Diastereoselective Michael reaction of chiral nickel(II) glycinate with nitroalkenes for asymmetric synthesis of β-substituted α,γ- diaminobutyric acid derivatives in water

Article abstract of DOI:10.1007/s00726-011-0870-x

We have developed the first operationally simple and environmentally benign protocol for the aqueous asymmetric Michael addition reaction of chiral nickel( II) glycinate with nitroalkenes. The reactions proceeded smoothly in the presence of TBAB (tetrabut

Full text of DOI:10.1007/s00726-011-0870-x

Amino Acids (2012) 42:1685–1694
DOI 10.1007/s00726-011-0870-x
ORIGINAL ARTICLE
Diastereoselective Michael reaction of chiral nickel(II) glycinate
with nitroalkenes for asymmetric synthesis of b-substituted
a,c-diaminobutyric acid derivatives in water
•
Jiang Wang Xun Ji Jianmei Shi
•
•
•
Haifeng Sun Hualiang Jiang Hong Liu
•
Received: 28 October 2010 / Accepted: 22 February 2011 / Published online: 8 March 2011
Ó Springer-Verlag 2011
Abstract We have developed the first operationally
simple and environmentally benign protocol for the aque-
ous asymmetric Michael addition reaction of chiral nick-
el(II) glycinate with nitroalkenes. The reactions proceeded
smoothly in the presence of TBAB (tetrabutyl ammonium
bromide) in neat water at room temperature and provided
good yields of b-substituted a,c-diaminobutyric acid
derivatives with excellent diastereoselectivities.
(Walsh et al. 2007). In this regard, the development of
asymmetric Michael reactions in water has been inten-
sively pursued (Giorgi et al. 2005; Vishnumaya and Singh
2007).
Chiral b-substituted a,c-diaminobutyric acid derivatives
are found in many biologically active compounds, and
chiral auxiliaries/ligands are used in asymmetric reactions
(Bellis et al. 2006; Dose et al. 2008; Lam et al. 2008; Tsai
et al. 2007). Chiral a,c-diaminobutyric acids are frequently
found in various bioactive compounds, such as HA-966
(Cervo et al. 2004), L-687414 (Hargreaves et al. 1993),
polymyxin B (Urban et al. 2011), and synthetic inhibitors
(Belliotti et al. 2005; Field et al. 2007) (Fig. 1). Catalytic
diastereoselective synthesis of these chiral building blocks
mainly relies on asymmetric Michael addition reactions.
Indeed, several examples of such reactions using chiral
auxiliaries have been reported (Caputo et al. 2006; Huang
et al. 2009; Yan et al. 2006). However, all these reactions
were performed in organic solvents. In this report, we have
focused on nickel(II) glycinate, which is important for
asymmetric synthesis of chiral amino acids (Belokon et al.
1985; Cai et al. 2004; Soloshonok et al. 2001; Taylor et al.
2004; Wang et al. 2008). While significant progress has
been made in the use of chiral nickel(II) glycinate in
asymmetric synthesis of enantiopure amino acids, the
development of diastereoselective Michael reactions using
nickel(II) glycinate has proven to be a challenging task
(Cai et al. 2001; Soloshonok et al. 2000, 2001). To the best
of our knowledge, the application of nickel(II) glycinate for
Michael reactions in water has not been described to date.
In this study, we report the efficient synthesis of optically
active b-substituted a,c-diaminobutyric acid derivatives
using asymmetric Michael addition reactions of chiral
nickel(II) glycinate with nitroalkenes (Lu et al. 2006; Luo
et al. 2009; Tsubogo et al. 2009; Zhu et al. 2009) in water;
Keywords Michael reaction Á Nickel(II) glycinate Á
Asymmetric synthesis Á Diaminobutyric acids
Introduction
Organic reactions in aqueous media are receiving consid-
erable attention in modern chemistry because of their
substantial environmental and economic advantages over
conventional reactions in organic solvents (Herrerias et al.
2007; Li 2005). As a reaction medium, water has attracted
the interest of both academia and industry because of its
useful properties such as safety, nontoxicity, inflammabil-
ity, low cost, and environmental friendliness (Li and Chen
2006; Lindstrom 2002). Indeed, water is preferred over
toxic organic solvents as a solvent in industrial procedures
Electronic supplementary material The online version of this
article (doi:10.1007/s00726-011-0870-x) contains supplementary
material, which is available to authorized users.
J. Wang Á X. Ji Á J. Shi Á H. Sun Á H. Jiang Á H. Liu (&)
State Key Laboratory of Drug Research, Shanghai Institute
of Materia Medica, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, 555 Zu chong zhi Road,
Shanghai 201203, People’s Republic of China
e-mail: hliu@mail.shcnc.ac.cn
123

1686
J. Wang et al.
in this process, the carbon–carbon bond and two stereo-
genic centers are efficiently created in a single reaction
with a high control of the relative and absolute stereo-
chemistry (Scheme 1).
(Table 1, entries 9 and 10). However, while higher tem-
perature (60°C) accelerated the reaction, it had a detri-
mental effect on the diastereoselectivity. From the
viewpoint of practical application, we chose NaOH as a
base, TBAB as a phase-transfer catalyst, and water as a
solvent to probe the generality of the Michael addition
process at ambient temperature (Table 1, entry 4). Single
X-ray crystal structure analysis revealed that the major
product was the syn diastereomer (Fig. 2).
Results and discussion
Our initial efforts were focused on establishing the optimal
conditions for the asymmetric Michael addition (Table 1).
Gratifyingly, in an initial screening of a set of phase-
transfer catalysts, TBAB (tetrabutyl ammonium bromide)
was found to be the best promoter (Table 1, entry 4). A
survey of the available bases revealed that sodium
hydroxide (NaOH) was the optimal base for the asym-
metric Michael reaction; the reaction with NaOH pro-
ceeded efficiently to provide a good yield giving the adduct
3a with an excellent de value (99%) and a good syn:anti
value (88:12). Similar results were obtained when the
catalyst loading was lowered to 0.5 equiv. (Table 1, entry
5). Under the same conditions, other bases such as potas-
sium hydroxide (KOH), potassium tert-butoxide (tBuOK),
and sodium carbonate (Na2CO3) provided lower yields and
diastereoselectivities (Table 1, entries 6–8). Further opti-
mization revealed that good yields and excellent diastere-
oselectivities were achieved when the reaction was
performed at various temperatures from 5 to 60°C using
NaOH as the base and TBAB as the phase-transfer catalyst
We then investigated the scope of the asymmetric
Michael addition reactions using these optimized reaction
conditions (Table 2). The new methodology provided a
facile approach to obtain a range of highly functionalized
chiral adducts 3 with the generation of two new stereogenic
centers with high diastereoselectivity. The reaction system
was inert to the steric effect. The three regioisomeric
nitroalkenes 2 effectively participated in the Michael
reactions while providing equally high levels of yield and
selectivity (Table 2, entries 1–4). In general, functionalized
aryl nitroalkenes are excellent substrates for the reaction,
regardless of the electronic effect. Nitroalkenes with either
electron-withdrawing or electron-donating groups at the
para position were good substrates (Table 2, entries 5–7).
4-Bromo- and 2,4-dichloro-substituted substrates also
reacted well under these conditions and showed high dia-
stereoselectivities (Table 2, entries 8 and 9). The process
could also be applied to heterocyclic compounds (Table 2,
entries 10–12). The less reactive aliphatic substrates also
Fig. 1 Structures of some
biologically important
compounds containing
a,c-diaminobutyric acid
motif
Me
N
N
OH
OH
H2N
H2N
O
O
HA-966
L-687,414
O
HO S OH
O
O
NH HN
H2N
O
O
HO
O
NH
HN
HN
NH2
O
O
H
N
H
N
N
H
N
H
O
O
O
NH2
NH HN
NH2
NH2
O
O
HO
PolymyxinB
123

Diastereoselective Michael reaction of chiral nickel(II) glycinate
1687
Scheme 1 Asymmetric
Michael reactions of a chiral
nickel(II) glycinate and
nitroalkenes
O
R
O
NO2
NO2
*
N
O
R
O
*
Ni
2
Ni
N
N
N
N
N
H2O
*
*
O
O
NaOH, TBAB
(S)-1
(S, 2S, 3R)-3
Gly MeOH
Ni(NO3)2
KOH NaH
6 N HCl
MeOH
Recovery >96%
O
O
R
N
H
N
.
NiCl2
NO2 HCl
+
*
HO
*
*
NH2
O
(S)-BPB
(2S, 3R)-4
Table 1 Optimization of the reaction conditions
O
O
Ph
NO2
*
O
H2O
O
*
NO2
Ni
Ni
N
N
N
N
+
N
N
O
NaOH, TBAB
*
*
O
(S)-1
2a
(S, 2S, 3R)-3a
Entry Base
PTC
–
Temp (°C) Yield (%)a syn:antib de (%)c
1
NaOH
23
0
–
–
2
NaOH TEBA 23
NaOH TEAB 23
NaOH TBAB 23
NaOH TBAB 23
60
53
68
64
69
62
54
72
70
65:35
64:36
88:12
86:14
82:18
78:22
74:26
68:32
87:13
43
3
56
4
5d
[99
[99
90
6
KOH
TBAB 23
7
tBuOK TBAB 23
Na2CO3 TBAB 23
NaOH TBAB 60
83
8
86
9
90
10
NaOH TBAB
5
[99
Reactions were run with 0.20 mmol of (S)-1, 0.21 mmol of 2a in
10 mL of water with 0.24 mmol base and 0.20 mmol PTC for 24 h
a
Yield of the major products after silica gel column chromatography
b
Determined by HPLC analysis
Fig. 2 The crystal structure of (S,2S,3R)-3a by X-ray analysis
c
Determined by chiral HPLC analysis (see Supporting Information
for details)
d
methanol/6 N HCl afforded a 96% yield of the target
amino acid (2S,3R)-2-amino-4-nitro-3-phenylbutanoic acid
(2S,3R)-4a, and (S)-BPB was recovered quantitatively with
enantioselectivity [99% (Scheme 2). The optically active
(2S,3R)-2-amino-4-nitro-3-phenylbutanoic acid (2S,3R)-4a
can be easily reduced to obtain a high yield of the corre-
0.5 equiv. catalyst was used
engaged in the reaction with good to high de values,
although they provided low yields (Table 2, entries 13–15).
The chiral ligand BPB (Scheme 2) can be easily recovered
quantitatively and reused after a simple procedure. The
decomposition of compound (S,2S,3R)-3a under standard
conditions by heating a suspension of (S,2S,3R)-3a in
sponding
(2S,3R)-2,4-diamino-3-phenylbutanoic
acid
(2S,3R)-5a (Scheme 3).
123

1688
J. Wang et al.
Table 2 Asymmetric Michael reactions of chiral nickel(II) glycinate (S)-1 with nitroalkenes 2
O
O
R
NO2
*
H2O
O
O
*
Ni
Ni
N
N
NO2
N
N
+
R
N
N
NaOH, TBAB
*
*
O
O
(S)-1
2
(S, 2S, 3R)-3
syn:antib
Entry
Product
R
Yield (%)a
de (%)c
1
(S,2S,3R)-3a
(S,2S,3R)-3b
(S,2S,3R)-3c
(S,2S,3R)-3d
(S,2S,3R)-3e
(S,2S,3R)-3f
(S,2S,3R)-3g
(S,2S,3R)-3h
(S,2S,3R)-3i
(S,2S,3R)-3j
(S,2S,3R)-3k
(S,2S,3R)-3l
(S,2S,3R)-3m
(S,2S,3R)-3n
(S,2S,3R)-3o
Ph
68
71
66
70
72
73
72
76
79
68
65
70
57
59
46
88:12
85:15
83:17
85:15
82:18
80:20
81:19
83:17
80:20
75:25
81:19
79:21
82:18
83:17
80:20
[99
97
2
2-Cl–C6H4
3-Cl–C6H4
4-Cl–C6H4
4-Me–C6H4
3
[99
97
4
5
97
6
4-OMe–C6H4
4-NO2–C6H4
4-Br–C6H4
2,4-Cl2–C6H4
2-furyl
98
7
94
8
97
9
98
10
11
12
13
14
15
[99
99
5-me-2-thiophenyl
2-naphthyl
Cy
77
98
i-Pr
97
t-Bu
96
Reactions were run with 0.20 mmol of (S)-1, 0.21 mmol of 2 in 10 mL of water with 0.24 mmol NaOH, and 0.20 mmol TBAB for 24 h under
ambient conditions
a
Yield of the major products after silica gel column chromatography
b
Determined by HPLC analysis
c
Determined by chiral HPLC analysis (see Supporting Information for details)
Conclusion
complexes in important carbon–carbon bond-forming
reactions in water.
In conclusion, we have established the first asymmetric
Michael addition reaction of chiral nickel(II) glycinate with
nitroalkenes in pure water. This transformation, which
results in the formation of carbon–carbon bond and two
stereogenic centers, enables the facile synthesis of good
yields of highly functionalized chiral b-substituted a,c-di-
aminobutyric acid derivatives with excellent diastereose-
lectivities. The reactions were efficient when performed
with electron-deficient, electron-rich, and sterically hin-
dered nitroalkenes and provide functionalized Michael
products with excellent diastereoselectivities. A broad
range of aryl-, heteroaryl-, and alkyl-derived nitroalkenes
can be employed under operationally simple and safe
conditions. The absolute configuration of one product was
determined. Further studies will focus on the mechanistic
aspects and further applications of other chiral nickel(II)
Experimental
The reagents (chemicals) were purchased from commercial
sources, and used without further purification. Petroleum
ether = PE. Analytical thin layer chromatography TLC
used HSGF 254 (0.15–0.20 mm thickness). All products
1
were characterized by their NMR and MS spectra. H and
13C NMR spectra were recorded in CDCl3 on a 300 MHz
instrument. Chemical shifts were reported downfield
from TMS. LR- and HRMS were measured on a Finnigan
MAT-95, LCQ-DECA spectrometer. Optical rotations
were reported as follows: [a]2D2 (ca. g/100 mL, solvent).
Analytical HPLC was carried out using the Dionex ASI-
100 automated sampler, Chiralpak IA column; loading loop:
123

Diastereoselective Michael reaction of chiral nickel(II) glycinate
1689
Scheme 2 Decomposition of
Ni(II) complex 3a to release
amino acid and recovery of the
ligand (S)-BPB
O
Ph
NO2
O
O
Ph
HCl/MeOH
O
N
Ni
NO2
+
N
H
N
+
NiCl2
HO
N
NH2
N
*
O
*
O
(S,2S,3R)-3a
(2S,3R)-4a
(S)-BPB
O
Ph
O
Ph
3,431 cm-1; MS (ESI, m/z): 647 [M ? H]?; HRMS (ESI)
calcd for C35H32N4NaNiO5 [M ? Na]? 669.1624, found
669.1620; HPLC (Chiralpak IA, i-propanol/n-hexane =
H2, Pd/C
NO2
NH2
HO
HO
NH2
NH2
40/60, flow rate 1.0 mL/min, k = 220 nm), tmajor
16.924 min, de [ 99%.
=
(2S,3R)-4a
(2S,3R)-5a
Scheme 3 Hydrogenation of 4a to afford the target amino acid 5a
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-(2-chloro-
phenyl) buranoic acid Schiff base complex 3b
5 lL; eluent: isocratic mixture n-hexane-i-PrOH (60:40);
flow rate 1 mL/min, k = 220 nm; unless otherwise stated.
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 71%; mp
98–100°C; [a]2D2 = ?1,324 (ca. 0.48 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.40 (d, J = 8.7 Hz, 1H),
7.93 (d, J = 7.5 Hz, 2H), 7.70–7.44 (m, 8H), 7.32–7.29
(m, 3H), 7.21–7.16 (m, 2H), 6.76–6.66 (m, 2H), 4.93–4.86
(m, 1H), 4.38–4.32 (m, 1H), 4.24–4.04 (m, 3H), 3.28–3.22
(m, 1H), 2.77–2.72 (m, 1H), 2.27–2.17 (m, 3H), 1.90–1.83
(m, 1H), 1.28–1.23 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3) d 180.1, 176.6, 173.2, 1,423.3, 136.6, 133.8, 133.0,
132.9, 131.4, 130.4, 130.2, 129.9, 129.6, 129.4, 128.8,
128.7, 128.1, 127.4, 126.8, 125.5, 123.2, 120.6, 75.9, 71.9,
70.5, 63.4, 56.9, 42.2, 30.8, 22.8 ppm; IR (KBr) 704, 752,
1,165, 1,256, 1,336, 1,439, 1,552, 1,585, 1,641, 1,672
(C=N), 2,852, 2,924, 3,433 cm-1; MS (ESI, m/z): 681
[M ? H]?; HRMS (ESI) calcd for C35H31ClN4NaNiO5
[M ? Na]? 703.1234, found 703.1226. HPLC (Chiralpak
IA, i-propanol/n-hexane = 40/60, flow rate 1.0 mL/min,
k = 220 nm), tminor = 7.658 min, tmajor = 19.521 min,
de = 97%.
General procedure for the synthesis of (S,2S,3R)-3a
The Ni(II) complex of glycine 1 (100 mg, 0.201 mmol)
was dissolved in water (10 mL). The nitrostyrene 2a
(31 mg, 0.211 mmol), NaOH (9.64 mg, 0.241 mmol), and
TBAB (6.80 mg, 0.201 mmol) were added under ambient
conditions. The reaction mixture was then stirred at room
temperature for 24 h. The crude reaction mixture was
concentrated, and then extracted with ethyl acetate (three
times). The combined organic layers were dried with
Na2SO4, concentrated and purified by flash column chro-
matography (petroleum ether/ethyl acetate) to give
(S,2S,3R)-3a as a red solid.
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-phenyl
buranoic acid Schiff base complex 3a
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 68%; mp
109–111°C; [a]2D2 = ?1,761 (ca. 0.24 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.26 (d, J = 8.4 Hz, 1H),
7.97 (d, J = 7.2 Hz, 2H), 7.63–7.54 (m, 6H), 7.37–7.29
(m, 5H), 7.20–7.15 (m, 3H), 6.75–6.67 (m, 2H), 4.93–4.85
(m, 1H), 4.41–4.29 (m, 2H), 4.18 (d, J = 12.6 Hz, 1H),
3.56–3.53 (m, 1H), 3.41 (d, J = 12.3 Hz, 1H), 3.23 (t,
J = 12.3 Hz, 1H), 2.89–2.81 (m, 1H), 2.24–2.12 (m, 2H),
1.95–1.78 (m, 2H), 1.50–1.44 (m, 1H) ppm; 13C NMR
(100 MHz, CDCl3) d 181.9, 176.5, 272.5, 143.5, 134.8,
133.9, 133.7, 133.1, 132.9, 131.9, 131.2, 130.4, 130.0,
129.9, 129.6, 129.5, 129.4, 129.1, 128.9, 128.8, 127.9,
126.8, 125.8, 123.6, 120.9, 75.4, 71.8, 68.2, 59.4, 54.9,
47.1, 31.3, 23.7 ppm; IR (KBr) 702, 752, 1,165, 1,256,
1,338, 1,439, 1,554, 1,583, 1,641, 1,668 (C=N), 2,922,
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-(3-chloro-
phenyl) buranoic acid Schiff base complex 3c
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 66%; mp
98–100°C; [a]2D2 = ?1,486 (ca. 0.42 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.23 (d, J = 8.7 Hz, 1H),
8.06 (d, J = 6.9 Hz, 2H), 7.51–7.48 (m, 2H), 7.34–7.29
(m, 3H), 7.20–7.06 (m, 5H), 6.95–6.94 (m, 1H), 6.66–6.61
(m, 1H), 6.55–6.54 (m, 1H), 6.43 (s, 1H), 6.17 (d,
J = 7.5 Hz, 1H), 4.92 (d, J = 10.8 Hz, 1H), 4.78–4.73 (m,
1H), 4.38 (d, J = 12.6 Hz, 1H), 4.17 (d, J = 6.9 Hz, 1H),
3.64–3.49 (m, 5H), 2.95–2.91 (m, 1H), 2.71–2.64 (m, 1H),
2.33–2.29 (m, 1H), 2.19–2.12 (m, 1H) ppm; 13C NMR
123

1690
J. Wang et al.
(100 MHz, CDCl3) d 180.3, 176.8, 172.5, 143.2, 134.6,
133.8, 133.1, 132.9, 131.4, 131.3, 130.3, 129.4, 128.9,
128.8, 128.7, 128.3, 127.8, 126.7, 125.6, 123.2, 120.7,
75.9, 71.4, 70.3, 63.6, 60.4, 57.2, 46.4, 30.6, 22.9, 21.0,
14.1 ppm; IR (KBr) 702, 754, 1,165, 1,256, 1,338, 1,439,
1,554, 1,641, 1,680 (C=N), 2,850, 2,922, 3,433 cm-1; MS
(ESI, m/z): 681 [M ? H]?; HRMS (ESI) calcd for C35H31
ClN4NaNiO5 [M ? Na]? 703.1234, found 703.1232.
HPLC (Chiralpak IA, i-propanol/n-hexane = 40/60,
flow rate 1.0 mL/min, k = 220 nm), tmajor = 9.844 min,
de [ 99%.
(KBr) 704, 1,165, 1,256, 1,338, 1,439, 1,552, 1,585, 1,641,
1,672 (C=N), 2,922, 3,431 cm-1; MS (ESI, m/z): 661
[M ? H]?; HRMS (ESI) calcd for C36H34N4NaNiO5
[M ? Na]? 683.1780, found 683.1764; HPLC (Chiralpak
IA, i-propanol/n-hexane = 40/60, flow rate 1.0 mL/min,
k = 220 nm), tminor = 8.417 min, tmajor = 17.224 min,
de = 97%.
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-(4-methoxy-
phenyl) buranoic acid Schiff base complex 3f
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 73%; mp
116–118°C; [a]2D2 = ?1,684 (ca. 0.43 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.26 (d, J = 8.4 Hz, 1H),
7.99 (d, J = 7.2 Hz, 2H), 7.63–7.61 (m, 3H), 7.32–7.28
(m, 3H), 7.18–7.06 (m, 6H), 6.76–6.70 (m, 3H), 4.91–4.84
(m, 1H), 4.35–4.18 (m, 4H), 3.86 (s, 3H), 3.56–3.51 (m,
1H), 3.44–3.40 (m, 1H), 3.29–3.23 (m, 1H), 2.98–2.91 (m,
1H), 2.21–2.14 (m, 2H) 2.00–1.93 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3) d 180.3, 176.8, 172.3, 160.2, 143.1,
133.8, 133.7, 133.2, 131.4, 130.4, 130.2, 129.4, 128.8,
12.87, 127.8, 126.7, 126.1, 125.6, 123.2, 120.6, 114.7,
76.0, 71.5, 70.4, 63.7, 57.4, 55.3, 53.4, 45.9, 30.5,
22.8 ppm; IR (KBr) 704, 754, 1,165, 1,256, 1,338, 1,439,
1,514. 1,552, 1,583, 1,641, 1,670 (C=N), 2,929,
3,435 cm-1; MS (ESI, m/z): 677 [M ? H]?; HRMS (ESI)
calcd for C36H34N4NaNiO6 [M ? Na]? 699.1730, found
699.1732; HPLC (Chiralpak IA, i-propanol/n-hexane =
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-(4-chloro-
phenyl) buranoic acid Schiff base complex 3d
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 70%; mp
105–107°C; [a]2D2 = ?1,197 (ca. 0.36 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.29 (d, J = 6.6 Hz, 1H),
7.98 (d, J = 5.4 Hz, 2H), 7.64–7.42 (m, 6H), 7.19–7.17
(m, 4H), 6.76–6.69 (m, 2H), 4.91–4.85 (m, 1H), 4.34–4.19
(m, 3H), 3.57–3.44 (m, 2H), 3.27 (t, J = 7.2 Hz, 1H),
2.98–2.94 (m, 1H), 2.29–2.14 (m, 3H), 1.99–1.93 (m, 1H)
ppm; 13C NMR (100 MHz, CDCl3) d 180.2, 176.7, 172.4,
143.1, 134.5, 133.7, 133.6, 133.1, 132.8, 131.4, 130.2,
129.4, 128.9, 128.7, 128.6, 127.7, 126.6, 125.5, 123.1,
120.6, 75.8, 70.4, 70.3, 63.6, 60.3, 57.2, 46.3, 30.5, 22.9,
20.9, 14.1 ppm; IR (KBr) 702, 1,165, 1,256, 1,338, 1,439,
1,553, 1,583, 1,643, 1,670 (C=N), 2,924, 3,433 cm-1; MS
(ESI, m/z): 681 [M ? H]?; HRMS (ESI) calcd for
40/60, flow rate 1.0 mL/min, k = 220 nm), tminor
9.086 min, tmajor = 17.865 min, de = 98%.
=
C35H31ClN4NaNiO5
[M ? Na]?
703.1234,
found
703.1229; HPLC (Chiralpak IA, i-propanol/n-hexane =
40/60, flow rate 1.0 mL/min, k = 220 nm), tminor
7.878 min, tmajor = 14.463 min, de = 97%.
=
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-(4-nitro-
phenyl) buranoic acid Schiff base complex 3g
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-p-tolyl
buranoic acid Schiff base complex 3e
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 72%; mp
148–150°C; [a]2D2 = ?1,529 (ca. 0.48 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.42 (d, J = 8.1 Hz, 2H),
8.30 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 6.6 Hz, 2H),
7.65–7.56 (m, 5H), 7.31–7.27 (m, 4H), 7.36–7.31 (m, 3H),
7.21–7.14 (m, 3H), 6.77–6.70 (m, 2H), 5.04–4.96 (m, 1H),
4.30–4.16 (m, 3H), 3.71–3.67 (m, 1H), 3.49–3.40 (m, 1H),
3.29–3.23 (m, 1H), 2.88–2.83 (m, 1H), 2.24–2.18 (m, 2H),
1.71–1.68 (m, 1H), 1.53–1.49 (m, 1H), 1.26 (s, 1H) ppm;
13C NMR (100 MHz, CDCl3) d 180.3, 176.3, 173.2, 148.6,
143.3, 141.9, 133.9, 133.7, 133.4, 133.0, 131.4, 130.5,
129.7, 129.6, 128.9, 128.8, 127.7, 126.6, 125.3, 124.4,
123.4, 120.9, 94.2, 75.4, 70.2, 63.7, 57.2, 46.4, 30.6, 29.7,
22.7 ppm; IR (KBr) 704, 754, 856, 1,165, 1,256, 1,346,
1,439, 1,522, 1,556, 1,645, 1,672 (C=N), 2,924,
3,435 cm-1; MS (ESI, m/z): 692 [M ? H]?; HRMS (ESI)
calcd for C35H31N5NaNiO7 [M ? Na]? 714.1475, found
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 72%; mp
121–123°C; [a]2D2 = ?1,595 (ca. 0.34 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.25 (d, J = 7.2 Hz, 1H),
7.97 (d, J = 5.1 Hz, 2H), 7.63–7.60 (m, 3H), 7.36–7.28
(m, 5H), 7.25–7.15 (m, 5H), 6.74–6.67 (m, 2H), 4.89–4.83
(m, 1H), 4.40–4.35 (m, 1H), 4.26 (d, J = 2.7 Hz, 1H), 4.20
(d, J = 9.3 Hz, 1H), 3.54–3.51 (m, 1H), 3.41 (d,
J = 9.3 Hz, 1H), 3.24 (t, J = 5.7 Hz, 1H), 2.93–2.87 (m,
1H), 2.44 (s, 3H), 2.25–2.21 (m, 1H), 2.13–2.07 (m, 1H),
1.98–1.95 (m, 2H) 1.51–1.45 (m, 1H) ppm; 13C NMR
(75 MHz, CDCl3) d 180.2, 176.9, 172.4, 143.2, 138.8,
133.9, 133.8, 133.2, 132.9, 131.5, 130.3, 130.1, 129.5,
129.3, 128.8, 128.7, 127.9, 126.7, 125.7, 123.2, 120.7,
76.0, 71.5, 70.4, 63.7, 57.3, 46.2, 30.5, 22.7, 21.2 ppm; IR
123

Diastereoselective Michael reaction of chiral nickel(II) glycinate
1691
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-furan-2-yl
buranoic acid Schiff base complex 3j
714.1497; HPLC (Chiralpak IA, i-propanol/n-hexane =
40/60, flow rate 1.0 mL/min, k = 220 nm), tminor
9.925 min, tmajor = 19.109 min, de = 94%.
=
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 68%; mp
93–95°C; [a]2D2 = ?1,632 (ca. 0.36 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.27 (d, J = 8.7 Hz, 1H),
7.97 (d, J = 7.2 Hz, 2H), 7.65–7.56 (m, 4H), 7.33–7.31
(m, 3H), 7.21–7.14 (m, 3H), 6.71–6.62 (m, 3H), 6.52–6.51
(m, 1H), 4.80–4.72 (m, 1H), 4.43–4.21 (m, 3H), 3.80–3.73
(m, 1H), 3.58–3.53 (m, 1H), 3.35–3.18 (m, 2H), 2.55–2.17
(m, 4H), 2.03–1.97 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3) d 180.2, 176.7, 172.8, 162.5, 148.9, 143.5, 143.1,
133.8, 133.7, 132.9, 132.8, 131.5, 130.3, 129.4, 129.3,
128.8, 128.7, 127.9, 126.5, 125.7, 123.3, 120.6, 111.3,
109.7, 74.4, 70.3, 63.5, 56.9, 39.7, 36.4, 31.4, 22.9 ppm; IR
(KBr) 704, 752, 1,165, 1,256, 1,338, 1,439, 1,556, 1,639,
1,672 (C=N), 2,852, 2,922, 3,435 cm-1; MS (ESI, m/z):
637 [M ? H]?; HRMS (ESI) calcd for C33H30N4NiO6
[M ? Na]? 659.1417, found 659.1422; HPLC (Chiralpak
IA, i-propanol/n-hexane = 40/60, flow rate 1.0 mL/min,
k = 220 nm), tmajor = 16.928 min, de [ 99%.
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-(4-bromo-
phenyl) buranoic acid Schiff base complex 3h
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 76%; mp
104–106°C; [a]2D2 = ?1,456 (ca. 0.52 g/100 mL, CHCl3);
1H NMR(300 MHz, CDCl3) d 8.26 (d, J = 8.7 Hz, 1H), 7.99
(d, J = 7.2 Hz, 2H), 7.71–7.61 (m, 5H), 7.31–7.27 (m, 4H),
7.23–7.15 (m, 5H), 6.72–6.69 (m, 2H), 4.92–4.84 (m, 1H),
4.30–4.24 (m, 2H), 4.20–4.16 (m, 1H), 3.47–3.42 (m, 2H),
3.38–3.30 (m, 1H), 3.27 (t, J = 7.8 Hz, 1H), 2.93–2.88 (m,
1H), 2.32–2.27 (m, 1H), 2.19–2.14 (m, 1H), 2.04–1.96 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3) d 180.3, 176.2,
171.1, 148.6, 142.0, 133.9, 133.7, 133.4, 133.1, 131.3, 130.9,
130.5, 129.7, 129.6, 128.9, 128.8, 127.7, 126.6, 125.3, 124.3,
120.9, 75.4, 71.1, 70.2, 63.8, 60.3, 57.2, 46.4, 30.6, 29.6, 22.7,
20.9, 14.1, 13.7 ppm; IR (KBr) 704, 754, 856, 1,165, 1,256,
1,346, 1,439, 1,522, 1,556, 1,645, 1,672 (C=N), 2,924,
3,435 cm-1; MS (ESI, m/z): 727 [M ? H]?; HRMS (ESI)
calcd for C35H31BrN4NaNiO5 [M ? Na]? 749.1350, found
749.1345; HPLC (Chiralpak IA, i-propanol/n-hexane = 40/
60, flow rate 1.0 mL/min, k = 220 nm), tminor = 9.29 min,
tmajor = 18.177 min, de = 97%.
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-(5-methy-
thiophene-3-yl) buranoic acid Schiff base complex 3k
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 65%; mp
95–97°C; [a]2D2 = ?1,643 (ca. 0.29 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.29 (d, J = 6.3 Hz, 1H),
7.98 (d, J = 5.4 Hz, 1H), 7.61–7.60 (m, 3H), 7.33–7.29
(m, 3H), 7.21–7.14 (m, 4H), 6.94–6.87 (m, 2H), 6.73–6.67
(m, 2H), 4.85–4.79 (m, 1H), 4.34–4.25 (m, 3H), 4.15–4.06
(m, 4H), 3.77–3.73 (m, 1H), 3.54–3.51 (m, 1H), 3.32–3.28
(m, 1H), 3.16–3.10 (m, 1H), 2.55 (s, 3H), 1.41–1.37(m,1H)
ppm; 13C NMR (100 MHz, CDCl3) d 179.9, 176.5, 172.3,
142.9, 140.4, 133.6, 133.4, 133.2, 133.0, 132.5, 131.2,
130.6, 130.0, 129.2, 128.6, 128.5, 128.4, 127.5, 126.8,
126.3, 125.9, 125.5, 123.0, 120.3, 76.1, 70.9, 70.2, 65.2,
63.9, 63.4, 60.0, 56.9, 41.2, 30.3, 22.4, 20.7, 18.8, 15.1,
13.9 ppm; IR (KBr) 704, 752, 1,165, 1,256, 1,338, 1,377,
1,439, 1,552, 1,581, 1,641, 1,668 (C=N), 2,922, 2,956,
3,060, 3,435 cm-1; MS (ESI, m/z): 667 [M ? H]?; HRMS
(ESI) calcd for C34H32N4NaNiO5S [M ? Na]? 689.1345,
found 689.1332; HPLC (Chiralpak IA, i-propanol/
n-hexane = 40/60, flow rate 1.0 mL/min, k = 220 nm),
tmajor = 13.860 min, de [ 99%.
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-(2,4-dichloro-
phenyl) buranoic acid Schiff base complex 3i
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 79%; mp
88–90°C; [a]2D2 = ?1,124 (ca. 0.38 g/100 mL, CHCl3); 1H
NMR (300 MHz, CDCl3) d 8.25 (d, J = 7.2 Hz, 1H),
7.97 (d, J = 5.1 Hz, 2H), 7.63–7.60 (m, 3H), 7.36–7.28
(m, 5H), 7.25–7.15 (m, 5H), 6.74–6.67 (m, 2H), 4.89–4.83
(m, 1H), 4.40–4.35 (m, 1H), 4.26 (d, J = 2.7 Hz, 1H), 4.20
(d, J = 9.3 Hz, 1H), 3.54–3.51 (m, 1H), 3.41 (d,
J = 9.3 Hz, 1H), 3.24 (t, J = 5.7 Hz, 1H), 2.93–2.87 (m,
1H), 2.44 (s, 3H), 2.25–2.21 (m, 1H), 2.13–2.07 (m, 1H),
1.98–1.95 (m, 2H) 1.51–1.45 (m, 1H) ppm; 13C NMR
(100 MHz, CDCl3) d 180.2, 176.9, 172.4, 143.2, 138.8,
133.9, 133.8, 133.2, 132.9, 131.5, 130.3, 130.1, 129.5,
129.3, 128.8, 128.7, 127.9, 126.7, 125.7, 123.2, 120.7,
76.0, 71.5, 70.4, 63.7, 57.3, 46.2, 30.5, 22.7, 21.2 ppm; IR
(KBr) 704, 1,165, 1,256, 1,338, 1,439, 1,552, 1,585, 1,641,
1,672 (C=N), 2,922, 3,431 cm-1; MS (ESI, m/z): 715
[M ? H]?; HRMS (ESI) calcd for C35H30Cl2N4NaNiO5
[M ? Na]? 737.0844, found 737.0856; HPLC (Chiralpak
IA, i-propanol/n-hexane = 40/60, flow rate 1.0 mL/min,
k = 220 nm), tminor = 7.506 min, tmajor = 20.102 min,
de = 98%.
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-naphthalen-
2-yl buranoic acid Schiff base complex 3l
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 70%; mp
123

1692
J. Wang et al.
100–102°C; [a]2D2 = ?1,573 (ca. 0.28 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.21 (d, J = 8.4 Hz, 1H),
8.03–7.76 (m, 7H), 7.64–7.55 (m, 7H), 7.42–7.35 (m, 4H),
7.19–7.09 (m, 3H), 6.77–6.67 (m, 2H), 5.06–4.99 (m, 1H),
4.54–4.47 (m, 1H), 4.35–4.34 (m, 1H), 4.15–3.96 (m, 3H),
3.77–3.71 (m, 1H), 3.26–3.22 (m, 1H), 3.05 (t, J = 9.0 Hz,
1H), 2.54–2.46 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3)
d 180.2, 176.5, 172.2, 143.0, 133.6, 133.5, 133.4, 133.1,
132.6, 131.8, 131.1, 130.7, 130.1, 129.8, 129.5, 129.3,
128.7, 128.5, 128.4, 128.2, 128.1, 127.6, 127.4, 126.6,
125.4, 123.0, 120.4, 75.6, 70.0, 63.5, 57.3, 46.3, 29.9, 20.8,
13.9 ppm; IR (KBr) 704, 752, 1,165, 1,256, 1,338, 1,439,
1,552, 1,641, 1,668 (C=N), 2,922, 3,057, 3,435 cm-1; MS
(ESI, m/z): 697 [M ? H]?; HRMS (ESI) calcd for
C39H34N4NaNiO5 [M ? Na]? 719.1780, found 719.1791;
HPLC (Chiralpak IA, i-propanol/n-hexane = 40/60, flow
rate 1.0 mL/min, k = 220 nm), tminor = 9.167 min,
tmajor = 18.461 min, de = 77%.
8.06 (d, J = 5.4 Hz, 2H), 7.57–7.49 (m, 3H), 7.35–7.33
(m, 2H), 7.22–7.12 (m, 4H), 6.89–6.85 (m, 2H), 4.71–4.66
(m, 1H), 4.41 (d, J = 9.6 Hz, 1H), 4.26–4.11 (m, 4H),
3.37–3.29 (m, 3H), 2.81–2.77 (m, 1H), 2.57–2.48 (m, 1H),
2.41–2.36 (m, 1H), 2.14–2.09 (m, 2H), 1.45 (s, 6H) ppm;
13C NMR (100 MHz, CDCl3) d 180.5, 177.8, 172.7, 142.7,
133.8, 132.8, 131.5, 130.3, 129.3, 128.9, 127.6, 126.7,
126.2, 123.2, 120.8, 114.7, 72.2, 70.4, 69.2, 65.4, 63.7,
57.1, 52.3, 45.9, 30.8, 28.4, 26.3, 23.9, 23.3, 17.2 ppm;
IR (KBr) 700, 756, 1,165, 1,259, 1,440, 1,551, 1,639,
1,674 (C=N), 2,962, 3,415 cm-1; MS (ESI, m/z): 613
[M ? H]?; HRMS (ESI) calcd for C32H34N4NaNiO5
[M ? Na]? 635.1780 found 635.1765; HPLC (Chir-
alpak IA, i-propanol/n-hexane = 40/60, flow rate 1.0 mL/
min, k = 220 nm), tminor = 8.19 min, tmajor = 17.216 min,
de = 97%.
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-tetrtbutoxyl
buranoic acid Schiff base complex 3o
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-cyclohexyl
buranoic acid Schiff base complex 3m
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 46%; mp
98–100°C; [a]2D2 = ?1,386 (ca. 0.43 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.35 (d, J = 9.0 Hz, 1H),
8.04 (d, J = 7.5 Hz, 2H), 7.56–7.54 (m, 3H), 7.34–7.30
(m, 3H), 7.17–7.12 (m, 2H), 6.96–6.94 (m, 1H), 6.67–6.54
(m, 2H), 4.92–4.85 (m, 1H), 4.45–4.41 (m, 1H), 4.37–4.23
(m, 1H), 3.64–3.47 (m, 5H), 3.26–3.25 (m, 1H), 2.81–2.74
(m, 1H) 2.59–2.53 (m, 1H), 2.46–2.42 (m, 1H) 1.56 (s, 9H)
ppm; 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 ppm; IR (KBr) 704, 752, 1,165, 1,256,
1,338, 1,375, 1,439, 1,470, 1,554, 1,586, 1,643, 1,670
(C=N), 2,924, 3,433 cm-1; MS (ESI, m/z): 627 [M ? H]?;
HRMS (ESI) calcd for C33H36N4NaNiO5 [M ? Na]?
649.1937, found 649.1252; HPLC (Chiralpak IA, i-propa-
nol/n-hexane = 40/60, flow rate 1.0 mL/min, k = 220 nm),
tminor = 10.422 min, tmajor = 20.165 min, de = 96%.
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 57%; mp
102–104°C; [a]2D2 = ?1,357 (ca. 0.40 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.30 (d, J = 6.6 Hz, 1H),
8. 03 (d, J = 5.1 Hz, 1H), 7.56–7.49 (m, 3H), 7.34–7.30
(m, 2H), 7.26–7.23 (m, 1H), 7.18–7.14 (m, 2H), 6.90
(d, J = 6.3 Hz, 1H), 6.68–6.59 (m, 2H), 4.73 (br, 2H),
4.62–4.56 (m, 1H), 4.39 (d, J = 9.3 Hz, 1H), 4.25–4.20
(m, 1H), 4.13 (m, 1H), 3.64–3.47 (m, 4H), 3.28–3.20
(m, 2H), 2.89–2.81 (m, 1H), 2.58–2.52 (m, 1H), 2.43–2.37
(m, 1H), 2.21–2.03 (m, 2H), 1.54–1.44 (m, 3H), 1.24–1.14
(m, 3H), 0.93–0.91 (m, 1H) ppm; 13C NMR (100 MHz,
CDCl3) d 180.2, 177.9, 172.9, 142.8, 133.9, 133.7, 133.2,
132.8, 131.5, 130.2, 129.3, 129.2, 128.9, 128.8, 127.9,
126.6, 125.9, 123.0, 120.7, 73.4, 70.6, 69.1, 63.7, 57.1,
46.3, 36.3, 33.6, 30.9 27.6, 26.8, 26.4, 25.9, 23.8 ppm; IR
(KBr) 704, 752, 1,165, 1,256, 1,336, 1,439, 1,551, 1,643,
1,672 (C=N), 2,854, 2,926, 3,442 cm-1; MS (ESI, m/z):
653 [M ? H]?; HRMS (ESI) calcd for C35H38N4NaNiO5
[M ? Na]? 675.2093, found 675.2094; HPLC (Chiralpak
IA, i-propanol/n-hexane = 40/60, flow rate 1.0 mL/min,
k = 220 nm), tminor = 8.74 min, tmajor = 24.082 min,
de = 98%.
Procedure for the synthesis of (2S,3R)-4a
The crystallized complex (S,2S,3R)-3a (1 g, 1.5 mmol)
was decomposed by refluxing a suspension in a mixture of
aqueous 6 N HCl (1 mL) and MeOH (15 mL) for 30 min,
until the red color of the solution disappeared, as described
previously. The reaction was cooled to room temperature
and then evaporated to dryness. Water (20 mL) was added
to the residue to form a clear solution, and this solution was
then separated by column chromatography on C18-reversed
phase (230–400 mesh) silica gel. Pure water as an eluent
Ni(II)-(S)-BPB/(2S,3R)-2-amino-4-nitro-3-isopropyl
buranoic acid Schiff base complex 3n
Obtained as a red solid by flash column chromatography
(petroleum ether/ethyl acetate 1:1), yield 59%; mp
100–102°C; [a]2D2 = ?1,572 (ca. 0.42 g/100 mL, CHCl3);
1H NMR (300 MHz, CDCl3) d 8.22 (d, J = 6.3 Hz, 1H),
123

Diastereoselective Michael reaction of chiral nickel(II) glycinate
1693
References
was employed to remove the green NiCl2 and excess HCl;
MeOH/Water (1/1) was then used to obtain optically pure
product (2S,3R)-4a (323 mg, 96%). The ligand BPB that
decomposed from (S,2S,3R)-3a was recovered by MeOH
eluent (571 mg, 96%), and the column chromatography
was washed with 100 mL MeOH, for further use.
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Obtained as a white solid by flash column chromatography
(MeOH/water 1:1), yield 96%; mp 248–250°C;
[a]2D2 = ?3.2 (ca. 0.34 g/100 mL, 6 N HCl); 1H NMR
(300 MHz, D2O) d 7.42–7.39 (m, 3H), 7.32–7.29 (m, 2H),
5.18 (d, J = 10.8 Hz, 1H), 4.56–4.41 (m, 2H), 4.15–4.11
(m, 1H) ppm; 13C NMR (100 MHz, D2O) d 169.1, 131.8,
129.7, 129.5, 128.4, 128.2, 75.8, 54.3, 43.4 ppm; IR (KBr)
706, 1,335, 1,381, 1,404, 1,498, 1,551, 1,614, 2,953, 3,246,
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Procedure for the synthesis of (2S,3R)-5a
In a hydrogenation flask was placed compound (2S,3R)-4a
(200 mg, 0.893 mmol) and methanol (10 mL) before the
addition of Pd/C. The resulting mixture was pressurized to
hydrogen and mechanically stirred at room temperature for
4 h. The reaction mixture was filtered and the filtrate was
concentrated in a rotary evaporator to afford the crude
product. The crude residue was purified by column chro-
matography on C18-reversed phase (230–400 mesh) silica
gel (water/methanol = 11/9) to give 5a as a white solid in
90% yield, and the column chromatography was washed
with 100 mL of methanol for further use.
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(2S,3R)-2-Amino-4-nitro-3-phenylbutanoic acid 5a
Obtained as a white solid by flash column chromatography
(MeOH/water 1:1), yield 90%; mp 242–244°C;
[a]2D2 = ?11.1 (ca. 0.48 g/100 mL, 6 N HCl); 1H NMR
(300 MHz, D2O) d 7.42–7.31 (m, 5H), 5.29–5.16 (m, 1H),
4.55–4.54 (m, 2H), 4.17–4.11 (m, 1H), ppm; 13C NMR
(100 MHz, D2O) d 169.1, 131.8, 129.7, 129.5, 129.4,
129.3, 129.2, 129.1, 128.9, 128.4, 128.0, 75.6, 75.4, 55.1,
54.2, 47.0, 43.3 ppm; MS (ESI, m/z): 195 [M ? H]?;
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Acknowledgments We gratefully acknowledge financial support
from the National Natural Science Foundation of China (Grants
20721003 and 20872153), the 863 Hi-Tech Program of China (Grants
2006AA020602 and 2006AA10A201), National S&T Major Projects
(2009ZX09301-001, 2009ZX09501-001 and 2009ZX09501-010).
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