Catalytic asymmetric 1,4-additions of β-keto esters to nitroalkenes promoted by a bifunctional homobimetallic Co2-schiff base complex

Article abstract of DOI:10.3390/molecules15010532

Catalytic asymmetric 1,4-addition of β-keto esters to nitroalkenes is described. 2.5 mol % of a homobimetallic Lewis acid/Bronsted base bifunctional Co₂-Schiff base complex smoothly promoted the reaction in excellent yield (up to 99%), diastereoselectivity, and enantioselectivity (up to >30:1 dr and 98% ee). Catalyst loading was successfully reduced to 0.1 mol %. Mechanistic studies suggested that intramolecular cooperative functions of the two Co-metal centers are important for high catalytic activity and stereoselectivity.

Full text of DOI:10.3390/molecules15010532

Molecules 2010, 15, 532-544; doi:10.3390/molecules15010532
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Catalytic Asymmetric 1,4-Additions of β-Keto Esters to
Nitroalkenes Promoted by a Bifunctional Homobimetallic
Co2-Schiff Base Complex
Makoto Furutachi, Zhihua Chen, Shigeki Matsunaga * and Masakatsu Shibasaki *
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
* Authors to whom correspondence should be addressed; E-Mails: smatsuna@mol.f.u-tokyo.ac.jp
(S.M.); mshibasa@mol.f.u-tokyo.ac.jp (M.S.).
Received: 24 December 2009; in revised form: 18 January 2010 / Accepted: 21 January 2010 /
Published: 22 January 2010
Abstract: Catalytic asymmetric 1,4-addition of β-keto esters to nitroalkenes is described.
2.5 mol % of a homobimetallic Lewis acid/Brønsted base bifunctional Co2-Schiff base
complex smoothly promoted the reaction in excellent yield (up to 99%),
diastereoselectivity, and enantioselectivity (up to >30:1 dr and 98% ee). Catalyst loading
was successfully reduced to 0.1 mol %. Mechanistic studies suggested that intramolecular
cooperative functions of the two Co-metal centers are important for high catalytic activity
and stereoselectivity.
Keywords: asymmetric catalysis; asymmetric synthesis; bifunctional catalyst; Michael
reaction; Schiff base
1. Introduction
Bifunctional concerto asymmetric catalysis is currently a hot research topic in organic synthesis.
Various chiral bifunctional metal- and organo-catalysts have been reported over the last decade [1–5].
Bifunctional asymmetric catalysts are useful for realizing high stereoselectivity and catalytic activity
via dual activation of both nucleophiles and electrophiles. As part of our ongoing research on this
issue, we recently reported the utility of bimetallic Schiff base 1 complexes (Figure 1), whose catalytic

Molecules 2010, 15
533
properties differ from those of well-established monometallic salen 2 complexes [6–8]. By utilizing
dinucleating Schiff bases, we developed heterobimetallic Cu/Sm [9], Pd/La [10–11], and Ga/Yb [12]
Schiff base complexes, including rare earth metals and homobimetallic Ni2 [13–18], Co2 [19], and Mn2 [20]
Schiff base 1 complexes and applied them to various enantioselective reactions (for selected examples
of related bifunctional bimetallic Schiff base catalysts, see ref [21–27]). In this manuscript, we report
the details of our efforts to expand the utility of bimetallic Schiff base catalysis for catalytic
asymmetric 1,4-addition of β-keto esters to nitroalkenes [28–42].
Figure 1. Structures of dinucleating Schiff base 1-H4, bimetallic M1/M2 Schiff base
complex and monometallic Co-salen 2a–2c complexes .
N
N
N
O
N
O
N
O
N
O
M1
M2
Co
OH HO
OH HO
OAc
O
O
X
X
dinucleating
Schiff base 1-H4
(R)-bimetallic M1/M2/1 complex
(R)-monometallic Co-2 complex
Co-2a: X = OMe, Co-2b: X = H
Co-2c: X = t-Bu
M1= M2= Co(III)-(OAc):
Co2(OAc)2-1 cat.
2. Results and Discussion
2.1. Homobimetallic Co2-Schiff Base Complex-catalyzed Asymmetric 1,4-Addition to Nitroalkenes
To find a suitable metal combination for the 1,4-addition reaction of β-keto esters to nitroalkenes,
we selected nitroalkene 3a and β-keto ester 4a as model substrates for the construction of adjacent
quaternary/tertiary carbon stereocenters [34–42]. The catalyst screening results are summarized in
Table 1. Heterobimetallic Schiff base Cu/Sm and Pd-La complexes smoothly promoted the reaction,
but neither diastereoselectivity nor enantioselectivity were satisfactory (entries 1–2).
A homobimetallic Ni2-Schiff base 1 complex (Figure 1) [13], which was suitable for 1,2-addition of β-
keto esters to imines, gave moderate enantioselectivity (entry 3, 74% ee). Among other metals
screened (entries 4–7), a Co2(OAc)2-1 complex[19] gave product 5aa in 95% ee (entry 4). Other
homobimetallic Mn2-1 [20], Cu2-1, and Zn2-1 catalysts resulted in poor enantioselectivity (entry 5:
32% ee, entry 6: 12% ee, entry 7: 8% ee). Because the bimetallic Co2(OAc)2-1 catalyst was stable
against air and moisture, the reaction was successfully performed using undistilled THF (containing
stabilizer and 220 ppm H2O) as a solvent under air atmosphere, and high enantioselectivity was
achieved at room temperature with 2.5 mol % catalyst (entry 8). Notably, high yield and
enantioselectivity were achieved even without solvent (entry 9, >99% conversion, 97% ee) under an
air atmosphere.

Molecules 2010, 15
Table 1. Screening of bimetallic M1/M2/Schiff base complexes for 1,4-addition of β-keto
534
ester 4a to nitroalkene 3a.
O
O
(R)-M1/M2/ 1
Ph
O2N
O2N
MeO2C
5aa
(x mol %)
+ MeO2C
Ph
solvent, rt
4a (1.1-1.5 equiv)a
3a
Entry M 1
M 2
cat. (mol %) time (h)
solvent (M)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (0.4)
THF (2.0)
neat
Dr b
3:1
% yield b % ee
1
Cu
Sm-OiPr 10
36
36
36
6
>99
>99
71
23
14 c
74
95
32
12 c
8
2
Pd
La-OiPr
Ni
10
10
10
4:1
3
Ni
6:1
4
Co-OAc
Co-OAc
26:1
3:1
86
5
Mn-OAc Mn-OAc 10
36
36
36
9
61
6
Cu
Cu
10
9:1
6
7
Zn
Zn
10
2:1
90
8 d
9 e
Co-OAc
Co-OAc
Co-OAc
Co-OAc
2.5
2.5
18:1
25:1
94
93
97
8
>99
a 1.5 equiv of 4a was used in entries 1–7, and 1.1 equiv of 4a in entries 8–9; b Yield and dr
were determined by 1H-NMR analysis of crude mixtures; c ent-4aa was obtained in major;
d
e
Undistilled THF with stabilizer containing 220 ppm H2O was used; Reaction was run
under an open-air atmosphere.
The substrate scope is summarized in Table 2. Because the Co2(OAc)2-1 catalyst is bench-stable
and storable, the catalyst stored under air at room temperature for more than three months was used in
Table 2 without loss of selectivity or reactivity. Furthermore, the reactions were performed under neat
conditions at room temperature (24–28 °C) under an open-air atmosphere. In entries 1–9, the
nitroalkene scope was investigated using β-keto ester 4a. Nitroalkenes 3b–3d with an electron-
withdrawing substituent on the aromatic ring at the para- or meta-position reacted smoothly, giving
products in 88%–94% yield, 30:1–>30:1 dr, and 97%–98% ee after 4–5 h (entries 2–4). The use of
ortho-substituted nitroalkene 3e slightly decreased the reactivity (77% yield, 14 h), but high diastereo-
and enantioselectivity were maintained (entry 5, 27:1 dr, 94% ee). Nitroalkenes 3f–3g with an
electron-donating substituent on the aromatic ring as well as β-heteroaryl nitroalkene 3h gave products
in high yield and stereoselectivity (entries 6–8). The Co2(OAc)2-1 catalyst also promoted the reaction
of less reactive β-alkyl-nitroalkene 3i, giving the product 5ia in 96% yield, >30:1 dr, and 95% ee
(entry 9). High diastereo- and enantioselectivity were also achieved with the six-membered ring β-keto
ester 4b (entry 10, >30:1 dr and 98% ee). The reaction rate, however, was decreased with β-keto ester
4b, and the product 5bb was obtained in 75% yield after 24 h. Acyclic β-keto ester 4c also gave
product 5ac in high enantioselectivity (96% ee), but the reactivity and diastereoselectivity were
decreased even with 10 mol % catalyst loading (entry 11, 73% yield, 3.3:1 dr). Trials to reduce catalyst
loading are summarized in entries 12–13. Co2(OAc)2-1 catalyst (0.2–0.1 mol %) promoted the reaction
of nitroalekene 3b with 4a under highly concentrated conditions (THF, 20 M), while maintaining high

Molecules 2010, 15
535
enantioselectivity. In entry 12, pure 5ba was isolated in 87% yield and 99% ee by recrystallization
without column chromatography purification.
Table 2. Catalytic asymmetric 1,4-addition of β-keto esters to nitroalkenes using
Co2(OAc)2-Schiff base 1 complex.a
O
R1
O
(R)-Co(III)2(OAc)2-1
R4O2C
O2N
(x mol %)
R3
O2N
R1
+
R3
R2
4 (1.1 equiv)
4a: R2, R3 = -(CH2)3-, R4 = Me
4b: R2, R3 = -(CH2)4-, R4 = Me
4c: R2 = Me, R3 = Me, R4 = Et
solvent, rt
R4O2C
R2
3
5
cat. (x
mol %)
2.5
time solvent (y
%
yieldc
>99
94
Entry
R 1
3
4
5
Dr b
% ee
(h)
8
M)
neat
1
2
Ph
3a 4a
3b 4a
3c 4a
3d 4a
3e 4a
3f 4a
3g 4a
3h 4a
3i 4a
3b 4b
3a 4c
3b 4a
3b 4a
5aa
5ba
5ca
5da
5ea
5fa
25:1
>30:1
>30:1
30:1
97
98
98
97
94
94
96
92
95
98
96
99
95
4-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
2-Br-C6H4
4-MeO-C6H4
4-Me-C6H4
2-furyl
2.5
4
neat
3
2.5
5
neat
95
4
2.5
4
neat
88
5
2.5
14
17
10
3
neat
27:1
77
6
2.5
neat
9:1
93
7
2.5
neat
5ga
5ha
5ia
22:1
93
8
2.5
neat
>30:1
>30:1
>30:1
3.3:1
>30:1
16:1
93
9
PhCH2CH2
4-Cl-C6H4
Ph
2.5
7
neat
96
10
11d
12
13
2.5
24
36
24
48
neat
5bb
5ac
5ba
5ba
75
10
neat
73
87e
4-Cl-C6H4
0.2
THF (20)
4-Cl-C6H4
0.1
THF (20)
98
a Reaction was performed under neat conditions at room temperature (24–28 °C) under air
b
1
atmosphere with 1.1 equiv of 4 unless otherwise noted; Dr was determined by H-NMR
analysis; c Isolated yield after purification by column chromatography (entries 1–11 and 13);
d 2.0 equiv of 4 was used; e 5ba was obtained in pure form by recrystallization of the crude
product without column chromatography purification.
2.2. Mechanistic Studies of Homobimetallic Co2(OAc)2-Schiff Base Complex
To gain mechanistic insight into the present homobimetallic Co2-catalysis, negative control
experiments using three monometallic Co-salen 2a–2c complexes with different substituents were
investigated (Scheme 1). In all cases, poor yield, and poor diastereoselectivity and enantioselectivity
were observed, suggesting that the bimetallic system is important for high catalytic activity as well as
stereoselectivity. In addition, initial rate kinetic studies using nitroalkene 3b and β-keto ester 4a
showed first-order dependency on the bimetallic Co2(OAc)2-Schiff base 1 complex (Figure 2). There
was a linear relationship between the enantiomeric excess of the Co2(OAc)2-1 catalyst and product 5aa

Molecules 2010, 15
536
(Figure 3). The results shown in Figure 2 and Figure 3 suggested that the active species in the present
reaction would be a monomeric Co2(OAc)2-1 catalyst. Thus, the intramolecular concerto functions of
the two Co metal centers are likely important in the present system, rather than intermolecular
concerto function of the two catalysts, which was reported for mono-metallic Co-salen complexes [8].
The postulated catalytic cycle of the reaction is shown in Scheme 2. We assume that β-keto ester
would coordinate to sterically less hindered outer Co-metal center of the Co2(OAc)2-1 catalyst. One of
Co-aryloxide (or Co-acetate) would deprotonate α-proton of β-keto esters to generate Co-enolate.
Inner Co-metal center would act as a Lewis acid to activate nitroalkenes in a similar manner as
observed in the monomeric Co-salen system. 1,4-Addition via bimetallic transition state followed by
protonation affords products and regenerates the Co2(OAc)2-1 catalyst.
Scheme 1. Negative control experiments using monomoetallic Co-salen 2a–2c complexes.
O
O
Ph
(R)-Co-cat
(5 mol %)
O2N
O2N
MeO2C
+
Ph
MeO2C
5aa
THF, rt, 8 h
3a
4a (1.1 equiv)
Co-2a: 2% yield, 10% ee, 3:1 dr
Co-2b: 23% yield, 4% ee, 2:1 dr
Co-2c:
trace
Figure 2. Initial rate kinetic studies of bimetallic Co2(OAc)2-1 catalyst.
Cl
O
(R)-Co2(OAc)2-1
O
O2N
(x mol %)
MeO2C
+
O2N
MeO2C
5ba
THF (1.0 mL), rt
Cl
3b (0.2 mmol)
4a (0.22 mmol)
initial conc. 0.22 M
initial conc. 0.2 M

Molecules 2010, 15
537
Figure 3. Linear relationship between% ee of bimetallic Co2(OAc)2-1 catalyst and% ee of
product 5aa.
O
O
Ph
Co2(OAc)2-1
O2N
(x % ee)
O2N
MeO2C
+
THF, rt
MeO2C
3a
4a
5aa
Scheme 2. Postulated catalytic cycle of the reaction.
*
*
O
N
O
N
N
O
N
MeO2C
Co OAc
O
Co OAc
O
enolate formation
Co OAc
O
Co OAc
HO
O
O
O
O
Co2(OAc)2-1
MeO
O
R
addition-
protonation
O2N
MeO2C
NO2
OMe
R
Co
O
NO2
nitroalkene activation
R
H
Co
O

Molecules 2010, 15
538
3. Experimental
3.1. General
Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier transform infrared
spectrophotometer. NMR spectra were recorded on JEOL JNM-LA500 spectrometer, operating at
500 MHz for 1H-NMR and 125.65 MHz for 13C-NMR. Chemical shifts in CDCl3 were reported in the
δ scale relative to CHCl3 (7.24 ppm) for 1H-NMR. For 13C-NMR, chemical shifts were reported on the
δ scale relative to CHCl3 (77.0 ppm) as an internal reference. Column chromatography was performed
with silica gel Merck 60 (230–400 mesh ASTM). Optical rotations were measured on a JASCO
P-1010 polarimeter. ESI mass spectra were measured on Waters micromass ZQ (for LRMS) and JEOL
JMS-T100LC AccuTOF spectrometer (for HRMS). FAB mass spectra (for HRMS) were measured on
a JEOL JMS-700 spectrometer. The enantiomeric excess (ee) was determined by HPLC analysis.
HPLC was performed on JASCO HPLC systems consisting of the following: pump, PU-2080 plus;
detector, UV-2075 plus, measured at 254 nm; column, DAICEL CHIRALCEL OD, CHIRALCEL
OD-H, or CHIRALPAK AD-H; mobile phase, hexane/2-propanol. Anhydrous Co(OAc)2 was
purchased from Aldrich and used as received.
3.2. Preparation of Co(III)2(OAc)2-Schiff Base 1 Complex
To a solution of (R)-Schiff base ligand 1-H4 (1049 mg, 2.0 mmol) in EtOH (20 mL), was added
Co(OAc)2 (708 mg, 4.0 mmol), and the mixture was stirred under air atmosphere for 12 h under reflux.
After cooling down to room temperature, H2O (10 mL) was added to the mixture and the mixture was
stirred for 1 h at room temperature under air atmosphere. The precipitate (Co2(OAc)2-1 complex) was
collected by filtration. Then, the solid was washed with H2O (×3), EtOH/hexane = 1:1 (×3), and Et2O.
The solid was dried under reduced pressure to afford the Co2(OAc)2-Schiff base 1 complex (1.047 g,
66% yield) as a brown solid. The complex was used for the asymmetric reaction without further
purification, and was stored under air at room temperature. Catalytic activity did not change for at least
6 months. Results in Tables 2 and 3 were collected using the Co2(OAc)2-1 complex stored for over
3 months. The structure was assigned to be Co2(OAc)2-1•2H2O based on elemental analysis after
recrystallization from THF/AcOEt. Anal. Calcd. for C38H30Co2N2O10 [Co2(OAc)2-1•2H2O]: C, 57.59;
H, 3.82; N, 3.53; Found: C, 57.84; H, 3.76; N, 3.58.
3.3. General Procedure for Catalytic Asymmetric 1,4-Additions of β-Keto Esters to Nitroalkenes under
Solvent-Free Conditions
To a vial were added Co2/Schiff base 1 catalyst (7.92 mg, 0.01 mmol) and β-keto ester 4a (55.3 µL,
0.44 mmol). After stirring the mixture for 5 min at room temperature, nitroalkene 3b (73.4 mg, 0.4 mmol)
was added at room temperature. The reaction mixture was stirred for 4 h at room temperature under air
1
atmosphere, and the crude residue was analyzed by H-NMR to determine the diastereomeric ratio.
The reaction mixture was purified by silica gel flash column chromatography (hexane/ethyl acetate = 3/1)
to afford 5ba (122.8 mg, 94% yield) as a colorless solid.

Molecules 2010, 15
539
(1S)-1-[(1R)-2-Nitro-1-phenylethyl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester (5aa) [34,35,37].
1
5aa is a known compound. colorless oil; IR (neat) ν 2956, 1751, 1725, 1552, 1230, 1149 cm−1; H
NMR (CDCl3) δ 1.76–2.06 (m, 4H), 2.30–2.40 (m, 2H), 3.74 (s, 3H), 4.06 (dd, J = 4.0, 11.0 Hz, 1H),
13
4.99 (dd, J = 11.0, 13.8 Hz, 1H), 5.14 (dd, J = 4.0, 13.8 Hz, 1H) , 7.20–7.32 (m, 5H); C NMR
(CDCl3) δ 19.3, 31.0, 37.9, 46.1, 53.0, 62.4, 76.3, 128.3, 128.8, 129.2, 135.2, 169.7, 212.2; ESI-MS
m/z 314 [M+Na]+; [α]D21.0 +41.7 (c 0.844, CHCl3); HPLC (DAICEL CHIRALCEL OD, hexane/2-
propanol = 90/10, flow 1.0 mL/min, detection at 220 nm) tR 14.8 min (major) and 21.5 min (minor).
Relative configuration of 5aa was determined by comparing the 1H-NMR and 13C-NMR data with the
reported data. Absolute configuration of 5aa was determined by comparison of the sign of optical
rotation with the reported data. Lit. [α]D25 + 36.5 (c, 0.84, CHCl3) [34,35].
(1S)-1-[(1R)-1-(4-Chlorophenyl)-2-nitroethyl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester
1
(5ba) [37]. Colorless solid; IR (KBr) ν 2960, 1724, 1554, 1218 cm−1; H-NMR (CDCl3) δ 1.76–1.95
(m, 3H), 1.97–2.08 (m, 1H), 2.28–2.40 (m, 2H), 3.71 (s, 3H), 4.00 (dd, J = 4.0, 11.0 Hz, 1H), 4.93
(dd, J = 11.0, 13.7 Hz, 1H), 5.11 (dd, J = 4.0, 13.7 Hz, 1H), 7.15–7.20 (m, 2H), 7.22–7.27 (m, 2H); 13C
NMR (CDCl3) δ 19.2, 31.2, 37.8, 45.5, 53.0, 62.1, 76.1, 128.9, 130.6, 133.8, 134.2, 169.6, 212.1;
ESI-MS m/z 348, 350 [M+Na]+; HRMS calcd. for C15H16ClNO5Cs [M+Cs]+: 457.9771, found
457.9763; [α]D25.6 +42.6 (c 1.05, CHCl3); HPLC (DAICEL CHIRALCEL OD, hexane/2-propanol = 90/10,
flow 1.0 mL/min, detection at 220 nm) tR 20.3 min (major) and 34.5 min (minor).
(1S)-1-[(1R)-1-(4-Bromophenyl)-2-nitroethyl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester (5ca).
1
Colorless solid; IR (KBr) ν 2958, 1756, 1720, 1552, 1232, 1155 cm−1; H-NMR (CDCl3) δ 1.77–1.99
(m, 3H), 2.00–2.12 (m, 1H), 2.31–2.42 (m, 2H), 3.73 (s, 3H), 4.00 (dd, J = 4.0, 11.5 Hz, 1H), 4.95 (dd,
J = 11.5, 14.4 Hz, 1H), 5.12 (dd, J = 4.0, 13.4 Hz, 1H), 7.12–7.16 (m, 2H), 7.40–7.44 (m, 2H);
13C-NMR (CDCl3) δ 19.2, 31.1, 37.7, 45.5, 52.9, 62.0, 76.0, 122.3, 130.9, 131.8, 134.2, 169.5, 212.0;
ESI-MS m/z 392, 394 [M+Na]+; HRMS calcd. for C15H16BrNO5Cs [M+Cs]+: 501.9266, found
501.9274; [α]D25.6 +40.2 (c 1.08, CHCl3); HPLC (DAICEL CHIRALCEL OD, hexane/2-propanol = 90/10,
flow 1.0 mL/min, detection at 220 nm) tR 25.0 min (major) and 37.6 min (minor).
(1S)-1-[(1R)-1-(3-Bromophenyl)-2-nitroethyl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester (5da).
1
Colorless oil; IR (neat) ν 2922, 1751, 1726, 1554, 1230, 1147 cm−1; H-NMR (CDCl3) δ 1.82–1.98
(m, 3H), 2.08–2.17 (m, 1H), 2.31–2.44 (m, 2H), 3.74 (s, 3H), 3.94 (dd, J = 4.0, 11.0 Hz, 1H), 4.97 (dd,
J = 11.0, 13.7 Hz, 1H), 5.17 (dd, J = 3.7, 13.7 Hz, 1H), 7.15–7.21 (m, 2H), 7.39–7.43 (m, 2H);
13C-NMR (CDCl3) δ 19.2, 31.5, 37.7, 45.7, 53.0, 62.0, 76.0, 122.7, 128.0, 130.2, 131.4, 132.2, 137.7,
169.6, 212.0; ESI-MS m/z 392, 394 [M+Na]+; HRMS calcd. for C15H16BrNO5Cs [M+Cs]+: 501.9266,
25.6
found 501.9272; [α]D
+13.1 (c 0.993, CHCl3); HPLC (DAICEL CHIRALCEL OD, hexane/2-
propanol = 90/10, flow 1.0 mL/min, detection at 220 nm) tR 21.7 min (major) and 27.2 min (minor).
(1S)-1-[(1S)-1-(2-Bromophenyl)-2-nitroethyl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester (5ea) [37].
1
Yellow solid; IR (KBr) ν 2960, 1724, 1554, 1242 cm−1; H-NMR (CDCl3) δ 1.85–1.98 (m, 2H),
2.04–2.15 (m, 1H), 2.16–2.24 (m, 1H), 2.44–2.50 (m, 2H), 3.72 (s, 3H), 4.48 (dd, J = 3.5, 10.7 Hz, 1H),
5.03 (dd, J = 10.7, 13.7 Hz, 1H), 5.45 (dd, J = 3.5, 13.7 Hz, 1H), 7.11 (ddd, J = 1.5, 7.5, 8.0 Hz, 1H),
7.28 (ddd, J = 1.2, 7.5, 8.0 Hz, 1H), 7.49 (dd, J = 1.5, 8.0 Hz, 1H), 7.55 (dd, J = 1.2, 8.0 Hz, 1H);

Molecules 2010, 15
540
13C-NMR (CDCl3) δ 19.2, 32.8, 37.7, 43.7, 52.8, 62.0, 76.9, 126.6, 128.2, 128.8, 129.5, 133.4, 136.3,
169.8, 212.4; ESI-MS m/z 392, 394 [M+Na]+; HRMS calcd. for C15H16BrNO5Cs [M+Cs]+: 501.9266,
25.6
found 501.9272; [α]D
–22.9 (c 0.926, CHCl3); HPLC (DAICEL CHIRALCEL OD, hexane/2-
propanol = 90/10, flow 1.0 mL/min, detection at 220 nm) tR 14.8 min (major) and 21.3 min (minor).
(1S)-1-[(1R)-1-(4-Methoxyphenyl)-2-nitroethyl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester
1
(5fa) [37]. Yellow solid; H-NMR (CDCl3) δ 1.75–2.07 (m, 4H), 2.27–2.43 (m, 2H), 3.73 (s, 3H),
3.75 (s, 3H), 4.03 (dd, J = 4.0, 11.0 Hz, 1H), 4.94 (dd, J = 11.0, 13.4 Hz, 1H), 5.08 (dd, J = 4.0,
13.4 Hz, 1H), 6.78–6.83 (m, 2H), 7.11–7.16 (m, 2H); 13C-NMR (CDCl3) δ 19.2, 30.7, 37.9, 45.4, 52.9,
55.0, 62.5, 76.4, 114.0, 126.8, 130.3, 159.2, 169.8, 212.3; ESI-MS m/z 344 [M+Na]+; HRMS calcd. for
C16H19NO6Cs [M+Cs]+: 454.0267, found 454.0271; [α]D26.4 +38.8 (c 0.210, CHCl3); HPLC (DAICEL
CHIRALCEL OD, hexane/2-propanol = 90/10, flow 1.0 mL/min, detection at 220 nm) tR 22.8 min
(major) and 28.5 min (minor).
(1S)-1-[(1R)-1-(4-Methylphenyl)-2-nitroethyl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester
1
(5ga) [37]. Colorless oil; IR (neat) ν 2956, 1751, 1725, 1554, 1230, 1149 cm−1; H-NMR (CDCl3)
δ 1.75–2.06 (m, 4H) , 2.28 (s, 3H), 2.28–2.40 (m, 2H), 3.74 (s, 3H), 4.03 (dd, J = 4.0, 11.0 Hz, 1H),
13
4.96 (dd, J = 11.0, 13.8 Hz, 1H), 5.11 (dd, J = 4.0, 13.8 Hz, 1H) , 7.02–7.12 (m, 4H); C-NMR
(CDCl3) δ 19.2, 20.9, 30.8, 37.9, 45.7, 52.9, 62.4, 76.3, 129.0, 129.4, 131.9, 137.9, 169.7, 212.2;
ESI-MS m/z 328 [M+Na]+; HRMS calcd. for C16H19NO5Cs [M+Cs]+: 438.0318, found 438.0329;
26.0
[α]D +24.0 (c 1.04, CHCl3); HPLC (DAICEL CHIRALCEL OD, hexane/2-propanol = 90/10, flow
1.0 mL/min, detection at 220 nm) tR 14.0 min (major) and 18.4 min (minor).
(1S)-1-[(1R)-1-Furan-2-yl-2-nitroethyl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester (5ha).
1
Yellow solid; IR (KBr) ν 2962, 1752, 1718, 1554, 1238, 1145, cm−1; H-NMR (CDCl3) δ 1.66–1.77
(m, 1H), 1.89–2.01 (m, 2H), 2.06–2.14 (m, 1H), 2.28–2.38 (m, 1H), 2.42–2.49 (m, 1H), 3.73 (s, 3H),
4.40 (dd, J = 4.3, 10.0 Hz, 1H), 4.87 (dd, J = 10.0, 13.4 Hz, 1H), 4.91 (dd, J = 4.3, 13.4 Hz, 1H), 6.16
13
(brd, J = 3.4 Hz, 1H), 6.25–6.29 (dd, J = 1.9, 3.4 Hz, 1H), 7.29–7.32 (m, 1H); C-NMR (CDCl3)
δ 19.3, 30.0, 37.8, 40.3, 53.0, 61.7, 74.3, 109.9, 110.7, 142.6, 148.9, 169.3, 211.9; ESI-MS m/z 304
[M+Na]+; HRMS calcd. for C13H15NNaO6 [M+Na]+: 304.0797, found 304.0787; [α]D25.6 +64.4 (c 1.03,
CHCl3); HPLC (DAICEL CHIRALCEL OD, hexane/2-propanol = 90/10, flow 1.0 mL/min, detection
at 220 nm) tR 12.8 min (major) and 20.0 min (minor).
(1S)-1-[(2R)-1-Nitro-4-phenylbutan-2-yl]-2-oxo-cyclopentanecarboxylic Acid Methyl Ester (5ia).
1
Colorless solid; IR (KBr) ν 2951, 2927, 1734, 1711, 1545, 1232 cm−1; H-NMR (CDCl3) δ 1.57–1.67
(m, 1H), 1.74–2.02 (m, 4H), 2.22–2.32 (m, 1H), 2.36–2.44 (m, 1H), 2.51–2.59 (m, 2H), 2.68–2.77
(m, 1H), 2.81–2.88 (m, 1H), 3.68 (s, 3H), 4.44 (dd, J = 5.5, 14.0 Hz, 1H), 4.95 (dd, J = 5.2, 14.0 Hz, 1H),
7.11–7.15 (m, 2H), 7.17–7.23 (m, 1H), 7.24–7.31 (m, 2H); 13C-NMR (CDCl3) δ 19.2, 31.2, 32.4, 33.9,
38.0, 39.9, 52.7, 62.7, 76.2, 126.3, 128.3, 128.5, 140.5, 169.8, 213.1; ESI-MS m/z 342 [M+Na]+;
25.5
HRMS calcd. for C17H21NNaO5 [M+Na]+: 342.1317, found 342.1325; [α]D +76.2 (c 1.08, CHCl3);
HPLC (DAICEL CHIRALCEL AD-H, hexane/2-propanol = 4/1, flow 1.0 mL/min, detection at 220 nm)
tR 7.3 min (major) and 7.9 min (minor).

Molecules 2010, 15
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(1S)-1-[(1R)-1-(4-Chlorophenyl)-2-nitroethyl]-2-oxo-cyclohexanecarboxylic Acid Methyl Ester (5bb).
Colorless oil; IR (neat) ν 2951, 1712, 1554, 1492, 1236 cm−1; 1H-NMR (CDCl3) δ 1.44–1.52 (m, 1H),
1.54–1.78 (m, 3H), 1.99–2.06 (m, 1H), 2.09–2.16 (m, 1H), 2.41–2.55 (m, 2H), 3.73 (s, 3H), 3.98 (dd,
J = 3.4, 11.3 Hz, 1H), 4.74 (dd, J = 11.3, 13.4 Hz, 1H), 5.01 (dd, J = 3.4, 13.4 Hz, 1H), 7.09–7.12 (m, 2H),
13
7.24–7.29 (m, 2H); C-NMR (CDCl3) δ 22.3, 27.7, 36.9, 41.3, 47.2, 52.6, 63.0, 77.3, 126.7, 130.7,
133.9, 134.2, 170.0, 206.7; ESI-MS m/z 362, 364 [M+Na]+; HRMS calcd. for C16H18ClNO5Cs
[M+Cs]+: 471.9928, found 471.9925; [α]D
–73.0 (c 1.03, CHCl3); HPLC (DAICEL CHIRALCEL
26.5
OD-H, hexane/2-propanol = 90/10, flow 1.0 mL/min, detection at 220 nm) tR 13.4 min (major) and
8.9 min (minor).
(2S,3R)-Ethyl 2-acetyl-2-methyl-4-nitro-3-phenylbutanoate (5ac). Colorless oil; IR (neat) ν 2923,
1734, 1710, 1552, 1093, 701 cm−1; 1H-NMR (CDCl3) δ 1.21 (s, 3H), 1.29 (t, J = 7.3Hz, 3H), 2.15 (s, 3H),
4.12 (dd, J = 3.4, 11 Hz, 1H), 4.26 (q, J = 7.3 Hz, 2H), 4.87 (dd, J = 3.4, 13.4 Hz, 1H), 4.94 (dd, J = 11,
13
13.4 Hz, 1H), 7.08– 7.15 (m, 2H), 7.25– 7.31 (m,3H); C-NMR (CDCl3) δ 14.0, 20.1, 26.5, 47.7,
62.1, 62.5, 77.5, 128.4, 128.8, 129.0, 135.4, 171.2, 204.2; ESI-MS m/z 316 [M+Na]+; HRMS calcd. for
25.0
C15H19NNaO5 [M+Na]+: 316.1161, found 316.1156; [α]D –53.1 (c 0.20, CHCl3); HPLC (DAICEL
CHIRALCEL OD, hexane/2-propanol = 40/10, flow 1.0 mL/min, detection at 220 nm) tR 7.1 min
(major) and 19.2 min (minor).
4. Conclusions
In summary, we developed a highly enantioselective catalytic asymmetric 1,4-addition of β-keto
esters to nitroalkenes for the construction of adjacent quaternary/tertiary carbon stereocenters.
Bifunctional Co2-Schiff base 1 complex smoothly promoted the reaction in excellent yield (up to
99%), diastereoselectivity, and enantioselectivity (up to >30:1 dr and 98% ee). Catalyst loading was
successfully reduced to 0.1 mol %. Mechanistic studies suggested that intramolecular cooperative
functions of the two Co-metal centers are important for high catalytic activity and stereoselectivity.
Acknowledgements
This work was supported by Grant-in-Aid for Scientific Research on Priority Areas (No. 20037010,
Chemistry of Concerto Catalysis) from MEXT, Takeda Science Foundation, and Kato Memorial
Bioscience Foundation.
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Sample Availability: Samples of the compounds Co2(OAc)2-1 and Ni2-1 are available from the authors.
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