A concise synthesis of enantiomerically pure aroyl-l-alanines and dihydroaroyl-l-alanines

Article abstract of DOI:10.2478/s11696-012-0246-z

Straightforward preparation of enantiomerically highly enriched N-substituted aroylalanines has been developed. This process involves the combination of crystallization-induced asymmetric transformation and a conjugate addition of N-nucleophiles to the corresponding aroylacrylic acids. Further transformations to 3,4-dichlorobenzoylalanine and aroyl-l-alanines via periodate oxidation and stereoselective reduction to N-substituted syn-4-aryl-4-hydroxy- 2-aminobutanoic acids are also described.

Full text of DOI:10.2478/s11696-012-0246-z

Chemical Papers 67 (1) 92–100 (2013)
DOI: 10.2478/s11696-012-0246-z
ORIGINAL PAPER
A concise synthesis of enantiomerically pure aroyl-L-alanines
and dihydroaroyl-L-alanines
Mária Gardiánová, Ľuboš Slížik, Anna Koreňová, František Považanec,
Dušan Berkeš*
Department of Organic Chemistry, Slovak University of Technology, Radlinského 9, 812 37, Bratislava, Slovakia
Received 31 March 2012; Revised 26 June 2012; Accepted 2 July 2012
Dedicated to Professor Štefan Toma on the occasion of his 75th birthday
Straightforward preparation of enantiomerically highly enriched N-substituted aroylalanines has
been developed. This process involves the combination of crystallization-induced asymmetric trans-
formation and a conjugate addition of N-nucleophiles to the corresponding aroylacrylic acids. Fur-
ther transformations to 3,4-dichlorobenzoylalanine and aroyl-l-alanines via periodate oxidation and
stereoselective reduction to N-substituted syn-4-aryl-4-hydroxy-2-aminobutanoic acids are also de-
scribed.
c
ꢀ 2012 Institute of Chemistry, Slovak Academy of Sciences
Keywords: crystallization-induced asymmetric transformation, periodate degradation, aroylala-
nine, amino acid
Introduction
(4R)-5-Bromodihydro-l-kynurenine was found to be
one of the most potent inhibitors of kynureninase
(Heiss et al., 2003).
The kynurenine pathway (KP) represents a major
route for the catabolism of tryptophan (Trp). Metabo-
lites in KP, generated by the Trp degradation, are
thought to play an important role in a wide range
of diseases and disorders including infectious dis-
eases, neurodegenerative disorders (e.g. Alzheimer’s
and Huntington’s disease), and also affective disorders
(e.g. schizophrenia, depression and anxiety, and au-
toimmune disorders) (Myint et al., 2012; Stone et al.,
2012; Zwilling et al., 2011).
From the known enzyme inhibitors of KP, substi-
tuted aroylalanines – structural analogues of kynure-
nine, represent the intensively studied derivatives
(Fig. 1). Among them, m-nitrobenzoylalanine (m-
NBA) and 3,4-dichlorobenzoylalanine (FCE28833)
possess kynurenine 3-monooxygenase (3-KMO) inhi-
bition activity (Natalini et al., 1995; Pellicciari et
al., 1994), and 4-ethylsulfonylbenzoylalanine (ESBA)
demonstrates kynurenine aminotransferease II (KAT
II) inhibition activity (Pellicciari et al., 2006, 2008).
In all cases, (S)-enantiomers were found to be ac-
tive stereoisomers. Several synthetic methods for the
synthesis of enantiomerically pure aroylalanines have
been developed based on different variants of enan-
tioselective alkylation of α-imino esters (Barfoot et
al., 2005; Ferraris et al., 2001; Nakamura et al., 2003)
or the chiron approach using amino acid derivatives as
chiral templates (Lin et al., 2001; Natalini et al., 1995).
The enantioselective N-heterocyclic carbene-catalyzed
intermolecular Stetter reaction has been applied re-
cently (Jousseaume et al., 2011).
Our research program is focused on the synthe-
sis and stereoselective transformations of substituted
γ-oxo and γ-hydroxy-α-amino acids via the applica-
tion of crystallization-induced asymmetric transfor-
mation (CIAT) (Anderson, 2005; Brands & Davies,
2006; Yoshioka, 2007). Highly diastereomerically en-
riched N-substituted γ-oxo-α-amino acids can be eas-
ily isolated from the equilibrated heterogeneous reac-
*Corresponding author, e-mail: dusan.berkes@stuba.sk

M. Gardiánová et al./Chemical Papers 67 (1) 92–100 (2013)
93
Fig. 1. Kynurenine and substituted aroylalanines as enzyme inhibitors of KP.
Fig. 2. CIAT applications of the synthesis of N-substituted aroylalanines; i) (S)-phenylendiamine or (R)-2-amino-2-phenylethanol,
methanol or ethanol, 40◦C, 60–85 %, d.r. > 97 : 3; ii) oxoethanoic acid, (S)-phenylendiamine, ethanol, 40◦C, 49–66 %, d.r.
> 98 : 2.
tion mixture by simple filtration using reversible di-
astereoselective aza-Michael addition or Mannich re-
actions and 1-phenylethylamine or chiral amino alco-
hols as chirality mediators. The observed stereochem-
istry of the major diastereomer is depicted in Fig. 2
and it was confirmed by all previously described exam-
ples (Berkeš et al., 2007; Jakubec et al., 2006a, 2006b,
2010; Kolarovic et al., 2001; Yamada et al., 1998).
A straightforward two-step synthesis of enan-
tiomerically pure halo- and nitro-substituted benzoy-
lalanines is presented in this work.
Melting points were determined on a Kofler hot
plate HMK (Analytik Dresden, Germany) and they
are uncorrected. Optical rotations were measured on
a POLAR L-µP (IBZ Messtechnik, Germany) and
P-1020 JASCO polarimeter (Japan) with a 10 cm
cell at the wavelength of the sodium line D (λ =
589 nm). Specific rotations are given in units of 10−1
×
deg cm2 g−1 and the concentrations are given in g per
100 mL. Elemental analyses were performed on Carlo
Erba NA 1500 CNS Analyzer (Carlo Erba, Italy) by
the Microanalytical Service of the Department of Ana-
lytical Chemistry of the Slovak University of Technol-
ogy. 1H NMR and 13C NMR spectra were recorded at
laboratory temperature using a Varian VXR-300 (Var-
Experimental
1
All chemicals were used as supplied without
further purification unless otherwise specified. (R)-
phenylglycine, (S)-phenylalanine, sodium periodate,
NaBH4, triethylamine, ethanol, methanol, tetrahydro-
furan, hydrochloric acid from Sigma–Aldrich chemical
Ltd., (USA), K2CO3, MnCl2 ·4H2O, I2 from Fluka
(Germany), and 1,4-dioxane and diethylether from
Acros Organics (Belgium). The starting substituted
(E)-4-aryl-4-oxo-2-butenoic acids (Ia–If ) were pre-
pared via the Friedel–Craft’s acylation of halogen-
substituted benzenes (Upreti et al., 1996) or the
condensation of nitroacetophenones with oxoethanoic
acid (glyoxylic acid) (Bianchi et al., 1988). (R)-
2-Amino-2-phenylethanol and (S)-2-amino-3-phenyl-
propanol were prepared from (R)-phenylglycine and
(S)-phenylalanine, respectively (McKennon et al.,
1993).
ian, USA) spectrometer operating at 300 MHz for H
NMR and at 75 MHz for 13C NMR spectra. Chemical
shifts are given in δ, and tetramethylsilane (TMS) was
used as an internal standard. Multiplicities of carbon
were assigned from a broadband decoupled analysis
combined with the ATP program.
HPLC experiments were carried out on a chro-
matography system Pye Unicam with PU 4021 UV de-
tector (Pye Unicam, UK). Detection was carried out
at 210–310 nm using HPLC columns: TSKgel ODS-
80TM (5 µm, 4.6 mm; Tosoh); Luna C18 (5 µm,
250 × 4.6 mm; Phenomenex). Mobile phases were: pH
3.2–3.5 aqueous phosphate buffer/acetonitrile (ϕr =
3 : 1 up to ϕr = 5 : 1), and 1.0 vol. % solution of
triethylamine in a mixture of methanol and water (ϕr
= 2 : 3) adjusted to pH 3.0 with phosphoric acid. The
volume injected was 20 µL.

94
M. Gardiánová et al./Chemical Papers 67 (1) 92–100 (2013)
Table 1. Characterization data of newly prepared compounds
wi(calc.)/%
wi(found)/%
Yield
M.p.
Compound
Formula
d.r.a
C
H
N
%
84
71
84
78
89
71
83
70
75
66
75
88
80
76
44
37
◦C
(major)
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IVa
IVb
IVc
IVd
IVe
IVf
C18H18FNO4
C18H17F2NO4
C18H18ClNO4
C18H17Cl2NO4
C18H18N2O6
C18H18N2O6
C19H20N2O6
C19H20N2O6
C18H20FNO4
65.25
65.01
5.48
5.29
4.23
4.41
126–128
133–135
162–165
174–176
131–133
170–172
179–182
155–156
202–204
186–188
202–204
186–188
216–219
181–183
191–193
172–173
> 99 : 1
(1’R,2S)-
61.89
61.61
4.91
5.19
4.01
4.41
> 99 : 1
(1’R,2S)-
62.16
61.77
5.22
5.19
4.03
4.41
> 94 : 6
(1’R,2S)-
56.56
56.61
4.48
4.19
3.66
3.41
> 97 : 3
(1’R,2S)-
60.33
59.92
5.06
4.90
7.82
7.41
> 99 : 1
(1’R,2S)-
60.33
60.55
5.06
5.43
7.82
48
> 97 : 3
(1’R,2S)-
61.28
60.82
5.41
5.33
7.52
7.78
> 98 : 2
(1’S,2R)-
61.28
61.55
5.41
5.13
7.52
7.48
> 97 : 3
(1’S,2R)-
64.85
64.49
6.05
5.69
4.20
4.29
> 97 : 3
(2R,4S)-
◦
◦
C18
C18
H
H
19F2NO4
20ClNO4
61.53
61.19
5.45
5.21
3.99
3.59
> 97 : 3
(2R,4S)-
61.80
61.59
5.76
5.29
4.00
3.64
> 97 : 3
(2R,4S)-
C18H19Cl2NO4
C18H20N2O6
C18H20N2O6
C19H22N2O6
C19H22N2O6
56.26
56.19
4.98
5.20
3.65
3.49
97 : 3
(2R,4S)-
59.99
59.53
5.59
5.68
7.77
7.41
97 : 3
(2R,4S)-
59.99
59.75
5.59
5.45
7.77
7.95
99 : 1
(2R,4S)-
IVg
IVh
60.95
60.71
5.92
5.62
7.48
7.69
96 : 4
(2S,4R)-
60.95
60.58
5.92
5.63
7.48
7.73
97 :3
(2S,4R)-
a) d.r. values of the filtered products were readily determined by the reverse phase HPLC analysis on a Spherisorb ODS-2 5 µm
column using a pH 3.3 phosphate buffer–CH3CN (ϕr = 3 : 1).
General procedure for the synthesis of N-
substituted 2-amino-4-aryl-4-oxobutanoic
acids (IIIa–IIIh)
General procedure for the synthesis of N-
substituted syn-2-amino-4-aryl-4-hydroxybuta-
noic acids (IVa–IVh)
To a vigorously stirred solution of substituted 4-
aryl-4-oxo-2-butenoic acid (2 mmol) in methanol or
ethanol (dioxane for Ic) (10–20 mL), (R)-2-amino-2-
phenylethanol (274 mg, 2.2 mmol) or (S)-2-amino-3-
phenylpropanol (332 mg, 2.2 mmol) was added in por-
tions. The mixture was stirred at room temperature
or at 40◦C for the required time (HPLC control). The
precipitated product was filtered off, washed with di-
ethylether (20 mL) and dried under reduced pressure
(50 Pa, 50◦C).
The starting amino acid III (1 mmol) was sus-
pended in methanol (25 mL). MnCl2 · 4H2O (40 mg;
0.2 mmol) was added and the mixture was placed
on an ultrasonic reactor for 1 min. The mixture was
cooled to 10◦C and NaBH4 (40 mg; 1 mmol) was added
slowly under stirring. After 30 min, the mixture was
quenched with water (25 mL) and 10 mass % K2CO3
(9 mL) and filtered off. Methanol was removed under
reduced pressure and pH was adjusted to 6 (1 M HCl).
After a short period of stirring (15 min), the precip-
itate was filtered off, washed with diethylether and

M. Gardiánová et al./Chemical Papers 67 (1) 92–100 (2013)
95
Table 2. NMR spectral dataa and specific rotation of newly prepared compounds
Compound
Spectral data
IIIa
1H NMR (acetone-d6), δ: 8.07 (dd, 2H, J = 5.6 Hz, J = 8.8 Hz, H-2ꢀꢀ, H-6ꢀꢀ), 7.82–7.66 (m, 2H, H-Ph), 7.52–7.45
(m, 3H, H-Ph), 7.27 (t, 2H, J = 8.7 Hz, H-3ꢀꢀ, H-5ꢀꢀ), 4.88 (dd, 1H, J = 4.3 Hz, J = 9.4 Hz, H-1ꢀ), 4.27 (t, 1H, J =
4.9 Hz, H-2), 4.23 (dd, 1H, J = 9.4 Hz, J = 11.5 Hz, H-2ꢀ), 4.03–3.99 (m, 2H, H-3), 3.97 (dd, 1H, J = 11.7 Hz, J =
4.3 Hz, H-2ꢀ)
13C NMR (acetone-d6), δ: 195.1 (C-4), 169.2 (C-1), 168.2 (C-4ꢀꢀ), 164.6 (C-1ꢀꢀ), 131.9, 131.8, 131.6 (C-Ph), 130.4,
129.8, 129.7, 116.3, 116.0 (CH-Ar), 65.7 (C-1ꢀ), 63.0 (C-2ꢀ), 53.6 (C-2), 39.5 (C-3)
[α]2D5 = +29.3◦ (c = 1, MeOH/1 M HCl, ϕr = 3 : 1)
IIIb
IIIc
IIId
1H NMR (acetone-d6), δ: 7.97–7.83 (m, 4H, H-2ꢀꢀ, H-5ꢀꢀ, H-6ꢀꢀ, H-Ph), 7.55–7.44 (m, 1H, H-Ph), 4.87 (dd, 1H, J =
4.3 Hz, J = 9.6 Hz, H-1ꢀ), 4.27 (t, 1H, J = 4.9 Hz, H-2), 4.22 (dd, 1H, J = 9.6 Hz, J = 11.8 Hz, H-2ꢀ), 4.04 (t, 2H,
J = 5.1 Hz, H-3), 3.96 (dd, 1H, J = 4.3 Hz, J = 11.8 Hz, H-2ꢀ)
13C NMR (acetone-d6), δ: 194.7 (C-4), 169.1 (C-1), 152.4 (C-F), 148.8 (C-F), 133.4 (C-1ꢀꢀ), 131.7 (C-Ph), 130.3,
129.8, 118.4, 118.2, 118.0, 117.7 (CH-Ar), 65.7 (C-1ꢀ), 63.0 (C-2ꢀ), 53.3 (C-2), 39.6 (C-3)
[α]2D5 = +26.0◦ (c = 1, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (acetone-d6), δ: 8.01 (d, 2H, J = 8.7 Hz, H-2ꢀꢀ, H-6ꢀꢀ), 7.86–7.82 (m, 2H, H—Ph), 7.55 (d, 2H, J = 8.7 Hz,
H-3ꢀꢀ, H-5ꢀꢀ), 7.57–7.48 (m, 3H, H-Ph), 4.89 (dd, 1H, J = 4.2 Hz, J = 9.6 Hz, H-1ꢀ), 4.32–4.25 (m, 2H, H-2, H-2ꢀ),
4.08 (d, 2H, J = 4.9 Hz, H-3), 3.95 (dd, 1H, J = 12.0 Hz, J = 4.2 Hz, H-2ꢀ)
13C NMR (acetone-d6), δ: 196.1 (C-4), 169.7 (C-1), 140.3, 135.2, 132.3 (C-Ar), 131.0–129.7 (CH-Ar), 66.1 (C-1ꢀ),
63.4 (C-2ꢀ), 53.6 (C-2), 39.8 (C-3)
[α]2D5 = +38.0◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (acetone-d6), δ: 8.10 (d, 1H, J = 1.7 Hz, H-2ꢀꢀ), 7.97 (dd, 1H, J = 1.5 Hz, J = 8.6 Hz, H-6ꢀꢀ), 7.83–7.80
(m, 2H, H-Ph), 7.73 (d, 1H, J = 8.4 Hz, H-5ꢀꢀ), 7.49–7.47 (m, 3H, H-Ph), 4.87 (dd, 1H, J = 3.8 Hz, J = 9.6 Hz,
H-1ꢀ), 4.37 (t, 1H, J = 4.8 Hz, H-2), 4.90–4.22 (m, 1H, H-2ꢀ), 4.15–4.05 (m, 2H, H-3), 3.96 (dd, 1H, J = 11.7 Hz, J
= 3.8 Hz, H-2ꢀ)
13C NMR (acetone-d6), δ: 195.0 (C-4), 169.5 (C-1), 138.0, 136.5, 133.2, 132.1 (C-Ar), 131.8–129.0 (CH-Ar), 66.0
(C-1ꢀ), 63.2 (C-2ꢀ), 53.4 (C-2), 39.8 (C-3)
[α]2D5 = +37.9◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
IIIe
IIIf
IIIg
1H NMR (acetone-d6), δ: 8.33 (d, 2H, J = 9.3 Hz, H-3ꢀꢀ, H-5ꢀꢀ), 8.25 (d, 2H, J = 9.0 Hz, H-2ꢀꢀ, H-6ꢀꢀ), 7.90–7.80
(m, 2H, H-Ph), 7.50–7.47 (m, 3H, H-Ph), 4.88 (dd, 1H, J = 4.2 Hz, J = 9.6 Hz, H-1ꢀ), 4.27 (dd, 1H, J = 9.6 Hz,
J = 11.8 Hz, H-2ꢀ), 4.31 (t, 1H, J = 4.9 Hz, H-2), 4.21 (dd, 1H, J = 5.1 Hz, J = 19.2 Hz, H-3), 4.13 (dd, 1H, J =
5.1 Hz, J = 19.2 Hz, H-3), 3.95 (dd, 1H, J = 11.7 Hz, J = 4.2 Hz, H-2ꢀ)
13C NMR (acetone-d6), δ: 194.4 (C-4), 170.0 (C-1), 150.6, 141.1, 132.2 (C-Ar), 132.2–124.5 (CH-Ar), 66.1 (C-1ꢀ),
63.3 (C-2ꢀ), 53.4 (C-2), 40.4 (C-3)
[α]2D5 = +36.9◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (acetone-d6), δ: 8.70 (t, 1H, J = 1.7 Hz, H-2ꢀꢀ), 8.50–8.44 (m, 2H, H-Ph), 7.90–7.82 (m, 3H, H-Ph), 7.53–
7.47 (m, 3H, H-Ph), 4.87 (dd, 1H, J = 4.3 Hz, J = 9.6 Hz, H-1ꢀ), 4.33 (t, 1H, J = 4.9 Hz, H-2), 4.25 (dd, 1H, J =
9.6 Hz, J = 11.7 Hz, H-2ꢀ), 4.23 (dd, 1H, J = 5.3 Hz, J = 19.2 Hz, H-3), 4.13 (dd, 1H, J = 5.1 Hz, J = 19.2 Hz,
H-3), 3.97 (dd, 1H, J = 11.7 Hz, J = 4.3 Hz, H-2ꢀ)
13C NMR (acetone-d6), δ: 195.5 (C-4), 169.7 (C-1), 149.3, 137.9, 135.2–123.5 (CH-Ar), 132.3 (C-Ar), 66.2 (C-1ꢀ),
63.4 (C-2ꢀ), 53.5 (C-2), 40.2 (C-3)
[α]2D5 = +24.8◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (acetone-d6/DCl), δ: 8.34 (d, 2H, J = 9.3 Hz, H-3ꢀꢀ, H-5ꢀꢀ), 8.29 (d, 2H, J =9.0 Hz, H-2ꢀꢀ, H-6ꢀꢀ), 7.40–7.22
(m, 5H, H-Ph), 4.96–4.88 (m, 1H, H-2), 4.27 (dd, 1H, J = 5.1 Hz, J = 19.2 Hz, H-3), 4.18 (dd, 1H, J = 4.8 Hz, J
= 19.3 Hz, H-3), 3.93–3.86 (m, 1H, H-1ꢀ), 3.81 (dd, 1H, J = 12.4 Hz, J = 3.6 Hz, H-2ꢀ), 3.74 (dd, 1H, J = 12.1 Hz,
J = 7.6 Hz, H-2ꢀ), 3.51 (dd, 1H, J = 4.8 Hz, J = 13.5 Hz, H-CH2-Ph), 3.13 (dd, 1H, J = 10.3 Hz, J = 13.5 Hz,
H-CH2-Ph)
13C NMR (acetone-d6/DCl), δ: 196.3 (C-4), 170.2 (C-1), 151.5, 141.0, 137.0 (C-Ar), 130.8–124.6 (CH-Ar), 62.7
(C-1ꢀ), 60.1 (C-2ꢀ), 54.2 (C-2), 40.2 (C-3), 33.8 (C-CH2-Ph)
[α]2D5 = –68.3◦ (c = 0.52, MeOH/1 M HCl, ϕr = 3 : 1)
IIIh
IVa
1H NMR (acetone-d6), δ: 8.76 (bs, 1H, H-2ꢀꢀ), 8.54–8.47 (m, 2H, Ph), 7.89 (t, 1H, J = 7.8 Hz, H-5ꢀꢀ), 7.43–7.23 (m,
3H, Ph), 7.42 (d, 2H, J = 6.8 Hz, H-4ꢀꢀ, H-6ꢀꢀ), 4.90 (bs, 1H, H-1ꢀ), 4.35 (dd, 1H, J = 3.4 Hz, J = 18.8 Hz, H-3),
4.26 (dd, 1H, J = 3.6 Hz, J = 19.0 Hz, H-3), 3.96–3.75 (m, 3H, H-2, H-2ꢀ), 3.56 (dd, 1H, J = 4.1 Hz, J = 13.7 Hz,
H-CH2-Ph), 3.19 (dd, 1H, J = 10.1 Hz, J = 13.5 Hz, H-CH2-Ph)
13C NMR (acetone-d6), δ: 195.8 (C-4), 170.0 (C-1), 149.2, 137.7, 136.9 (C-Ar), 135.2–123.4 (CH-Ar), 62.8 (C-1ꢀ),
60.1 (C-2ꢀ), 54.2 (C-2), 40.0 (C-3), 33.8 (C-CH2-Ph)
[α]2D5 = –62.5◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (NaOD/D2O), δ: 7.45–7.40 (m, 3H, H-Ph), 7.36–7.33 (m, 2H, H-Ph), 7.24–7.20 (m, 2H, H-Ar), 7.10–7.04
(m, 2H, H-Ar), 3.79–3.64 (m, 4H, H-4,H-1ꢀ, H-2ꢀ), 2.82 (t, 2H, J = 7.3 Hz, H-2), 1.97–1.89 (m, 2H, H-3)
13C NMR (NaOD/D2O), δ: 184.0 (C-1), 163.0 (C-4ꢀꢀ), 143.5 (C-Ar), 142.0, 133.5–132.0 (CH-Ar), 119.0, 118.0
(CH-Ar), 75.5 (C-4), 68.5 (C-2ꢀ), 67.5 (C-1ꢀ), 62.5 (C-2), 44.0 (C-3)
[α]2D5 = +9.8◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)

96
M. Gardiánová et al./Chemical Papers 67 (1) 92–100 (2013)
Table 2. (continued)
Compound
Spectral data
IVb
IVc
IVd
IVe
1H NMR (NaOD/D2O), δ: 7.59–7.35 (m, 5H, H-Ph), 7.26–7.12 (m, 3H, H-Ar), 3.76 (m, 3H, H-4, H-1ꢀ, H-2ꢀ), 2.85
(t, 1H, J = 5.1 Hz, H-2), 1.98–1.94 (m, 2H, H-3)
13C NMR (NaOD/D2O), δ: 183.9 (C-1), 142.4, 141.8 (C-F), 131.4–130.8 (CH-Ar), 131.3, 130.7 (C-Ar), 125.3, 120.0,
119.8, 117.9, 117.7 (CH-Ar), 74.5 (C-4), 68.4 (C-2ꢀ), 65.0 (C-1ꢀ), 62.1 (C-2), 44.0 (C-3)
[α]2D5 = +9.2◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (NaOD/D2O), δ: 7.45–7.40 (m, 3H, H-Ph), 7.36–7.33 (m, 2H, H-Ph), 7.24–7.20 (m, 2H, H-Ar), 7.10–7.04
(m, 2H, H-Ar), 3.79–3.64 (m, 4H, H-4, H-1ꢀ, H-2ꢀ), 2.82 (t, 2H, J = 7.26 Hz, H-2), 1.97–1.89 (m, 2H, H-3)
13C NMR (NaOD/D2O), δ: 184.0 (C-1), 163.0 (C-4ꢀꢀ), 143.5 (C-Ar), 142.0, 133.5–132.0 (CH-Ar), 119.0, 118.0
(CH-Ar), 75.5 (C-4), 68.5 (C-2ꢀ), 67.5 (C-1ꢀ), 62.5 (C-2), 44.0 (C-3)
[α]2D5 = +9.8◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (NaOD/D2O), δ: 7.59–7.35 (m, 5H, H-Ph), 7.26–7.12 (m, 3H, H-Ar), 3.76 (m, 3H, H-4, H-1ꢀ, H-2ꢀ), 2.85
(t, 1H, J = 5.1 Hz, H-2), 1.98–1.94 (m, 2H, H-3)
13C NMR (NaOD/D2O), δ: 183.9 (C-1), 142.4, 141.8 (C-F), 131.4–130.8 (CH-Ar), 131.3, 130.7 (C-Ar), 125.3, 120.0,
119.8, 117.9, 117.7 (CH-Ar), 74.5 (C-4), 68.4 (C-2ꢀ), 65.0 (C-1ꢀ), 62.1 (C-2), 44.0 (C-3)
[α]2D5 = +9.2◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (acetone-d6,), δ: 8.14 (d, 2H, J = 8.5 Hz, H-3ꢀꢀ, H-5ꢀꢀ), 7.75–7.68 (m, 2H, H-Ph), 7.69 (d, 2H, J = 8.5 Hz,
H-2ꢀꢀ, H-6ꢀꢀ), 7.53–7.44 (m, 3H, H-Ar), 5.24 (dd, 1H, J = 3.8 Hz, J = 8.8 Hz, H-4), 4.74 (dd, 1H, J = 3.8 Hz, J =
6.2 Hz, H-1ꢀ), 4.27 (dd, 1H, J = 7.7 Hz, J = 11.5 Hz, H-2ꢀ), 4.09 (dd, 1H, J = 3.8 Hz, J = 11.7 Hz, H-2ꢀ), 3.95 („t“,
1H, J = 5.1 Hz, J = 5.8 Hz, H-2), 2.55–2.40 (m, 2H, H-3)
13C NMR (acetone-d6,), δ: 169.8 (C-1), 152.4, 148.1, 132.7 (C-Ar), 130.7–124.2 (CH-Ar), 70.9 (C-4), 65.3 (C-1ꢀ),
63.2 (C-2ꢀ), 57.2 (C-2), 38.7 (C-3)
[α]2D5 = +30.5◦ (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1)
IVf
1H NMR (NaOD/D2O), δ: 8.05–7.95 (m, 2H, H-2ꢀꢀ, H-4ꢀꢀ), 7.48–7.38 (m, 2H, H-5ꢀꢀ, H-6ꢀꢀ), 7.30–7.19 (m, 5H, H-Ph),
4.72 (t, 1H, J = 6.9 Hz, H-4), 3.67–3.52 (m, 3H, H-1ꢀ, H-2ꢀ), 2.60 (dd, 1H, J = 4.7 Hz, J = 8.1 Hz, H-2), 1.98–1.81
(m, 2H, H-3)
13C NMR (NaOD/D2O), δ: 184.4 (C-1), 150.5, 148.4, 142.3 (C-Ar), 136.0–124.2 (CH-Ar), 74.7 (C-4), 68.7 (C-2ꢀ),
66.1 (C-1ꢀ), 62.0 (C-2), 44.3 (C-3)
[α]2D0 = +19.2◦ (c = 0.52, MeOH/1 M HCl, ϕr = 3 : 1)
IVg
IVh
1H NMR (NaOD/D2O), δ: 8.27 (d, 2H, J = 8.8 Hz, H-3ꢀꢀ, H-5ꢀꢀ), 7.57 (d, 2H, J = 8.8 Hz, H-2ꢀꢀ, H-6ꢀꢀ), 7.44–7.39
(m, 5H, H-Ph), 3.60–3.38 (m, 3H), 2.92–2.67 (m, 3H), 2.05–1.85 (m, 2H, H-3)
13C NMR (NaOD/D2O), δ: 184.4 (C-1), 154.1, 149.8, 141.8 (C-Ar), 132.2–126.7 (CH-Ar), 74.7 (C-4), 66.0 (C-2ꢀ),
63.0 (C-1ꢀ), 62.3 (C-2), 44.1 (C-3), 39.6 (C-CH2-Ph)
[α]2D5 = –78.0◦ (c = 0.53, MeOH/1 M HCl, ϕr = 3 : 1)
1H NMR (NaOD/D2O), δ: 8.05–7.95 (m, 2H, H-2ꢀꢀ, H-4ꢀꢀ), 7.48–7.38 (m, 2H, H-5ꢀꢀ, H-6ꢀꢀ), 7.30–7.19 (m, 5H, H-Ph),
4.72 (t, 1H, J = 6.9 Hz, H-4), 3.67–3.52 (m, 3H, H-1ꢀ, H-2ꢀ), 2.60 (dd, 1H, J = 4.7 Hz, J = 8.1 Hz, H-2), 1.98–1.81
(m, 2H, H-3)
13C NMR (NaOD/D2O), δ: 184.4 (C-1), 150.5, 148.4, 142.3 (C-Ar), 136.0–124.2 (CH-Ar), 74.7 (C-4), 68.7 (C-2ꢀ),
66.1 (C-1ꢀ), 62.0 (C-2), 44.3 (C-3)
[α]2D5 = –64.4◦ (c = 0.51, MeOH/1 M HCl, ϕr = 3 : 1)
a) Atom numbering corresponds to the numbering in Fig. 3.
dried. Crude γ-hydroxy-α-amino acids were recrystal-
lized from the EtOH/H2O mixture (ϕr =7 : 3).
Results and discussion
The starting substituted (E)-4-aryl-4-oxo-2-bute-
noic acids Ia–If were prepared via the Friedel–
Craft’s acylation of halogen-substituted benzenes (Up-
reti et al., 1996) or via the condensation of ni-
troacetophenones with glyoxylic acid (Bianchi et al.,
1988).
The key step in our synthesis of substituted aroy-
lalanines is represented by the regiospecific and, in
tandem with CIAT, highly diastereoselective conju-
gate addition of (R)-2-amino-2-phenylethanol or (S)-
2-amino-3-phenylpropanol to the unsaturated acids
Ia–If (Jakubec et al., 2006a, 2006b; Kolarovic et al.,
2001). Reaction conditions were mild (25–40◦C, 1–7
days) and in both chiral nucleophiles, the respective
adducts IIIa–IIIh were obtained in good yields (70–
Oxidative cleavage of N-substituted γ-oxo-α-
amino acids
To a suspension of N-substituted γ-oxo-α-amino
acid III (0.6 mmol) in water (5–8 mL) and methanol
(0–2 mL), sodium periodate (128 mg; 0.6 mmol), and
triethylamine (2 drops) were added. The mixture was
placed on an ultrasonic reactor for 1 min. The re-
sulting suspension was stirred at laboratory temper-
ature for 10 min. Methanol was evaporated under
reduced pressure and the formed precipitate was fil-
tered off, washed with a small amount of diethylether
and dried to obtain the corresponding (2S)-2-amino-
4-aryl-4-oxobutanoic acid.

M. Gardiánová et al./Chemical Papers 67 (1) 92–100 (2013)
Table 3. Characterization data of (S)-aroylalanines (Va–Ve)
97
Published data
[α]2D5
Yield
%
M.p.
◦C
[α]2D5a
M.p.
◦C
Compound
Reference
◦
◦
Va
Vb
Vc
Vd
Ve
47
31
55
56
66
186–188 (decomp) +47.2 189–190 (decomp) +42.2 (c = 0.1, 6 M HCl) Golubev et al. (1996)
178–180 (decomp) +35.8
181–183 (decomp) +38.1
154–157 (decomp) +32.1
176–179 (decomp) +47.1
195–196
204–206b
nd
+33.3 (c = 1, 95 % EtOH) Varasi et al. (1999)
c
–
Varasi et al. (1999)
+29.4 (c = 0.25, 1 M HCl) Jousseaume et al. (2011)
c
178–179
–
Pellicciari et al. (1994)
a) (c = 0.50, MeOH/1 M HCl, ϕr = 3 : 1); b) hydrogen chloride salt; c) racemic form; decomp – decomposes, nd – not detectable.
89 %) and excellent stereoselectivity by simple filtra-
tion (d.r. up to 99 : 1).
tion mixture showed high gelation ability at the be-
ginning of the reaction. However, in the progress of
the transformation, the product started to precipitate
gradually and after several days it could be isolated
via filtration.
In order to establish the expected stereochemi-
cal development of (R)-2-amino-2-phenylethanol ad-
dition to Ib at 25◦C and Ie at 40◦C, the reactions
were monitored by HPLC (Spherisorb ODS-2, 5 µm;
250 × 4.6 mm). As can be seen from Fig. 4, the ratio of
both diastereoisomeric products IIIb and IIIe, formed
in the reaction mixture, was approximately equal at
the initial stage. However, as the CIAT progressed
in time, the (R,S)-diastereoisomer clearly became the
major adduct of the transformation with the concomi-
tant decline of the content of its (2R,1S)-configured
diastereoisomer. Thus, after 8 days of stirring at room
temperature or after 24 h of stirring at 40◦C and sub-
sequent filtration of the heterogeneous reaction mix-
ture, IIIb was obtained in a 71 % yield with 98 % de
and IIIe was obtained in a 89 % yield with 98 % de
(Tables 1 and 2). An analogous stereochemical course
was observed for the addition of (R)-phenylglycinol
which led to other derivatives, IIIa–IIIf, and for the
CIAT process using (S)-phenylalaninol which resulted
in derivatives IIIg–IIIh. In each case, the major di-
astereoisomer showed (S)- stereochemistry at a new
stereogenic center, as determined by a comparison of
the optical rotation of the parent oxoamino acids Va–
Vg which were obtained by the cleavage of the IIIa–
IIIg with periodate, with those reported in literature
(Table 3).
The reaction medium plays a crucial role in the
success or failure of the CIAT process (Sakai et al.,
2004). Reaction conditions were optimized to balance
the solubility and the rate of diastereoisomers equili-
bration. Moreover, high gelation ability in some sol-
vents also complicates the optimization. Ethanol has
been identified as the only suitable solvent for the
derivative IIIa. Extremely high gelation was observed
in dichloromethane or dioxane; moreover, using the
methanol/water mixture (ϕr = 2 : 1) resulted in a too
low rate of equilibration and the ratio of diastereoiso-
mers reached 70 : 30 only after one week of intensive
agitation.
Next, the synthesis of substituted dihydrobenzoyl-
l-alanines IVa–IVh was studied. In our previous pa-
per (Berkeš et al., 2005), the highly diastereose-
lective reduction of N-substituted 2-amino-4-aryl-4-
oxobutanoic acids to the corresponding N-substituted
syn-α-amino-γ-hydroxybutanoic acids was described.
In case of oxoamino acids derived from (R)-phenyl-
glycinol (IIIa–IIIf), application of the NaBH4/MnCl2
· 4H2O reductive system led to the formation of the
desired syn-γ-hydroxy-α-amino acids IVa–IVf in good
yields (66–88 % of the crystallized products) and ex-
cellent syn : anti selectivity (de 94–98 %) (Fig. 3 and
Table 1). Manganese(II) chloride is an indispensable
reagent in this highly diastereoselective reduction re-
action due to its complexation with the 2-amino-4-oxo
moiety forming a six-membered chelate ring (Berkeš
et al., 2000).
The moderate yields of crystalline (S)-phenyl-
alaninol derivatives IVg, IVh (37–44 %) were caused
by their high gelation ability. This ability of enan-
tiomerically pure oxo- or hydroxy-amino acids was de-
scribed previously (Berkeš et al., 2000; Jakubec et al.,
2006b). Thus, the prepared syn-(2R,4S,1ꢀS)-4-aryl-4-
hydroxy-2-(1ꢀ-benzyl-2ꢀ-hydroxyethylamino) butanoic
acids IVg, IVh provide another example fitting the
close gelation–chiral structure relationship (Hanabusa
et al., 1999).
Final step of the aroylalanines Va–Ve synthesis
required the removal of the substituent on nitrogen
by one of the known procedures. Attempts to depro-
tect the oxoamino acids under acidic hydrogenolytic
conditions (H2/Pd, cat. HCl, MeOH) failed because
of the concomitant carbonyl reduction. Known ap-
plications of lead tetraacetate for the phenylglycinol
degradation (Mokhallalati & Pridgen, 1993; Stalker
et al., 2002; Warmuth et al., 2001) caused a prob-
lem with the parasitic reactions, e.g. α-acetoxylation
to carbonyl (Jursic et al., 2010; Numazawa et al.,
2001). Finally, neutral oxidative conditions employing
In case of the 4-chloroderivative IIIc, dioxane had
to be used. In both cases (IIIa and IIIc), the reac-

98
M. Gardiánová et al./Chemical Papers 67 (1) 92–100 (2013)
Fig. 3. Synthesis of N-substituted aroylalanines (IIIa–IIIh) and their stereoselective reduction to the corresponding hydroxy-
aminobutanoic acids (IVa–IVh).
Fig. 4. Diastereomer distribution (HPLC experiments): 0.26 M of Ia in ethanol with (R)-2-amino-2-phenylethanol (1.1 eq.) at
25◦C (a), 0.22 M of Ie in methanol with (R)-2-amino-2-phenylethanol (1.1 eq.) at 40◦C (b); – (1ꢀR,2S)-IIIb (a),
(1ꢀR,2R)-IIIb (a), ꢀ – (1ꢀR,2S)-IIIe (b), ꢁ – (1ꢀR,2R)-IIIe (b).
–
•
sodium periodate were used (Awasthi et al., 2005).
Such type of transformation in the aqueous solution,
previously developed in our laboratory (Jakubec et
al., 2006a), when applied to (R)-phenylglycinol deriva-
tives IIIa–IIIe, furnishes the desired free amino acids
Va–Ve in poor to acceptable yields (31–66 %). Lower
yields were caused by high solubility and instability
of the products in aqueous solvent, which consider-
ably complicated the work-up and subsequent purifi-
cation of target Va–Ve. The volume of the solvent
had to be optimized to allow the precipitation of the
desired oxoamino acid from the reaction media and
to maintain sufficient solubility of the side products
(mainly NaIO3). In case of 3-nitro derivative IIIf,
isolation of Vf failed completely. The failure in case
of (S)-phenylalaninol derivatives IIIg and IIIh was
due to a phenylacetaldehyde byproduct formation and
its exhaustive degradation. It can be assumed that
N-dealkylation proceeds via a mechanism analogous
to the oxidative cleavage of 1,2-diols with periodate.

M. Gardiánová et al./Chemical Papers 67 (1) 92–100 (2013)
99
Fig. 5. Oxidative degradation of N-substituted aroylalanines (IIIa–IIIe).
This hypothesis is strongly supported by the fact that
benzaldehyde was isolated from the reaction mixture.
Finally, the oxidative N-dealkylation proceeds without
observable racemization (Fig. 5).
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The determination of relative and/or absolute con-
figurations was carried out by comparison of litera-
ture data with the results obtained from polarimetric
and HPLC experiments. Asymmetric induction of pri-
mary amino alcohols leads to the formation of (R,S)-
derivatives (Jakubec et al., 2006a, 2006b; Kolarovic et
al., 2001). The comparison of the measured value of
specific rotation of Va, Vb, Vd with literature data for
these compounds (Table 3) also confirmed the abso-
lute (S)-configuration.
Conclusions
A two-step highly stereocontrolled synthesis of
several halo- and nitro-substituted benzoyl-l-alanines
was developed from accessible 4-aryl-4-oxobutenoic
acids and (R)-phenylglycinol. In the first step, a tan-
dem of the aza-Michael addition and CIAT afforded a
high degree of stereocontrol and a simple separation
of the desired N-substituted aroyl-l-alanines via filtra-
tion. The rapid periodate oxidative degradation of the
amino alcohol moiety under the thoroughly controlled
conditions afforded the targeted (S)-4-aryl-2-amino-
4-oxobutanoic acids in moderate to good yields and
excellent optical purity. Further study of this trans-
formation is currently in progress to be reported in
due course.
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Acknowledgements. Financial support from the Slovak
Grant Agency (VEGA) No. 1/0441/11 is gratefully acknowl-
edged.
Hanabusa, K., Maesaka, Y., Kimura, M., & Shirai, H. (1999).
New gelators based on 2-amino-2-phenylethanol: Close ge-
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