M; pH 7.8) in the presence of sucrose (3 g),
followed by adsorption on Celite (17 g) (Sigma). Heteroaromatic
aldehydes were from Aldrich. 2-Cyanopyridine and 4-cyanopyri-
dine were from Fluka. Diethylamine (DEA), triethylamine (TEA)
and glacial acetic acid (AcOH) were from Aldrich. Triethylammo-
nium acetate buffer (TEAA) was prepared by adding AcOH to a
0.1% aqueous solution of TEA to give pH 4.1. The solvents were of
the highest analytical grade.
0.05 M substrate, 1 mL i-Pr2O, 0.5 equiv of H2O at 25 °C after 3 h.
According to HPLC (Section 4).
Contains 20% (w/w) lipase adsorbed on Celite in the presence of sucrose.
b
c
Racemic compounds 3b–g were also hydrolysed with excellent
enantioselectivities (E >200) under the optimum conditions, that
is, with 0.5 equiv of H2O in the presence of 30 mg mLꢁ1 lipase PS
in i-Pr2O at 25 °C. The preparative-scale resolutions of 3a–g were
performed. The products were characterized by good enantiomeric
excess (ee P 97%) at close to 50% conversion. The results are re-
ported in Table 5 and in Section 4.
2.3. Transformations of the enantiomers
The transformations involving the hydrolysis of 4a–g with
aqueous HCl afforded 6a–g (ee P 97%) (Scheme 4). Treatment of
Optical rotations were measured with a Perkin–Elmer 341
polarimeter. 1H NMR and 13C NMR spectra were recorded on a
Table 5
Lipase PS-catalysed hydrolysis of 3a-ga
Time (h)
Conv. (%)
E
b-Amino acidꢀHCl (6a–g)
b-Amino acid (5a–g)
Yield (%)
Isomer
ee (%)
½
a 2D5
ꢂ
(H2O)
Yield (%)
Isomer
ee (%)
½ ꢂ (H2O)
a 2D5
3a
3b
3c
3d
3e
3f
40
60
47
60
42
67
24
50
49
50
50
50
50
50
>200
>200
>200
>200
>200
>200
>200
40
44
49
46
46
45
43
(R)
(R)
(R)
(R)
(R)
(R)
(R)
>99b
97b
+4.1d
+5.4f
+5.3h
+4.1d
+4.0i
+9.7f
+3.2j
46
46
44
44
43
42
45
(S)
(S)
(S)
(S)
(S)
(S)
(S)
>99b
>99b
>99c
>99b
>99c
>99b
98b
ꢁ5.1e
ꢁ5.8g
ꢁ6.7i
ꢁ3.1d
ꢁ3.2f
>99c
>99b
>99c
98b
ꢁ18.2f
ꢁ11.7j
3g
97b
30 mg mLꢁ1 lipase PS in i-Pr2O, 0.5 equiv of H2O at 25 °C.
According to HPLC.
According to GC.
c 0.33.
c 0.41.
c 0.32.
c 0.52.
c 0.42.
c 0.34.
c 0.36.
a
b
c
d
e
f
g
h
i
j

1774
G. Tasnádi et al. / Tetrahedron: Asymmetry 20 (2009) 1771–1777
HOOC
COOEt
NH2
COOEt
NH2
H2O, lipase PS
(R)
Ar
(S)
Ar
+
i-Pr2O, 25 °C
H2N
5a-g
Ar
3a-g
4a-g
Scheme 3. Lipase PS-catalysed enantioselective hydrolysis of 3a–g (for the meanings of letters a–g, see Schemes 1 and 2).
were added malonic acid (1 equiv) and NH4OAc (2 equiv). The mix-
ture was refluxed for 6 h. The resulting precipitated crystals were
filtered off, washed with Me2CO and recrystallized.
COOEt
NH2
COOH
18% aq. HCl reflux
or
9% aq. HCl, 25 °C
(R)
(R)
.
Ar
Ar
NH2 HCl
4.2.1. ( )-3-Amino-3-(3-pyridyl)propanoic acid 2a
Yield: 0.39 g (44%), white crystals; mp 225–228 °C (recrystal-
lized from H2O/Me2CO) lit.27 mp 224–228 °C. The 1H NMR data
are in accordance with those reported in the literature.27 13C
NMR (100.62 MHz, D2O) d (ppm): 40.5, 51.2, 125.7, 133.5, 137.4,
148.0, 149.9, 177.3.
4a-g
6a-g
COOH
NH2
COOH
22% HCl/EtOH
(S)
(S)
.
Ar
Ar
NH2 HCl
7a-g
5a-g
4.2.2. ( )-3-Amino-3-(2-furyl)propanoic acid 2b
Yield: 0.34 g (44%), brown crystals; mp 222–225 °C (decomp.)
(recrystallized from H2O/Me2CO) lit.17 mp 219–221 °C). The 1H
NMR data are in accordance with those reported in the literature.17
13C NMR (100.62 MHz, D2O) d (ppm): 38.1, 46.6, 109.7, 111.3,
144.6, 149.3, 177.4.
Scheme 4. Transformation of 4a–g to 6a–g and 5a–g to 7a–g (for the meanings of
letters a–g, see Schemes 1 and 2).
Bruker Avance DRX 400 spectrometer. Melting points were deter-
mined on a Kofler apparatus. Elemental analyses (CHNS) corre-
sponded closely (within 3%) with the calculated ones in all cases.
In a typical small-scale enzyme test, racemic 3a (0.05 M solu-
tion) in an organic solvent or in a 1/1 (v/v) mixture of i-Pr2O and
H2O or in neat H2O (1 mL) was added to the enzyme tested (10,
20, 30, 40, 50 or 75 mg mLꢁ1), followed by H2O (0, 0.5, 1 or
5 equiv). The mixture was shaken at 3, 25 or 45 °C.
The ee values for the unreacted b-amino ester and the b-amino
acid enantiomers produced were determined by HPLC or GC as
follows:
Compounds 4a, 4b, 4d and 5a, 5b, 5d: HPLC [4a, 4b, 4d were
pre-column hydrolysed with aq HCl to 6a, 6b, 6d]; Chirobiotic
TAG column (4.6 mm ꢃ 250 mm); eluent: MeOH/AcOH/TEA (100/
0.1/0.1); flow rate: 0.8 mL minꢁ1 for 5a, 5b, 0.3 mL minꢁ1 for 5d;
detection at 205 nm; retention times (min) for 5a: 33.70, 6a:
26.95; 5b: 12.98, 6b: 14.25; 5d: 39.62, 6d: 36.86.
4.2.3. ( )-3-Amino-3-(3-furyl)propanoic acid 2c
Yield: 0.18 g (23%), dark-brown crystals; mp 232–235 °C (de-
comp.) (recrystallized from H2O/Me2CO) lit.21 mp >250 °C. The 1H
NMR data are in accordance with those reported in the literature.21
13C NMR (100.62 MHz, D2O) d (ppm): 39.5, 45.0, 108.2, 121.4,
141.2, 144.7, 177.5.
4.2.4. ( )-3-Amino-3-(2-thienyl)propanoic acid 2d
Yield: 0.36 g (42%), white crystals; mp 225–228 °C (recrystal-
lized from H2O/Me2CO) lit.21 mp 225–228 °C. The 1H NMR data
are in accordance with those reported in the literature.21 13C
NMR (100.62 MHz, D2O) d (ppm): 41.6, 48.9, 108.2, 127.9, 128.3,
128.4, 177.6.
Compounds 4c, 4e and 5c, 5e: GC [5c, 5e were pre-column
derivatized26 with (i) CH2N2 (Caution! derivatization with CH2N2
should be performed under a well-working hood) and (ii) 5c with
(PrCO)2O, 5e with (EtCO)2O in the presence of 4-dimethylamino-
pyridine; 4c with (PrCO)2O; and 4e with (EtCO)2O]; Chirasil-L-Val
column (20 m), 130 °C for 4c and 5c, 140 °C for 4e and 5e; column
flow: 0.7 mL minꢁ1; retention times (min) for 4c: 43.78 (antipode:
44.58); 5c: 33.98 (antipode: 32.09); 4e: 43.13 (antipode: 44.55);
5e: 34.44 (antipode: 33.20).
4.2.5. ( )-3-Amino-3-(3-thienyl)propanoic acid 2e
Yield: 0.35 g (41%), pale-brown crystals; mp 237–239 °C
(recrystallized from H2O/Me2CO) lit.21 mp 239–242 °C. The 1H
NMR data are in accordance with those reported in the literature.21
13C NMR (100.62 MHz, D2O) d (ppm): 40.6, 48.8, 124.7, 126.3,
128.2, 136.9, 177.3.
4.3. General procedure for the syntheses of racemic b-amino
esters 3a–e
Compounds 4f and 5f: HPLC, [5f was pre-column derivatized26
with CH2N2, and 4f was pre-column hydrolysed with aq HCl to 6f,
then derivatized with CH2N2]; Chiralpak IA column (4.6 mm ꢃ
250 mm); eluent: n-hexane (0.1% DEA)/EtOH (80/20); flow rate:
0.5 mL minꢁ1; detection at 250 nm; retention times (min) for 5f:
30.11, 6f: 25.88.
Compounds 4g and 5g: HPLC [4g was pre-column hydrolysed
with aq HCl to 6g]; Chirobiotic TAG column (4.6 mm ꢃ 250 mm);
eluent: TEAA/MeOH (20/80); flow rate: 0.15 mL minꢁ1; detection
at 250 nm; retention times (min) for 5g: 67.80, 6g: 70.85.
To 40 mL of EtOH were added dropwise 0.47 mL (1.3 equiv) of
SOCl2, with the temperature being kept under ꢁ10 °C with saline
ice. To this solution, 2a–e (5 mmol) was added. The mixture was
stirred at 0 °C for 30 min, and then at room temperature for 3 h,
and then finally heated at reflux for 1 h. The solvent was evapo-
rated off and the resulting 3a–fꢀHCl were recrystallized from EtOH
and Et2O. Treatment of 3a–eꢀHCl with aqueous K2CO3 resulted in
the 3a–e as oils.
4.2. General procedure for the synthesis of racemic b-amino
acids 2a–e
4.3.1. Ethyl ( )-3-amino-3-(3-pyridyl)propanoate
hydrochloride 3aꢀHCl
Yield: 0.83 g (82%), white crystals; mp 168–171 °C (recrystal-
lized from EtOH). The 1H NMR and 13C NMR data are in accordance
with those reported in the literature.28
The synthesis was based on a modified Rodionov synthesis.19 To
a solution of the corresponding 1a–e (5 mmol) in EtOH (40 mL)

G. Tasnádi et al. / Tetrahedron: Asymmetry 20 (2009) 1771–1777
1775
4.3.2. Ethyl ( )-3-amino-3-(2-furyl)propanoate hydrochloride
3bꢀHCl
4.5.1. Ethyl ( )-3-amino-3-(2-pyridyl)propanoate 3f
Yield: 0.80 g (82%). 1H NMR (400 MHz, CDCl3) d (ppm): 1.23–
1.27 (3H, t, J = 7.14 Hz, CH2CH3), 2.69–2.91 (2H, m, CH2CO), 4.13–
4.18 (2H, m, CH2CH3), 4.44–4.48 (1H, m, CH), 7.18–7.19 (1H, m,
Ar), 7.36–7.38 (1H, m, Ar), 7.67–7.68 (1H, m Ar), 8.57–8.58 (1H,
m, Ar). 13C NMR (100.62 MHz, CDCl3) d (ppm): 14.6, 43.4, 54.2,
60.9, 121.4, 122.6, 137.1, 149.7, 172.3.
Yield: 1.01 g (92%), brown crystals; mp 95–97 °C. The 1H NMR
data are in accordance with those reported in the literature.21 13C
NMR (100.62 MHz, D2O) d (ppm): 13.7, 36.2, 45.5, 63.1, 110.4,
111.4, 145.0, 148.2, 171.9.
4.3.3. Ethyl ( )-3-amino-3-(3-furyl)propanoate hydrochloride
3cꢀHCl
4.5.2. Ethyl ( )-3-amino-3-(4-pyridyl)propanoate 3g
Yield: 0.72 g (74%); 1H NMR (400 MHz, CDCl3) d (ppm): 1.19–
1.22 (3H, t, J = 7.15 Hz, CH2CH3), 2.63–2.71 (2H, m, CH2CO), 4.13–
4.19 (2H, m, CH2CH3), 4.41–4.44 (1H, m, CH), 7.30–7.33 (2H, m,
Ar), 8.57–8.59 (2H, m, Ar). 13C NMR (100.62 MHz, CDCl3) d
(ppm): 14.6, 44.0, 52.1, 61.2, 121.8, 150.5, 153.7, 171.7.
Yield: 0.93 g (85%), brown crystals; mp 118–120 °C. The 1H
NMR data are in accordance with those reported in the literature.21
13C NMR (100.62 MHz, D2O) d (ppm): 13.7, 38.0, 44.2, 63.0, 108.8,
120.4, 141.4, 144.8, 171.8.
4.3.4. Ethyl ( )-3-amino-3-(2-thienyl)propanoate
hydrochloride 3dꢀHCl
4.6. General procedure for the preparative-scale resolutions of
3a–g
Yield: 1.07 g (91%), off-white crystals; mp 109–111 °C. The 1H
NMR data are in accordance with those reported in the literature.21
13C NMR (100.62 MHz, D2O) d (ppm): 14.0, 39.5, 47.7, 63.4, 128.4,
128.5, 128.8, 137.8, 172.1.
Racemic compounds 3a–g (3 mmol) were dissolved in i-Pr2O
(25 mL). Lipase PS (0.75 g, 30 mg mLꢁ1) and H2O (27
lL, 1.5 mmol)
were added and the mixture was shaken in an incubator shaker at
25 °C for 24–67 h (Table 4). The reaction was stopped by filtering
off the enzyme at 50% conversion. The solvent was evaporated
off and the residues (R)-4a–g were immediately hydrolysed either
by refluxing with 6 mL of 18% aqueous HCl solution for 5 h (4a, 4f
and 4g) or by shaking with 6 mL of 9% aqueous HCl at 25 °C (4b–e)
for 12 h to give (R)-6a–gꢀHCl. The filtered-off enzyme was washed
with distilled H2O (3 ꢃ 15 mL), and the H2O was evaporated off,
yielding the crystalline (S)-5a–g. When (S)-5a–g (50 mg) were
treated with 22% HCl/EtOH (5 mL), (S)-7a–g were obtained.
4.3.5. Ethyl ( )-3-amino-3-(3-thienyl)propanoate
hydrochloride 3eꢀHCl
Yield: 1.04 g (88%), brown crystals; mp 88–90 °C. The 1H NMR
data are in accordance with those reported in the literature.21 13C
NMR (100.62 MHz, D2O) d (ppm): 13.7, 38.5, 47.5, 63.0, 125.4,
126.2, 128.6, 136.2, 172.2.
4.4. Synthesis of b-enamino esters 2f and 2g
Compounds 2f and 2g were synthesized by a decarboxylative
Blaise reaction according to a literature method.24 To the solution
of the corresponding 1f and 1g (5 mmol) in CH2Cl2 (5 mL) were
added KOOCCH2COOEt (1.5 equiv), dry ZnCl2 (0.5 equiv) and
Hünig’s base (0.1 equiv). After refluxing for 7 h under a nitrogen
atmosphere, the mixture was cooled to room temperature and sat-
urated NH4Cl solution (5 mL) was added. The organic layer was
separated, dried over Na2SO4 and concentrated in vacuo, resulting
in the crude solid.
4.6.1. Hydrochloride salt of (R)-3-amino-3-(3-pyridyl)propanoic
acid 6a
Yield: 243 mg (40%), white crystals; recrystallized from MeOH
and Et2O; ½a 2D5
¼ þ4:1 (c 0.33, H2O); mp 220–223 °C (with de-
ꢂ
comp.); ee >99%. 1H NMR (400 MHz, D2O) d (ppm): 3.26–3.41
(2H, m, CH2), 5.18–5.22 (1H, t, J = 6.98 Hz, CH), 8.24–8.28 (1H, m,
Ar), 8.83–8.85 (1H, m, Ar), 8.95–8.97 (1H, m, Ar), 9.07 (1H, m,
Ar). 13C NMR (100.62 MHz, D2O) d (ppm): 37.6, 49.1, 128.6,
136.2, 141.8, 143.2, 146.0, 172.6. When 4a was treated with 5%
TFA/EtOH (5 mL), 4aꢀTFA was obtained {yellow oil, ½a D25
¼ ꢁ2:3 (c
ꢂ
4, DMF) lit.14a
½
a 2D5
ꢂ
¼ þ3:3 (c 10, DMF) for the (S) enantiomer}.
4.4.1. Ethyl 3-amino-3-(2-pyridyl)propenoate 2f
Yield: 0.82 g (85%), pale-yellow crystals; mp 58–59 °C (recrys-
tallized from n-hexane). The 1H NMR and 13C NMR data are in
accordance with those reported in the literature.24
4.6.2. (S)-3-Amino-3-(3-pyridyl)propanoic acid 5a
Yield: 230 mg (46%), white crystals; recrystallized from H2O
and Me2CO; ½a 2D5
¼ ꢁ5:1 (c 0.41, H2O); mp 212–215 °C (with de-
ꢂ
comp.); ee >99%. The 1H NMR (400 MHz, D2O) and 13C NMR
4.4.2. Ethyl 3-amino-3-(4-pyridyl)propenoate 2g
(100.62 MHz, D2O) d (ppm) data for 5a are similar to those for 2a.
Yield: 0.80 g (83%), yellow crystals; mp 109–111 °C (recrystal-
lized from n-hexane/EtOAc 2/1). 1H NMR (400 MHz, DMSO-d6) d
(ppm): 1.19–1.22 (3H, t, J = 7.10 Hz, CH2CH3), 4.05–4.10 (2H, m,
CH2CH3), 4.90 (1H, s, CH), 7.57–7.59 (2H, m, Ar), 8.65–8.66 (2H,
m, Ar). 13C NMR (100.62 MHz, DMSO-d6) d (ppm): 14.9, 59.2,
83.4, 121.7, 143.4, 151.0, 158.5, 169.7 (the signals of C2,C6 and
C3,C5 are overlapping).
4.6.3. Hydrochloride salt of (S)-3-amino-3-(3-pyridyl)propanoic
acid 7a
Quantitative yield, white crystals; ½a D25
¼ ꢁ3:9 (c 0.33; H2O);
ꢂ
mp 218–220 °C (with decomp.); ee >99%. The 1H NMR (400 MHz,
D2O) and 13C NMR (100.62 MHz, D2O) d (ppm) data for 7a are sim-
ilar to those for 6a.
4.5. Synthesis of racemic b-amino esters 3f and 3g
4.6.4. Hydrochloride salt of (R)-3-amino-3-(2-furyl)propanoic
acid 6b
To a solution of 2f or 2g (5 mmol) in EtOH (30 mL) were added
0.96 g (10 wt %) of Pd(OH)2 (20% on carbon) and AcOH (2 equiv).
The mixture was hydrogenated at atmospheric pressure at room
temperature for 24 h. The reaction was stopped by filtering the cat-
alyst off. The solvent was evaporated off, resulting in the acetate
salt of 3f or 3g as a brown oil. Treatment of 3fꢀAcOH and 3gꢀAcOH
with aqueous K2CO3 resulted in the formation of free 3f and 3g as
yellow oils.
Yield: 253 mg (44%), off-white crystals; recrystallized from
EtOH and Et2O; ½a D25
¼ þ5:4 (c 0.32; H2O); mp 170–173 °C;
ꢂ
ee = 97%. 1H NMR (400 MHz, D2O) d (ppm): 3.17–3.20 (2H, m,
CH2), 4.94–4.98 (1H, m, CH), 6.56–6.58 (1H, m, Ar), 6.64–6.65
(1H, m, Ar), 7.65–7.66 (1H, m, Ar). 13C NMR (100.62 MHz, D2O) d
(ppm): 35.9, 45.5, 110.2, 111.4, 144.9, 148.3, 173.9. When 4b
(20 mg) was treated with 22% HCl/EtOH (5 mL), 4bꢀHCl was

1776
G. Tasnádi et al. / Tetrahedron: Asymmetry 20 (2009) 1771–1777
obtained {brown oil, ½a D25
(c 1.00, MeOH)}.
ꢂ
¼ þ9:3 (c 0.97, MeOH) lit.21
½
a 2D5
ꢂ
¼ þ9:5
4.6.12. Hydrochloride salt of (S)-3-amino-3-(2-thienyl)propanoic
acid 7d
Quantitative yield, off-white crystals; ½a D25
¼ ꢁ3:1 (c 0.33, H2O);
ꢂ
4.6.5. (S)-3-Amino-3-(2-furyl)propanoic acid 5b
mp 184–187 °C; ee >99%. The 1H NMR (400 MHz, D2O) and 13C
NMR (100.62 MHz, D2O) d (ppm) data for 7d are similar to those
for 6d.
Yield: 213 mg (46%), white crystals; recrystallized from H2O
and Me2CO; ½a 2D5
ꢂ
¼ ꢁ5:8 (c 0.52, H2O) lit.11b
½
a 2D5
ꢂ
¼ þ12:9 (c 1.00,
H2O) for (+)-3-amino-3-(2-furyl)propanoic acid, which could be as-
signed to the L series,11b but the absolute configuration was not gi-
ven; mp 208–211 °C (with decomp.) lit.11b mp 205–207 °C (with
decomp.); ee >99%. The 1H NMR (400 MHz, D2O) and 13C NMR
(100.62 MHz, D2O) d (ppm) data for 5b are similar to those for 2b.
4.6.13. Hydrochloride salt of (R)-3-amino-3-(3-thienyl)propanoic
acid 6e
Yield: 274 mg (44%), brown crystals; recrystallized from EtOH
and Et2O; ½a 2D5
¼ þ4:0 (c 0.34, H2O); mp >150 °C (with decomp.);
ꢂ
ee >99%. 1H NMR (400 MHz, D2O) d (ppm): 3.20–3.25 (2H, m,
CH2), 5.15–5.18 (1H, t, J = 7.00 Hz, CH), 7.18–7.21 (1H, m, Ar),
7.35–7.36 (1H, m, Ar), 7.61–7.62 (1H, m, Ar). 13C NMR
(100.62 MHz, D2O) d (ppm): 38.9, 47.4, 128.1, 128.2, 128.4, 145.3,
174.0. When 4e (20 mg) was treated with 22% HCl/EtOH (5 mL),
4.6.6. Hydrochloride salt of (S)-3-amino-3-(2-furyl)propanoic
acid 7b
Quantitative yield, off-white crystals; ½a D25
¼ ꢁ4:9 (c 0.32, H2O);
ꢂ
mp 197–200 °C; ee >99%. The 1H NMR (400 MHz, D2O) and 13C
NMR (100.62 MHz, D2O) d (ppm) data for 7b are similar to those
for 6b.
4eꢀHCl was obtained {brown oil, ½a D25
ꢂ
¼ þ2:3 (c 1.00, MeOH) lit.21
½
a 2D5
ꢂ
¼ þ1:00 (c 1.00, MeOH)}.
4.6.7. Hydrochloride salt of (R)-3-amino-3-(3-furyl)propanoic
acid 6c
4.6.14. (S)-3-Amino-3-(3-thienyl)propanoic acid 5e
Yield: 221 mg (43%), white crystals; recrystallized from H2O
Yield: 282 mg (49%), off-white crystals; recrystallized from
and Me2CO; ½a 2D5
¼ ꢁ3:2 (c 0.32, H2O); mp 220–222 °C (with de-
ꢂ
EtOH and Et2O; ½a D25
¼ þ5:3 (c 0.42, H2O); mp >145 °C (with de-
ꢂ
comp.); ee >99%. The 1H NMR (400 MHz, D2O) and 13C NMR
comp.); ee >99%. 1H NMR (400 MHz, D2O) d (ppm): 3.11–3.24
(2H, m, CH2), 4.87–4.91 (1H, m, CH), 6.68 (1H, m, Ar), 7.66 (1H,
m, Ar), 7.78 (1H, m, Ar). 13C NMR (100.62 MHz, D2O) d (ppm):
37.6, 44.3, 108.8, 121.0, 142.0, 145.3, 174.0. When 4c (20 mg)
was treated with 22% HCl/EtOH (5 mL), 4cꢀHCl was obtained
(100.62 MHz, D2O) d (ppm) data for 5e are similar to those for 2e.
4.6.15. Hydrochloride salt of (S)-3-amino-3-(3-thienyl)propanoic
acid 7e
Quantitative yield, pale-brown crystals; ½a D25
¼ ꢁ3:6 (c 0.34,
ꢂ
{brown oil, ½a 2D5
ꢂ
¼ þ6:4 (c 1.30, MeOH) lit.21
½
a 2D5
ꢂ
¼ þ7:25 (c 1.00,
H2O); mp >140 °C (with decomp.); ee >99%. The 1H NMR
(400 MHz, D2O) and 13C NMR (100.62 MHz, D2O) d (ppm) data
for 7e are similar to those for 6e.
MeOH)}.
4.6.8. (S)-3-Amino-3-(3-furyl)propanoic acid 5c
Yield: 203 mg (44%), white crystals; recrystallized from H2O
and Me2CO; ½a 2D5
¼ ꢁ6:7 (c 0.34, H2O); mp >219 °C (with decomp.);
ꢂ
4.6.16. Hydrochloride salt of (R)-3-amino-3-(2-pyridyl)propanoic
acid 6f
ee >99%. The 1H NMR (400 MHz, D2O) and 13C NMR (100.62 MHz,
Yield: 262 mg (45%), white crystals; recrystallized from MeOH
D2O) d (ppm) data for 5c are similar to those for 2c.
and Et2O; ½a 2D5
ꢂ
¼ þ9:7 (c 0.32, H2O); mp 155–158 °C; ee = 98%. 1H
NMR (400 MHz, D2O) d (ppm): 3.24–3.30 (2H, m, CH2), 5.00–5.05
(1H, m, CH), 7.61–7.67 (2H, m, Ar), 8.07–8.12 (1H, m, Ar), 8.69–
8.72 (1H, m, Ar). 13C NMR (100.62 MHz, D2O) d (ppm): 37.1, 51.1,
125.2, 127.4, 145.5, 145.7, 172.8.
4.6.9. Hydrochloride salt of (S)-3-amino-3-(3-furyl)propanoic
acid 7c
Quantitative yield, off-white crystals; ½a D25
¼ ꢁ4:6 (c 0.42, H2O);
ꢂ
mp >142 °C (with decomp.); ee >99%. The 1H NMR (400 MHz, D2O)
and 13C NMR (100.62 MHz, D2O) d (ppm) data for 7c are similar to
those for 6c.
4.6.17. (S)-3-Amino-3-(2-pyridyl)propanoic acid 5f
Yield: 209 mg (42%), white crystals; recrystallized from H2O
and Me2CO; ½a 2D5
¼ ꢁ18:2 (c 0.32; H2O); mp 208–210 °C; ee
ꢂ
4.6.10. Hydrochloride salt of (R)-3-amino-3-(2-thienyl)propanoic
acid 6d
>99%. 1H NMR (400 MHz, D2O) d (ppm): 3.25–3.28 (2H, m, CH2),
5.02–5.05 (1H, t, J = 6.82 Hz, CH), 7.65–7.77 (2H, m, Ar), 8.13–
8.19 (1H, m, Ar), 8.70–8.71 (1H, m, Ar). 13C NMR (100.62 MHz,
D2O) d (ppm): 40.2, 53.3, 122.7, 124.7, 138.9, 148.2, 153.7, 176.8.
Yield: 287 mg (46%), off-white crystals; recrystallized from
EtOH and Et2O; ½a D25
¼ þ4:1 (c 0.33, H2O); mp 183–186 °C; ee
ꢂ
>99%. 1H NMR (400 MHz, D2O) d (ppm): 3.20–3.25 (2H, m, CH2),
5.15–5.18 (1H, t, J = 7.00 Hz, CH), 7.18–7.21 (1H, m, Ar), 7.35–
7.36 (1H, m, Ar), 7.61–7.62 (1H, m, Ar). 13C NMR (100.62 MHz,
D2O) d (ppm): 38.9, 47.4, 128.1, 128.2, 128.4, 137.6, 173.2. When
4d (20 mg) was treated with 22% HCl/EtOH (5 mL), 4dꢀHCl was ob-
4.6.18. Hydrochloride salt of (S)-3-amino-3-(2-pyridyl)propanoic
acid 7f
Quantitative yield, white crystals; ½a D25
¼ ꢁ8:6 (c 0.31; H2O);
ꢂ
mp 159–162 °C; ee >99%. The 1H NMR (400 MHz, D2O) and 13C
NMR (100.62 MHz, D2O) d (ppm) data for 7f are similar to those
for 6f.
tained {yellow oil, ½a D25
ꢂ
¼ þ6:8 (c 1.07, MeOH) lit.21
½
a 2D5
ꢂ
¼ þ4:6 (c
1.00, MeOH)}.
4.6.11. (S)-3-Amino-3-(2-thienyl)propanoic acid 5d
Yield: 228 mg (44%), white crystals; recrystallized from H2O
4.6.19. Hydrochloride salt of (R)-3-amino-3-(4-pyridyl)propanoic
acid 6g
and Me2CO; ½a 2D5
ꢂ
¼ ꢁ9:9 (c 0.41, H2O) lit.11b
½
a 2D5
ꢂ
¼ þ15:3 (c 1.00,
H2O) for (+)-3-amino-3-(2-thienyl)propanoic acid, which could
be assigned to the L series,11b but the absolute configuration was
not given; mp 212–215 °C (with decomp.) lit.11b mp 206–208 °C
(with decomp.); ee >99%. The 1H NMR (400 MHz, D2O) and 13C
NMR (100.62 MHz, D2O) d (ppm) data for 5d are similar to those
for 2d.
Yield: 251 mg (43%), white crystals; recrystallized from MeOH
and Et2O; ½a 2D5
¼ þ3:2 (c 0.36, H2O); mp >195 °C (with decomp.);
ꢂ
ee = 97%. 1H NMR (400 MHz, D2O) d (ppm): 3.29–3.39 (2H, m,
CH2), 5.20–5.24 (1H, m, CH), 8.25–8.28 (2H, m, Ar), 8.95–8.98
(2H, m, Ar). 13C NMR (100.62 MHz, D2O) d (ppm): 37.5, 50.8,
126.5, 142.8, 155.9, 173.1.

G. Tasnádi et al. / Tetrahedron: Asymmetry 20 (2009) 1771–1777
1777
Teffera, Y.; Fenyk-Melody, J.; Schmidt, J. A.; MacCoss, M.; Hagmanna, W. K.
Bioorg. Med. Chem. Lett. 2002, 12, 611.
8. Georg, G. I.; Harriman, G. C. B.; Hepperle, M.; Clowers, J. S.; Vander Velde, D. G.
J. Org. Chem. 1996, 61, 2664.
9. (a) Shen, B.; Johnston, J. N. Org. Lett. 2008, 10, 4397; (b) Wenzel, A. G.; Jacobsen,
E. N. J. Am. Chem. Soc. 2002, 124, 12964; (c) Saidi, M. R.; Azizi, N. Tetrahedron:
Asymmetry 2002, 13, 2523.
10. (a) Zhong, H. M.; Cohen, J. H.; Abdel-Magid, A. F.; Kenney, B. D.; Maryanoff, C.
A.; Shah, R. D.; Villani, F. J., Jr.; Zhang, F.; Zhang, X. Tetrahedron Lett. 1999, 40,
7721; (b) Cohen, J. H.; Abdel-Magid, A. F.; Almond, H. R.; Maryanoff, C. A.
Tetrahedron Lett. 2002, 43, 1977; (c) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S.
W.; Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J. D.; Grabowski, E. J. J.; Tillyer, R.
D.; Spindler, F.; Malan, C. J. Am. Chem. Soc. 2004, 126, 9918; (d) Xiao, Y.; Sun, Y.;
Rosner, T.; Rivera, N. R.; Krska, S. W.; Clausen, A. M.; Armstrong, J. D.; Spindler,
F.; Malan, C. PCT Int. Appl. WO 097733, 2005.
11. (a) Boesch, H.; Cesco-Cancian, S.; Hecker, L. R.; Hoekstra, W. J.; Justus, M.;
Maryanoff, C. A.; Scott, L.; Shah, R. D.; Solms, G.; Sorgi, K. L.; Stefanick, S. M.;
Thurnheer, U.; Villani, F. J.; Walker, D. G. Org. Process Res. Dev. 2001, 5, 23; (b)
Kuwata, S.; Yamada, T.; Shinogi, T.; Yamagami, N.; Kitabashi, F.; Miyazawa, T.;
Watanabe, H. Bull. Chem. Soc. Jpn. 1979, 52, 3326.
4.6.20. (S)-3-Amino-3-(4-pyridyl)propanoic acid 5g
Yield: 224 mg (45%), white crystals; recrystallized from H2O
and Me2CO; ½a 2D5
¼ ꢁ11:7 (c 0.36, H2O); mp 220–223 °C (with de-
ꢂ
comp.); ee = 98%. 1H NMR (400 MHz, D2O) d (ppm): 2.92–2.95 (2H,
m, CH2), 4.77–4.78 (1H, t, J = 7.09 Hz, CH), 7.56–7.58 (2H, m, Ar),
8.66–8.67 (2H, m, Ar). 13C NMR (100.62 MHz, D2O) d (ppm): 40.5,
55.0, 122.8, 146.1, 150.0, 176.4.
4.6.21. Hydrochloride salt of (S)-3-amino-3-(4-pyridyl)propanoic
acid 7g
Quantitative yield, white crystals; ½a D25
¼ ꢁ3:6 (c 0.35, H2O); mp
ꢂ
>191 °C (with decomp.); ee = 98%. The 1H NMR (400 MHz, D2O) and
13C NMR (100.62 MHz, D2O) d (ppm) data for 7g are similar to
those for 6g.
Acknowledgements
12. (a) Davis, F. A.; Szewczyk, J. M.; Reddy, R. E. J. Org. Chem. 1996, 61, 2222; (b)
Tang, T. P.; Ellman, J. A. J. Org. Chem. 1999, 64, 12; (c) Tang, T. P.; Ellman, J. A. J.
Org. Chem. 2002, 67, 7819; (d) Koriyama, Y.; Nozawa, A.; Hayakawa, R.;
Shimizu, M. Tetrahedron 2002, 58, 9621; (e) Higashiyama, K.; Kyo, H.;
Takahashi, H. Synlett 1998, 489.
The authors acknowledge the receipt of Grants K 71938 and T
049407 from the Hungarian Scientific Research Fund (OTKA), and
a Bolyai Fellowship for EF.
13. Awasthi, A. K.; Boys, M. L.; Cain-Janicki, K. J.; Colson, P.-J.; Doubleday, W. W.;
Duran, J. E.; Farid, P. N. J. Org. Chem. 2005, 70, 5387.
14. (a) Rico, J. G.; Lindmark, R. J.; Rogers, T. E.; Bovy, P. R. J. Org. Chem. 1993, 58,
7948; (b) Bull, S. D.; Davies, S. G.; Fox, D. J.; Gianotti, M.; Kelly, P. M.; Pierres, C.;
Savory, E. D.; Smith, A. D. J. Chem. Soc., Perkin Trans. 1 2002, 1858.
15. Walther, J.; de Lange, B.; Broxterman, Q. B.; Pöchlauer, P.; van der Sluis, M.;
Uiterweerd, P.; Falk, H.; Zuckerstätter, G. PCT Int. Appl. WO 063682, 2005.
16. Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 2001, 12, 2351.
17. (a) Park, S.; Forró, E.; Grewal, H.; Fülöp, F.; Kazlauskas, R. J. Adv. Synth. Catal.
2003, 345, 986; (b) Forró, E.; Paál, T.; Tasnádi, G.; Fülöp, F. Adv. Synth. Catal.
2006, 348, 917; (c) Tasnádi, G.; Forró, E.; Fülöp, F. Tetrahedron: Asymmetry
2007, 18, 2841.
References
1. (a) Enantioselective Synthesis of b-Amino Aids; Juaristi, E., Soloshonok, V. A., Eds.,
2nd ed.; Wiley-VHC: New York, 2005; (b) Fülöp, F. Chem. Rev. 2001, 101, 2181;
(c) Fülöp, F.; Martinek, T. A.; Tóth, G. K. Chem. Soc. Rev. 2006, 35, 323.
2. Kawata, S.; Ashizawa, S.; Hirama, M. J. Am. Chem. Soc. 1997, 119, 12012.
3. Adamczyk, M.; Reddy, R. E. Tetrahedron: Asymmetry 2001, 12, 1047.
4. (a) Hoekstra, W. J.; Maryanoff, B. E.; Damiano, B. P.; Andrade-Gordon, P.; Cohen,
J. H.; Costanzo, M. J.; Haertlein, B. J.; Hecker, L. R.; Hulshizer, B. L.; Kauffman, J.
A.; Keane, P.; McComsey, D. F.; Mitchell, J. A.; Scott, L.; Shah, R. D.; Yabut, S. C. J.
Med. Chem. 1999, 42, 5254; (b) Lawson, E. C.; Hoekstra, W. J.; Addo, M. F.;
Andrade-Gordon, P.; Damiano, B. P.; Kauffman, J. A.; Mitchell, J. A.; Maryanoff,
B. E. Bioorg. Med. Chem. Lett. 2001, 11, 2619; (c) Damiano, B. P.; Mitchell, J. A.;
Giardino, E.; Corcoran, T.; Haertlein, B. J.; de Garavilla, L.; Kauffman, J. A.;
Hoekstra, W. J.; Maryanoff, B. E.; Andrade-Gordon, P. Thromb. Res. 2001, 104,
113; (d) Hanson, J.; de Leval, X.; David, J.-L.; Supuran, C.; Pirotte, B.; Dogné, J.-
M. Curr. Med. Chem. Cardiovasc. Hematol. Agents 2004, 2, 157.
18. Forró, E.; Fülöp, F. Chem. Eur. J. 2007, 13, 6397.
19. Tasnádi, G.; Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 2008, 19, 2072.
20. (a) Gröger, H.; Trauthwein, H.; Drauz, K.; Buchholz, S.; Sacherer, C.; Werner, H.
PCT Int. Appl. WO 080854, 2003.; (b) Gröger, H.; Trauthwein, H.; Buchholz, S.;
Drauz, K.; Sacherer, C.; Godfrin, S.; Werner, H. Org. Biomol. Chem. 2004, 2, 1977;
(c) Nakamatsu, T.; Kawasaki, H.; Watanabe, K.; Nakazawa, M.; Izawa, K. Eur.
Patent 1624052, 2006.
21. Solymár, M.; Fülöp, F.; Kanerva, L. T. Tetrahedron: Asymmetry 2002, 13, 2383.
22. Yamamoto, Y.; Miyata, H.; Konegawa, T.; Sakata, K. U.S. Patent 0178433, 2006.
23. Chase, M.; Clayton, R.; Landis, B.; Banerjee, A. U.S. Patent 0009151, 2005.
24. Lee, J. H.; Choi, B. S.; Chang, J. H.; Lee, H. B.; Yoon, J.-Y.; Lee, J.; Shin, H. J. Org.
Chem. 2007, 72, 10261.
5. Meissner, R. S.; Perkins, J. J.; Duong, L. T.; Hartman, G. D.; Hoffman, W. F.; Huff,
J. R.; Ihle, N. C.; Leu, C.-T.; Nagy, R. M.; Naylor-Olsen, A.; Rodan, G. A.; Rodan, S.
B.; Whitman, D. B.; Wesolowski, G. A.; Duggan, M. E. Bioorg. Med. Chem. Lett.
2002, 12, 25.
6. Yan, S.; Larson, G.; Wu, J. Z.; Appleby, T.; Ding, Y.; Hamatake, R.; Hong, Z.; Yao,
N. Bioorg. Med. Chem. Lett. 2007, 17, 63.
25. Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 2008, 19, 1005.
26. Forró, E. J. Chromatogr., A 2009, 1216, 1025.
7. Lin, L. S.; Kopka, I. E.; Mumford, R. A.; Magriotis, P. A.; Lanza, T., Jr.; Durette, P.
L.; Kamenecka, T.; Young, D. N.; de Laszlo, S. E.; McCauley, E.; Van Riper, G.;
Kidambi, U.; Egger, L. A.; Tong, X.; Lyons, K.; Vincent, S.; Stearns, R.; Colletti, A.;
27. Lebedev, A. V.; Lebedeva, A. B.; Sheludyakov, V. D.; Kovaleva, E. A.; Ustinova, O.
L.; Kozhevnikov, I. B. Russ. J. Gen. Chem. 2005, 75, 1113.
28. Muller, G. W. U.S. Patent 5698579, 1997.