Inexpensive chemical method for preparation of enantiomerically pure phenylalanine

Article abstract of DOI:10.1007/s00726-013-1656-0

Here, we report the most inexpensive procedure for chemical synthesis of enantiomerically pure phenylalanine. As a source of chirality, we use the ultimately inexpensive chiral auxiliary, 1-(phenyl)ethylamine, incorporated into the specially designed ligands which form the corresponding intermediate Ni(II) complexes with racemic phenylalanine. Diastereomerically pure Ni(II) complexes, containing either (S)- or (R)-phenylalanine, were disassembled to produce enantiomerically pure target amino acid, along with recycling the chiral ligand. All reactions were conducted under operationally convenient conditions, featuring high yields and thus underscoring attractive cost structure of this method.

Full text of DOI:10.1007/s00726-013-1656-0

Amino Acids
DOI 10.1007/s00726-013-1656-0
ORIGINAL ARTICLE
Inexpensive chemical method for preparation
of enantiomerically pure phenylalanine
•
Hiroki Moriwaki Daniel Resch Hengguang Li
•
•
•
•
•
´
Iwao Ojima Ryosuke Takeda Jose Luis Acen˜a
Vadim Soloshonok
Received: 11 October 2013 / Accepted: 17 December 2013
Ó Springer-Verlag Wien 2014
Abstract Here, we report the most inexpensive proce-
dure for chemical synthesis of enantiomerically pure
phenylalanine. As a source of chirality, we use the ulti-
mately inexpensive chiral auxiliary, 1-(phenyl)ethylamine,
incorporated into the specially designed ligands which
form the corresponding intermediate Ni(II) complexes with
racemic phenylalanine. Diastereomerically pure Ni(II)
complexes, containing either (S)- or (R)-phenylalanine,
were disassembled to produce enantiomerically pure target
amino acid, along with recycling the chiral ligand. All
reactions were conducted under operationally convenient
conditions, featuring high yields and thus underscoring
attractive cost structure of this method.
Introduction
Asymmetric synthesis of tailor-made a-amino acids (Sol-
oshonok et al. 1999a) has always been in focus of organic
chemistry. Besides being in the league of very special
‘‘molecules of life’’, amino acids play an important role in
food and health care industries. In particular, production of
many sophisticated pharmaceuticals is based on amino
acids as source of chirality and essential functionalities
(Wang et al. 2001, 2004; Breuer et al. 2004; Gallos et al.
2005). Truly immense amount of research data on synthesis
of amino acids has been reported, featuring virtually all
imaginable methodological approaches (O’Donnell and
¨
Eckrich 1978; Schollkopf et al. 1981; Williams et al. 1988;
Keywords Phenylalanine ꢀ Schiff bases ꢀ Ni(II)
Fitzi and Seebach 1988; Duthaler 1994; Soloshonok et al.
1994, 1997a, 2009a; Lygo and Wainwright 1997; Corey
et al. 1997; Ooi et al. 1999; Chinchilla et al. 2000; Solos-
honok 2002; Park et al. 2002, 2007; Shibuguchi et al. 2002;
complexes ꢀ Stereogenic nitrogen ꢀ Asymmetric synthesis
´
Solladie-Cavallo et al. 2002; Maruoka and Ooi 2003; Ma
´
2003; Najera and Sansano 2007; Kukhar et al. 2009;
Sorochinsky and Soloshonok 2010; Soloshonok and Soro-
chinsky 2010; Acen˜a et al. 2012, 2013; Sorochinsky et al.
2013a, b). However, high cost of preparation of amino acids
via asymmetric synthesis renders the purely chemical
methods prohibitively expensive for large-scale production
(Fogassy et al. 2005). Therefore, the current industrial
preparation of enantiomerically pure amino acids is based
on chemical synthesis of racemates followed by enzymatic
resolutions (Breuer et al. 2004; Soloshonok and Izawa
2009). The major advantage of biocatalytic processes is that
they can be conducted under operationally convenient
conditions (Ellis et al. 2003a; Soloshonok et al. 2006) and
therefore have attractive cost structure. Consequently, to
devise a sound synthetic methodology that can rival enzy-
matic reactions, one should pay due attention to the reaction
H. Moriwaki ꢀ D. Resch ꢀ H. Li ꢀ I. Ojima
Department of Chemistry, Institute of Chemical Biology and
Drug Discovery, State University of New York at Stony Brook,
Stony Brook, NY 11794-3400, USA
H. Moriwaki ꢀ R. Takeda
Hamari Chemicals Ltd., 1-4-29 Kunijima,
Higashi-Yodogawa-ku, Osaka 533-0024, Japan
J. L. Acen˜a ꢀ V. Soloshonok (&)
Department of Organic Chemistry I, Faculty of Chemistry,
University of the Basque Country UPV/EHU,
´
20018 San Sebastian, Spain
e-mail: vadym.soloshonok@ehu.es
V. Soloshonok
IKERBASQUE, Basque Foundation for Science,
48011 Bilbao, Spain
123

H. Moriwaki et al.
conditions and cost of the reagents. In context of practi-
cality, the Ni(II) complex of glycine Schiff base 1 (Fig. 1)
(Belokon et al. 1983, 1985a, 1998; Ueki et al. 2003a) has
some attractive features. In particular, its homologation via
alkyl halide alkylation (Tang et al. 2000, Qiu et al. 2000;
Soloshonok et al. 2001), aldol (Soloshonok et al. 1993,
1995, 1996), Mannich (Soloshonok et al. 1997b; Wang et al.
2008) and Michael (Soloshonok et al. 1999b, 2000a, 2005a)
addition reactions can be conducted at ambient temperature
in commercial grade solvents. Achiral analogs of 1, com-
plexes 2a,b (Ueki et al. 2003b) are also useful glycine
equivalents for homologation under asymmetric PTC
(Belokon et al. 2001, 2003) and Michael addition reactions
(Soloshonok et al. 2000b, 2004; Yamada et al. 2006).
Recently, we introduced a modular design (Soloshonok
et al. 2005b, c; Ellis et al. 2006) of a new generation of
nucleophilic glycine equivalents of general formula 3
(Fig. 2). This approach offers remarkable structural flexi-
bility allowing to control physicochemical properties and
reactivity of the corresponding Ni(II) complexes (Ellis
et al. 2003b, Yamada et al. 2008; Soloshonok et al. 2009b).
Apparent success has been achieved in application of this
design for preparation of ligand 4, useful for deracemiza-
tion of racemic amino acids (Soloshonok et al. 2009a) and
(S)- to (R)-enantiomers interconversion (Sorochinsky et al.
2013a, b). Here, we report application of this new type of
ligands/Ni(II) complexes for development of the most
inexpensive chemical preparation of enantiomerically pure
amino acids, demonstrated on example of phenylalanine.
Materials and methods
General procedure for preparation of ligands 10a,b
Secondary amine 9 (Soloshonok and Ueki 2010) (0.500 g,
1 equiv), N,N-diisopropylethylamine (1.5 equiv), alkyl
halide (1.1 equiv in the case of BnBr and 3.5 equiv in the
case of MeI) and 10 mL of MeCN were placed in a round-
bottom flask and stirred at room temperature under nitro-
gen. After completion of the reaction (monitored by TLC),
the reaction mixture was evaporated to dryness under
vacuum. The residue was dissolved in 5 mL of CH2Cl2 and
washed with 5 mL of water. The aqueous layer was washed
with 3 9 5 mL fractions of CH2Cl2. The collected organic
fractions were dried over MgSO4 and the solvent was
removed under vacuum to yield the crude product. Ana-
lytically pure samples of 10a,b were obtained by column
chromatography (Hex/EtOAc).
1
10a: Mp 80–82 °C; [a]2D5 ?23.7 (c 1.55, CHCl3). H-
NMR d 1.54 (d, J = 6.9 Hz, 3H), 2.44 (s, 3H), 3.12 (d,
J = 16.8 Hz, 1H), 3.25 (d, J = 16.8 Hz, 1H), 3.82 (q,
J = 6.6 Hz, 1H), 6.87–6.92 (m, 1H), 7.15–7.22 (m, 1H),
7.25–7.28 (m, 2H), 7.50–7.72 (m, 7H), 7.73–7.92 (m, 2H),
8.69 (d, J = 8.7 Hz, 1H), 11.67 (bs, 1H).
1
10b: Oil; [a]2D5 ?28.1 (c 3.81, CHCl3). H-NMR d 1.43
(d, J = 6.9 Hz, 3H), 1.47 (s, 1H), 3.02 (d, J = 16.8 Hz,
1H), 3.22 (d, J = 16.8 Hz, 1H), 3.36 (d, J = 12.9 Hz, 1H),
3.72 (d, J = 13.2 Hz, 1H), 3.84 (q, J = 7.2 Hz, 1H),
6.96–7.01 (m, 4H), 7.13–7.20 (m, 3H), 7.37–7.48 (m, 8H),
7.55–7.57 (m, 1H), 7.78–7.81 (m, 2H), 8.44 (dd, J = 7.5,
1.2 Hz, 1H), 11.22 (bs, 1H).
Ph
N
N
N
N
O
N
O
O
N
O
General procedure for preparation of Ni(II)-complexes
11a,b–14a,b by the reaction of ligands 10a,b with rac-
phenylalanine
Ni
Ni
O
O
Ph
R
To a flask containing methanol solution of ligand (S)-
10a,b (1 equiv), NiCl2 (2 equiv) and racemic phenylalanine
(2.0 equiv), were added K2CO3 (6 equiv), and the reaction
mixture was stirred at 50 °C. The progress of the reaction
was monitored by TLC and upon completion (consumption
of ligand 10a,b), the reaction mixture was poured into ice
water containing 5 % acetic acid. The target product was
extracted three times with CH2Cl2. The combined organic
layer was dried over anhydrous MgSO4 and evaporated
under vacuum. After evaporation of the solvents and silica
gel column chromatography, the target complexes 11a,b–
14a,b were obtained in diastereomerically pure form.
(SC,RN,SC)-11a: Mp 164–170 °C; [a]2D5 ?1711.6 (c 0.01,
CHCl3). 1H-NMR d 1.46 (3H, s), 2.25 (d, J = 7.2 Hz, 3H),
2.64 (dd, J = 13.5, 5.1 Hz, 1H), 2.86 (d, J = 16.2 Hz,
1H), 3.03 (dd, J = 13.5, 3.3 Hz, 1H), 3.07 (d,
J = 16.2 Hz, 1H), 3.94 (q, J = 6.9 Hz, 1H), 4.29 (t,
2
a
b
1
(S)-
R = Me ( ), Ph ( )
Fig. 1 Chiral 1 and achiral 2a,b equivalents of nucleophilic glycine
Me
Me
Me
Ph
H
R''
Ni
R''
R'
R'
N
N
O
N
O
N
O
O
NH
O
R
Ph
3
4
Fig. 2 New generation of Ni(II)-complexes of amino acids 3 and 4
123

Preparation of enantiomerically pure phenylalanine
Br
J = 1.8 Hz, 1H), 6.76–6.80 (m, 2H), 7.06–7.08 (m, 1H),
7.16–7.19 (m, 2H), 7.26–7.36 (m, 5H), 7.46–7.60 (m, 7H),
8.44 (d, J = 8.4 Hz, 1H). 13C-NMR d 18.7, 38.9, 39.6,
62.4, 65.6, 71.3, 121.1, 123.6, 127.0, 127.2, 127.6, 127.7,
128.4, 128.8, 129.0, 129.1, 129.2, 130.0, 130.1, 131.5,
132.7, 133.4, 133.6, 133.7, 136.2, 142.7, 170.7, 174.7,
178.1.
(SC,RN,SC)-11b: Mp 228–229 °C; [a]2D5 ?1417.4
(c 0.01, CHCl3). 1H-NMR d 2.22 (d, J = 6.9 Hz, 3H), 2.76
(d, J = 17.1 Hz, 1H), 2.78 (d, J = 12.0 Hz, 1H),
3.10–3.30 (m, 2H), 3.95 (q, J = 6.6 Hz, 1H), 4.11 (d,
J = 12.0 Hz, 1H), 4.12 (d, J = 17.1 Hz, 1H), 4.20 (t,
J = 6.3 Hz, 1H), 6.57–6.61 (m, 3H), 6.94–7.18 (m, 4H),
7.21–7.38 (m, 13H), 7.49–7.53 (m, 2H), 8.07 (d,
J = 7.8 Hz, 1H), 8.31 (d, J = 7.2 Hz, 2H). 13C-NMR d
20.1, 40.7, 56.3, 65.1, 65.9, 71.5, 120.4, 123.2, 125.6,
127.1, 127.4, 127.8, 128.5, 128.6, 128.7, 128.8, 128.9,
129.0, 129.6, 129.8, 130.4, 131.5, 132.2, 133.3, 134.0,
135.0, 135.1, 135.6, 142.3, 171.3, 178.1, 178.4.
(SC,SN,SC)-12a: Mp 216–218 °C; [a]2D5 ?1550.8 (c 0.01,
CHCl3). 1H-NMR d 1.67 (d, J = 6.9 Hz, 3H), 2.42 (d,
J = 15.9 Hz, 1H), 2.63 (s, 3H), 3.08 (dd, J = 12.0, 5.1 Hz,
1H), 3.19 (dd, J = 14.2, 4.5 Hz, 1H), 3.49 (q, J = 6.9 Hz,
1H), 3.99 (d, J = 15.9 Hz, 1H), 4.25 (t, J = 6.0 Hz, 1H),
6.77–6.88 (m, 3H), 7.08–7.11 (m, 2H), 7.21–7.35 (m, 8H),
7.40–7.43 (m, 4H), 7.51–7.54 (m, 3H), 8.65 (d,
J = 8.7 Hz, 1H).
(SC,RN,RC)-13a: Mp 104–105 °C; [a]2D5 -1634.1
(c 0.01, CHCl3). 1H-NMR d 1.74 (s, 3H), 1.97 (d,
J = 6.9 Hz, 3H), 2.66 (dd, J = 13.2, 5.4 Hz, 1H), 2.91 (d,
J = 16.8 Hz, 1H), 2.99 (dd, J = 13.2, 3.0 Hz, 1H), 3.20
(d, J = 16.8 Hz, 1H), 3.43 (q, J = 6.9 Hz, 1H), 4.24 (t,
J = 2.1 Hz, 1H), 6.76 (d, J = 4.2 Hz, 2H), 7.06 (d,
J = 6.6 Hz, 1H), 7.22–7.31 (m, 6H), 7.42–7.63 (m, 10H),
8.14 (d, J = 8.4 Hz, 1H).
(SC,RN,RC)-13b: Mp 261–264 °C; [a]2D5 -1756.4
(c 0.01, CHCl3). 1H-NMR d 2.14 (d, J = 6.6 Hz, 3H),
2.71 (d, J = 16.2 Hz, 1H), 3.00–3.15 (m, 2H), 3.23
(d, J = 14.4 Hz, 1H), 3.58 (d, J = 16.2 Hz, 1H), 3.69
(d, J = 14.2 Hz, 1H), 6.67–6.72 (m, 2H), 7.00–7.24
(m, 5H), 7.26–7.75 (m, 17H). 13C-NMR d 20.1, 39.0,
60.1, 62.5, 64.6,71.1, 120.7, 124.8, 127.0, 127.2, 127.6,
128.2, 128.4, 128.6, 128.9, 129.0, 129.9, 130.9, 131.5,
131.8, 132.0, 133.0, 133.8, 136.5, 137.0, 142.3, 170.6,
175.7, 177.8.
(SC,SN,RC)-14b: Mp 245–247 °C; [a]2D5 -1880.8
(c 0.01, CHCl3). 1H-NMR d 1.54 (d, J = 6.9 Hz, 3H),
2.60–2.75 (m, 2H), 3.32 (d, J = 17.7 Hz, 1H), 3.58 (d,
J = 11.7 Hz, 1H), 3.83 (t, J = 7.2 Hz, 1H), 4.32–4.38 (m,
1H), 4.33 (d, J = 16.5 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H),
5.81 (d, J = 7.5 Hz, 1H), 6.39–6.56 (m, 4H), 6.98–7.72
(m, 8H), 7.28–7.64 (m, 8H), 8.13 (d, J = 7.8 Hz, 1H), 8.20
(d, J = 8.7 Hz, 1H), 8.55 (d, J = 6.9 Hz, 2H).
NH2
O
6
O
NH
O
Br
COBr
7
98%
8
Me
Ph
H
Me
Ph
R
Me
Ph
N
N
NH2
Hünig's
base/RI
O
NH
O
O
NH
O
(S)-5
>95%
quant.
9
10
a
b
R = Me ( ), Bn ( )
Scheme 1 Synthesis of ligands 10a,b
General procedure for disassembly of the Ni(II)
complexes, isolation of phenylalanines (S)-15, (R)-16
and recycling of chiral ligands 10a,b
To a solution of MeOH and 3 N HCl at 70 °C was added
complex 11a,b, 13a,b (14.5 mL MeOH/11 mL of 3 N HCl/
1 g of complex 11a,b, 13a,b). The solution was stirred for
30 min (disappearance of red color) and then evaporated
under vacuum. The residue was treated with 50 mL of DI
water and 15 mL CH2Cl2 and then organic and aqueous layers
were separated and evaporated under vacuum. Ligands 10a,b
were recovered with 95–98 % yields by the evaporation of the
organic layer. Following the evaporation of aqueous layer, the
crystalline residue was dissolved in the minimum amount of
DI water and placed on an ion-exchange column using Dowex
50 X 2-100 resin. The column was first washed with DI water
until neutral, followed by 8 % aqueous ammonium hydroxide
(200 mL) to elute acids 15, 16. This solution was evaporated
to afford target (S)- and (R)-phenylalanines in 93–95 % yield.
The Ni(II) was eluted with concentrated HCl after the column
was returned to neutral pH with DI water.
Results and discussion
To develop the most inexpensive chemical method for
preparation of enantiomerically pure amino acids, we deci-
ded to use ultimately inexpensive chiral auxiliary,
1-(phenyl)ethylamine 5 (Juaristi et al. 1998, 1999)
(Scheme 1), readily available in both enantiomeric forms. In
contrast to the design of ligand 4, bearing 2-amino-2-meth-
ylpropanoic acid, we chose the simplest case of glycine
moiety, expecting high yield and uncomplicated synthesis of
the target ligand.
First, o-aminobenzophenone 6 (Scheme 1) was acylated
with 2-bromoacetyl bromide 7 (Soloshonok et al. 2007) to
give product 8 in 98 % yield. Without additional
123

H. Moriwaki et al.
Scheme 2 Synthesis of
diastereomeric complexes
11a,b–14a,b
rac -Phe (2 equiv)
NiCl2 (2 equiv)
K2CO3 (6 equiv)
reflux in MeOH
Me
Me
R
R
N
N
O
O
N
N
O
N
O
Ni
+
Ni
+
10a b
,
Ph
Ph
O
N
O
12a b
11a,b (SC,RN,SC)
,
(SC,SN,SC)
Me
R
Me
R
N
N
O
O
O
N
O
+
Ni
+
Ni
Ph
Ph
O
N
N
O
N
13a,b (SC,RN,RC)
14a,b (SC,SN,RC)
purification, compound 8 was reacted with (S)-amine 5
using previously reported procedure with application of
Hu¨nig’s base (Moore et al. 2005), giving rise to product 9
in quantitative yield. Under the same conditions, NH
functionality in 9 was alkylated to afford ligands 10a,b in
excellent yields.
Again, without additional purification, ligands
10a,b were heated in MeOH at 50 °C, in the presence of
racemic Phe, NiCl2 and K2CO3. The formation of the
corresponding Ni(II) complexes took place at relatively
high rate and upon completion, the reaction mixtures were
poured into icy water containing 5 % acetic acid. Analysis
of the stereochemical outcome of the reactions (NMR,
TLC) revealed that in the case of ligand 10a, three dia-
stereomeric complexes had been formed in a ratio of 9/61/
30. The reaction of ligand 10b was more stereoselective as
only two major complexes were isolated in a ratio of *63/
37 with only trace amounts of the third diastereomer.
Scheme 2 shows all four possible diastereomeric com-
plexes 11–14 expected in the reactions under study. Ste-
reochemical assignments of the products obtained have
Fig. 3 Crystallographic structure of (SC,RN,SC)-11b
about 1.5 ppm observed in the case of ligands 10a,b. The
case of down-fielded chemical shifts of methyl groups
located above or under Ni atoms is well documented in
chemistry of the compounds of this kind (Belokon et al.
1985b, 1986, 1988), and therefore can serve as a reference
for the (R) absolute configuration of the stereogenic
nitrogen in this study. Furthermore, compound (SC,RN,SC)-
11b has optical rotation ?1,417.4 ([a]2D5) which is the result
of non-planar, twisted structure of the chelate rings around
Ni atom. In particular, the phenylalanine-containing five-
membered ring and the adjacent six-membered ring are
down and up, respectively, relatively to the Ni coordination
plane. This twisted arrangement of the chelate rings in
(SC,RN,SC)-11b gives rise to the axial chirality of
(S) absolute configuration, which is responsible for positive
optical rotation and its remarkable magnitude. By contrast,
if the phenylalanine moiety is of (R) configuration, the
twist of the chelate rings will result in (R) configured axial
chirality and the corresponding Ni(II) complex will have
1
been made based on their crystallographic, H-NMR data
and chiroptical properties.
Thus, the major product obtained in the reaction of N-
benzyl ligand 10b was subjected to single crystal X-ray
analysis which revealed its (SC,RN,SC) absolute configura-
tion (compound 11b) (Figs. 3, 4). As one can see in Fig. 4,
the methyl group of the (phenyl)ethylamine moiety is
located in close proximity to the Ni atom, which can
explain (Soloshonok et al. 1999c) its unusual down-fielded
(2.22 ppm) chemical shift in its 1H-NMR spectrum, as
compared to uninfluenced, ‘‘normal’’ chemical shift of
123

Preparation of enantiomerically pure phenylalanine
COOH
Ph
Ph
11a,b (SC,RN,SC)
13a,b (SC,RN,RC)
+
+
(S )-10a,b
(S )-10a,b
NH2
(S )-15
3N HCl
MeOH
reflux
COOH
NH2
16
(R)-
Scheme 3 Disassembly of Ni(II) complexes and isolation of target
(S)- and (R)-phenylalanines
Regardless the incomplete diastereoselectivity in the pro-
ducts formation and chromatographic purification, the cost of
thus prepared (S)- and (R)-phenylalanines, including silica
gel, all reagents and solvents, is very attractive and well below
of any other chemical approach reported thus far in the liter-
Fig. 4 Crystallographic structure of (SC,RN,SC)-11b showing the
exposure of a-(phenyl)ethylamine’s methyl to the Ni(II) atom
Table 1 1H-NMR and chiroptical data for diastereomeric complexes
11a,b–14a,b
´
ature (Yue et al. 2007; Khamduang et al. 2009; Cardenas-
´
Fernandez et al. 2012; Yasukawa and Asano 2012). These
Compound
Yield (%)
[a]2D5
d (Me)
preliminaryresultsclearlysuggest thattheapproachdescribed
here has certain practical potential, which is currently being
explored using various derivatives of 1-(phenyl)ethylamine
and other chiral amines to improve the stereochemical out-
come of the Ni(II) complexes formation and overall effi-
ciency, generality and scalability of the method.
R=Me
R=Bn
(Sc,RN,Sc)-11a
(Sc,SN,Sc)-12a
(Sc,RN,Rc) 13a
(Sc,SN,Rc)-14a
(Sc,RN,Sc)-11b
(Sc,SN,Sc)-12b
(Sc,RN,Rc)-13b
(Sc,SN,Rc)-14b
61
9
?1711.6
?1550.8
-1634.1
2.22
1.64
1.99
30
0
63
0
?1417.4
2.22
37
Trace
-1756.4
-1880.8
2.19
1.55
Conclusions
In conclusion, this work has demonstrated that simple
structural design of new generation modular ligands bear-
ing 1-(phenyl)ethylamine moiety as a source of stereo-
chemical information, can be effectively used for quite
inexpensive preparation of enantiomerically pure (S)- and
(R)-phenylalanines. While the present results have some
shortcomings, such as incomplete stereoselectivity and
chromatographic separation, they provide an inspirational
prospect for the development of improved and truly prac-
tical methodology.
negative optical rotation of a similar magnitude (Wang
et al. 2011). Consequently, the sign of optical rotation can
be reliably used as a reference to assign the a-absolute
configuration of the amino acid residue.
Chemical shifts of the (phenyl)ethylamine methyl group
and optical rotations of the products obtained are collected in
Table 1. Based on these data, we can assign the absolute
configurations of all compounds obtained. Thus, in the reac-
tion of ligand 10a the products are (61 %) 11a (SC,RN,SC),
(9 %) 12a (SC,SN,SC) and (30 %) 13a (SC,RN,RC). In the
reaction of ligand 10b, the products are (63 %) 11b
(SC,RN,SC), (37 %) 13b (SC,RN,RC) and trace amount of 14b
(SC,SN,RC). Obviously, for the purpose of preparation of
enantiomerically pure (S)-phenylalanine, the complexes
(SC,RN,SC)-11a and (SC,SN,SC)-12a can be combined, as they
contain amino acid of the same (S) configuration.
Acknowledgments We thank IKERBASQUE, Basque Foundation
for Science; Basque Government (SAIOTEK S-PE12UN044), Span-
ish Ministry of Science and Innovation (CTQ2010-19974) and Ha-
mari Chemicals (Osaka, Japan) for generous financial support.
Conflict of interest The authors declare that they have no conflict
of interest.
Diastereomerically pure complexes (SC,RN,SC)-11a,
(SC,RN,RC)-13a, (SC,RN,SC)-11b and (SC,RN,RC)-13b were
obtained by column chromatography. Each of these pro-
ducts was disassembled using standard conditions shown in
Scheme 3. Chiral ligands 10a,b were easily recycled
(*95 %) and the target (S)- and (R)-phenylalanines were
isolated using ion-exchange column in 85–90 % yields.
References
Acen˜a JL, Sorochinsky AE, Soloshonok VA (2012) Recent advances
in asymmetric synthesis of a-(trifluoromethyl)-containing a-
amino acids. Synthesis 44:1591–1602
Acen˜a JL, Sorochinsky AE, Moriwaki H, Sato T, Soloshonok VA
(2013) Synthesis of fluorine-containing a-amino acids in
123

H. Moriwaki et al.
enantiomerically pure form via homologation of Ni(II) com-
plexes of glycine and alanine Schiff bases. J Fluor Chem
155:21–38
and defined chiral quaternary ammonium salt under phase
transfer conditions. J Am Chem Soc 119:12414–12415
Duthaler RO (1994) Recent developments in the stereoselective
synthesis of a-amino acids. Tetrahedron 50:1539–1560
Ellis TK, Martin CH, Tsai GM, Ueki H, Soloshonok VA (2003a)
Efficient synthesis of sterically constrained symmetrically a, a-
disubstituted a-amino acids under operationally convenient
conditions. J Org Chem 68:6208–6214
Ellis TK, Martin CH, Ueki H, Soloshonok VA (2003b) Efficient,
practical synthesis of symmetrically a, a-disubstituted a-amino
acids. Tetrahedron Lett 44:1063–1066
Ellis TK, Ueki H, Yamada T, Ohfune Y, Soloshonok VA (2006)
Design, synthesis, and evaluation of a new generation of modular
nucleophilic glycine equivalents for the efficient synthesis of
sterically constrained a-amino acids. J Org Chem 71:8572–8578
Fitzi R, Seebach D (1988) Resolution and use in a-amino acid
synthesis of imidazolidinone glycine derivatives. Tetrahedron
44:5277–5292
Belokon YN, Zel’tzer E, Bakhmutov VI, Saporovskaya MB, Ryzhov
MG, Yanovsky AI, Struchkov YT, Belikov VM (1983) Asym-
metric synthesis of threonine and partial resolution and retro-
racemization of a-amino acids via copper(II) complexes of their
Schiff bases with (S)-2-N-(N’-benzylprolyl)aminobenzaldehyde
and (S)-2-N-(N’-benzylprolyl)aminoacetophenone. Crystal and
molecular structure of a copper(II) complex of glycine Schiff
base with (S)-2-N-(N’benzylprolyl)aminoacetophenone. J Am
Chem Soc 105:2010–2017
Belokon YN, Bulychev AG, Vitt SV, Struchkov YT, Batsanov AS,
Timofeeva TV, Tsyryapkin VA, Ryzhov MC, Lysova LA,
Bakhmutov VI, Belikov VM (1985a) General method of
diastereo- and enantioselective synthesis of b-hydroxy-a-amino
acids by condensation of aldehydes and ketones with glycine.
J Am Chem Soc 107:4252–4259
Belokon YN, Maleyev VI, Vitt SV, Ryzhov MG, Kondrashov YD,
Golubev SN, Vauchskii YP, Kazika AI, Novikova MI, Krasutskii
PA, Yurchenko AG, Dubchak IL, Shklover VE, Struchkov YT,
Bakhmutov VI, Belikov VM (1985b) Enantioselectivity of
nickel(II) and copper(II) complexes of Schiff bases derived
from amino acids and (S)-o-[(N-benzylprolyl)amino]-acetophe-
none or (S)-o-[(N-benzylprolyl)amino]benzaldehyde. Crystal and
molecular structures of [Ni{(S)-bap-(S)-Val}] and [Cu{(S)-bap-
(S)-Val}]. J Chem Soc Dalton Trans 17–26
Belokon YN, Bulychev AG, Ryzhov MG, Vitt SV, Batsanov AS,
Struchkov YT, Bakhmutov VI, Belikov VM (1986) Synthesis of
enantio- and diastereo-isomerically pure b- and c-substituted
glutamic acids via glycine condensation with activated olefins.
J Chem Soc Perkin Trans 1 1865–1872
Belokon YN, Bulychev AG, Pavlov VA, Fedorova EB, Tsyryapkin
VA, Bakhmutov VI, Belikov VM (1988) Synthesis of enantio-
and diastereoiso-merically pure substituted prolines via conden-
sation of glycine with olefins activated by a carbonyl group.
J Chem Soc Perkin Trans 1 2075–2083
Belokon YN, Tararov VI, Maleev VI, Savel’eva TF, Ryzhov MG
(1998) Improved procedures for the synthesis of (S)-2-[N-(N0-
benzylprolyl)amino]-benzophenone (BPB) and Ni(II) complexes
of Schiff’s bases derived from BPB and amino acids. Tetrahe-
dron Asymmetry 9:4249–4252
Fogassy E, Nogradi M, Palovics E, Schindler J (2005) Resolution of
enantiomers by non-conventional methods. Synthesis 1555–1568
Gallos JK, Sarli VC, Massen ZS, Varvogli AC, Papadoyanni CZ,
Papasyrou SD, Argyropoulos NG (2005) A new strategy for the
stereoselective synthesis of unnatural a-amino acids. Tetrahe-
dron 61:565–574
´
Juaristi E, Escalante J, Leon-Romo JL, Reyes A (1998) Recent
applications of a-phenylethylamine (a-PEA) in the preparation
of enantiopure compounds. Part 1: incorporation in chiral
catalysts. Part 2: a-PEA and derivatives as resolving agents.
Tetrahedron Asymmetry 9:715–740
´
Juaristi E, Leon-Romo JL, Reyes A, Escalante J (1999) Recent
applications of a-phenylethylamine (a-PEA) in the preparation
of enantiopure compounds. Part 3: a-PEA as chiral auxiliary.
Part 4: a-PEA as chiral reagent in the stereodifferentiation of
prochiral substrates. Tetrahedron Asymmetry 10:2441–2495
Khamduang M, Packdibamrung K, Chutmanop J, Chisti Y,
Srinophakun P (2009) Production of L-phenylalanine from
glycerol by a recombinant Escherichia coli. J Ind Microbiol
Biotechnol 36:1267–1274
Kukhar VP, Sorochinsky AE, Soloshonok VA (2009) Practical
synthesis of fluorine-containing a- and b-amino acids: recipes
from Kiev, Ukraine. Future Med Chem 1:793–819
Lygo B, Wainwright PG (1997) A new class of asymmetric phase-
transfer catalysts derived from chincona alkaloids: application in
the enantioselective synthesis of a-amino acids. Tetrahedron Lett
38:8595–8598
Ma J-A (2003) Recent developments in the catalytic asymmetric
synthesis of a- and b-amino acids. Angew Chem Int Ed
42:4290–4299
Maruoka K, Ooi T (2003) Enantioselective amino acid synthesis by
chiral phase-transfer catalysis. Chem Rev 103:3013–3028
Moore JL, Taylor SM, Soloshonok VA (2005) An efficient and
operationally convenient general synthesis of tertiary amines by
direct alkylation of secondary amines with alkyl halides in the
presence of Hunig’s base. ARKIVOC 287–292
Belokon YN, Kochetkov KA, Churkina TD, Ikonnikov NS, Larionov
ˇ
ˇ
OV, Harutyunyan S, North M, Vyskosil S, Kagan HB (2001)
Highly efficient catalytic synthesis of a-amino acids under
phase-transfer conditions with a novel catalyst/substrate pair.
Angew Chem Int Ed 40:1948–1951
Belokon YN, Bespalova NB, Churkina TD, Cisarova I, Ezernitskaya
MG, Harutyunyan SR, Hrdina R, Kagan HB, Kocovsky P,
Kochetkov KA, Larionov OV, Lyssenko KA, North M, Polasek
M, Peregudov AS, Prisyazhnyuk VV, Vyskocil S (2003)
Synthesis of a-amino acids via asymmetric phase transfer-
catalyzed alkylation of achiral nickel(II) complexes of glycine-
derived Schiff bases. J Am Chem Soc 125:12860–12871
Breuer M, Ditrich K, Habicher T, Hauer B, Kebeler M, Stu¨rmer R,
Zelinski T (2004) Industrial methods for the production of
optically active intermediates. Angew Chem Int Ed 43:788–824
´
Najera C, Sansano JM (2007) Catalytic asymmetric synthesis of a-
amino acids. Chem Rev 107:4584–4671
O’Donnell MJ, Eckrich TM (1978) The synthesis of amino acid
derivatives by catalytic phase-transfer alkylations. Tetrahedron
Lett 19:4625–4628
Ooi T, Kameda M, Maruoka K (1999) Molecular design of a C2-
symmetric chiral phase-transfer catalyst for practical asymmetric
synthesis of a-amino acids. J Am Chem Soc 121:6519–6520
Park H-G, Jeong B-S, Yoo M-S, Lee J-H, Park M-K, Lee Y-J, Kim
M-J, Jew S-S (2002) Highly enantioselective and practical
chincona-derived phase-transfer catalysts for the synthesis of a-
amino acids. Angew Chem Int Ed 41:3036–3038
´
´
´
´
´
´
Cardenas-Fernandez M, Lopez C, Alvaro G, Lopez-Santın J (2012) L-
Phenylalanine synthesis catalyzed by immobilized aspartate
aminotransferase. Biochem Eng J 63:15–21
´
´
Chinchilla R, Mazon P, Najera C (2000) Asymmetric synthesis of a-
amino acids using polymer-supported Cinchona alkaloid-derived
ammonium salts as chiral phase-transfer catalysts. Tetrahedron
Asymmetry 11:3277–3281
Corey EJ, Xu F, Noe MC (1997) A rational approach to catalytic
enantioselective enolate alkylation using a structurally rigidified
123

Preparation of enantiomerically pure phenylalanine
Park H, Kim KM, Lee A, Ham S, Nam W, Chin J (2007) Bioinspired
chemical inversion of L-amino acids to D-amino acids. J Am
Chem Soc 129:1518–1519
Qiu W, Soloshonok VA, Cai C, Tang X, Hruby VJ (2000)
Convenient, large-scale asymmetric synthesis of enantiomeri-
cally pure trans-cinnamylglycine and -a-alanine. Tetrahedron
56:2577–2582
¨
Schollkopf U, Groth U, Deng C (1981) Enantioselective syntheses of
(R)-amino acids using L-valine as chiral agent. Angew Chem Int
Ed Engl 20:798–799
Shibuguchi T, Fukuta Y, Akachi Y, Sekine A, Ohshima T, Shibasaki
M (2002) Development of new asymmetric two-center catalysts
in phase-transfer reactions. Tetrahedron Lett 43:9539–9543
Soloshonok VA, Cai C, Hruby VJ, Van Meervelt L, Mischenko N
(1999a) Stereochemically defined C-substituted glutamic acids
and their derivatives. 1. An efficient asymmetric synthesis of
(2S,3S)-3-methyl- and -3-trifluoromethylpyroglutamic acids.
Tetrahedron 55:12031–12044
Soloshonok VA, Cai C, Hruby VJ (1999b) Asymmetric Michael
addition reactions of chiral Ni(II)-complex of glycine with (N-
trans-enoyl)oxazolidines: improved reactivity and stereochemi-
cal outcome. Tetrahedron Asymmetry 10:4265–4269
Soloshonok VA, Cai C, Hruby VJ, Van Meervelt L (1999c) Asymmetric
synthesis of novel highly sterically constrained (2S,3S)-3-methyl-3-
trifluoromethyl- and (2S,3S,4R)-3-trifluoromethyl-4-methylpyro-
glutamic acids. Tetrahedron 55:12045–12058
´
Solladie-Cavallo A, Sedy O, Salisova M, Schmitt M (2002) Stereo-
differentiation in chiral 1,4-oxazin-2-one derived from
Soloshonok VA, Cai C, Hruby VJ (2000a) Toward design of a
practical methodology for stereocontrolled synthesis of v-
constrained pyroglutamic acids and related compounds. Virtu-
ally complete control of simple diastereoselectivity in the
Michael addition reactions of glycine Ni(II) complexes with
N-(enoyl)oxazolidinones. Tetrahedron Lett 41:135–139
Soloshonok VA, Cai C, Hruby VJ (2000b) A unique case of face
diastereoselectivity in the Michael addition reactions between
Ni(II)-complexes of glycine and chiral 3-(E-enoyl)-1,3-oxazoli-
din-2-ones. Tetrahedron Lett 41:9645–9649
Soloshonok VA, Tang X, Hruby VJ (2001) Large-scale asymmetric
synthesis of novel sterically constrained 20,60-dimethyl- and
a,20,60-trimethyltyrosine and -phenylalanine derivatives via
alkylation of chiral equivalents of nucleophilic glycine and
alanine. Tetrahedron 57:6375–6382
a
2-hydroxy-2-methyl-1-tetralone: a reagent for deracemization
of amino acids. Eur J Org Chem 3042–3049
Soloshonok VA (2002) Highly diastereoselective Michael addition
reactions between nucleophilic glycine equivalents and b-
substituted-a, b-unsaturated carboxylic acid derivatives; a gen-
eral approach to the stereochemically defined and sterically v
constrained a-amino acids. Curr Org Chem 6:341–364
Soloshonok VA, Izawa K (eds) (2009) Asymmetric Synthesis and
Application of a-Amino Acids. ACS Symposium Series, vol.
1009. American Chemical Society, Washington DC
Soloshonok VA, Sorochinsky AE (2010) Practical methods for the
synthesis of symmetrically a,a-disubstituted a-amino acids.
Synthesis 2319–2344
Soloshonok VA, Ueki
H
(2010) Towards modular design of
Soloshonok VA, Ueki H, Tiwari R, Cai C, Hruby VJ (2004) Virtually
complete control of simple and face diastereoselectivity in the
Michael addition reactions between achiral equivalents of a
nucleophilic glycine and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-
oxazolidin-2-ones: practical method for preparation of b-substi-
chiroptically switchable molecules based on formation and
cleavage of metal–ligand coordination bonds. Synthesis 49–56
Soloshonok VA, Kukhar VP, Galushko SV, Svistunova NY, Avilov
DV, Kuzmina NA, Raevski NI, Struchkov YT, Pisarevsky AP,
Belokon YN (1993) General method for the synthesis of
enantiomerically pure b-hydroxy-a-amino acids, containing
fluorine atoms in the side chains. Case of stereochemical
distinction between methyl and trifluoromethyl groups. X-ray
crystal and molecular structure of the nickel(II) complex of
(2S,3S)-2-(trifluoromethyl)threonine. J Chem Soc Perkin Trans
1 3143–3155
tuted pyroglutamic acids and prolines.
69:4984–4990
J
Org Chem
Soloshonok VA, Cai C, Yamada T, Ueki H, Ohfune Y, Hruby VJ
(2005a) Michael addition reactions between chiral equivalents of
a nucleophilic glycine and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-
oxazolidin-2-ones as a general method for efficient preparation
of b-substituted pyroglutamic acids. Case of topographically
controlled stereoselectivity. J Am Chem Soc 127:15296–15303
Soloshonok VA, Ueki H, Ellis TK (2005b) New generation of
nucleophilic glycine equivalents. Tetrahedron Lett 46:941–944
Soloshonok VA, Ueki H, Ellis TK, Yamada T, Ohfune Y (2005c)
Application of modular nucleophilic glycine equivalents for
truly practical asymmetric synthesis of b-substituted pyroglu-
tamic acids. Tetrahedron Lett 46:1107–1110
Soloshonok VA, Ohkura H, Yasumoto M (2006) Operationally
convenient asymmetric synthesis of (S)- and (R)-3-amino-4,4,4-
trifluorobutanoic acid. Part I: enantioselective biomimetic trans-
amination of isopropyl 4,4,4-trifluoro-3-oxobutanoate. J Fluor
Chem 127:924–929
Soloshonok VA, Hayashi T, Ishikawa K, Nagashima N (1994) Highly
diastereoselective aldol reaction of fluoroalkyl aryl ketones with
methyl isocyanoacetate catalyzed by silver(I)/triethylamine.
Tetrahedron Lett 35:1055–1058
Soloshonok VA, Avilov DV, Kukhar VP, Tararov VI, Saveleva TF,
Churkina TD, Ikonnikov NS, Kochetkov KA, Orlova SA,
Pysarevsky AP, Struchkov YT, Raevsky NI, Belokon YN (1995)
Asymmetric aldol reactions of chiral Ni(II)-complex of glycine
with aldehydes. Stereodivergent synthesis of syn-(2S)- and syn-
(2R)-b-alkylserines. Tetrahedron Asymmetry 6:1741–1756
Soloshonok VA, Avilov DV, Kukhar VP (1996) Asymmetric aldol
reactions of trifluoromethyl ketones with a chiral Ni(II) complex
of glycine: stereocontrolling effect of the trifluoromethyl group.
Tetrahedron 52:12433–12442
Soloshonok VA, Kacharov AD, Avilov DV, Ishikawa K, Nagashima
N, Hayashi T (1997a) Transition metal/base-catalyzed aldol
reactions of isocyanoacetic acid derivatives with prochiral
ketones, a straightforward approach to stereochemically defined
b, b-disubstituted-b-hydroxy-a-amino Acids. Scope and limita-
tions. J Org Chem 62:3470–3479
Soloshonok VA, Ueki H, Moore JL, Ellis TK (2007) Design and
synthesis of molecules with switchable chirality via formation
and cleavage of metal-ligand coordination bonds. J Am Chem
Soc 129:3512–3513
Soloshonok VA, Ellis TK, Ueki H, Ono T (2009a) Resolution/
deracemization of chiral a-amino acids using resolving reagents
with flexible stereogenic centers.
131:7208–7209
J
Am Chem Soc
Soloshonok VA, Avilov DV, Kukhar VP, Van Meervelt L, Mischenko
N (1997b) Highly diastereoselective aza-aldol reactions of a
chiral Ni(II) complex of glycine with imines. An efficient
asymmetric approach to 3-perfluoroalkyl-2,3-diamino acids.
Tetrahedron Lett 38:4671–4674
Soloshonok VA, Ueki H, Ellis TK (2009b) New generation of
modular nucleophilic glycine equivalents for the general
synthesis of a-amino acids. Synlett 704–715
Sorochinsky AE, Soloshonok VA (2010) Asymmetric synthesis of
fluorine-containing amines, amino alcohols, a- and b-amino
123

H. Moriwaki et al.
acids mediated by chiral sulfinyl group.
131:127–139
J
Fluor Chem
Wang J, Shi T, Deng G, Jiang H, Liu H (2008) Highly enantio- and
diastereoselective Mannich reactions of chiral Ni(II) glycinates
with amino sulfones. Efficient asymmetric synthesis of aromatic
a, b-diamino acids. J Org Chem 73:5870–8563
Wang J, Lin D, Zhou S, Ding X, Soloshonok VA, Liu H (2011)
Asymmetric synthesis of sterically and electronically demanding
linear x-trifluoromethyl containing amino acids via alkylation of
chiral equivalents of nucleophilic glycine and alanine. J Org
Chem 76:684–687
Sorochinsky AE, Ueki H, Acen˜a JL, Ellis TK, Moriwaki H, Sato T,
Soloshonok VA (2013a) Chemical approach for interconversion
of (S)- and (R)-a-amino acids. Org Biomol Chem 11:4503–4507
Sorochinsky AE, Ueki H, Acen˜a JL, Ellis TK, Moriwaki H, Sato T,
Soloshonok VA (2013b) Chemical deracemization and (S) to
(R) interconversion of some fluorine-containing a-amino acids.
J Fluor Chem 152:114–118
Tang X, Soloshonok VA, Hruby VJ (2000) Convenient, asymmetric
synthesis of enantiomerically pure 20,60-dimethyltyrosine (DMT)
via alkylation of chiral equivalent of nucleophilic glycine.
Tetrahedron Asymmetry 11:2917–2925
Ueki H, Ellis TK, Martin CH, Boettiger TU, Bolene SB, Soloshonok
VA (2003a) Improved synthesis of proline-derived Ni(II)
complexes of glycine: versatile chiral equivalents of nucleophilic
glycine for general asymmetric synthesis of a-amino acids. J Org
Chem 68:7104–7107
Williams RM, Sinclair PJ, Zhai W (1988) Asymmetric synthesis of b-
carboxyaspartic acid. J Am Chem Soc 110:482–483
Yamada T, Okada T, Sakaguchi K, Ohfune Y, Ueki H, Soloshonok
VA (2006) Efficient asymmetric synthesis of novel 4-substituted
and configurationally stable analogues of thalidomide. Org Lett
8:5625–5628
Yamada T, Sakaguchi K, Shinada T, Ohfune Y, Soloshonok VA (2008)
Efficient asymmetric synthesis of the functionalized pyrogluta-
mate core unit common to oxazolomycin and neooxazolomycin
using Michael reaction of nucleophilic glycine Schiff base with a,
b-disubstituted acrylate. Tetrahedron Asymmetry 19:2789–2795
Ueki H, Ellis TK, Martin CH, Soloshonok VA (2003b) Efficient
large-scale synthesis of picolinic acid-derived nickel(II) com-
plexes of glycine. Eur J Org Chem 1954–1957
Yasukawa K, Asano
Y (2012) Enzymatic synthesis of chiral
Wang L, Brock A, Herberich B, Schultz PG (2001) Expanding the
genetic code of Escherichia coli. Science 292:498–500
Wang M-X, Lin S-J, Liu J, Zheng Q-Y (2004) Efficient biocatalytic
synthesis of highly enantiopure a-alkylated arylglycines and
amides. Adv Synth Catal 346:439–445
phenylalanine derivatives by a dynamic kinetic resolution of
corresponding amide and nitrile substrates with a multi-enzyme
system. Adv Synth Catal 354:3327–3332
Yue H, Yuan Q, Wang W (2007) Enhancement of L-phenylalanine
production by b-cyclodextrin. J Food Eng 79:878–884
123