Highly diastereoselective conjugate addition-elimination of chiral nickel(II) glycinate with activated allylic acetates for asymmetric synthesis of glutamic acid derivatives

Article abstract of DOI:10.1055/s-0028-1088075

A practically feasible, diastereoselective conjugate addition-elimination reaction of a chiral nickel(II) complex of glycine 1 with allylic acetates 2 is described. The reaction pathway was successfully controlled, and the desired formation of a carbon-ca

Full text of DOI:10.1055/s-0028-1088075

1744
FEATURE ARTICLE
Highly Diastereoselective Conjugate Addition–Elimination of Chiral
Nickel(II) Glycinate with Activated Allylic Acetates for Asymmetric Synthesis
of Glutamic Acid Derivatives
A
symmetr
i
ic Syn
a
G
l
n
utamic
A
cid
g
D
erivatives Wang, Jianmei Shi, Xiaodong Zhang, Daizong Lin, Hualiang Jiang, Hong Liu*
The Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, P. R. of China
Fax +86(21)50807088; E-mail: hliu@mail.shcnc.ac.cn
Received 13 March 2009; revised 23 March 2009
which operational convenience and wide applications are
Abstract: A practically feasible, diastereoselective conjugate addi-
used has remained an elusive goal.7
tion–elimination reaction of a chiral nickel(II) complex of glycine 1
with allylic acetates 2 is described. The reaction pathway was suc-
cessfully controlled, and the desired formation of a carbon–carbon
bond was exclusively obtained with high diastereoselectivity. This
reaction is an attractive route for the asymmetric synthesis of previ-
ously unavailable chainlike glutamic acid derivatives.
The use of the nickel(II) complex of the chiral Schiff base
of glycine for the atom- and step-economical synthesis of
functional and enantiopure a-amino acids has attracted
considerable interest both in academia and industry. The
numerous environmental and economic advantages of this
method make it highly attractive for chemical syntheses.
The notable merits of synthetic methods of employing the
nickel(II) complex are high efficiency, low cost, and min-
imal environmental impact. Belokon and Soloshonok et
al. developed efficient, large-scale synthesis of the nick-
el(II) complex, which has made the starting materials
readily available and inexpensive.8 These methods can
generate various functionalized amino acids and are ex-
pected to have many applications in synthesis. Nickel(II)
complexes are widely used for aldol condensations,9
Michael additions,10 and C-alkylation reactions.11 Recent-
ly, efforts have been made toward the development of
asymmetric Mannich reactions for the synthesis of syn-
a,b-diamino acids.12 However, to the best of our knowl-
edge, nickel(II) complexes have not yet been used in con-
jugate addition–elimination reactions. In this paper, we
describe a practically feasible, diastereoselective conju-
gate addition–elimination of a chiral nickel(II) complex of
glycine 1 with activated allylic acetates 2, which can
progress to the asymmetric synthesis of enantiopure
glutamic acid derivatives (Scheme 1).
Key words: nickel(II) complex, asymmetric synthesis, glutamic
acid, amino acids
Glutamic acid is the most abundant excitatory neurotrans-
mitter in the mammalian nervous system. Its derivatives
are used as fundamental building blocks for the synthesis
of molecules that are important for the pharmaceutical and
agrochemical industries, such as peptides, proteins, and
other natural products.1 In particular, glutamic acid deriv-
atives are structural components of ligands for various
types of glutamate receptors, which are potential thera-
peutic agents.2 Asymmetric synthesis of glutamic acid de-
rivatives is a difficult and challenging task. A number of
potential methods have been developed for the synthesis
of these compounds.3 One of the most efficient methods
of preparation of 3-substituted pyroglutamic acid deriva-
tives is 1,4-addition of glycine derivatives to a,b-unsatur-
ated esters or amides.4 Recently, Kobayashi et al. reported
an effective method for the asymmetric 1,4-addition syn-
thesis of 3-substituted glutamic acids derivatives in good
enantiomeric excess.5 O’Donnell et al. described the
enantioselective synthesis of 4-substituted glutamic acid
derivatives efficiently catalyzed by a chiral phase-transfer
catalyst;6 however, it requires long reaction times (30–48
h) and an expensive phase-transfer catalysts, etc. How-
ever, no examples of the preparation of chainlike, 4-sub-
stituted glutamic acid derivatives by the asymmetric
synthesis reaction have been reported. Various method-
ological and structural shortcomings of the literature ap-
proaches render these methods of limited synthetic
application, in particular for the preparation of chainlike
glutamic acid derivatives on a relatively large scale.
Clearly, the development of improved procedures in
As a model reaction, the addition–elimination reaction of
the chiral (S)-nickel(II) complex of glycine with (S)-2-
[(N-benzylprolyl)amino]benzophenone [(S)-BPB], (S)-1,
and ethyl 2-[acetoxy(4-nitrophenyl)methyl]acrylate (2a)
was investigated and the reaction conditions were opti-
mized. The results are summarized in Table 1. First, cesi-
um hydroxide monohydrate was selected as the base with
dichloromethane as the solvent. This reaction afforded the
conjugate addition–elimination adduct (S,2R)-3a in high
yield (92%) but with poor diastereomeric excess (10%)
(entry 1). Subsequently, a variety of alternative bases
were investigated for this reaction. High diastereoselec-
tivities (entries 2–4) were observed when sodium hydride,
1,8-diazabicyclo[5.4.0]undec-7-ene, and potassium hy-
droxide were used as the base. In particular, potassium hy-
droxide turned out to be an effective and a highly
diastereoselective base. Following this, a variety of sol-
vents were investigated for this conjugate addition–elimi-
SYNTHESIS 2009, No. 10, pp 1744–1752
x
x.
x
x
.
2
0
0
9
Advanced online publication: 27.04.2009
DOI: 10.1055/s-0028-1088075; Art ID: Z04109SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
Asymmetric Synthesis of Glutamic Acid Derivatives
1745
Jiang Wang received her vision of Professor Hong tions of nickel(II) complex-
B.S. in pharmaceutical engi- Liu at the Center for Drug es in the asymmetric
neering from the China Discovery and Design, synthesis of enantiopure
Pharmaceutical University, Shanghai Institute of Mate- amino acids and asymmetric
Nanjing, China. At present ria Medica, Shanghai, Chi- synthesis of pharmacologi-
she is working in medicinal na. Her research interests cally active molecules.
chemistry under the super- are focused on the applica-
Jianmei Shi received her sion of Professor Hong Liu Her research interests in-
B.S. in Medical Workers at the Center for Drug Dis- clude asymmetric synthesis
College, Shanghai, China, covery and Design, Shang- amino acids and synthesis of
in 2006. She is working at hai Institute of Materia pharmacologically active
present under the supervi- Medica, Shanghai, China. molecules.
Xiaodong Zhang received vision of Professor Hong focused on the development
his B.S. in organic chemis- Liu at the Center for Drug and catalytic applications of
try from the Nanjing Uni- Discovery and Design, nickel(II) complexes in the
versity, Nanjing. At present Shanghai Institute of Mate- asymmetric synthesis of
his is working in medicinal ria Medica, Shanghai, Chi- enantiopure amino acids.
chemistry under the super- na. His research interests are
Daizong Lin received his supervision of Professor ests are focused on the de-
B.S. in organic chemistry Hong Liu at the Center for velopment and catalytic
from the Nanjing Universi- Drug Discovery and De- applications of nickel(II)
ty, Nanjing, China, in 2008. sign, Shanghai Institute of complexes in the asymmet-
He started his M.S. on me- Materia Medica, Shanghai, ric synthesis of enantiopure
dicinal chemistry under the China. His research inter- amino acids.
Prof. Hualiang Jiang re- covery and Design, Shang- research has found recogni-
ceived his Ph.D. in medici- hai Institute of Materia tion by a variety of scientific
nal
chemistry
from Medica. His research inter- prizes and research awards,
Shanghai Institute of Mate- ests include computer aided international lectureships,
ria Medica, under the super- drug discovery, medicinal and the invitation to join the
vision of Professor Ruyun Ji chemistry, organic chemis- advisory boards of scientific
and Professor Kaixian Chen try, and the chemistry of journals.
in 1995. He is now the head pharmacologically interest-
of the Center for Drug Dis- ing molecules. His scientific
Prof. Hong Liu received at Shanghai Institute of Ma- Galveston. Her research in-
her M.S. and Ph.D. in me- teria Medica, she joined the terests include medicinal
dicinal chemistry from the Shanghai Institute of Mate- chemistry, organic chemis-
China Pharmaceutical Uni- ria Medica and is now a try, computer modeling, and
versity, under the supervi- Group Leader. As a visiting pharmacologically active
sion of Professor Weiyi Scientist, she stayed with molecules, especially those
Hua. After a postdoctoral Professor James Halpert at targeting tumors and diabe-
stay with Professor Ruyun Ji the University of Texas tes.
and Professor Kaixian Chen Medical
Branch
at
Synthesis 2009, No. 10, 1744–1752 © Thieme Stuttgart · New York

1746
J. Wang et al.
FEATURE ARTICLE
R
O
OAc
O
O
COOEt
O
*
R
OEt
O
Ni
N
Ni
N
2
N
*
N
*
N
N
CH2Cl2, KOH
O
O
(S)-1
(S,2R)-3
Gly MeOH
Ni(NO3)2
KOH NaH
6 M HCl
MeOH
>96% recovery
O
O
NiCl2
OEt
+
N
*
R
H
.
HCl
N
*
NH2
HOOC
O
(S)-BPB
(R)-4
Scheme 1 Stereoselective synthesis of enantioenriched glutamic acid derivatives via a chiral nickel(II) complex with allylic acetates
nation reaction with potassium hydroxide as the base and The results suggest that this reaction can be regarded as a
an arbitrary reaction time of two hours. Solvent screening model reaction to 4-aryl-substituted alkylidene glutamic
(entries 4–8) revealed that while acetonitrile and acetone acids. This reaction was inert to steric effects. All the three
afforded good results, the best combination of yield and regioisomeric methylphenyl-substituted allylic acetates 2
diastereoselectivity could be realized when using dichlo- employed in the conjugate addition–elimination reactions
romethane (entry 4). The representative results in entries afforded the desired products in high yields, and high se-
1–8 suggest that the diastereoselectivity depends to a sig- lectivities (entries 3–5). In general, functionalized aryl al-
nificant extent on the reaction conditions, while the ther- lylic acetates were found to be excellent substrates for this
modynamically controlled stereochemical outcome is reaction, regardless of the electronic effect. Aromatic sys-
only slightly influenced by the nature of the base and the tems bearing electron-donating and electron-withdrawing
solvent used. Further optimization studies showed that re- groups could also be tolerated (entries 1–10); moreover,
actions carried out with potassium hydroxide as the base this reaction could be extended to heterocyclic com-
and dichloromethane as the solvent, and in which the tem- pounds as well (entries 11–13). It is worth mentioning that
peratures ranged 50 to –60 °C (entries 9–13) afforded neither the position nor the electronic properties of the
good product yields and high diastereoselectivities were substituent on the aromatic ring had a significant impact
achieved. The reaction rate was improved when the reac- on the diastereoselectivity of the reaction. The (R)-diaste-
tion was performed at a slightly elevated temperature (50 reomer was obtained as the product, as indicated by single
°C), presumably because of an increase in the solubility of crystal X-ray structural analysis (Figure 1).
the potassium hydroxide. On the other hand, the de values
decreased when the reaction was carried out at low tem-
perature. After optimizing the base, solvent, and tempera-
ture, the reaction was performed by using the following
protocol: (S)-1 was treated with ethyl 2-[acetoxy(4-nitro-
phenyl)methyl]acrylate (2a, 1.05 equiv) in the presence of
To demonstrate the isolation of the target amino acid
(R)-4 from the nickel(II) complexes (S,2R)-3, (S,2R)-3a
was decomposed under standard conditions to yield the
previous unavailable amino acid (R)-4a. The products are
a novel type of chainlike, 4-substituted, 5-esterified
glutamic acid derivative. Several distinguished features of
potassium hydroxide (10.0 equiv) at ambient temperature
the product deserved to be mentioned: (i) it is the first syn-
in dichloromethane for two hours to afford the conjugate
thesis of chainlike, 5-esterified glutamic acid derivatives;
(ii) the geometry of all these target amino acids include an
E-double bond; and (iii) broad substrate scope: both aro-
addition–elimination adduct (S,2R)-3a in high yield and
with high diastereoselectivity.
After the reaction conditions had been optimized, we in- matic and heterocyclic substituted amino acids can be ob-
vestigated the substrate scope of the conjugate addition– tained. The chiral ligand (S)-BPB (Scheme 2) could be
elimination reaction. The results are summarized in easily recovered in quantitative yields by a simple proce-
Table 2. The reaction was found to have a broad substrate dure and then reused. Decomposition of the (S,2R)-3a
scope and afforded products with high yields and high complex and isolation of amino acid (R)-4a was per-
diastereoselectivities with a number of 4-aryl-substituted formed under standard conditions by heating a suspension
allylic acetates 2. Phenyl rings with different substituents of (S,2R)-3a in methanol–6 M hydrochloric acid to afford
and other aromatic groups could be used in this reaction. the target amino acid, metal ions, and (S)-BPB. The (S)-
Synthesis 2009, No. 10, 1744–1752 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Synthesis of Glutamic Acid Derivatives
1747
Table 1 Optimization of the Reaction Conditionsa
O2N
O
OAc
O
O
COOEt
O
*
OEt
O
Ni
N
Ni
N
O2N
N
*
2a
N
*
N
N
O
O
(S)-1
(S,2R)-3a
Entry
1
Base
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
acetone
THF
Temp (°C)
Yield (%)
92
deb (%)
10
CsOH
NaH
23
23
2
86
90
3
DBU
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
23
84
85
4
23
95
>99
94
5
23
93
6
23
93
97
7
23
92
82
8
DMF
23
85
80
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50
93
98
10
11
12
13
0
86
97
–20
–40
–60
82
84
77
80
75
78
a Conditions: (S)-1 (0.20 mmol), 2a (0.24 mmol), base (2.0 mmol), solvent (10 mL), 2 h.
b Determined by chiral HPLC analysis.
BPB could be recovered by extraction into dichlo- like, 4-substituted, 5-esterified glutamic acid derivatives
romethane and reused to form the nickel(II) complex of via a conjugate addition–elimination reaction. A broad
glycine in near quantitative yield, thereby eliminating any range of aryl- and heteroaryl-derived allylic acetates
concern regarding the poor atom economy of this method. could be employed in this reaction under operationally
convenient conditions, without the need for an inert atmo-
In summary, we have developed a highly diastereoselec-
sphere, dried solvents, and very low temperatures. Thus,
tive and practically feasible route to a novel type of chain-
the experimental procedure is simple and cost-effective.
O2N
O
COOEt
O
*
O
O
OEt
NH2
6 M HCl
MeOH
N
*
Ni
N
H
+
NiCl2
⋅HCl
+
N
*
N
*
O2N
N
HOOC
O
O
(S,2R)-3a
(S)-BPB
(R)-4a
ee >99%
Scheme 2 Decomposition of nickel(II) complex (S,2R)-3a to release amino acid (R)-4a and recovery of the ligand (S)-BPB
Synthesis 2009, No. 10, 1744–1752 © Thieme Stuttgart · New York

1748
J. Wang et al.
FEATURE ARTICLE
Table 2 Conjugate Addition–Elimination Reactions of (S)-Nickel(II) Complex 1 with Allylic Acetates 2a
R
O
OAc
O
O
COOEt
O
*
R
OEt
O
Ni
N
Ni
N
2
N
*
N
*
N
N
CH2Cl2, KOH
O
O
(S)-1
(S,2R)-3
Entry
1
Product
R
Yield (%)
95
deb (%)
>99
98
(S,2R)-3a
(S,2R)-3b
(S,2R)-3c
(S,2R)-3d
(S,2R)-3e
(S,2R)-3f
(S,2R)-3g
(S,2R)-3h
(S,2R)-3i
(S,2R)-3j
(S,2R)-3k
(S,2R)-3l
(S,2R)-3m
4-O2NC6H4
Ph
2
93
3
2-MeC6H4
3-MeC6H4
4-MeC6H4
92
98
4
93
98
5
91
98
6
4-MeOC6H4
4-FC6H4
90
98
7
94
98
8
4-ClC6H4
4-BrC6H4
2,6-F2C6H3
2-furyl
93
98
9
94
98
10
11
12
13
92
97
91
>99
98
3-thienyl
2-naphthyl
92
90
98
a Conditions: (S)-1 (0.20 mmol), 2 (0.24 mmol), KOH (2.0 mmol), CH2Cl2 (10 mL), r.t., 2 h.
b Determined by chiral HPLC analysis (see Supporting Information for details).
The absolute configuration of one of the products was de-
termined. Owing to the high chemical yields of the prod-
ucts of the conjugate addition–elimination reaction and
the simplicity of the experimental procedure, this reaction
can be employed for the multigram-scale preparation of
glutamic acid derivatives. Additional investigations into
the reaction mechanism and synthetic applications of this
reaction are in progress; the results thereof will be report-
ed in the future.
The reagents (chemicals) were purchased from commercial sources
and used without further purification. Petroleum ether = PE. Ana-
lytical TLC used HSGF 254 (0.15–0.20 mm thickness). All prod-
ucts were characterized by their NMR and MS spectra. 1H and 13
C
NMR spectra were recorded in CDCl3 on a 300 MHz instrument
downfield from TMS. LR- and HRMS were measured on a Finni-
gan MAT-95, LCQ-DECA spectrometer. Optical rotations were re-
ported as follows: [a]D22 (c g/100 mL, solvent).
Figure 1 The crystal structure of (S,2R)-3a by X-ray crystal struc-
ture analysis
Analytical HPLC was carried out using the Dionex ASI-100 auto-
mated sampler, Chiralpak IA column; loading loop: 5 mL; eluent:
isocratic mixture n-hexane–i-PrOH (60:40); flow rate: 1 mL/min,
l = 220 nm, unless otherwise stated.
Synthesis 2009, No. 10, 1744–1752 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Synthesis of Glutamic Acid Derivatives
1749
Synthesis of (S,2R)-3; General Procedure
[a]D22 +1910.7 (c 0.30, CHCl3).
The Ni(II) complex of glycine 1 (100 mg, 0.201 mmol) was dis-
solved in CH2Cl2 (10 mL). The allylic acetate 2 (0.241 mmol) and
KOH (113 mg, 2.01 mmol) were added at r.t. The mixture was then
stirred at r.t. for 2 h. The crude mixture was concentrated, and then
washed with H2O (3 ×) and brine (3 ×); the combined aqueous phas-
es were extracted with CH2Cl2 (3 ×). The combined organic layers
were dried (Na2SO4), concentrated, and purified by flash column
chromatography (PE–EtOAc) to give (S,2R)-3 as a red solid.
IR (KBr): 708, 756, 1163, 1257, 1333, 1439, 1519, 1591, 1633,
1668 (C=N), 1718 (C=O), 2868, 2924, 3059, 3435 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.20 (d, J = 8.7 Hz, 1 H), 8.03 (d,
J = 7.5 Hz, 2 H), 7.84 (s, 1 H), 7.48–7.29 (m, 5 H), 7.23–7.02 (m, 7
H), 6.87 (d, J = 7.5 Hz, 1 H), 6.64–6.52 (m, 2 H), 4.32 (d, J = 12.3
Hz, 1 H), 4.21 (t, J = 14.1 Hz, 1 H), 3.98–3.92 (m, 1 H), 3.43–3.32
(m, 4 H), 3.04–2.99 (m, 2 H), 2.51–2.46 (m, 1 H), 2.32–2.28 (m, 1
H), 2.16 (s, 3 H), 1.97–1.95 (m, 1 H), 1.82–1.79 (m, 2 H), 1.13 (t,
J = 14.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 180.5, 177.9, 170.9, 166.9, 142.4,
136.8, 134.7, 133.6, 132.2, 131.4, 130.0, 129.5, 128.8, 128.4, 127.5,
126.1, 123.2, 120.4, 70.2, 63.1, 60.8, 57.4, 33.6, 30.5, 29.7, 23.8,
19.9, 14.1.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(4-Nitrobenzylidene)-L-
glutamate Schiff Base Complex 3a
Following the general procedure using 2a and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3a as a red solid;
yield: 95%; mp 119–120 °C; HPLC: tR = 32.75 min (major); >99%
de.
MS (EI): m/z = 699 [M]+.
HRMS (EI): m/z [M]+ calcd for C40H39N3NiO5: 699.2243; found:
[a]D22 +3311.8 (c 0.44, CHCl3).
IR (KBr): 706, 756, 1165, 1256, 1346, 1439, 1519, 1591, 1641,
699.2245.
1675 (C=N), 1713 (C=O), 2929, 2958, 3434 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.58 (d, J = 9.6 Hz, 1 H), 7.97 (d,
J = 9.0 Hz, 2 H), 7.91 (s, 1 H), 7.62–7.59 (m, 2 H), 7.51–7.28 (m, 9
H), 7.26–7.20 (m, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 6.71 (d, J = 4.2
Hz, 2 H), 4.70 (d, J = 13.2 Hz, 1 H), 4.19 (t, J = 12.6 Hz, 1 H), 4.08–
3.94 (m, 3 H), 3.68 (d, J = 13.2 Hz, 1 H), 3.62–3.58 (m, 1 H), 3.30–
3.26 (m, 2 H), 2.67–2.63 (m, 1 H), 2.41–2.28 (m, 1 H), 2.06–2.03
(m, 1 H), 1.79–1.63 (m, 2 H), 1.18 (t, J = 14.4 Hz, 3 H).
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(3-Methylbenzylidene)-L-
glutamate Schiff Base Complex 3d
Following the general procedure using 2d, and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3d as a red solid;
yield: 93%; mp 119–121 °C; HPLC: tR = 8.353 (minor), 16.327 min
(major); 98% de.
[a]D22 +2103.2 (c 0.54, CHCl3).
13C NMR (100 MHz, CDCl3): d = 180.4, 177.8, 171.5, 166.7, 147.3,
142.5, 141.8, 139.6, 133.5, 132.5, 131.5, 129.7, 129.5, 128.9, 128.2,
127.4, 125.9, 123.8, 123.2, 120.5, 70.3, 69.4, 63.4, 61.5, 57.4, 32.4,
30.4, 23.7, 14.1.
MS (EI): m/z = 730 [M]+.
HRMS (EI): m/z [M]+ calcd for C39H36N4NiO7: 730.1937; found:
IR (KBr): 706, 754, 1165, 1257, 1333, 1439, 1545, 1591, 1632,
1670 (C=N), 1718 (C=O), 2935, 2978, 3026, 3446 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25 (d, J = 8.7 Hz, 1 H), 8.03 (d,
J = 7.5 Hz, 2 H), 7.87 (s, 1 H), 7.50–7.44 (m, 2 H), 7.31–7.28 (m, 2
H), 7.23–7.10 (m, 8 H), 7.00–6.92 (m, 1 H), 6.62–6.55 (m, 2 H),
4.32 (d, J = 12.3 Hz, 1 H), 4.20 (t, J = 13.2 Hz, 1 H), 4.00–3.93 (m,
1 H), 3.48–3.20 (m, 6 H), 2.74–2.71 (m, 1 H), 2.36–2.32 (m, 1 H),
2.27 (s, 3 H), 2.12–1.85 (m, 3 H), 1.13 (t, J = 14.1 Hz, 3 H).
730.1937.
13C NMR (100 MHz, CDCl3): d = 180.4, 178.1, 171.1, 167.4, 142.8,
142.4, 138.2, 135.1, 133.6, 132.2, 131.4, 129.6, 129.1, 128.7, 127.4,
125.9, 125.6, 123.1, 120.3, 70.4, 63.1, 60.9, 57.2, 32.8, 30.5, 23.4,
21.2, 14.0.
MS (EI): m/z = 699 [M]+.
HRMS (EI): m/z [M]+ calcd for C40H39N3NiO5: 699.2243; found:
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-Benzylidene-L-glutamate
Schiff Base Complex 3b
Following the general procedure using 2b and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3b as a red solid;
yield: 93%; mp 107–108 °C; HPLC: tR = 8.97 min (minor), 20.435
min (major); 98% de.
[a]D22 +1551.3 (c 0.61, CHCl3).
699.2248.
IR (KBr): 704, 754, 1099, 1165, 1256, 1334, 1441, 1543, 1591,
1638, 1678 (C=N), 1707 (C=O), 2931, 2976, 3442 cm–1.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(4-Methylbenzylidene)-L-
glutamate Schiff Base Complex 3e
Following the general procedure using 2e and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3e as a red solid;
yield: 91%; mp 121–123 °C; HPLC: tR = 8.351 (minor), 19.368 min
(major); 98% de.
1H NMR (300 MHz, CDCl3): d = 8.26 (d, J = 9.0 Hz, 1 H), 8.04 (d,
J = 6.9 Hz, 2 H), 7.86 (s, 1 H), 7.47–7.28 (m, 8 H), 7.25–7.09 (m, 5
H), 6.97 (d, J = 8.1 Hz, 1 H), 6.66–6.56 (m, 2 H), 4.34 (d, J = 12.6
Hz, 1 H), 4.26 (t, J = 7.2 Hz, 1 H), 4.01–3.92 (m, 2 H), 3.45–3.38
(m, 4 H), 3.29–3.23 (m, 2 H), 2.69–2.67 (m, 1 H), 2.44–2.40 (m, 1
H), 2.05–2.01 (m, 2 H), 1.14 (t, J = 14.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 180.3, 178.2, 171.2, 167.4, 142.5,
135.1, 133.6, 132.3, 131.4, 129.5, 128.9, 128.5, 127.5, 126.1, 123.2,
120.4, 70.4, 69.8, 63.2, 61.0, 57.3, 33.2, 30.5, 23.6, 14.1.
[a]D22 +1484.2 (c 0.37, CHCl3).
IR (KBr): 704, 754, 1175, 1256, 1335, 1441, 1545, 1589, 1639,
1678 (C=N), 1701 (C=O), 2927, 2958, 3061, 3446 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.26 (d, J = 9.6 Hz, 1 H), 8.03 (d,
J = 8.1 Hz, 2 H), 7.83 (s, 1 H), 7.48–7.30 (m, 5 H), 7.25–7.24 (m, 1
H), 7.22–7.11 (m, 6 H), 7.02 (d, J = 7.5 Hz, 1 H), 6.65–6.58 (m, 2
H), 4.33 (d, J = 12.6 Hz, 1 H), 4.24 (t, J = 13.8 Hz, 1 H), 3.99–3.92
(m, 1 H), 3.50–3.27 (m, 6 H), 2.73–2.69 (m, 1 H), 2.45–2.41 (m, 1
H), 2.34 (s, 3 H), 2.04–1.98 (m, 3 H), 1.13 (t, J = 13.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 180.3, 178.4, 171.2, 167.8, 159.9,
142.5, 142.4, 133.7, 133.5, 132.3, 131.4, 130.8, 129.5, 128.9, 128.6,
127.5, 127.3, 126.3, 126.1, 123.1, 120.4, 114.1, 70.5, 69.9, 63.2,
60.9, 57.2, 55.3, 33.2, 30.5, 23.5, 14.1.
MS (EI): m/z = 685 [M]+.
HRMS (EI): m/z [M]+ calcd for C39H37N3NiO5: 685.2087; found:
685.2094.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(2-Methylbenzylidene)-L-
glutamate Schiff Base Complex 3c
Following the general procedure using 2c and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3c as a red solid;
yield: 92%; mp 184–186 °C; HPLC: tR = 8.154 (minor), 22.657 min
(major); 98% de.
MS (EI): m/z = 699 [M]+.
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J. Wang et al.
FEATURE ARTICLE
HRMS (EI): m/z [M]+ calcd for C40H39N3NiO5: 699.2243; found:
(m, 5 H), 3.13–3.06 (m, 1 H), 2.74–2.65 (m, 1 H), 2.50–2.38 (m, 1
699.2235.
H), 2.06–1.89 (m, 3 H), 1.14 (t, J = 14.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 180.4, 178.0, 171.2, 167.1, 142.4,
141.0, 134.3, 133.6, 132.3, 131.4, 130.1, 129.6, 129.2, 128.9, 128.4,
127.4, 126.0, 123.2, 120.5, 70.4, 69.6, 63.2, 61.2, 57.3, 32.9, 30.5,
23.6, 14.1.
MS (EI): m/z = 719 [M]+.
HRMS (EI): m/z [M]+ calcd for C39H36ClN3NiO5: 719.1697; found:
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(4-Methoxybenzylidene)-L-
glutamate Schiff Base Complex 3f
Following the general procedure using 2f and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3f as a red solid;
yield: 90%; mp 125–127 °C; HPLC: tR = 9.442 (minor), 21.007 min
(major); 98% de.
[a]D22 +1563.8 (c 0.59, CHCl3).
719.1706.
IR (KBr): 704, 754, 1165, 1256, 1335, 1439, 1589, 1639, 1678
(C=N), 1705 (C=O), 2924, 2976, 3435 cm–1.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(4-Bromobenzylidene)-L-
glutamate Schiff Base Complex 3i
Following the general procedure using 2i and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3i as a red solid;
yield: 94%; mp 106–108 °C; HPLC: tR = 9.677 (minor), 20.750 min
(major); 98% de.
1H NMR (300 MHz, CDCl3): d = 8.27 (d, J = 8.1 Hz, 1 H), 8.03 (d,
J = 7.5 Hz, 2 H), 7.80 (s, 1 H), 7.47–7.30 (m, 5 H), 7.26–7.25 (m, 3
H), 7.22–7.03 (m, 3 H), 6.84 (d, J = 8.7 Hz, 2 H), 6.61–6.60 (m, 2
H), 4.35 (d, J = 12.3 Hz, 1 H), 4.26 (t, J = 13.2 Hz, 1 H), 3.99–3.92
(m, 1 H), 3.80 (s, 3 H), 3.51–3.38 (m, 6 H), 2.78–2.74 (m, 1 H),
2.47–2.37 (m, 1 H), 2.05–1.92 (m, 3 H), 1.13 (t, J = 14.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 180.2, 178.2, 171.2, 167.6, 142.6,
138.5, 133.6, 132.2, 131.4, 129.5, 128.7, 127.6, 126.1, 123.1, 120.4,
70.4, 69.9, 63.1, 60.9, 57.2, 33.1, 30.4, 23.5, 21.3, 14.1.
[a]D22 +1709.4 (c 0.55, CHCl3).
IR (KBr): 704, 754, 1165, 1256, 1335, 1439, 1587, 1639, 1678
(C=N), 1709 (C=O), 2929, 2956, 3435 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.22 (d, J = 7.8 Hz, 1 H), 8.03 (d,
J = 6.9 Hz, 2 H), 7.76 (s, 1 H), 7.50–7.28 (m, 7 H), 7.24–7.07 (m, 5
H), 7.01 (d, J = 7.2 Hz, 1 H), 6.66–6.54 (m, 2 H), 4.33 (d, J = 12.6
Hz, 1 H), 4.19 (t, J = 7.8 Hz, 1 H), 3.99–3.95 (m, 1 H), 3.49–3.23
(m, 4 H), 3.10–3.04 (m, 2 H), 2.73–2.67 (m, 1 H), 2.48–2.40 (m, 1
H), 2.06–1.95 (m, 3 H), 1.14 (t, J = 14.4 Hz, 3 H).
MS (EI): m/z = 715 [M]+.
HRMS (EI): m/z [M]+ calcd for C40H39N3NiO6: 715.2192; found:
715.2189.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(4-Fluorobenzylidene)-L-
glutamate Schiff Base Complex 3g
Following the general procedure using 2g, and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3g as a red solid;
yield: 94%; mp 100–102 °C; HPLC: tR = 8.536 (minor), 19.031 min
(major); 98% de.
13C NMR (100 MHz, CDCl3): d = 180.3, 177.9, 171.2, 167.1, 142.4,
140.9, 134.1, 133.4, 132.3, 131.8, 131.4, 130.4, 129.6, 129.2, 128.8,
128.4, 127.4, 126.1, 123.3, 122.6, 120.5, 70.3, 69.5, 63.2, 61.1,
57.3, 32.9, 30.5, 23.6, 22.6, 14.1.
MS (EI): m/z = 763 [M]+.
HRMS (EI): m/z [M]+ calcd for C39H36BrN3NiO5: 763.1192; found:
[a]D22 +1316.4 (c 0.32, CHCl3).
763.1156.
IR (KBr): 704, 754, 1165, 1256, 1335, 1441, 1589, 1639, 1678
(C=N), 1709 (C=O), 2931, 2958, 3442 cm–1.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(2,6-Difluorobenzylidene)-L-
glutamate Schiff Base Complex 3j
Following the general procedure using 2j and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3j as a red solid;
yield: 92%; mp 111–113 °C; HPLC: tR = 10.865 (minor), 21.884
min (major); 97% de.
1H NMR (300 MHz, CDCl3): d = 8.22 (d, J = 8.7 Hz, 1 H), 8.03 (d,
J = 7.5 Hz, 2 H), 7.80 (s, 1 H), 7.49–7.46 (m, 2 H), 7.37–7.30 (m, 4
H), 7.26–7.10 (m, 5 H), 7.03–7.01 (m, 2 H), 6.65–6.55 (m, 2 H),
4.33 (d, J = 12.3 Hz, 1 H), 4.23–4.17 (m, 1 H), 4.00–3.93 (m, 1 H),
3.49–3.33 (m, 5 H), 3.18–3.12 (m, 1 H), 2.74–2.65 (m, 1 H), 2.48–
2.40 (m, 1 H), 2.07–1.91 (m, 3 H), 1.14 (t, J = 14.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 180.3, 178.1, 171.3, 167.4, 163.8,
161.3, 142.5, 141.3, 133.5, 132.3, 131.1, 130.8, 129.6, 128.5, 127.4,
126.0, 123.2, 120.5, 115.8, 115.6, 70.4, 69.7, 63.2, 61.1, 57.3, 38.9,
34.0, 32.8, 30.5, 22.9, 20.1, 19.1, 14.4, 11.4.
[a]D22 +1653.3 (c 0.34, CHCl3).
IR (KBr): 704, 754, 1165, 1254, 1336, 1439, 1587, 1639, 1678
(C=N), 1713 (C=O), 2872, 2926, 3433 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.26 (d, J = 9.3 Hz, 1 H), 8.01 (d,
J = 7.2 Hz, 2 H), 7.68 (s, 1 H), 7.50–7.39 (m, 3 H), 7.31–7.27 (m, 2
H), 7.24–7.09 (m, 5 H), 6.90–6.85 (m, 2 H), 6.65–6.55 (m, 2 H),
4.33 (d, J = 12.9 Hz, 1 H), 4.13–4.08 (m, 1 H), 4.04–3.87 (m, 1 H),
3.44–3.39 (m, 4 H), 3.12–2.94 (m, 2 H), 2.53–2.48 (m, 1 H), 2.40–
2.34 (m, 1 H), 2.07–1.97 (m, 3 H), 1.13 (t, J = 14.1 Hz, 3 H).
MS (EI): m/z = 703 [M]+.
HRMS (EI): m/z [M]+ calcd for C39H36FN3NiO5: 703.1992; found:
703.2002.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(4-Chlorobenzylidene)-L-
glutamate Schiff Base Complex 3h
Following the general procedure using 2h and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3h as a red solid;
yield: 93%; mp 105–107 °C; HPLC: tR = 8.994 (minor), 19.395 min
(major); 98% de.
13C NMR (100 MHz, CDCl3): d = 180.5, 177.9, 171.8, 166.2, 160.9,
158.4, 142.5, 133.7, 132.2, 131.3, 130.3, 129.8, 129.4, 128.7, 127.3,
125.8, 122.8, 120.3, 112.5, 111.7, 111.4, 70.1, 63.2, 61.4, 57.4,
33.8, 30.5, 29.6, 23.6, 20.9, 14.1.
MS (EI): m/z = 721 [M]+.
HRMS (EI): m/z [M]+ calcd for C39H35F2N3NiO5: 721.1898; found:
[a]D22 +1832.9 (c 0.69, CHCl3).
721.1903.
IR (KBr): 704, 754, 1092, 1256, 1335, 1439, 1589, 1639, 1678
(C=N), 1709 (C=O), 2870, 2956, 3446 cm–1.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(2-Furylmethylene)-L-
glutamate Schiff Base Complex 3k
Following the general procedure using 2k and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3k as a red solid;
yield: 91%; mp 110–112 °C; HPLC: tR = 8.91 (minor), 15.723 min
(major); >99% de.
1H NMR (300 MHz, CDCl3): d = 8.22 (d, J = 8.7 Hz, 1 H), 8.03 (d,
J = 7.2 Hz, 2 H), 7.79 (s, 1 H), 7.50–7.28 (m, 7 H), 7.23–7.11 (m, 5
H), 7.01 (d, J = 7.5 Hz, 1 H), 6.66–6.55 (m, 2 H), 4.33 (d, J = 12.3
Hz, 1 H), 4.19 (t, J = 14.4 Hz, 1 H), 4.02–3.95 (m, 1 H), 3.49–3.26
Synthesis 2009, No. 10, 1744–1752 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Synthesis of Glutamic Acid Derivatives
1751
[a]D22 +1605.6 (c 0.44, CHCl3).
HRMS (EI): m/z [M]+ calcd for C43H39N3NiO5: 735.2243; found:
735.2266.
IR (KBr): 706, 754, 1209, 1256, 1335, 1439, 1589, 1637, 1676
(C=N), 1701 (C=O), 2931, 2976, 3442 cm–1.
Synthesis of (R)-4a·HCl; Typical Procedure
1H NMR (300 MHz, CDCl3): d = 8.26 (d, J = 8.7 Hz, 1 H), 8.04 (d,
J = 7.5 Hz, 2 H), 7.55 (s, 1 H), 7.43–7.27 (m, 6 H), 7.22–7.07 (m, 5
H), 6.62–6.59 (m, 3 H), 4.35 (d, J = 12.9 Hz, 1 H), 4.27 (t, J = 13.2
Hz, 1 H), 4.04–3.96 (m, 1 H), 3.67–3.30 (m, 6 H), 2.97–2.92 (m, 1
H), 2.53–2.47 (m, 1 H), 2.11–2.02 (m, 3 H), 1.11 (t, J = 14.4 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 180.2, 178.5, 171.1, 167.9, 150.5,
144.7, 142.6, 133.6, 132.1, 131.4, 129.4, 129.1, 128.7, 127.5, 126.1,
123.2, 123.0, 120.3, 116.2, 112.2, 70.6, 69.8, 63.2, 60.4, 57.2, 33.1,
30.5, 23.6, 14.1.
The crystallized complex (S,2R)-3a (1 g, 1.37 mmol) was decom-
posed by refluxing a suspension in a mixture of aq 6 M HCl (1 mL)
and MeOH (15 mL) for 30 min, until the red color of the soln had
disappeared, as described previously. The reaction was cooled to r.t.
and then evaporated to dryness. H2O (20 mL) was added to the res-
idue to form a clear soln, and this soln was then separated by column
chromatography [C18-reversed phase (230–400 mesh) silica gel].
Pure H2O was employed as eluent to remove the green NiCl2 and
excess HCl; MeOH–H2O (1:1) was then used to obtain enantiomer-
ically pure product (R)-4a·HCl (363 mg, 96%).
[a]D22 +11.1 (c 0.53, 6 M HCl).
MS (EI): m/z = 675 [M]+.
HRMS (EI): m/z [M]+ calcd for C37H35N3NiO6: 675.1879; found:
675.1882.
The ligand BPB that decomposed from (S,2R)-3a was recovered by
using MeOH as eluent (505 mg, 96%), and the chromatography col-
umn was washed with MeOH (100 mL) for further use.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(3-Thienylmethylene)-L-
glutamate Schiff Base Complex 3l
Following the general procedure using 2l and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3l as a red solid;
yield: 92%; mp 112–114 °C; HPLC: tR = 9.956 (minor), 21.054 min
(major); 98% de.
5-Ethyl (2R,E)-4-(4-Nitrobenzylidene)-L-glutamate (4a)·HCl
Following the typical procedure using 3a and separation by flash
column chromatography (MeOH–H2O, 1:1) gave 4a as a white sol-
id; yield: 96%; mp 148–150 °C; HPLC (flow rate 1.0 mL/min,
l = 254 nm): tR = 40.492 min (major); >99% ee.
[a]D22 +11.1 (c 0.53, 6 M HCl).
[a]D22 +1332.7 (c 0.22, CHCl3).
IR (KBr): 852, 1257, 1346, 1519, 1598, 1624, 1703 (C=O), 2985,
3427 cm–1.
IR (KBr): 704, 754, 1165, 1257, 1335, 1439, 1589, 1637, 1674
(C=N), 1701 (C=O), 2870, 2928, 3442 cm–1.
1H NMR (300 MHz, D2O): d = 8.36 (d, J = 9.3 Hz, 2 H), 8.02 (s, 1
H), 7.66 (d, J = 11.1 Hz, 2 H), 4.40 (q, J = 21.3 Hz, 2 H), 3.95 (t,
J = 15.0 Hz, 1 H), 3.18–3.00 (m, 2 H), 1.42 (t, J = 14.4 Hz, 3 H).
13C NMR (100 MHz, D2O): d = 170.7, 168.4, 147.3, 142.1, 141.1,
129.7, 128.8, 123.8, 62.6, 51.7, 27.5, 13.4.
MS (ESI): m/z = 309 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C14H16N2O6: 331.0906;
1H NMR (300 MHz, CDCl3): d = 8.24 (d, J = 8.4 Hz, 1 H), 8.06 (d,
J = 7.8 Hz, 2 H), 7.79 (s, 1 H), 7.48–7.28 (m, 7 H), 7.24–7.11 (m, 5
H), 6.66–6.57 (m, 2 H), 4.35 (d, J = 12.9 Hz, 1 H), 4.27 (t, J = 13.2
Hz, 1 H), 4.02–3.95 (m, 1 H), 3.70–3.41 (m, 6 H), 2.94–2.82 (m, 1
H), 2.53–2.44 (m, 1 H), 2.11–2.00 (m, 3 H), 1.14 (t, J = 14.1 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 180.3, 178.5, 171.3, 168.1, 142.5,
136.0, 135.8, 133.6, 132.3, 131.4, 129.6, 128.7, 127.4, 126.0, 123.1,
120.4, 70.5, 69.6, 63.3, 61.2, 57.4, 32.9, 30.5, 23.6, 14.1.
found: 331.0922.
MS (EI): m/z = 691 [M]+.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
HRMS (EI): m/z [M]+ calcd for C37H35N3NiO5S: 691.1651; found:
691.1636.
Ni(II)–(S)-BPB/5-Ethyl (2R,E)-4-(2-Naphthylmethylene)-L-
glutamate Schiff Base Complex 3m
Acknowledgment
Following the general procedure using 2m and separation by flash
column chromatography (PE–EtOAc, 2:3) gave 3m as a red solid;
yield: 90%; mp 103–105 °C; HPLC: tR = 7.895 (minor), 23.465 min
(major); 98% de.
This work was supported by the National Natural Science Founda-
tion of China (Grants 20721003 and 20872153), International Col-
laboration Projects (Grants 2007DFB30370 and 20720102040),
and the 863 Hi-Tech Program of China (Grants 2006AA020602).
[a]D22 +1438.5 (c 0.38, CHCl3).
IR (KBr): 704, 752, 1165, 1256, 1335, 1439, 1589, 1639, 1676
(C=N), 1707 (C=O), 2926, 3057, 3433 cm–1.
References
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1H NMR (300 MHz, CDCl3): d = 8.21 (d, J = 8.4 Hz, 1 H), 8.01–
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H), 2.43–2.36 (m, 1 H), 2.21–2.04 (m, 2 H), 1.86–1.80 (m, 1 H),
1.16 (t, J = 14.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 180.3, 178.1, 171.0, 167.2, 165.7,
162.3, 162.2, 159.8, 142.4, 142.2, 140.1, 133.4, 133.1, 132.9, 132.6,
132.1, 131.3, 129.5, 128.6, 128.3, 127.5, 127.3, 126.6, 126.3, 126.0,
125.4, 123.2, 120.4, 117.3, 111.7, 70.3, 69.6, 64.1, 62.9, 60.9, 57.1,
32.9, 30.2, 22.9, 14.0.
MS (EI): m/z = 735 [M]+.
Synthesis 2009, No. 10, 1744–1752 © Thieme Stuttgart · New York

1752
J. Wang et al.
FEATURE ARTICLE
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Synthesis 2009, No. 10, 1744–1752 © Thieme Stuttgart · New York