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Cite this: Org. Biomol. Chem., 2013, 11,
4503
Received 18th March 2013,
Accepted 12th May 2013
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Chemical approach for interconversion of (S)- and
(R)-α-amino acids
Alexander E. Sorochinsky,a,b,c Hisanori Ueki,d José Luis Aceña,a Trevor K. Ellis,e
Hiroki Moriwaki,f Tatsunori Satof and Vadim A. Soloshonok*a,b
Here we report a general method for the preparation of unnatural (R)-α-amino acids via complexation of
α-( phenyl)ethylamine derived chiral reagent (S)-3 with various (S)-α-amino acids. The reactions proceed
DOI: 10.1039/c3ob40541a
with synthetically useful chemical yields and thermodynamically controlled diastereoselectivity. Chiral
reagent (S)-3 can be conveniently recovered and reused without any loss of enantiomeric purity and
www.rsc.org/obc
reactivity.
Introduction
D-α-Amino
acids are rare in nature as compared with the
corresponding L-enantiomers. Being “foreign” to the chemistry
of life, naturally occurring D-α-amino acids have an important
role in defense mechanisms (cell wall, venoms) of many microorganisms and plants. D-Amino acids have also been detected
in a variety of peptides synthesized by animal cells, and several
enzymes producing or metabolizing D-amino acids have been
discovered.1 In recent decades, D-α-amino acids have been
increasingly important in the development of new fields of
biochemistry, in particular, enzymology, drug discovery and
immune responses. However, the key driving factor for growth
in the D-amino acids market is their applications in the
pharmaceutical industry for the manufacture of pharmaceutical drugs and intermediates.2 Currently, commercially
available D-α-amino acids are produced by biocatalytic
methods, which are economically attractive, but have certain
substrate limitations and rather low chemical efficiency.3 On
the other hand, synthetic approaches, such as asymmetric synthesis and resolving reagents, can enjoy a potentially greater
structural generality and overall efficiency, providing a cost
structure comparable to biocatalytic methods.
a
Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque
Country UPV/EHU, 20018 San Sebastián, Spain. E-mail: vadym.soloshonok@ehu.es;
Fax: +34 943-015270; Tel: +34 943-015177
b
IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
c
Institute of Bioorganic Chemistry & Petrochemistry, National Academy of Sciences of
Ukraine, Murmanska 1, Kyiv 02660, Ukraine
d
International Center for Materials Nanoarchitectonics (MANA), National Institute
for Materials Science (NIMS), 1-1, Namiki, Tsukuba, Ibaraki 305-0044, Japan
e
Department of Chemistry and Physics, 100 Campus Dr., Weatherford,
OK 73096-3098, USA
f
Hamari Chemicals Ltd, 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024,
Japan
This journal is © The Royal Society of Chemistry 2013
Fig. 1
Chiral reagents 1–3 for the resolution/deracemization of α-amino acids.
Taking into account that many L-amino acids are available
from inexpensive and renewable natural sources, the development of chemical methods for the conversion of L-α-amino
acids to the corresponding D-enantiomers seems to be of great
synthetic potential. Recently, the Solladié-Cavallo4 group as
well as the groups of Kim and Chin5 reported compounds 1
and 2 (Fig. 1), respectively, as useful new reagents for resolution/deracemization or interconversion of (R) and (S)-α-amino
acids. In the case of compound (R)-1, the chiral amino acid
forms a cyclic imino-ester allowing for reasonably good α-(R)
stereocontrol (dr ∼ 90/10) by the quaternary stereogenic center.
By contrast, reagent 2 does not form cyclic intermediates.
Org. Biomol. Chem., 2013, 11, 4503–4507 | 4503
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Organic & Biomolecular Chemistry
However, the intricate network of hydrogen bonding, involving
the urea moiety and the hydroxyl group, provides for a high
level (dr ∼ 95/5) of asymmetric induction in controlling the
stereochemistry of the amino acid residue. The advantages of
the design of reagents 1 and 2 are that they are recyclable, nonracemizable, available in both enantiomeric forms and react
with unprotected amino acids under mild conditions. As for
disadvantages, one can mention their high cost and incomplete diastereoselectivity.
Recently, our group has designed reagent 3 and demonstrated its application to the deracemization of α-amino acids.6
While deracemization and interconversion of (R)- and (S)α-amino acids involve similar reaction chemistry (enolization
followed by diastereoselective protonation), one might agree
that this type of new application of reagent 3 should be separately studied and supported by experimental data. Here we
report our results on the interconversion of (R)- and (S)α-amino acids using both enantiomeric forms of reagent 3. We
also disclose additional modifications of the reaction conditions allowing for an improvement of the reactivity and performance of reagent 3.
Results and discussion
Our long-standing interest in the chemistry of achiral7,8 and
chiral9,10 Ni(II)-complexes of amino acid Schiff bases and their
application to the general and scalable11 asymmetric synthesis
of α-amino acids led us to the discovery of a modular design12
of nucleophilic glycine and higher amino acid equivalents of
general formula 413 (Fig. 2). A major advantage of this
modular design is that the careful choice of four basic structural blocks ( phenone, acid, amine and amino acid) provides
virtually unlimited structural flexibility, and rational control of
the physicochemical properties and reactivity of derivatives 4.
Furthermore, Ni(II)-complexes 4 can be assembled and disassembled under operationally convenient conditions and are
quite inexpensive. In particular, for the design of reagent 3
Scheme 1
Fig. 2
Modular design of a new generation of Ni(II)-complexes of amino acids.
(Fig. 1) we use α-( phenyl)ethylamine, the most inexpensive
and readily available, in both enantiomeric forms, chiral
auxiliary.14
According to a previous study,6 upon complexation with
α-amino acids, (R)-configured reagent 3 gives preference to
α-(S) absolute configuration of the corresponding amino acid
residues. Therefore, for the interconversion of natural (S)amino acid to (R)-enantiomers, we used reagent 3 with the
opposite (S) configuration (Scheme 1). Furthermore, one of the
issues to be improved was the slow reaction rates of reagent 3
with amino acids, requiring several days for complete consumption of 3. We found that the application of absolute
EtOH, K2CO3 and Ni(OAc)2·4H2O instead of KOH and Ni(NO3)2·6H2O, respectively, allowed for a noticeable increase of
the reaction rates.
Thus, the reactions of reagent (S)-3 with unbranched
amino acids (S)-5a–d were completed within 24 h (Table 1,
entries 1–4) affording the products 6a–d with >84% yields.
By analogy with the previous results,6 the thermodynamically
controlled absolute configuration of the stereogenic centers
in compounds 6a–d were assigned to be (S)(SN)(R). Further
confirmation of the α-(R) configuration of the amino acids in
complexes 6a–d came from the chiroptical properties of free
amino acids 7a–d which matched the literature data reported
for α-(R) amino acids 7a–d. The reaction of (S)-phenylalanine
5e with reagent (S)-3 gave very similar results (entry 5) to
Reactions of reagent (S)-3 with (S)-amino acids to yield (R)-amino acids.
4504 | Org. Biomol. Chem., 2013, 11, 4503–4507
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Table 1
Paper
Reactions of reagent (S)-3 with amino acids (S)-5a–j
6a–j
7a–j
a
Entry
R
Base
Yield
(%)
de
(%)
Yield
(%)
eeb
(%)
1
2
3
4
5
6
7
8
9
10
Me (a)
Et (b)
n-Pr (c)
n-Bu (d)
Bn (e)
i-Pr (f)
i-Bu (g)
(CH2)2SMe (h)
(CH2)2OH (i)
(CH2)2CONH2 ( j)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DBU
DBU
87
93
88
84
83
47
53
95
93
59
>95
>95
>95
>95
>95
∼40
∼70
>95
>95
>95
71
68
65
72
71
N/A
N/A
88
84
N/A
97
97
98
98
99
N/A
N/A
98
99
N/A
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a
standard reaction conditions.17 In particular, in the case of
unbranched amino acids this approach has an obvious synthetic advantage over the literature methods in terms of the
practicality, cost structure and stereochemical outcome. On
the other hand, the presented method has some limitations
and cannot be applied to highly sterically constrained amino
acids as well as to derivatives bearing functional groups incompatible with the basic reaction conditions, capable of coordination to Ni(II).
Experimental
Determined by 1H NMR analysis of the crude reaction mixtures.
b
Determined by HPLC analysis, see ref. 16 for the conditions.
General procedure for the preparation of Ni(II)-complexes 6a–j
by the reaction of (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1phenyl-ethylamino)acetamide (S)-3 with the corresponding
amino acids (S)-5a–j
that obtained for the unbranched amino acids 5a–d, allowing
preparation of the corresponding (R)-amino acid 7e in good
overall yield. By contrast, the reactions of bulkier amino
acids valine 5f (entry 6) and leucine 5e (entry 7) occurred at
relatively slow rates and provided incomplete diastereoselectivity (40% and 70% de, respectively). Of particular interest were the reactions of functionalized (S)-amino acids
methionine 5h, homoserine 5i and glutamine 5j. In the case
of (S)-methionine 5h, the standard reaction conditions can
be used, as in the case of non-functionalized derivatives 5a–
g, allowing preparation of the thermodynamically controlled
diastereomer 6h and (R)-7h, after disassembly of the
complex, in good chemical yield and enantiomeric purity
(entry 8). On the other hand, the application of K2CO3 as a
base in the reactions of reagent (S)-3 with homoserine (S)-5i
and glutamine (S)-5j resulted in the formation of substantial
amounts of byproducts and low yields of the target products
6i,j. However, the use of DBU as a base for these reactions
remedied this problem and allowed for the preparation of
homoserine-containing complex 6i in high chemical yield
(entry 9). The DBU-catalyzed reaction of glutamine (S)-5j
(entry 10) with reagent (S)-3 was less successful (59% yield),
probably due to the partial hydrolysis of the amide functionality. Extension of this method to other functionalized
amino acids as well as sterically constrained α-quaternary
derivatives was much less successful, thus demonstrating the
limitations in the reactivity and applications of reagent 3.
Enantiomerically pure samples of (R)-amino acids 7 can be
obtained by recrystallization or SDE (self-disproportionation
of enantiomers) via achiral chromatography.15
To a flask containing an ethanol solution of reagent (S)-3 (1
eq.), Ni(OAc)2·4H2O (4 eq.) and racemic amino acid (2.0 eq.)
was added K2CO3 (15 eq.), and the reaction mixture was stirred
at 60–70 °C. Note: in the case of the reactions of homoserine
(S)-5i and glutamine (S)-5j, DBU was used as the base instead
of K2CO3. The progress of the reaction was monitored by TLC,
and upon completion (consumption of reagent 3), the reaction
mixture was poured into ice water. The target product was
extracted three times with CH2Cl2. The combined organic layer
was dried over anhydrous MgSO4 and evaporated in vacuum.
After the evaporation of the solvents and silica-gel column
chromatography, the target complexes 6a–j were obtained in
diastereomerically pure forms.
Ni(II) complex of (R)-alanine Schiff base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-ethylamino)-acetamide
1
6a. M.p. 270.2 °C (decomp.). [α]25
D = −756.0 (c 1.01, CHCl3). H
NMR (300 MHz, CDCl3): δ 1.42 (3 H, d, J = 7.0 Hz), 1.58 (3 H,
s), 1.68 (3 H, d, J = 6.7 Hz), 2.53 (1 H, bs), 2.95 (3 H, s), 3.80
(1 H, q, J = 7.0 Hz), 3.89 (1 H, m), 6.58 (1 H, m), 6.66 (1 H, m),
6.84 (1 H, bd, J = 7.9 Hz), 7.04–7.15 (2 H, m), 7.17–7.28 (4 H,
m), 7.39–7.57 (3 H, m), 8.04 (1 H, d, J = 8.8 Hz), 8.21 (2 H, bd,
J = 7.3 Hz). 13C NMR (75.5 MHz, CDCl3): δ 21.0, 22.1, 22.6,
33.3, 57.5, 64.9, 65.1, 120.2, 123.4, 126.8, 127.4, 127.6, 128.2,
128.6, 128.7, 129.2, 129.4, 131.7, 132.8, 133.5, 140.3, 142.2,
169.6, 180.4, 180.9. HRMS: m/z calcd for C28H29N3NaNiO3
[M + Na]+ 536.1460, found 536.1418.
Ni(II) complex of (R)-2-aminobutyric acid Schiff base with
(S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-ethylamino)acetamide 6b. M.p. 277.5 °C (decomp.). [α]25
D = −983.5 (c 1.07,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.37 (3 H, m), 1.56 (3 H,
s), 1.61–1.75 (2 H, m), 1.66 (3 H, d, J = 6.9 Hz), 2.70–3.00 (1 H,
m), 2.87 (3 H, s), 3.82 (1 H, dd, J = 6.8, 4.1 Hz), 3.87 (1 H, dd,
J = 6.9, 3.1 Hz), 6.54–6.66 (2 H, m), 6.85 (1 H, m), 7.01–7.12
(2 H, m), 7.13–7.25 (3 H, m), 7.35–7.56 (3 H, m), 8.06 (1 H, dd,
J = 8.7, 1.7 Hz), 8.24 (2 H, bd, J = 7.5 Hz). 13C NMR (75.5 MHz,
CDCl3): δ 9.58, 22.3, 23.3, 27.5, 33.3, 57.8, 65.3, 69.9, 120.4,
123.4, 126.8, 127.1, 127.6, 127.9, 128.5, 128.8, 128.9, 129.3,
129.6, 132.0, 133.2, 134.1, 140.4, 142.5, 170.1, 179.8, 180.4.
Conclusions
In conclusion, this work has demonstrated that various (S)α-amino acids can be interconverted to the corresponding (R)α-enantiomers via reaction with chiral reagent (S)-3 followed
by disassembly of the intermediate Ni(II)-complexes under
This journal is © The Royal Society of Chemistry 2013
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HRMS: m/z calcd for C29H32N3NiO3 [M + H]+ 528.1797, found
528.1666.
Ni(II) complex of (R)-2-aminopentanoic acid Schiff base with
(S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-ethylamino)acetamide 6c. M.p. 293.5 °C (decomp.). [α]25
D = −973.5 (c 1.05,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.33 (3 H, m), 1.56 (3 H,
s), 1.58–1.77 (4 H, m), 1.65 (3 H, d, J = 6.9 Hz), 2.69–2.92 (1 H,
m), 2.88 (3 H, s), 3.81 (1 H, dd, J = 6.8, 4.1 Hz), 3.88 (1 H, dd,
J = 6.9, 3.1 Hz), 6.55–6.66 (2 H, m), 6.84 (1 H, m), 7.00–7.12
(2 H, m), 7.12–7.26 (3 H, m), 7.35–7.57 (3 H, m), 8.05 (1 H, dd,
J = 8.7, 1.7 Hz), 8.23 (2 H, bd, J = 7.5 Hz). 13C NMR (75.5 MHz,
CDCl3): δ 9.55, 18.9, 22.5, 23.2, 28.6, 33.9, 59.8, 65.9, 71.2,
121.5, 123.9, 127.3, 126.9, 127.8, 128.4, 128.6, 128.8, 128.9,
129.2, 129.8, 132.7, 133.4, 134.0, 141.0, 142.1, 171.2, 178.7,
180.3. HRMS: m/z calcd for C30H34N3NiO3 [M + H]+ 542.1954,
found 542.1911.
Ni(II) complex of (R)-2-aminohexanoic acid Schiff base with
(S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-ethylamino)acetamide 6d. M.p. 250.0 °C (decomp.). [α]25
D = −893.7 (c 1.03,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.32 (3 H, m), 1.56 (3 H,
s), 1.57–1.80 (6 H, m), 1.65 (3 H, d, J = 6.9 Hz), 2.71–2.99 (1 H,
m), 2.88 (3 H, s), 3.81 (1 H, dd, J = 6.8, 4.1 Hz), 3.88 (1 H, dd,
J = 6.9, 3.1 Hz), 6.55–6.67 (2 H, m), 6.84 (1 H, m), 7.01–7.13
(2 H, m), 7.12–7.26 (3 H, m), 7.35–7.55 (3 H, m), 8.05 (1 H, dd,
J = 8.7, 1.7 Hz), 8.25 (2 H, bd, J = 7.5 Hz). 13C NMR (75.5 MHz,
CDCl3): δ 9.51, 20.5, 22.3, 23.2, 27.4, 33.5, 56.8, 66.5, 70.3,
121.2, 123.3, 126.5, 127.2, 127.8, 127.9, 128.5, 128.8, 128.9,
129.3, 129.6, 132.1, 133.2, 134.2, 140.4, 142.5, 170.7, 179.3,
180.5. HRMS: m/z calcd for C31H36N3NiO3 [M + H]+ 556.2110,
found 556.2012.
Ni(II) complex of (R)-phenylalanine Schiff base with (S)-N-(2benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-ethylamino)-acetamide 6e. M.p. 281 °C (decomp.). [α]25
D = −501.3 (c 1.08,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.58 (3 H, d, J = 7.0 Hz),
2.17 (6 H, s), 2.22 (1 H, bs), 2.68 (1 H, dd, J = 13.8, 5.6 Hz), 3.07
(1 H, dd, J = 13.8, 4.4 Hz), 3.75 (1 H, qd, J = 7.0, 3.2 Hz), 4.11
(1 H, dd, J = 5.6, 4.4 Hz), 6.59 (1 H, dd, J = 8.2, 2.0 Hz), 6.64 (1 H,
ddd, J = 8.2, 6.4, 1.17 Hz), 7.02–7.61 (14 H, m), 8.09 (2 H, bd,
J = 7.3 Hz), 8.17 (1 H, dd, J = 8.8, 1.2 Hz). 13C NMR (75.5 MHz,
CDCl3): δ 22.1, 23.1, 32.8, 39.1, 57.4, 64.9, 70.1, 120.1, 123.0,
126.7, 126.9, 127.2, 127.7, 127.8, 128.3, 128.7, 128.9, 129.1,
129.6, 130.1, 132.1, 133.3, 134.1, 135.5, 140.3, 142.9, 170.5,
179.0, 180.2. HRMS: m/z calcd for C34H33N3NiO3 [M + H]+
612.1773, found 612.1725.
Ni(II) complex of (R)-valine Schiff base with (R)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-ethylamino)-acetamide 6f.
M.p. 294.5 °C (decomp.). [α]25
D = −2043.0 (c 1.10, CHCl3).
1
H NMR (300 MHz, CDCl3): δ 0.73 (3 H, d, J = 6.7 Hz), 1.56 (3
H, s), 1.65–1.85 (1 H, m), 1.69 (3 H, d, J = 6.9 Hz), 1.75 (3 H, d,
J = 6.2 Hz), 2.83 (3 H, s), 3.08 (1 H, bd, J = 2.3 Hz), 3.66 (1 H, d,
J = 3.1 Hz), 3.86 (1 H, m), 6.55–6.66 (2 H, m), 6.85 (1 H, bd, J =
7.7 Hz), 7.02 (1 H, m), 7.05 (1 H, m), 7.12–7.18 (2 H, m), 7.22
(1 H, bd, J = 7.2 Hz), 7.42 (1 H, m), 7.43–7.57 (2 H, m), 8.15
(1 H, d, J = 8.5 Hz), 8.22 (2 H, bd, J = 7.4 Hz). 13C NMR
(75.5 MHz, CDCl3): δ 17.7, 19.8, 22.1, 23.1, 32.8, 34.1, 57.7,
65.0, 73.8, 120.1, 123.0, 126.9, 129.9, 127.6, 127.9, 128.2, 128.5,
4506 | Org. Biomol. Chem., 2013, 11, 4503–4507
Organic & Biomolecular Chemistry
128.8, 129.3, 129.3, 131.9, 133.2, 134.1, 140.6, 142.6, 170.0,
178.1, 180.8. HRMS: m/z calcd for C30H34N3NiO3 [M + H]+
542.1954, found 542.1964.
Ni(II) complex of (R)-amino-4-methylpentanoic acid Schiff
base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenylethylamino)-acetamide 6g. M.p. 274.5 °C (decomp.). [α]25
D =
−1011.9 (c 1.12, CHCl3). 1H NMR (300 MHz, CDCl3): δ 0.76
(3 H, d, J = 6.7 Hz), 0.77 (3 H, d, J = 6.7 Hz), 1.01 (1 H, m), 1.56
(3 H, s), 1.55–1.70 (2 H, m), 1.65 (3 H, d, J = 6.9 Hz), 2.88 (3 H, s),
3.84 (1 H, m), 3.88 (1 H, m), 6.53–6.65 (2 H, m), 6.85 (1 H, m),
6.98–7.11 (2 H, m), 7.14–7.25 (3 H, m), 7.36–7.55 (3 H, m), 8.04
(1 H, dd, J = 8.7, 1.7 Hz), 8.22 (2 H, bd, J = 7.5 Hz). 13C NMR
(75.5 MHz, CDCl3): δ 9.55, 9.56, 18.7, 22.3, 23.7, 29.1, 34.7,
50.2, 66.2, 71.8, 122.0, 123.8, 127.4, 126.8, 127.9, 128.5, 128.6,
128.8, 128.9, 129.3, 130.1, 132.5, 133.3, 134.0, 141.4, 141.9,
172.3, 179.9, 181.0. HRMS: m/z calcd for C31H36N3NiO3 [M +
H]+ 556.2110, found 556.2743.
Ni(II) complex of (R)-2-amino-4-(methylthio)butanoic acid
Schiff base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1phenyl-ethylamino)-acetamide 6h. M.p. 230.1 °C (decomp.).
1
[α]25
D = −951.0 (c 1.04, CHCl3). H NMR (300 MHz, CDCl3):
δ 1.58 (3 H, s), 1.68 (3 H, d, J = 6.7 Hz), 1.81–2.18 (2 H, m), 2.19
(3 H, s), 2.45–2.52 (1 H, m), 2.53 (1 H, bs), 2.95 (3 H, s),
3.18–3.35 (1 H, m), 3.88 (1 H, m), 6.57 (1 H, m), 6.66 (1 H, m),
6.85 (1 H, bd, J = 7.9 Hz), 7.05–7.15 (2 H, m), 7.17–7.27 (4 H,
m), 7.38–7.57 (3 H, m), 8.05 (1 H, d, J = 8.8 Hz), 8.22 (2 H, bd,
J = 7.3 Hz). 13C NMR (75.5 MHz, CDCl3): δ 17.8, 22.1, 22.6, 30.1,
33.3, 33.9, 57.6, 65.0, 65.5, 120.7, 123.5, 126.7, 127.3, 127.6,
128.4, 128.6, 128.8, 129.2, 129.5, 131.8, 132.6, 133.7, 140.9,
143.4, 170.1, 180.7, 181.2. HRMS: m/z calcd for C30H34N3NiO3S
[M + H]+ 574.1674, found 574.1593.
Ni(II) complex of (R)-2-amino-4-hydroxybutanoic acid Schiff
base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenylethylamino)-acetamide 6i. M.p. 293.7 °C (decomp.). [α]25
D =
−830.0 (c 0.98, CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.58 (3 H,
s), 1.68 (3 H, d, J = 6.7 Hz), 1.99 (2 H, m), 2.11 (1 H, m), 2.53 (1
H, bs), 2.95 (3 H, s), 3.41–3.67 (3 H, m), 3.92 (1 H, m), 6.56 (1
H, m), 6.68 (1 H, m), 6.84 (1 H, bd, J = 7.9 Hz), 7.03–7.16 (2 H,
m), 7.16–7.28 (4 H, m), 7.40–7.55 (3 H, m), 8.05 (1 H, d, J = 8.8
Hz), 8.20 (2 H, bd, J = 7.3 Hz). 13C NMR (75.5 MHz, CDCl3):
δ 22.1, 22.6, 33.3, 38.3, 57.6, 58.2, 64.7, 64.9, 120.3, 123.5, 127.0,
127.4, 127.68, 128.1, 128.5, 128.7, 129.3, 129.8, 131.5, 133.0,
133.7, 140.1, 142.9, 169.1, 180.9, 181.0. HRMS: m/z calcd for
C29H32N3NiO4 [M + H]+ 544.1746, found 544.1672.
Ni(II) complex of (R)-2-amino-4-carbamoylbutanoic acid (glutamine) Schiff base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl2-(1-phenyl-ethylamino)-acetamide 6j. M.p. 297.5 °C. [α]25
D =
−936.0 (c 1.08, CHCl3). (decomp.). 1H NMR (300 MHz, CDCl3):
δ 1.55 (3 H, s), 1.68 (3 H, d, J = 6.7 Hz), 2.15 (2 H, m), 2.24
(2 H, m), 2.60 (1 H, bs), 2.94 (3 H, s), 3.78 (1 H, m), 3.91 (1 H, m),
6.28 (2 H, bs), 6.55 (1 H, m), 6.69 (1 H, m), 6.81 (1 H, bd, J =
7.9 Hz), 7.07–7.16 (2 H, m), 7.15–7.27 (4 H, m), 7.40–7.55 (3 H,
m), 8.05 (1 H, d, J = 8.8 Hz), 8.20 (2 H, bd, J = 7.3 Hz). 13C NMR
(75.5 MHz, CDCl3): δ 22.4, 23.2, 29.5, 33.0, 33.3, 57.6, 64.7,
65.4, 120.1, 123.5, 126.8, 127.4, 127.6, 128.3, 128.6, 128.8,
129.3, 129.8, 131.6, 132.5, 134.0, 140.4, 142.5, 170.0, 175.9,
This journal is © The Royal Society of Chemistry 2013
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Organic & Biomolecular Chemistry
180.7, 181.3. HRMS: m/z calcd for C30H33N4NiO4 [M + H]+
571.1855, found 571.1798.
Published on 13 May 2013. Downloaded on 18/02/2014 13:49:00.
General procedure for the decomposition of complexes 6a–j,
isolation of target amino acids 7a–j and recovery of chiral
reagent (S)-3
A solution of diastereomerically pure complexes 6a–j
(25 mmol) in MeOH (50 mL) was added to a stirring solution
of 3 N HCl in MeOH at 70 °C. Upon the disappearance of the
red color (about 5–10 min), the reaction mixture was evaporated under vacuum. Water (85 mL) was added and the resulting mixture was treated with an excess of concentrated NH4OH
and extracted with CH2Cl2 or CHCl3. The organic extracts were
dried over magnesium sulfate and evaporated in vacuum to
give (>95%) ligand (S)-3. The aqueous solution was evaporated
in vacuum, dissolved in a minimum amount of water, and
passed through the cation-exchange resin Dowex 50X2 100 to
afford analytically pure samples of the target amino acids
(91–95%) 7a–j.
Acknowledgements
We thank IKERBASQUE, Basque Foundation for Science, the
Basque Government (SAIOTEK S-PE12UN044) and Hamari
Chemicals (Osaka, Japan) for generous financial support.
Notes and references
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