A homodinuclear cobalt complex for the catalytic asymmetric Michael reaction of β-ketoesters to nitroolefins

Article abstract of DOI:10.1039/c8ob00773j

A homodinuclear Co₂/aminophenol sulfonamide complex has been developed for the asymmetric Michael reaction of β-ketoesters with nitroolefins. This procedure is capable of tolerating a wide range of substrates and excellent results (up to 99% yield, >99: 1 dr and 98% ee) can also be obtained. Moreover, the reaction could be carried out on a 50 mmol scale without any decrease in the enantioselectivity and reactivity. On the basis of the results of mechanistic studies, we proposed that the Co₂/2a complex would be the active species and a possible catalytic cycle was described.

Full text of DOI:10.1039/c8ob00773j

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A Homodinuclear Cobalt Complex for Catalytic Asymmetric
Michael Reaction of β-Ketoesters to Nitroolefins
Guanghui Chen,a‡ Guojuan Liang,a‡ Yiwu Wang,b Ping Denga and Hui Zhoua
Received 00th January 20xx,
Accepted 00th January 20xx
A homodinuclear Co2/aminophenol sulfonamide complex has been developed for the asymmetric Michael reaction of β-
ketoesters with nitroolefins. The procedure is capable of tolerating a wide range of substrate and excellent results (up to
99% yield, >99:1 dr and 98% ee) can also be obtained. Moreover, the reaction could be carried out on a 50 mmol scale
without any decrease in the enantioselectivity and reactivity. On the basis of the results of mechanistic studies, we
DOI: 10.1039/x0xx00000x
www.rsc.org/
proposed that the Co2/2a complex would be the active species and
a possible catalytic cycle was described.
In the preliminary study, aminophenol sulfonamide ligand 2a
(Scheme 1) was complexed with various metal salts to catalyze
the asymmetric Michael reaction of β-ketoesters 3a with
nitroolefins 4a. A significant effect of the central metal ion on
the diastereoselectivity and enantioselectivity was observed,
as shown in Table 1. Products of low ee and dr were observed
with
Introduction
Chiral bimetallic catalysts have become a powerful tool in
asymmetric reactions.1 Over the past decades, intensive
efforts have been devoted to the development of new families
of bimetallic asymmetric catalysts.2-6 BINOL,2 linked BINOL,3
GluCAPO/FujiCAPO,4 Schiff base,5 bis-ProPhenol,6 AzePhenol7
etc. have been successfully developed as multidentate ligands
to construct bimetallic complexes. As part of our ongoing
studies of cooperative bimetallic complexes in asymmetric
catalysis, we recently reported a new type of aminophenol
sulfonamide ligands and their complexes of Cu/Sm8a and
Ni/Ni,8b as well as the utility in enantioselective Henry and
Mannich reactions. The Michael addition is one of the
powerful tools for synthesis of functionalized organic
molecules.9 The asymmetric Michael addition of cyclic β-
ketoesters to nitroolefins provides a convenient and direct
O
NH
O
O
NH
N
Ph
Ph
Ph
NH
Cu
N
Ni
Ni
Sm OiPr
O
O
O
Ph
SO2
O
O
N
N
S
S
N
OO
H
O2S
Ar
Ar
p-Tolyl
p-Tolyl
Ni2/2b
Cu/Sm/1
route towards nitrogen-containing ketoesters with
a
quaternary carbon stereocenter.10 Although great progress has
been achieved, the achievement of high enantioselectivities
with low catalyst loading remains an ongoing goal. Compared
with organocatalysts, metal complexes are capable of
combining with enolized β-ketoesters to form a chelate-
ordered transition state. Herein, we report a homodinuclear
2a: Ar = 4-Me-C6H4
2b: Ar = 4-NO2-C6H4
2c: Ar = 4-MeO-C6H4
2d: Ar = 4-tBu-C6H4
2e: Ar = 1-Naphthyl
2f: Ar = 2-Naphthyl
Ph
Ph
NH
OH HN
HN
Ph
Ph
Ph
Ph
NH
O
O
NH
Ph
Co
Co
NH
S
N
N
Ph
O
Ts
Ts
O
O
O
S
O
Ar
Ar
Co2/2a
Co complex (Scheme 1) for the 1,4-addition of β-ketoesters to Scheme 1. Aminophenol sulfonamide ligands and dinuclear complexes.
nitroolefins.
Ni(acac)2, Zn(acac)2, Fe(acac)2, Fe(acac)3, Mn(acac)2, Mn(acac)3,
or Zr(acac)2 as the Lewis acid (Table 1, entries 2-8).
Fortunately, the corresponding Co(acac)2 complex could
catalyze the reaction to give 5aa in >30:1 dr and 90% ee (Table
1, entry 1). Different cobalt salts were also screened and
Co(acac)2 gave the best results (Table 1, entries 9-12).
Results and discussion
Further optimization of the reaction conditions was aimed
at exploring the effectiveness of Co(acac)2 with other
aminophenol sulfonamide ligands (Table 2). With regard to the
chiral backbone moiety, (R,R)-1,2-diphenylethylenediamine
derived ligands were found to give superior selectivity to (R,R)-
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1,1'-binaphthyl-2,2'-diamine derived ones (Table 2, entries 1
Subsequently, we examined the effect of solvents in the
vs. 2). Then the benzenesulfonyl moiety of the ligands was presence of 10 mol% 2a-Co(acac)2 complex. As shown in Table
screened. The bulkier group or electron-withdrawing 4. Excellent selectivities were obtained in most of the solvents
substituent provide worse results (Table 2, entries 3, and 5-7). examined (Table 4, entries 2-6). When the halogenated
The electron-donating substituent on the benzenesulfonyl hydrocarbons were used as solvents, the reaction rate was
moiety maintained the selectivities with decreasing yield much improved (Table 4, entries 2-4). Therefore, CH2ClCH2Cl
(Table 2, entry 4). Accordingly, 2a with para-methyl was chosen as the best solvent for this reaction considering
substituted benzenesulfonyl group was chosen as the best the reactivity and selectivity (Table 4, entry 3).
ligand for the next investigation.
Table 3. Screening of bases in the asymmetric Michael reaction of β-ketoesters 3 with
nitroolefins 4a.a
Table 1. Screening of central metal ions in the asymmetric Michael reaction of β-
ketoesters 3 with nitroolefins 4a.a
10 mol% 2a
O
20 mol% Co(acac)2
20 mol% base
O
Ph
10 mol% 2a
20 mol% Metal salt
20 mol% N-methyl morpholine
Ph
NO2
+
COOEt
O
NO2
O
Ph
THF, rt
Ph
COOEt
NO2
+
COOEt
NO2
THF, rt
3a
4a
5aa
COOEt
3a
4a
5aa
Entry
Base
NMMd
Et3N
Time (h)
Yield (%) b
drc
>30:1
13:1
18:1
5:1
eec
90
80
87
42
22
21
Entry
Metal salt
Co(acac)2
Ni(acac)2
Zn(acac)2
Fe(acac)2
Fe(acac)3
Mn(acac)2
Mn(acac)3
Zr(acac)2
Co(OAc)2
CoCl2
Yield (%)b
77
drc
eec
1
2
3
4
5
6
19
12
22
19
12
12
77
86
56
57
89
88
1d
>30:1
3:1
6:1
5:1
5:1
5:1
5:1
4:1
3:1
4:1
2:1
6:1
90
2
iPr2NEt
DMAPe
KOAc
2
90
3
81
6
6:1
4
55
8
K2CO3
5:1
5
45
8
6
69
0
a All reactions were carried out on 0.2 mmol scale (nitroolefin) and β-ketoester (2
equiv.) in THF (0.5 mL) at rt. b Isolated yield. c Determined by chiral HPLC. d NMM
= N-methyl morpholine. e DMAP = 4-dimethylaminopyridine.
7
76
0
8
99
0
9
35
8
10
11
12
86
20
26
2
Table 4. Effect of solvent in the asymmetric Michael reaction of β-ketoesters 3 with
nitroolefins 4a. a
Co(ClO4)2
Co(O-iPr)2
87
89
10 mol% 2a
20 mol% Co(acac)2
20 mol% N-methyl morpholine
O
a
O
Ph
Unless otherwise noted, all reactions were carried out on 0.2 mmol scale
Ph
NO2
(nitroolefin) and β-ketoester (2 equiv.) in THF (0.5 mL) at rt for 36 h. b Isolated
yield. c Determined by chiral HPLC. d The reaction time was 19 h.
+
COOEt
NO2
rt
COOEt
3a
4a
5aa
Table 2. Ligand screening in the asymmetric Michael reaction of β-ketoesters 3 with
nitroolefins 4a.a
Entry
Base
THF
Time (h)
Yield (%) b
drc
eec
90
96
98
95
90
94
1
2
3
4
5
6
19
2
77
97
99
97
98
99
>30:1
>30:1
>50:1
21:1
10 mol% L
CH2Cl2
O
O
20 mol% Co(acac)2
Ph
ClCH2CH2Cl
CH3Cl
2
20 mol% N-methyl morpholine
Ph
NO2
+
COOEt
NO2
THF, rt
4
COOEt
CH3CN
12
12
>30:1
>30:1
3a
4a
5aa
Toluene
a All reactions were carried out on 0.2 mmol scale (nitroolefin) and β-ketoester (2
equiv.) in a certain solvent (0.5 mL). b Isolated yield. c Determined by chiral HPLC.
Entry
Ligand
1
Time (h)
Yield (%) b
drc
3:1
eec
9
1
2
3
4
5
6
7
4
19
77
22
61
51
46
53
2a
19
10
10
10
10
10
>30:1
9:1
90
36
91
84
72
86
To reduce the catalyst loading, the catalytic system was
further optimized, with the results summarized in Table 5.
When the catalyst loading was reduced from 10 mol% to 2
mol%, a lower reaction rate was obtained with smaller ee
(Table 5, entries 1-3). When the ratio of 2a to Co(acac)2 was
changed from 1:2 to 1:1, a greatly reduced ee was obtained
with smaller dr and reaction rate (Table 5, entries 3 vs. 4). To
our delight, when the molar ratio of 2a/Co(acac)2 was
increased from 1:2 to 1:3 or 1:4, the product was obtained
with higher enantioselectivity (Table 5, entries 3 vs. 5-7). The
reaction rate could recovery and the selectivities were
maintained when the amount of base increased to 40 mol%
(Table 5, entries 8 vs 1 and 6). The screening of temperature
showed 0 oC was the best (Table 5, entries 8-11). The molar
2b
2c
>30:1
23:1
18:1
29:1
2d
2e
2f
a
All reactions were carried out on 0.2 mmol scale (nitroolefin) and β-ketoester
(2 equiv.) in THF (0.5 mL). b Isolated yield. c Determined by chiral HPLC.
Next, different bases were examined. As shown in Table 3,
the selectivities of the reaction decreased when more alkaline
amines or inorganic bases were used instead of N-methyl
morpholine probably becacuse of a stronger background
reaction.
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ratio of nitroolefin to ketoester could reduce to 1:1.1 with an and slightly lower ee (Table 5, entries 16 vs. 14 and 15). Hence,
acceptable reaction time (Table 5, entries 13 vs. 10 and 12). On we found that treat of β-ketoester 3a and nitroolefin 4a in the
the basis of these results, the catalyst loading successfully presence of 2a (1 mol%) and Co(acac)2 (3 mol%) together with
reduced to 1 mol% with maintained yield, dr, and ee (Table 5, N-methyl morpholine (40 mol%) gave the desired product 5aa
entry 14). At the ratio of 1:4 (2a/Co(acac)2), the catalyst in 99% yield with >50:1 dr and 98% ee.
loading could reduce to 0.5 mol% with double reaction time
Table 5. Further optimization of the reaction.a
x mol% 2a
O
y mol% Co(acac)2
z mol% N-methyl morpholine
CH2ClCH2Cl
O
Ph
Ph
NO2
+
COOEt
NO2
COOEt
3a
4a
5aa
Entry
1
x
10
5
y
20
10
4
Ratio of 2a/Co
1/2
z
Molar ratio of nitroolefin to ketoester
T (oC)
rt
Time (h)
Yield (%)b
drc
eec
98
97
91
16
93
96
96
98
96
98
97
98
98
97
84
94
20
20
20
20
20
20
20
40
40
40
40
40
40
40
40
40
1:2
1:2
2
99
98
77
42
73
76
74
91
71
99
96
96
99
99
81
97
>50:1
>50:1
>30:1
9:1
2
1/2
rt
12
23
23
23
23
23
3
3
2
1/2
1:2
rt
4
2
2
1/1
1:2
rt
5
2
5
1/2.5
1/3
1:2
rt
>30:1
>30:1
>30:1
>50:1
>30:1
>50:1
>50:1
>50:1
>50:1
>50:1
>30:1
>50:1
6
2
6
1:2
rt
7
2
8
1/4
1:2
rt
8
2
6
1/3
1:2
rt
9
2
6
1/3
1:2
35
0
3
10
11
12
13
14d
15e
16e
2
6
1/3
1:2
3
2
6
1/3
1:2
-10
0
3
2
6
1/3
1:1
23
12
12
72
24
2
6
1/3
1:1.1
1:1.1
1:1.1
1:1.1
0
1
3
1/3
0
0.5
0.5
1.5
2
1/3
0
1/4
0
a Unless otherwise noted, all reactions were carried out on 0.2 mmol scale (nitroolefin) and β-ketoester in CH2ClCH2Cl (0.5 mL). b Isolated yield. c Determined by chiral
d
e
HPLC. The reaction was carried out on 0.4 mmol scale (nitroolefin) and β-ketoester in CH2ClCH2Cl (1.0 mL). The reaction was carried out on 0.8 mmol scale
(nitroolefin) and β-ketoester in CH2ClCH2Cl (2.0 mL).
Under the optimal reaction conditions (Table 5, entry 14), a selectivities (Table 7, entries 1-3). Ethyl acetoacetate (3e) gave
variety of nitroolefin substrates including aryl substrates with the corresponding product in high enantioselectivities (99%
electron-donating substituents or electron-withdrawing and 99% ee) with high reactivity on 1 mol% catalyst loading,
substituents, heteroaromatic, aliphatic, condensed-ring and α, but the diastereoselectivity was decreased sharply (1:1 dr,
β-unsaturated nitroolefins were investigated and the desired Table 7, entry 4).
products were obtained in excellent yields (only one
To gain a preliminary insight into the mechanism, the
exception, Table 6, entry 2) with excellent diastereomeric relationship between the ee values of ligand 2a and product
ratios and excellent ee (Table 6, entries 1-19). For the less 5aa at different ratios of 2a to Co(acac)2 (1:2, 1:3 and 1:4) was
reactive aliphatic nitroolefins, more catalyst loading was investigated (Figure 1).11 A perfect linear effect was observed
required (Table 6, entries 20 and 21). Some substrates were at these examined ratios with the addition of N-methyl
selected to try the catalyst loading of 0.5 mol% and the morpholine, which suggested that the monomeric catalyst
corresponding products were obtained in good to excellent might be the active species. Without the addition of N-methyl
yields with excellent dr and ee, while the reaction time was morpholine, to our surprise, resulted in a negative non-linear
prolonged (Table 6, entries 22-25). Moreover, the reaction effect. This change in non-linear effect indicated either a
could be carried out on a 50 mmol scale without any decrease change in mechanism or a structural change of the chiral
in the enantioselectivity and reactivity (Table 6, entry 26).
catalyst. The ESI-MS studies were also carried out.12 All the
Other β-ketoesters were also reacted in this catalytic system spectrums of the 1:1, 1:2, 1:3, and 1:4 2a/Co(acac)2 mixture
and the scope and limitations of β-ketoesters are summarized whether or not to add the N-methyl morpholine displayed ions
in Table 7. The reaction conditions were optimized for each β- at m/z 1078 and 1096, which corresponded to Co2/2a
ketoesters. When five-membered oxygen heterocycle (3b), six- Moreover, all the spectrums of the mixture of nitroolefin 4a
membered ring (3c), and acyclic 3-substutited β-ketoesters (3d and 2a/Co(acac)2 in the ratios of 1:2, 1:3, and 1:4 whether or
were used in this asymmetric transformation, increased not to add the N-methyl morpholine displayed ions at m/z
catalyst loading was required for good reactivities and 1227, 1228 or 1245, which corresponded to [Co2/2a 4a]. On
.
)
+
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the basis of these analysis, we speculated that the Co2/2a the enolate oxygen is coordinated to Co in the more Lewis
complex (Figure 1)13 would be the active species.
acidic equatorial position for maximal activation, whereas the
keto functionality is positioned by a suitable Co by avoiding the
steric repulsion of Ts (TS1-I vs., TS1-II, Figure 2).
Table 6. Asymmetric Michael addition of ethyl 2-oxocyclopentanecarboxylate to
different nitroolefins. a
1 mol% 2a
O
3 mol% Co(acac)2
O
R
40 mol% N-methyl morpholine
R
NO2
+
COOEt
NO2
0 oC, CH2ClCH2Cl
COOEt
3a
4
5
Entry
1
R
Time (h)
12
Yield (%) b
99
drc
eec
97
97
97
97
96
97
96
96
97
97
97
97
94
95
95
Ph (5aa)
>50:1
>99:1
>30:1
>50:1
>99:1
>99:1
>30:1
>30:1
>30:1
>30:1
>30:1
>50:1
>30:1
>50:1
>50:1
2
2-MeC6H4 (5ab)
3-MeC6H4 (5ac)
4-MeC6H4 (5ad)
42
70
3
42
99
4
15
99
5
4-MeOC6H4 (5ae)
4-FC6H4 (5af)
48
99
6
12
99
7
2-BrC6H4 (5ag)
4-BrC6H4 (5ah)
2-ClC6H4 (5ai)
12
97
8
12
99
9
12
99
10
11
12
13
14
15
3-ClC6H4 (5aj)
12
98
4-ClC6H4 (5ak)
2-NO2C6H4 (5al)
3-NO2C6H4 (5am)
4-NO2C6H4 (5an)
12
97
12
99
12
99
48
99
48
98
(5ao)
2-furyl (5ap)
2-thienyl (5aq)
1-naphthyl (5ar)
2-naphthyl (5as)
n-butyl (5at)
n-octyl (5au)
Ph (5aa)
16
17
12
48
99
99
96
98
99
93
97
80
92
98
98
>50:1
>30:1
>99:1
>50:1
>99:1
>99:1
>50:1
29:1
94
95
97
98
97
98
94
98
92
91
97
18
62
19
48
20d
21e
22f
23f
24f
25f
26g
12
8
20
3
24
4
2
1
4-MeOC6H4 (5ae)
2-ClC6H4 (5ai)
2-naphthyl (5as)
Ph (5aa)
120
84
7
5
>50:1
>50:1
>50:1
9
6
120
12
12
10
11
a
Unless otherwise noted, all reactions were carried out on 0.4 mmol scale
(nitroolefin) and β-ketoester (1.1 equiv.) in CH2ClCH2Cl (1.0 mL) with 2a (1 mol%)
b
c
and Co(acac)2 (3 mol%). Isolated yield. Determined by 1H NMR spectroscopy
and chiral HPLC. d 2 mol% of 2a and 6 mol% of Co(acac)2 were used. 5 mol% of
e
Figure 1. Non-linear effect and the structure of the dinuclear Co-aminophenol
f
2a and 15 mol% of Co(acac)2 were used. The reaction was carried out on 0.8
sulfonamide complex optimized by DFT.
mmol scale (nitroolefin) and β-ketoester (1.1 equiv.) in CH2ClCH2Cl (2.0 mL) with
2a (0.5 mol%) and Co(acac)2 (2 mol%). g The reaction was carried out on 50 mmol
scale (nitroolefin) and β-ketoester (1.1 equiv.) in CH2ClCH2Cl (125 mL) with 2a (1
mol%) and Co(acac)2 (3 mol%).
O
HN
O
O
NH
N
O
Co
Co
O
COOEt
TsN
NTs
O
R
N
O
The postulated catalytic cycle is summarized in Figure 2.14
We assume that the β-keto ester would coordinate to the
acetylacetone-complexed Co with the assistance of N-methyl
morpholine to generate a new Co-enolate. The nitroolefin
would be activated by another Co. The Co2/2a regenerates
with the help of N-methyl morpholine after the 1,4-addition
via bimetallic transition state and deprotonation. We think
more than one Co2/2a would be involved in the transition
state without the addition of N-methyl morpholine, which is
why a negative non-linear effect was observed without the
addition of N-methyl morpholine. TS1 and TS2 are proposed to
rationalize the asymmetric induction. As illustrated in Figure 2,
NO2
COOEt
OEt
EtO
O
Co
O
O
HN
O
O
NH
HN
O2SN
O
O
NH
Co
Co
O
Co
O2SN
NTs
N
O
NTs
N
O
O
R
O
OEt
O
N+
O-
TS1-I favored
TS1-II disfavored
O
HN
O
O
NH
Co
Co
O
NO2
TsN
NTs
R
O
TS2
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Figure 2. Postulated catalytic cycle.
Table 7. Scope and limitations of β-ketoesters.a
x mol% 2a
O
O
O
O
O
Ph
y mol% Co(acac)2
z mol% N-methyl morpholine
0 oC or rt, CH2ClCH2Cl
Ph
NO2
+
R1
OR3
3c: R1, R2 = -(CH2)4-, R3 = Et
3d: R1 = Me, R2 = Me, R3 = Et
3e: R1 = Me, R2 = H, R3 = Et
NO2
R1
O
R2
COOR3
R2
3b
3b-3e
4a
5
Entry
1d
3
5
x
y
9
z
T (oC)
Time (h)
12
Yield (%) b
drc
7:1
eec
94
3b
3c
3d
3e
5ba
5ca
5da
5ea
3
10
5
40
20
40
40
0
rt
0
99
87
97
99
2e
20
15
3
62
>30:1
>99:1
1:1
98
3e
4f
62
98
1
0
12
99/99
a Unless otherwise noted, all reactions were carried out on 0.2 mmol scale (nitroolefin) and β-ketoester (1.1 equiv. or 2 equiv.) in CH2ClCH2Cl (0.5 mL). b Isolated yield. c
Determined by 1H NMR spectroscopy and chiral HPLC. d 1.1 equiv. β-Ketoester was used. e 2 equiv. β-Ketoester was used. f The reaction was carried out with 0.4 mmol
scale (nitroolefin) and β-ketoester (1.1 equiv.) in CH2ClCH2Cl (1.0 mL).
oxocyclopentanecarboxylate 3a (0.44 mmol, 1.1 equiv.), N-
methyl morpholine (0.16 mmol, 40 mol%) and CH2ClCH2Cl (0.5
Conclusions
ml) were successively added. The stirring was continued until
the reaction proceeded completely. The residue was purified
We have developed a new homodinuclear Co aminophenol
by column chromatography (PE/EA =1:30 to 1:8) on silica gel to
sulfonamide complex for the asymmetric Michael addition of
afford
5.
β-ketoesters to nitroolefins. This simple experimental protocol
affords various optically active nitrogen-containing ketoesters
with a quaternary carbon stereocenter in high yields (up to
99%) with excellent diastereomeric ratios (up to >99:1) and
excellent enantioselectivities (up to 98%) with 0.5-10 mol%
catalyst. Moreover, the reaction could be carried out on 50
mmol scale without any decrease in the enantioselectivity and
reactivity. Further efforts are underway for the application of
the desired catalyst to other reactions.
(R)-ethyl
1-((S)-2-nitro-1-phenylethyl)-2-oxocyclopentane
carboxylate (5aa): Pale yellow oil; 121.1 mg, 99% yield with
>50:1 dr and 97% ee: [α]26D = -24.8 (c 0.94, CHCl3) (ref.10k: [α]20
D
= +5.5 (c 1.0, CHCl3, 91:9 dr, 97% ee)); 1H NMR (600 MHz,
CDCl3) δ 7.34-7.22 (m, 5H), 5.16 (dd, J = 13.6, 3.8 Hz, 1H), 5.00
(dd, J = 13.6, 11.0 Hz, 1H), 4.24-4.14 (m, 2H), 4.06 (dd, J = 11.0,
3.7 Hz, 1H), 2.38-2.30 (m, 2H), 2.04-1.86 (m, 3H), 1.83-1.77 (m,
1H), 1.26 (t, J = 7.3 Hz, 3H). HPLC (Chiralcel ODH column),
hexane/2-propanol 80:20, flow rate = 1 mL/min, 210 nm. tR
(major diastereomer) = 12.8 min (major enantiomer), 8.7 min
(minor enantiomer); tR(minor diastereomer) = 10.4 min (major
enantiomer), 7.6 min (minor enantiomer).
Experimental Section
General: Commercial reagents were used as purchased. NMR
spectra were recorded in the deuterated solvents as stated,
using residual non-deuterated solvent as internal standard.
High resolution mass spectra were recorded with a Bruker
Solari XFT-ICR-MS system. The enantiomeric excess (ee) was
determined by HPLC analysis using the corresponding
commercial chiral column as stated in the experimental
procedures at 23 oC with UV detector at 210 nm. Optical
rotations were measured on a commercial polarimeter and are
(R)-ethyl
1-((S)-2-nitro-1-o-tolylethyl)-2-oxocyclopentane
carboxylate (5ab): Pale yellow oil; 89.9 mg, 70% yield, >99:1
1
dr, 97% ee; ; [α]26D = +16.2 (c 0.66, CHCl3); H NMR (600 MHz,
CDCl3) δ 7.37-7.34 (m, 1H), 7.17-7.12 (m, 3H), 5.25 (dd, J =
13.4, 3.8 Hz, 1H), 4.94 (dd, J = 13.3, 10.9 Hz, 1H), 4.37 (dd, J =
10.8, 3.8 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 2.40-2.34
(m, 2H), 2.18-2.10 (m, 1H), 1.99-1.90 (m, 3H), 1.25 (s, 3H). The
ee value was determined by HPLC analysis using a Chiralcel
ODH column, hexane/2-propanol 98:2, flow rate = 1 mL/min,
T
reported as follows: [α]D (c = g/100 mL, solvent). The
210 nm. tR (major diastereomer)
= 19.6 min (major
aminophenol sulfonamide ligands were prepared according to
the literature.8 The absolute configuration of 5aa
enantiomer), 14.9 min (minor enantiomer); tR (minor
diastereomer) = 13.2 min (major enantiomer), 11.2 min (minor
enantiomer).
,
5ai-5ak
,
5ap
, 5ar, 5ba, 5ca, 5da, and 5ea was determined by
comparison of the HPLC retention time and optical rotations
with the literature data.10k,10l,10n,10q,10r,10s The absolute
(R)-ethyl
1-((S)-2-nitro-1-m-tolylethyl)-2-oxocyclopentane
carboxylate (5ac): Pale yellow oil; 126.8 mg, 99% yield, >30:1
1
stereochemistry of 5ab-5ah
, 5al-5an, 5ao, 5aq, 5as, 5at, and
dr, 97% ee; [α]26D = –22.6 (c 1.20, CHCl3); H NMR (600 MHz,
5au was assigned by analogy.
CDCl3) δ 7.17 (t, J = 7.6 Hz, 1H), 7.08-7.02 (m, 3H), 5.16 (dd, J =
13.6, 3.7 Hz, 1H), 5.00 (dd, J = 13.6, 11.0 Hz, 1H), 4.24-4.16 (m,
2H), 4.01 (dd, J = 10.9, 3.7 Hz, 1H), 2.39-2.31 (m, 2H), 2.31 (s,
3H), 2.07-1.87 (m, 3H), 1.85-1.77 (m, 1H), 1.27 (t, J = 7.1 Hz,
3H). The ee value was determined by HPLC analysis using a
General procedure for the asymmetric Michael Reaction of β-
ketoesters with nitroolefins: Ligand 2a (0.004 mmol, 1 mol%)
and Co(acac)2 (0.012 mmol, 3 mol%) were stirred in CH2ClCH2Cl
o
(0.5 ml) at 35 C for 30 min. The reaction mixture was cooled
to
0 4 (0.4 mmol), ethyl 2-
oC and then nitroolefins
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Chiralcel ODH column, hexane/2-propanol 98:2, flow rate = 1 (major diastereomer) = 6.8 min (major enantiomer), 6.4 min
mL/min, 210 nm. tR (major diastereomer) = 18.0 min (major (minor enantiomer); tR (minor diastereomer) = 7.8 min (major
enantiomer), 13.1 min (minor enantiomer); tR (minor enantiomer), 8.3 min (minor enantiomer).
diastereomer) = 14.4 min (major enantiomer), 10.9 min (minor (R)-ethyl 1-((S)-1-(4-bromophenyl)-2-nitroethyl)-2-oxocyclo
enantiomer).
pentanecarboxylate (5ah): Pale yellow oil; 153.1 mg, 99%
1
(R)-ethyl
1-((S)-2-nitro-1-p-tolylethyl)-2-oxocyclopentane yield, >30:1 dr, 96% ee; [α]26D = –29.6 (c 0.94, CHCl3); H NMR
carboxylate (5ad): Pale yellow oil; 127.1 mg, 99% yield, >50:1 (600 MHz, CDCl3) δ 7.44-7.40 (m, 2H), 7.17-7.14 (m, 2H), 5.15
dr, 97% ee; [α]26D = –34.3 (c 0.89, CHCl3) [ref.10k: [α]20D = +24.0 (dd, J = 13.7, 3.7 Hz, 1H), 4.96 (dd, J = 13.7, 11.2 Hz, 1H), 4.21-
(c 0.25, CHCl3) in 92:8 dr and 97% ee]; 1H NMR (600 MHz, 4.14 (m, 2H), 4.01 (dd, J = 11.1, 3.7 Hz, 1H), 2.41-2.31 (m, 2H),
CDCl3) δ 7.11 (dd, J = 20.6, 8.1 Hz, 4H), 5.14 (dd, J = 13.5, 3.8 2.09-2.01 (m, 1H), 1.95-1.87 (m, 2H), 1.86-1.80 (m, 1H), 1.25 (t,
Hz, 1H), 4.98 (dd, J = 13.4, 11.1 Hz, 1H), 4.25-4.15 (m, 2H), 4.05 J = 7.1 Hz, 3H). The ee value was determined by HPLC analysis
(dd, J = 11.0, 3.8 Hz, 1H), 2.39-2.30 (m, 2H), 2.29 (s, 3H), 2.04- using a Chiralcel ODH column, hexane/2-propanol 70:30, flow
1.95 (m, 2H), 1.94-1.87 (m, 1H), 1.84-1.77 (m, 1H), 1.27 (t, J = rate = 1 mL/min, 210 nm. tR (major diastereomer) = 12.2 min
7.2 Hz, 3H). The ee value was determined by HPLC analysis (major enantiomer), 8.2 min (minor enantiomer); tR (minor
using a Chiralcel ODH column, hexane/2-propanol 98:2, flow diastereomer) = 9.4 min (major enantiomer), 6.9 min (minor
rate = 1 mL/min, 210 nm. tR (major diastereomer) = 19.5 min enantiomer).
(major enantiomer), 15.2 min (minor enantiomer); tR (minor (R)-ethyl 1-((R)-1-(2-chlorophenyl)-2-nitroethyl)-2-oxocyclo
diastereomer) = 14.5 min (major enantiomer), 12.3 min (minor pentanecarboxylate (5ai): Pale yellow oil; 135.4 mg, 99% yield,
enantiomer).
>30:1 dr, 97% ee; [α]26D = +11.5 (c 0.85, CHCl3) [ref.10k: [α]20
=
D
(R)-ethyl 1-((S)-1-(4-methoxyphenyl)-2-nitroethyl)-2-oxocyclo –23.0 (c 0.5, CHCl3) in 92:8 dr and 94% ee]; 1H NMR (500 MHz,
pentanecarboxylate (5ae): Yellow oil; 133.7 mg, 99% yield, CDCl3) δ 7.53 (d, J = 7.5 Hz, 1H), 7.32 (dd, J = 7.8, 1.2 Hz, 1H),
>99:1 dr, 96% ee; [α]26D = –30.0 (c 0.97, CHCl3) [ref.10k: [α]20
=
7.23–7.13 (m, 2H), 5.44 (dd, J = 13.9, 3.4 Hz, 1H), 5.04 (dd, J =
D
+32.6 (c 0.5, CHCl3) in 87:13 dr and 85% ee]; 1H NMR (600 13.4, 11.3 Hz, 1H), 4.49 (dd, J = 10.6, 3.1 Hz, 1H), 4.14 (q, J =
MHz, CDCl3) δ 7.17 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 7.2 Hz, 2H), 2.47–2.34 (m, 2H), 2.20 (m, 1H), 2.07–1.97 (m, 1H),
5.11 (dd, J = 13.4, 3.8 Hz, 1H), 4.95 (dd, J = 13.3, 11.2 Hz, 1H), 1.93–1.83 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H). The ee value was
4.24-4.15 (m, 2H), 4.04 (dd, J = 11.1, 3.8 Hz, 1H), 3.76 (s, 3H), determined by HPLC analysis using a Chiralcel ODH column,
2.39-2.29 (m, 2H), 2.01-1.94 (m, 2H), 1.94 – 1.87 (m, 1H), 1.84- hexane/2-propanol 90:10, flow rate = 1 mL/min, 210 nm. tR
1.76 m, 1H), 1.26 (t, J = 7.2 Hz,3H). The ee value was (major diastereomer) = 10.3 min (major enantiomer), 9.7 min
determined by HPLC analysis using a Chiralcel ODH column, (minor enantiomer); tR(minor diastereomer) = 12.7 min (major
hexane/2-propanol 90:10, flow rate = 1 mL/min, 210 nm. tR enantiomer), 9.1 min (minor enantiomer).
(major diastereomer) = 19.6 min (major enantiomer), 15.8 min (R)-ethyl
(minor enantiomer); tR (minor diastereomer) = 11.6 min (major pentanecarboxylate (5aj): Pale yellow oil; 133.7 mg, 98% yield,
enantiomer), 14.6 min (minor enantiomer).
>30:1 dr, 97% ee; [α]26D = –17.6 (c 0.94, CHCl3) [ref.10k: [α]20
(R)-ethyl
1-((S)-1-(4-fluorophenyl)-2-nitroethyl)-2-oxocyclo +22.0 (c 0.5, CHCl3) in 91:9 dr and 92% ee]; 1H NMR (600 MHz,
1-((S)-1-(3-chlorophenyl)-2-nitroethyl)-2-oxocyclo
=
D
pentanecarboxylate (5af): Pale yellow oil; 128.5 mg, 99% CDCl3) δ 7.28-7.20 (m, 3H), 7.17-7.14 (m, 1H), 5.18 (dd, J =
yield, >99:1 dr, 97% ee; [α]26D = –23.9 (c 0.77, CHCl3) [ref.10k
:
13.9, 3.6 Hz, 1H), 4.98 (dd, J = 13.9, 11.0 Hz, 1H), 4.19 (q, J =
[α]20D = + 33.3 (c 0.30, CHCl3) in 99:1 dr and 92% ee]; H NMR 7.1 Hz, 2H), 3.96 (dd, J = 11.0, 3.5 Hz, 1H), 2.42-2.30 (m, 2H),
(600 MHz, CDCl3) δ 7.26-7.22 (m, 2H), 6.99-6.94 (m, 2H), 5.13 2.14-2.06 (m, 1H), 1.95-1.82 (m, 3H), 1.25 (t, J = 7.2 Hz, 3H).
(dd, J = 13.6, 3.7 Hz, 1H), 4.95 (dd, J = 13.6, 11.2 Hz, 1H), 4.20- The ee value was determined by HPLC analysis using a Chiralcel
4.14 (m, 2H), 4.03 (dd, J = 11.1, 3.7 Hz, 1H), 2.39-2.30 (m, 2H), ODH column, hexane/2-propanol 90:10, flow rate = 1 mL/min,
1
2.06-1.97 (m, 1H), 1.94-1.87 (m, 2H), 1.85-1.77 (m, 1H), 1.24 (t, 210 nm. tR (major diastereomer)
= 14.8 min (major
J = 7.1 Hz, 3H). The ee value was determined by HPLC analysis enantiomer), 10.7 min (minor enantiomer); tR (minor
using a Chiralcel ODH column, hexane/2-propanol 90:10, flow diastereomer) = 9.3 min (major enantiomer), 12.3 min (minor
rate = 1 mL/min, 210 nm. tR (major diastereomer) = 18.1 min enantiomer).
(major enantiomer), 10.7 min (minor enantiomer); tR (minor (R)-ethyl
1-((S)-1-(4-chlorophenyl)-2-nitroethyl)-2-oxocyclo
diastereomer) = 13.7 min (major enantiomer), 9.2 min (minor pentanecarboxylate (5ak): Pale yellow oil; 132.3 mg, 97%
yield, >30:1 dr, 97% ee; [α]26D = –22.9 (c 0.94, CHCl3) [ref.10k
enantiomer).
:
1
(R)-ethyl 1-((R)-1-(2-bromophenyl)-2-nitroethyl)-2-oxocyclo [α]20D = +37.0 (c 1.0, CHCl3) in 91:9 dr and 93% ee]; H NMR
pentanecarboxylate (5ag): Pale yellow oil; 149.7 mg, 97% (600 MHz, CDCl3) δ 7.27-7.23 (m, 2H), 7.22-7.19 (m, 2H), 5.14
1
yield, >30:1 dr, 96% ee; [α]26D = +13.7 (c 0.97, CHCl3); H NMR (dd, J = 13.7, 3.7 Hz, 1H), 4.95 (dd, J = 13.6, 11.2 Hz, 1H), 4.21-
(600 MHz, CDCl3) δ 7.58-7.54 (m, 2H), 7.31-7.27 (m, 1H), 7.15- 4.14 (m, 2H), 4.01 (dd, J = 11.1, 3.6 Hz, 1H), 2.39-2.30 (m, 2H),
7.10 (m, 1H), 5.46 (dd, J = 13.8, 3.5 Hz, 1H), 5.05 (dd, J = 13.6, 2.07-1.99 (m, 1H), 1.95-1.86 (m, 2H), 1.85-1.78 (m, 1H), 1.24 (t,
10.7 Hz, 1H), 4.50 (dd, J = 10.6, 3.5 Hz, 1H), 4.19 (q, J = 7.1 Hz, J = 7.1 Hz, 3H). The ee value was determined by HPLC analysis
2H), 2.48 (t, J = 7.6 Hz, 2H), 2.24-2.17 (m, 1H), 2.12-2.05 (m, using a Chiralcel ODH column, hexane/2-propanol 90:10, flow
1H), 1.98-1.88 (m, 2H), 1.25 (t, J = 7.1 Hz, 3H). The ee value was rate = 1 mL/min, 210 nm. tR (major diastereomer) = 15.6 min
determined by HPLC analysis using a CHIRALPAK IA column, (major enantiomer), 10.7 min (minor enantiomer); tR (minor
hexane/2-propanol 90:10, flow rate = 1 mL/min, 210 nm. tR
6 | J. Name., 2012, 00, 1-3
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diastereomer) = 12.1 min (major enantiomer), 9.1 min (minor diastereomer) = 13.2 min (major enantiomer), 11.2 min (minor
enantiomer).
enantiomer).
1-((S)-2-nitro-1-(2-nitrophenyl)ethyl)-2-oxocyclo (R)-ethyl
(R)-ethyl
1-((S)-1-(furan-2-yl)-2-nitroethyl)-2-oxocyclo
pentanecarboxylate (5al): Yellow oil; 139.2 mg, 99% yield, pentanecarboxylate (5ap): Pale yellow oil; 117.4 mg, 99%
1
>50:1 dr, 97% ee; [α]26D = –79.7 (c 0.95, CHCl3); H NMR (600 yield, >50:1 dr, 94% ee; [α]26D = –45.6 (c 0.99, CHCl3) [ref.10k
:
1
MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), [α]20D = +20.0 (c 0.5, CHCl3) in 95:5 dr and 98% ee]; H NMR
7.59 (t, J = 7.7 Hz, 1H), 7.46-7.41 (m, 1H), 5.36 (dd, J = 14.3, 3.5 (600 MHz, CDCl3) δ 7.32 (d, J = 1.0 Hz, 1H), 6.29 (dd, J = 3.1, 1.8
Hz, 1H), 5.05 (dd, J = 14.3, 10.7 Hz, 1H), 4.65 (dd, J = 10.7, 3.5 Hz, 1H), 6.18 (d, J = 3.2 Hz, 1H), 4.96-4.86 (m, 2H), 4.43 (dd, J =
Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.55-2.42 (m, 2H), 2.22-2.16 10.3, 4.1 Hz, 1H), 4.25-4.15 (m, 2H), 2.49-2.43 (m, 1H), 2.37-
(m, 1H), 2.05-1.99 (m, 2H), 1.95-1.87 (m, 1H), 1.24 (t, J = 7.1 2.30 (m, 1H), 2.15-2.08 (m, 1H), 2.00-1.93 (m, 2H), 1.77-1.68
Hz, 3H). The ee value was determined by HPLC analysis using a (m, 1H), 1.27 (t, J = 7.1 Hz, 3H). The ee value was determined
CHIRALPAK IA column, hexane/2-propanol 90:10, flow rate = 1 by HPLC analysis using a CHIRALPAK IC column, hexane/2-
mL/min, 210 nm. tR (major diastereomer) = 11.6 min (major propanol 70:30, flow rate = 0.7 mL/min, 210 nm. tR (major
enantiomer), 9.9 min (minor enantiomer); tR (minor diastereomer) = 14.5 min (major enantiomer), 11.8 min (minor
diastereomer) = 13.5 min (major enantiomer), 14.6 min (minor enantiomer); tR (minor diastereomer) = 23.6 min (major
enantiomer).
enantiomer), 11.6 min (minor enantiomer).
1-((S)-2-nitro-1-(3-nitrophenyl)ethyl)-2-oxocyclo (R)-ethyl 1-((S)-2-nitro-1-(thiophen-2-yl)ethyl)-2-oxocyclo
(R)-ethyl
pentanecarboxylate (5am): Pale yellow oil; 139.0 mg, 99% pentanecarboxylate (5aq): Pale yellow oil; 123.8 mg, 99%
1
yield, >30:1 dr, 94% ee; [α]26D = –16.5 (c 0.77, CHCl3); H NMR yield, >30:1 dr, 95% ee; [α]26D = –24.8 (c 0.94, CHCl3) [ref.10k
:
(600 MHz, CDCl3) δ 8.23 – 8.21 (m, 1H), 8.17-8.13 (m, 1H), 7.68 [α]20D = +43.0 (c 0.50, CHCl3) in 94:6 dr and 94% ee]; H NMR
(d, J = 7.7 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 5.27 (dd, J = 14.1, 3.5 (600 MHz, CDCl3) δ 7.22 (d, J = 5.0 Hz, 1H), 6.95 (d, J = 3.1 Hz,
Hz, 1H), 5.06 (dd, J = 14.0, 11.2 Hz, 1H), 4.26-4.16 (m, 2H), 4.09 1H), 6.91 (dd, J = 4.9, 3.7 Hz, 1H), 5.12 (dd, J = 13.6, 3.5 Hz, 1H),
(dd, J = 11.1, 3.5 Hz, 1H), 2.48-2.41 (m, 1H), 2.34-2.29 (m, 1H), 4.92 (dd, J = 13.6, 10.6 Hz, 1H), 4.40 (dd, J = 10.6, 3.4 Hz, 1H),
2.19-2.11 (m, 1H), 1.99-1.85 (m, 3H), 1.27 (t, J = 7.1 Hz, 3H). 4.21 (q, J = 7.1 Hz, 2H), 2.46-2.35 (m, 2H), 2.14-2.06 (m, 2H),
The ee value was determined by HPLC analysis using a 2.03-1.96 (m, 1H), 1.92-1.84 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H).
CHIRALPAK ADH column, hexane/2-propanol 90:10, flow rate = The ee value was determined by HPLC analysis using a Chiralcel
1 mL/min, 210 nm. tR (major diastereomer) = 15.8 min (major ODH column, hexane/2-propanol 90:10, flow rate = 1 mL/min,
1
enantiomer), 15.1 min (minor enantiomer); tR (minor 210 nm. tR (major diastereomer)
= 17.2 min (major
diastereomer) = 18.4 min (major enantiomer), 16.8 min (minor enantiomer), 10.8 min (minor enantiomer); tR (minor
enantiomer).
diastereomer) = 15.1 min (major enantiomer), 9.4 min (minor
1-((S)-2-nitro-1-(4-nitrophenyl)ethyl)-2-oxocyclo enantiomer).
(R)-ethyl
pentanecarboxylate (5an): White solid; 139.7 mg, 99% yield, (R)-ethyl 1-((S)-1-(naphthalen-1-yl)-2-nitroethyl)-2-oxocyclo
>50:1 dr, 95% ee; [α]26D = –27.5 (c 0.70, CHCl3) [ref.10k: [α]20
pentanecarboxylate (5ar): Yellow oil; 136.7 mg, 96% yield,
+43.6 (c 0.5, CHCl3) in 91:9 dr and 90% ee]; 1H NMR (600 MHz, >99:1 dr, 97% ee; [α]26D = –25.6 (c 0.33, CHCl3) [ref.10k: [α]20
=
D
=
D
CDCl3) δ 8.16 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 5.23 +34.0 (c 0.5, CHCl3) in 91:9 dr and 93% ee]; 1H NMR (600 MHz,
(dd, J = 14.0, 3.5 Hz, 1H), 5.04 (dd, J = 14.0, 11.2 Hz, 1H), 4.23 – CDCl3) δ 8.21 (d, J = 8.6 Hz, 1H), 7.80 (dd, J = 25.7, 8.1 Hz, 2H),
4.08 (m, 2H), 4.11 (dd, J = 11.1, 3.5 Hz, 1H), 2.47-2.40 (m, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.58-7.53 (m, 1H), 7.48 (t, J = 7.4 Hz,
2.36-2.31 (m, 1H), 2.16-2.08 (m, 1H), 1.99-1.93 (m, 1H), 1.91- 1H), 7.43 (t, J = 7.7 Hz, 1H), 5.51 (dd, J = 13.7, 3.8 Hz, 1H), 5.14
1.85 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H). The ee value was (dd, J = 13.7, 10.4 Hz, 1H), 5.01 (dd, J = 10.4, 3.8 Hz, 1H), 4.24-
determined by HPLC analysis using a CHIRALPAK ASH column, 4.15 (m, 2H), 2.41-2.34 (m, 1H), 2.27-2.16 (m, 2H), 1.91-1.82
hexane/2-propanol 90:10, flow rate = 1 mL/min, 210 nm. tR (m, 3H), 1.23 (t, J = 7.1 Hz, 3H). The ee value was determined
(major diastereomer) = 43.4 min (major enantiomer), 47.2 min by HPLC analysis using a CHIRALPAK IC column, hexane/2-
(minor enantiomer); tR (minor diastereomer) = 64.9 min (major propanol 80:20, flow rate = 1 mL/min, 210 nm. tR (major
enantiomer), 39.9 min (minor enantiomer).
(R)-ethyl 1-((S)-1-nitro-4-phenylbut-3-en-2-yl)-2-oxocyclo enantiomer); tR (minor diastereomer) = 18.4 min (major
pentanecarboxylate (5ao): Pale yellow oil; 129.1 mg, 98% enantiomer), 11.1 min (minor enantiomer).
yield, >50:1 dr, 95% ee; [α]26D = –67.2 (c 0.91, CHCl3) [ref.10k
(R)-ethyl 1-((S)-1-(naphthalen-2-yl)-2-nitroethyl)-2-oxocyclo
diastereomer) = 16.0 min (major enantiomer), 12.2 min (minor
:
[α]20D = +58.5 (c 1.0, CHCl3) in 91:9 dr and 92% ee]; 1H NMR pentanecarboxylate (5as): Pale yellow oil; 139.6 mg, 98%
(600 MHz, CDCl3) δ 7.33-7.26 (m, 4H), 7.25-7.21 (m, 1H), 6.50 yield, >50:1 dr, 98% ee; [α]26D = –31.2 (c 1.20, CHCl3) [ref.10k
:
(d, J = 15.8 Hz, 1H), 6.12 (dd, J = 15.8, 9.6 Hz, 1H), 4.99 (dd, J = [α]20D = +34.0 (c 0.5, CHCl3) in 92:8 dr and 94% ee]; H NMR
12.7, 3.4 Hz, 1H), 4.62 (dd, J = 12.7, 10.4 Hz, 1H), 4.20 (q, J = (600 MHz, CDCl3) δ 7.80-7.76 (m, 3H), 7.72 (s, 1H), 7.49-7.44
7.1 Hz, 2H), 3.52-3.46 (m, 1H), 2.48-2.41 (m, 2H), 2.32-2.24 (m, (m, 1H), 7.39 (dd, J = 8.6, 1.5 Hz, 1H), 5.25 (dd, J = 13.7, 3.8 Hz,
1H), 2.12-2.05 (m, 1H), 2.04-1.96 (m, 2H), 1.26 (t, J = 7.1 Hz, 1H), 5.14 (dd, J = 13.7, 11.0 Hz, 1H), 4.25-4.19 (m, 3H), 2.40-
3H). The ee value was determined by HPLC analysis using a 2.30 (m, 2H), 2.05-1.97 (m, 2H), 1.95-1.87 (m, 1H), 1.85-1.77
Chiralcel ODH column, hexane/2-propanol 90:10, flow rate = 1 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H). The ee value was determined
mL/min, 210 nm. tR (major diastereomer) = 14.7 min (major by HPLC analysis using a Chiralcel ODH column, hexane/2-
enantiomer), 16.3 min (minor enantiomer); tR (minor propanol 70:30, flow rate = 1 mL/min, 210 nm. tR (major
1
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Journal Name
diastereomer) = 11.5 min (major enantiomer), 28.8 min (minor CHIRALPAK IC column, hexane/2-propanol 90:10, flow rate = 1
enantiomer); tR (minor diastereomer)
enantiomer), 14.8 min (minor enantiomer).
(R)-ethyl
=
9.7 min (major mL/min, 210 nm. tR (major diastereomer, 98% ee) = 17.9 min
(major enantiomer), 14.8 min (minor enantiomer); tR (minor
1-((S)-1-nitropentan-2-yl)-2-oxocyclopentane diastereomer) = 27.0 min (major enantiomer), 13.9 min (minor
carboxylate (5at): Colourless oil; 107.8 mg, 99% yield, >99:1 enantiomer).
1
dr, 97% ee; [α]26D = –48.3 (c 0.76, CHCl3); H NMR (600 MHz, (2R,3S)-ethyl
2-acetyl-2-methyl-4-nitro-3-phenylbutanoate
CDCl3) δ 4.87 (dd, J = 14.0, 4.8 Hz, 1H), 4.36 (dd, J = 14.0, 5.6 (5da): Colourless oil ; 56.7 mg, 97% yield, >99:1 dr, 98% ee;
Hz, 1H), 4.20-4.12 (m, 2H), 2.86-2.80 (m, 1H), 2.61-2.55 (m, [α]23 = +52.46 (c 0.75, CHCl3) [Ref.10r: [α]25D = –69.9 (c 0.93,
D
1H), 2.47-2.39 (m, 1H), 2.33-2.25 (m, 1H), 2.05-1.98 (m, 2H), CHCl3) in 91:9 dr and 99% ee]; 1H NMR (500 MHz, CDCl3) δ
1.97-1.90 (m, 1H), 1.46-1.36 (m, 2H), 1.29-1.22 (m, 5H), 0.89 (t, 7.32–7.27 (m, 3H), 7.12–7.10 (m, 2H), 4.99–4.86 (m, 2H), 4.28
J = 7.0 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 213.28, 169.35, (q, J = 7.1 Hz, 2H), 4.14 (dd, J = 10.9, 3.3 Hz, 1H), 2.17 (s, 3H),
76.48, 62.84, 61.91, 40.42, 38.19, 32.44, 31.05, 20.79, 19.39, 1.30 (t, J = 7.2 Hz, 3H), 1.23 (s, 3H). The ee value was
13.92. The ee value was determined by HPLC analysis using a determined by HPLC analysis using a Chiralcel ODH column,
CHIRALPAK IC column, hexane/2-propanol 98:2, flow rate = 1 hexane/2-propanol 90:10, flow rate = 0.9 mL/min, 210 nm. tR
mL/min, 210 nm. tR (major diastereomer) = 26.5 min (major (major diastereomer, 98% ee) = 27.2 min (major enantiomer),
enantiomer), 31.3 min (minor enantiomer); tR (minor 10.9 min (minor enantiomer); tR (minor diastereomer) = 17.8
diastereomer) = 32.8 min (major enantiomer), 28.5 min (minor min (major enantiomer), 12.0 min (minor enantiomer).
+
enantiomer); ESI-HRMS calcd for C13H21NNaO5 [M+Na]+: (3R)-ethyl 2-acetyl-4-nitro-3-phenylbutanoate (5ea): White
294.1312, found 294.1312.
(R)-ethyl
wax; 110.2 mg, 99% yield (~1:1 mixture of diastereomers), 99%
1-((S)-1-nitrononan-2-yl)-2-oxocyclopentane and 99% ee; [α]19D = –56.22 (c 0.96, CHCl3) [Ref.10s: [α]24
=
D
carboxylate (5au): Colourless oil; 122.1 mg, 93% yield, >99:1 +50.5 (c 1.00, CHCl3) in ~1:1 dr and 93% ee]; 1H NMR (400 MHz,
dr, 98% ee; [α]26D = –40.7 (c 0.69, CHCl3); H NMR (600 MHz, CDCl3) δ 7.29–7.16 (m, 5H), 4.87–4.71 (m, 2H), 4.25–4.14 (m,
1
CDCl3) δ 4.87 (dd, J = 14.0, 4.9 Hz, 1H), 4.36 (dd, J = 14.0, 5.6 2H), 4.09 (d, J = 10.0 Hz, 0.5H), 4.01 (d, J = 9.7 Hz, 0.5H), 3.94
Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 2.84-2.78 (m, 1H), 2.60-2.54 (q, J = 7.1 Hz, 1H), 2.27–2.01 (s, 3H), 1.27–0.94 (t, J = 7.1 Hz,
(m, 1H), 2.46-2.39 (m, 1H), 2.33-2.25 (m, 1H), 2.04-1.97 (m, 3H). The ee value was determined by HPLC analysis using a
2H), 1.97-1.90 (m, 1H), 1.36-1.22 (m, 15H), 0.86 (t, J = 7.0 Hz, CHIRALPAK ADH column, hexane/2-propanol 90:10, flow rate =
3H); 13C NMR (151 MHz, CDCl3) δ 213.28, 169.33, 76.44, 62.88, 0.8 mL/min, 210 nm. tR (first diastereomer, 99% ee) = 15.2 min
61.90, 40.66, 38.19, 31.65, 31.04, 30.27, 29.43, 28.96, 27.61, (major enantiomer), 10.9 min (minor enantiomer); tR (second
22.54, 19.40, 14.01, 13.92. The ee value was determined by diastereomer, >99% ee) = 16.5 min (major enantiomer), 29.9
HPLC analysis using a Chiralcel ODH column, hexane/2- min (minor enantiomer).
propanol 98:2, flow rate = 1 mL/min, 210 nm. tR (major
diastereomer) = 9.1 min (major enantiomer), 7.2 min (minor
Conflicts of Interest
enantiomer); tR (minor diastereomer)
= 8.0 min (major
enantiomer), 7.6 min (minor enantiomer); ESI-HRMS calcd for
C17H29NNaO5+ [M+Na]+: 350.1938, found 350.1937.
There are no conflicts to declare.
(R)-3-acetyl-3-((S)-2-nitro-1-phenylethyl)-dihydrofuran-2(3H)-
one (5ba): White solid; 54.9 mg, 99% yield, 7:1 dr, 94% ee;
[α]19 = +17.0 (c 0.59, CH2Cl2) [Ref.10n: [α]r.t. = –4 (c 0.41,
Acknowledgements
D
D
We are grateful for the generous financial support by the
National Nature Science Foundation of China (21672031),
Fundamental and Advanced Research Projects of Chongqing
City (cstc2016jcyjA0250 and cstc2017jcyjAX0352), Scientific
and Technological Research Program of Chongqing Municipal
Education Commission (KJ1702014).
1
CH2Cl2) in 67:33 dr and 73% ee]; H NMR (500 MHz, CDCl3) δ
7.30–7.27 (m, 3H), 7.23–7.18 (m, 2H), 5.00 (dd, J = 13.4, 11.3
Hz, 1H), 4.67 (dd, J = 13.4, 3.6 Hz, 1H), 4.28 (dd, J = 11.2, 3.4
Hz, 1H), 4.05–3.99 (m, 1H), 3.31–3.24 (m, 1H), 2.53–2.46 (m,
6.5 Hz, 1H), 2.28 (s, 3H), 2.23–2.15 (m, 1H). The ee value was
determined by HPLC analysis using a Chiralcel ODH column,
hexane/EtOH 80:20, flow rate = 1 mL/min, 210 nm. tR (major
diastereomer, 94% ee) = 16.5 min (major enantiomer), 10.9
min (minor enantiomer); tR (minor diastereomer) = 37.5 min
(major enantiomer), 14.4 min (minor enantiomer).
Notes and references
1
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D
1
1.02, CHCl3) in 98:2 dr and 99% ee]; H NMR (500 MHz, CDCl3)
δ 7.23–7.15 (m, 3H), 7.09–7.06 (m, 2H), 5.00 (dd, J = 13.5, 3.2
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2H), 1.67–1.53 (m, 3H), 1.43–1.35 (m, 1H), 1.18 (t, J = 7.1 Hz,
3H). The ee value was determined by HPLC analysis using a
8 | J. Name., 2012, 00, 1-3
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1057; (j) B. M. Trost, M. J. Bartlett, Acc. Chem. Res., 2015, 48
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DOI: 10.1039/C8OB00773J
A Homodinuclear Cobalt Complex for Catalytic Asymmetric Michael Reaction
of βꢀKetoesters to Nitroolefins
Guanghui Chen, Guojuan Liang, Yiwu Wang, Ping Deng, and Hui Zhou*
Ph
Ph
NH
N
O
O
NH
Co
Ph
Ph
O
O
Co
R4
N
O
R1
OR3
O
Ts
Ts
NO2
R2
+
R1
(0.5-10 mol%)
COOR3
R2
R4
N-methyl morpholine
CH2ClCH2Cl, 0 oC or rt up to 99% yield, >99:1 dr
NO2
91-99% ee