Organocatalytic conjugate addition of α-nitroacetates to β,γ-unsaturated α-keto esters and subsequent decarboxylation: Synthesis of optically active δ-nitro-α-keto esters

Article abstract of DOI:10.1016/j.tet.2012.09.014

Organocatalytic asymmetric conjugate addition of tert-butyl nitroacetates to β,γ-unsaturated α-keto esters has been developed. The subsequent in situ hydrolysis-decarboxylation of the adducts provided 5-nitro-2-oxopentanoates. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst. A number of γ-aryl, γ-alkyl, and γ-heteroaryl β,γ-unsaturated α-keto esters and α-substituted tert-butyl nitroacetates were examined in the transformation. Generally 5-nitro-2-oxopentanoates were obtained in good yields (up to 97%) and enantioselectivities (up to 94% ee). The products were readily transformed to chiral proline derivatives by catalytic hydrogenation.

Full text of DOI:10.1016/j.tet.2012.09.014

Tetrahedron 68 (2012) 9397e9404
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Organocatalytic conjugate addition of
esters and subsequent decarboxylation: synthesis of optically active
-nitro- -keto esters
a-nitroacetates to b,g-unsaturated a-keto
d
a
*
Rui-jiong Lu, Wen-tao Wei, Jin-jia Wang, Shao-zhen Nie, Xue-jing Zhang, Ming Yan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2012
Received in revised form 25 August 2012
Accepted 4 September 2012
Available online 10 September 2012
Organocatalytic asymmetric conjugate addition of tert-butyl nitroacetates to
esters has been developed. The subsequent in situ hydrolysisedecarboxylation of the adducts provided
5-nitro-2-oxopentanoates. A pyrrolidine-based thiourea-tertiary amine was identified as the best cata-
b,g-unsaturated a-keto
lyst. A number of g-aryl, g-alkyl, and g-heteroaryl b,g-unsaturated a-keto esters and a-substituted tert-
butyl nitroacetates were examined in the transformation. Generally 5-nitro-2-oxopentanoates were
obtained in good yields (up to 97%) and enantioselectivities (up to 94% ee). The products were readily
transformed to chiral proline derivatives by catalytic hydrogenation.
Keywords:
Organocatalysis
Asymmetric conjugate addition
Nitroacetate
Ó 2012 Elsevier Ltd. All rights reserved.
b,g-Unsaturated a-keto ester
Hydrolysisedecarboxylation
1. Introduction
acyloxy-pen-2-enoates in good yields and enantioselectivities. Af-
ter a two-step acidic hydrolysis, 5-nitro-2-oxo-pentanoates could
In the recent decade, asymmetric organocatalysis has evolved as
a powerful tool for the synthesis of chiral compounds.1 Organo-
catalytic asymmetric conjugate addition (OACA) of various nucle-
ophiles to Michael acceptors has made great success.2 Nitro
compounds are readily available and highly useful nucleophiles for
be obtained in moderate yields and with good enantioselectivities.
Although the method provides a synthetic route to 5-nitro-2-oxo-
pentanoates, it is not satisfactory enough considering the two-step
hydrolytic procedure and moderate yield. In addition,
a-nitro-
ketones are not commercially available and must be prepared in the
laboratory. In a controlled experiment, we observed that the
organocatalytic reaction of nitromethane and b,g-unsaturated a-
OACA. The OACA reactions of nitroalkanes with
aldehydes, ketones, and nitroalkenes have been extensively stud-
ied.3 However the OACA of nitroalkanes to
-unsaturated -keto
a,b-unsaturated
b,
g
a
keto esters provided preferentially 1,2- and 1,4-double addition
esters proved to be troublesome due to the competitive
1,2-addition. To the best of our knowledge, there is no established
method for the direct conjugate addition of nitroalkanes to
products (Scheme 1, Eq. 3).7 The results implicate that the in-
troduction of a-carbonyl groups to nitroalkanes can improve the
selectivity for 1,4-addition. We speculate that nitroacetates are the
attractive surrogates of nitroalkanes for the regioselective 1,4-
b,g-unsaturated a-keto esters. Such a reaction can provide valuable
synthetic intermediate 5-nitro-2-oxopentanoates.4 Deng and co-
workers reported that the 1,2-addition is preferential in 60-
addition to b,g-unsaturated a-keto esters.
Nitroacetates have been used as the source of stabilized carb-
anions for organic synthesis.8 The nitro and ester groups provide
diversified derivation pathways. For example, they can be used as
masked amino acids. In addition, the decarboxylation and deni-
tration lead to further structural diversity. In recent years, OACA of
nitroacetates to enones9 and maleimides10 have been developed.
Lu, Kim and their co-workers reported the OACA of nitroacetates to
enones using 9-amino-9-deoxyepicinchona alkaloids as the cata-
lysts.9a,b Wang, Kim and their co-workers found that chiral bi-
functional thioureas are also efficient catalysts for the reaction.9c,d
The resulting adducts were transformed to a series of chiral
demethyl quinine catalyzed reaction of nitroalkanes and
-unsaturated
-keto esters (Scheme 1, Eq. 1).5 Jørgensen and co-
workers found that the reaction of nitromethane and -un-
saturated -keto esters provided 1,2-addition products exclusively
in the presence of chiral bisoxazoline-Cu(II) catalysts (Scheme 1, Eq.
2).6 Recently we reported an efficient OACA of
-nitroketones to
-unsaturated
-keto esters.7 The reaction gave 5-nitro-2-
g-alkyl-
b
,g
a
b,g
a
a
b
,g
a
* Corresponding author. E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.014

9398
R.-jiong Lu et al. / Tetrahedron 68 (2012) 9397e9404
Scheme 1. Addition of nitromethane to b,g-unsaturated a-keto esters.
Table 1
derivatives by the decarboxylation, the denitration, and the cata-
lytic hydrogenation. Herein we report the OACA of nitroacetates to
Screening of organocatalystsa
O
OEt
O
b,g-unsaturated a-keto esters. The subsequent acidic hydrolysis
and the decarboxylation provided 5-nitro-2-oxo-pentanoates in
good yields and enantioselectivities.
catalyst
O
O
O2N
Ph
(10 mol %)
OMe
O2N
+
Ph
OEt
OMe
toluene, rt
O
O
1a
2a
3a
2. Results and discussion
Entry
Catalyst
Time/min
Yieldb/%
drc
eed/%
1
2
3
4
5
6
7
5a
5b
5c
5d
5e
5f
10
5
1440
60
5
60
98
97
60
98
98
95
92
1:1
1:1
1:1
1:1
1:1
1:1
1:1
49/47
61/57
11/9
47/43
47/49
23/18
ꢀ11/ꢀ15
The reaction between ethyl nitroacetate 1a and
-keto ester 2a was chosen as the model reaction. A number of
organocatalysts 5ae5g (Scheme 2) were examined and the results
are summarized in Table 1.
Organocatalysts 5a, 5b, 5de5g were found to promote the re-
action efficiently. The product 3a was obtained as a pair of in-
separable diastereoisomers in excellent yields. Pyrrolidine-based
thiourea-tertiary amine 5b provided better enantioselectivity than
Takemoto’s catalyst 5a (Table 1, entry 1 vs entry 2). Piperidine-
based thiourea-tertiary amine 5c showed much lower catalytic
b,g-unsaturated
a
5g
240
a
The reactions were carried out with 1a (0.220 mmol), 2a (0.200 mmol), and
catalyst (0.020 mmol) in toluene (2.0 mL) at room temperature.
b
Isolated yields.
c
Determined by 1H NMR analysis of the crude products.
d
Determined by chiral HPLC.
CF3
CF3
CF3
activity and enantioselectivity (Table 1, entry 3). The small struc-
tural difference between 5b and 5c seems to result in the significant
difference in their catalytic behaviors. The similar phenomena were
also observed in our recent studies.7,11 1,2-Diphenyl-ethane-1,2-
diamine derived thiourea 5d and quinine derived thiourea 5e
gave inferior enantioselectivities (Table 1, entries 4 and 5). Quinine
5f and 60-demethyl quinine 5g also led to low enantioselectivities
(Table 1, entries 6 and 7). No diastereoselectivity was achieved and
almost equal amount of diastereoisomers was obtained in all cases.
Using 5b as the catalyst, the effect of reaction solvent, catalysts
loading, and reaction temperature were examined and the results
are summarized in Table 2. The reaction proceeded very quickly in
dichloromethane and toluene. The TLC analysis indicated the
complete transformation of 2a in just 5 min. The product 3a was
obtained in excellent yields and moderate enantioselectivities
(Table 2, entries 1 and 2). The improved enantioselectivities could
be achieved in ether and 1,2-dichloroethane (DCE) (Table 2, entries
3 and 4). Lower reaction rates were observed in tetrahydrofuran
and ethyl acetate (Table 2, entries 5 and 6). More polar solvents,
such as methanol and N,N-dimethylformamide significantly
S
S
S
F3C
N
H
N
H
F3C
N
H
N
H
F3C
N
H
N
H
N
N
S
N
5a
5b
5c
N
CF3
CF3
S
O
H
F3C
N
H
N
H
F3C
N
N
H
N
H
N
N
5d
5e
N
O
H
OH
H
HO
HO
N
N
5f
5g
Scheme 2. Organocatalysts 5ae5g.

R.-jiong Lu et al. / Tetrahedron 68 (2012) 9397e9404
9399
Table 2
comparing the optical rotation and retention time of HPLC with our
previous report.7 To make the method more synthetically attrac-
tive, the reaction was carried out in one pot. After the conjugate
addition was completed, TFA was directly added to the reaction
mixture without the isolation of 3d. The product 4a was obtained
smoothly in 82% yield and with 90% enantioselectivity (Scheme 1,
Eq. 2). The result confirms that the one pot reaction works well.
Optimization of reaction conditionsa
O
OEt
O
O
O
O2N
Ph
5b (x mol %)
solvent
OMe
O2N
+
Ph
OEt
OMe
O
O
1a
3a
2a
Entry
Solvent
x
T (ꢁC)
Time/h
Yieldb,c/%
eed/%
OBu-t
O
1
2
3
4
5
6
7
8
Toluene
CH2Cl2
DCE
Ether
THF
EtOAc
MeOH
DMF
DCE
DCE
DCE
DCE
DCE
10
10
10
10
10
10
10
10
5
2
5
5
5
rt
rt
rt
rt
rt
rt
rt
rt
0.08
0.08
0.08
0.16
24
4
4
10
0.5
4
98
98
98
95
90
95
95
98
98
90
97
97
95
61/57
50/48
78/72
77/72
67/65
76/75
25/20
5/3
81/76
25/22
83/78
86/80
85/80
O2N
O2N
Ph
O
O
TFA
OMe
(1)
OMe
Ph
DCE, 5 h
O
O
4a
92% yield, 90% ee
3d
9
rt
rt
0
5b (5 mol %)
DCE, -20°C
O2N
Ph
10
11
12
13
O
(i)
O
O
12
24
24
OMe
+
OMe
(2)
O2N
Ph
(ii)
TFA, rt
OBu-t
ꢀ20
O
ꢀ30
O
1d
2a
4a
82% yield, 90% ee
a
The reactions were carried out with 1a (0.220 mmol), 2a (0.200 mmol), and 5b
in solvent (2.0 mL).
Scheme 3. Hydrolysis and subsequent decarboxylation.
b
Isolated yields.
c
The ratios of two diastereoisomers were almost 1/1 in all runs as determined by
To explore the substrate scope, a series of
b,g-unsaturated
a-keto
1H NMR analysis of the crude products.
d
esters 2ae2o and tert-butyl nitroacetate 1d, 1fe1g were examined
Determined by chiral HPLC.
in the one pot reaction. The results are summarized in Table 4.
Generally good yields and enantioselectivities were obtained for
aryl- -unsaturated -keto esters (Table 4, entries 1e9). The elec-
tronic property of the substituent at -phenyl exerts small effect on
the enantioselectivity. The electron-withdrawing groups gave
slightly better enantioselectivities than the electron-donating
g-
decreased the enantioselectivity (Table 2, entries 7 and 8). Slightly
better enantioselectivity was obtained when the catalyst loading
was reduced to 5 mol % (Table 2, entry 9). Further reduction of the
catalyst loading led to the loss of the enantioselectivity (Table 2,
entry 10). Decreasing the reaction temperature showed the favor-
able effect on the enantioselectivities (Table 2, entries 13e15). The
best enantioselectivity was obtained at ꢀ20 ꢁC.
b,g
a
g
groups (Table 4, entries 2e7).
ester 2j is also the suitable substrate (Table 4, entry 10). The ester
group of -unsaturated -keto esters showed tiny effect on the
enantioselectivity, but better yields were obtained for the substrates
with more bulk ester groups (Table 4, entries 11e13 vs entry 1).
Alkyl- -unsaturated -keto esters 2n and 2o are also applicable for
g-Heteroaryl-b,g-unsaturated a-keto
b,g
a
With the optimal reaction conditions in hand, the influence of
the ester group of nitroacetates was investigated and the results are
summarized in Table 3. In contrast to the report of Lu and co-
workers,9a all tested nitroacetates provided the adducts with ex-
cellent yields and good enantioseletivities (Table 3, entries 1e5).
Except the case of benzyl ester, the enantioselectivity increased
with the volume of ester groups (t-Bu>i-Pr>Et>Me).
While treating the product 3d with trifluoroacetic acid (TFA) at
room temperature, the hydrolysis of tert-butyl ester and sub-
sequent decarboxylation occurred to give methyl 5-nitro-2-
oxopentanoate 4a in good yield and enantioselectivity (Scheme 3,
Eq. 1). The absolute configuration of 4a was determined as R by
g-
b,g
a
the reaction. Slightly lower enantioselectivities and similar yields
were obtained (Table 4, entries 14 and 15). Although the extended
reaction time was required for tert-butyl
the product 4p was obtained with good enantioselectivity and in
a reasonable yield (Table 4, entry 16). The reaction of tert-butyl
a-methyl-nitroacetate 1f,
a-
ethyl-nitroacetate 1g only gave moderate yield and enantiose-
lectivity (Table 4, entry 17). The bigger steric hindrance of 1g obvi-
ously decreases its reactivity and the enantioselectivity of the
reaction.
The products 3 and 4 can be readily transformed to highly
functionalized proline derivatives, which are otherwise difficult to
access.12 For example, 3a and 4a were hydrogenated over Raney
Ni.4 2-Ethyl-5-methyl 3-phenylpyrrolidine-2,5-dicarboxylate 6
and methyl 4-phenylpyrrolidine-2-carboxylate 7 were obtained
with good yields, diastereoselectivities and enantioselectivities
(Scheme 4).
Table 3
Conjugate addition of nitroacetates 1ae1e to 2aa
O
O
R
O
O2N
O
O
5b
(5 mol %)
OMe
O2N
R
+
OMe
O
DCE, -20°C
O
O
1a-1e
2a
3a-3e
3. Conclusions
Entry
1
R
Product
Yieldb,c/%
eed/%
In summary, we have developed an organocatalytic asymmetric
conjugate addition of nitroacetates to b,g-unsaturated a-keto es-
ters. A pyrrolidine-based thiourea-tertiary amine was identified as
the best catalyst. The subsequent acidic hydrolysis and de-
carboxylation could be carried out in one pot. Valuable 5-nitro-2-
oxopentanoates were prepared in good yields and enantiose-
1
2
3
4
5
1a
1b
1c
1d
1e
Et
Me
i-Pr
t-Bu
Bn
3a
3b
3c
3d
3e
97
90
92
93
91
86/80
84/79
88/90
90/88
83/90
a
The reactions were carried out with 1ae1e (0.220 mmol), 2a (0.200 mmol), and
5b (0.010 mmol) in 1,2-dichloroethane (2.0 mL) at ꢀ20 ꢁC.
lectivities. A number of
g-aryl,
g
-alkyl, and
g-heteroaryl b,g-un-
b
Isolated yields.
saturated -keto esters and
a
a-substituted nitroacetates are
c
The ratios of two diastereoisomers were almost 1/1 in all runs as determined by
1H NMR analysis of the crude products.
applicable in the transformation. The products could be trans-
formed to highly functionalized proline derivatives via catalytic
d
Determined by chiral HPLC.

9400
R.-jiong Lu et al. / Tetrahedron 68 (2012) 9397e9404
Table 4
Scope of the substratesa
O2N
R2
R1
O
O
5b
(5 mol %)
O
TFA, rt
+
O
O2N
O
R2
R3
OBu-t
DCE, -20°C
R3
R1
1d, f, g
O
O
4a-4q
2a-2o
Entry
1
R1
R2
R3
Time/h
Product
Yieldb/%
eec/%
1
2
3
4
5
6
7
8
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1d
1f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
4-MeeC6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C2H5
Allyl
i-Pr
24
36
48
24
24
24
24
24
24
48
24
24
24
24
24
72
96
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
82
82
85
84
82
81
80
85
87
81
94
90
97
85
87
72
65
90
90
90
92
92
94
94
92
92
88
85
90
88
86
86
90d
72d
4-MeOeC6H4
4-FeC6H4
4-CleC6H4
4-BreC6H4
4-NO2eC6H4
2-FeC6H4
3-CleC6H4
Thiophene-2-yl
C6H5
C6H5
C6H5
i-Pr
c-Hex
9
10
11
12
13
14
15
16
17
C2H5
C2H5
CH3
CH3
CH3
C2H5
C6H5
C6H5
1g
a
The reactions were carried out with 1 (0.220 mmol), 2 (0.200 mmol), and 5b (0.010 mmol) in 1,2-dichloroethane (2.0 mL) at ꢀ20 ꢁC.
b
c
Isolated yields.
Determined by chiral HPLC.
d
Ee value of the major diastereoisomer. The ratio of two diastereoisomers was 3/1 as determined by 1H NMR analysis of the crude products.
OEt
Optical rotations were measured on a PerkineElmer 341 digital
O2N
20
O
O
polarimeter and are reported as [
a]
(c in gram per 100 mL of
D
RaneyNi, H2 (40 bar)
40°C,4 h
solvent). The flash column chromatography was carried out over
silica gel (230e400 mesh), purchased from Qingdao Haiyang
Chemical Co. Ltd. Melting points were recorded on an electro-
thermal digital melting point apparatus and were uncorrected. TLC
analysis was performed on precoated silica gel GF254 slides, and
visualized by UV irradiation. Infrared (IR) spectra were recorded on
a Bruker Tensor 37 spectrophotometer. Infrared (IR) peaks are
represented as frequency of absorption (cmꢀ1). Unless otherwise
stated, all reagents were obtained from commercial sources and
used as received. The solvents were used as commercial anhydrous
grade without further purification. Enantiomeric excesses were
determined by HPLC using a Daicel Chiralpak IC, AD-H or OJ-H
column (4.6 mmꢂ25 cm) and eluting with hexane/i-PrOH solution.
O
N
H
OMe
O
O
OEt
OMe
6
3a
yield: 81%
dr: 3:1
dr: 1:1
ee: 86%/80%
ee: 86%/80%
O2N
O
RaneyNi, H2 (40 bar)
40°C, 4 h
O
OMe
N
H
OMe
O
4a
7
ee: 90%
yield: 77%
dr: >20:1
ee: 90%
Scheme 4. Reductive amination of product 3a and 4a.
4.2. General procedure for conjugate addition of
acetates to -unsaturated -keto esters
a-nitro-
b,g
a
hydrogenation. The present results suggest that nitroacetates can
be used as the practical surrogates of nitroalkanes for the conjugate
A mixture of a-nitroacetate (0.22 mmol), b,g-unsaturated a-keto
ester (0.20 mmol) and, 5b (0.01 mmol) in 1,2-dichloroethane
(2.0 mL) was stirred for 24 h at ꢀ20 ꢁC. After the evaporation of
the solvent under vacuum, the residue was purified by flash chro-
matography over silica gel (petroleum ether/ethyl acetate¼10:1).
addition reaction with b,g-unsaturated a-keto esters. The applica-
tions of this strategy for other organocatalytic conjugate additions
are currently under investigation in our laboratory.
4. Experimental section
4.1. General information
4.3. Spectral data of products 3aee
4.3.1. (3R)-1-Ethyl 6-methyl 2-nitro-5-oxo-3-phenylhexanedioate
(3a). Prepared according to the general procedure Section 4.2 as
a colorless oil (62.7 mg, 97% yield), a mixture of two inseparable
1H and13C NMR spectra were recorded on a Bruker Advance
400 MHz spectrometer as solutions in CDCl3 or CD3OD. Chemical
shifts in 1H NMR spectra are reported in parts per million (ppm,
d)
diastereoisomers. 1H NMR (400 MHz, CDCl3)
d 7.34e7.23 (m, 10H),
downfield from the internal standard Me4Si (TMS,
Chemical shifts in 13C NMR spectra are reported relative to the
central line of the chloroform signal (
abbreviations are used to designate chemical shift mutiplicities:
s¼singlet, d¼doublet, m¼multiplet. High-resolution mass spectra
were obtained with Shimadazu LCMS-IT-TOF mass spectrometer.
d
¼0 ppm).
5.46 (d, J¼9.9 Hz, 1H), 5.40 (d, J¼8.9 Hz, 1H), 4.42e4.19 (m, 4H),
4.15e3.99 (m, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.64 (dd, J¼18.6, 9.5 Hz,
1H), 3.48e3.41 (m, 2H), 3.31 (dd, J¼18.6, 4.0 Hz, 1H), 1.29 (t,
J¼7.1 Hz, 3H), 1.06 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
¼77.0 ppm). The following
d
190.2, 190.2, 163.4, 162.9, 160.5, 160.5, 137.0, 136.0, 129.1, 129.0,
128.4, 128.4, 128.4, 128.0, 91.1, 91.0, 63.5, 63.1, 53.2, 53.2, 41.6, 41.4,

R.-jiong Lu et al. / Tetrahedron 68 (2012) 9397e9404
9401
41.1, 40.9, 13.8, 13.6; IR (thin film)
n
/cmꢀ1: 1753, 1602, 1564, 1163,
9.6 Hz, 1H), 3.39 (qd, J¼18.7, 6.2 Hz, 2H), 3.26 (d, J¼18.5 Hz, 1H); 13
C
1070, 950, 861, 549, 521; HRMS (ESI) calcd for C15H17NO7 (MꢀH)ꢀ:
NMR (100 MHz, CDCl3)
d
190.2, 190.1, 163.3, 162.8, 160.4, 160.4,
322.0932, found: 322.0928; [
tiomeric excess was determined by HPLC with a Chiralpak OJ-H
a
]
20þ30.0 (c 1.0, CH2Cl2). The enan-
136.9, 135.9, 133.9, 133.9, 129.1, 129.1, 129.0, 128.8, 128.8, 128.7,
128.5, 128.5, 128.4, 128.4, 128.4, 128.1, 91.1, 90.9, 68.9, 68.7, 53.2,
D
column (hexane/i-PrOH¼85:15,
l¼208 nm, 0.8 mL/min),
41.5, 41.4, 41.1, 41.0; IR (thin film) n
/cmꢀ1: 3011, 2959, 1754, 1735,
tmajor¼30.9 min, tminor¼44.7 min, 86% ee; tmajor¼38.1 min,
tminor¼54.7 min, 80% ee.
1554, 1305, 1255, 1169, 772, 751, 706, 570, 555; HRMS (ESI) calcd for
C20H19NO7 (MꢀH)ꢀ: 384.1089, found: 384.1087; [
a
]
20þ23.4 (c 1.0,
D
CH2Cl2). The enantiomeric excess was determined by HPLC with
4.3.2. (3R)-Dimethyl 2-nitro-5-oxo-3-phenylhexanedioate (3b).
Prepared according to the general procedure Section 4.2 as
a colorless oil (55.7 mg, 90% yield), a mixture of two inseparable
a
Chiralpak OJ-H column (hexane/i-PrOH¼40:60,
l
¼208 nm,
1.0 mL/min), tmajor¼48.7 min, tminor¼83.5 min, 83% ee;
tmajor¼70.1 min, tminor¼145.3 min, 90% ee.
diastereoisomers. 1H NMR (400 MHz, CDCl3)
d 7.37e7.28 (m, 8H),
7.26 (d, J¼1.6 Hz, 2H), 5.49 (d, J¼9.9 Hz, 1H), 5.43 (d, J¼8.6 Hz, 1H),
4.33 (ddd, J¼12.5, 9.6, 6.1 Hz, 2H), 3.84 (s, 3H), 3.84 (s, 3H), 3.83 (s,
3H), 3.71e3.60 (m, 4H), 3.49e3.42 (m, 2H), 3.35 (dd, J¼18.7,
4.4. General procedure for conjugate addition of
a-nitro-
acetates to -unsaturated -keto esters and subsequent
b,
g
a
decarboxylation
4.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 190.2, 190.2, 163.9, 163.3,
160.6, 160.5, 137.0, 136.1, 129.1, 129.1, 128.4, 128.4, 128.3, 128.0,
A mixture of tert-butyl a-nitroacetate (0.22 mmol), b,g-un-
91.0, 90.9, 53.8, 53.5, 53.2, 53.1, 41.6, 41.2, 41.0, 41.0; IR (thin film)
saturated a-keto ester (0.20 mmol), and 5b (0.01 mmol) in 1,2-
n
/cmꢀ1: 2957, 2924, 2853, 1757, 1732, 1595, 1553, 1172, 1052, 940,
dichloroethane (2.0 mL) was stirred for 24 h at ꢀ20 ꢁC. Then TFA
861, 549, 521; HRMS (ESI) calcd for C14H15NO7 (MꢀH)ꢀ: 308.0776,
(670 mL) was added and the mixture was stirred for 5 h at room
found: 308.0779; [
excess was determined by HPLC with a Chiralpak AD-H column
a
]
20þ35.6 (c 1.0, CH2Cl2). The enantiomeric
temperature. The reaction was quenched with saturated aqueous
NaHCO3 (5 mL). The organic layer was separated and the aqueous
layer was extracted with dichloromethane (5 mLꢂ3). The combined
organic layer was dried over anhydrous Na2SO4, filtered, and
evaporated under vacuum. The residue was purified by flash
chromatography over silica gel (petroleum ether/ethyl
acetate¼5:1).
D
(hexane/i-PrOH¼90:10, ¼208 nm, 0.8 mL/min), tmajor¼21.0 min,
l
tminor¼23.0 min, 84% ee; tmajor¼26.7 min, tminor¼29.0 min, 79% ee.
4.3.3. (3R)-1-Isopropyl 6-methyl 2-nitro-5-oxo-3-phenylhexanedioate
(3c). Prepared according to the general procedure Section 4.2 as
a colorless oil (62.1 mg, 92% yield), a mixture of two inseparable
diastereoisomers. 1H NMR (400 MHz, CDCl3)
d
7.35e7.26 (m, 10H),
4.5. Spectral data of products 4aeq
5.43 (d, J¼9.8 Hz, 1H), 5.37 (d, J¼9.2 Hz, 1H), 5.16e5.04 (m, 1H), 4.87
(dt, J¼12.4, 6.2 Hz, 1H), 4.31 (ddd, J¼13.1, 9.6, 5.3 Hz, 2H), 3.83 (s, 3H),
3.81 (s, 3H), 3.62 (dd, J¼18.6, 9.6 Hz, 1H), 3.45 (d, J¼6.7 Hz, 2H), 3.29
(dd, J¼18.6, 3.7 Hz, 1H), 1.28 (t, J¼5.8 Hz, 6H), 1.13 (d, J¼6.2 Hz, 3H),
4.5.1. (R)-Methyl 5-nitro-2-oxo-4-phenylpentanoate (4a). Prepared
according to the general procedure Section 4.4 as a colorless oil
(41.2 mg, 82% yield). 1H NMR (400 MHz, CDCl3)
d 7.37e7.27 (m, 3H),
0.96 (d, J¼6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
190.2, 190.2,
7.25e7.21 (m, 2H), 4.66 (qd, J¼12.6, 7.4 Hz, 2H), 4.14e4.00 (m, 1H),
162.9, 162.4, 160.6, 160.5, 137.1, 136.0, 129.0, 129.0, 128.5, 128.4, 128.3,
128.1, 91.2, 91.2, 71.9, 71.4, 53.1, 53.1, 41.7, 41.6, 41.2, 40.9, 21.4, 21.3,
3.84 (s, 3H), 3.43 (dd, J¼18.8, 7.4 Hz, 1H), 3.31 (dd, J¼18.8, 6.8 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 190.8, 160.6, 137.9, 129.2, 128.2,
21.2, 21.0; IR (thin film)
n
/cmꢀ1: 1730, 1602, 1356, 1162, 1074, 1065,
127.4, 79.2, 53.2, 42.2, 38.6; IR (thin film) n
/cmꢀ1: 3363, 2960, 2920,
947, 861, 549, 523; HRMS (ESI) calcd for C16H19NO7 (MꢀH)ꢀ:
2851, 1758, 1562, 1379, 1296, 1261, 1093, 1070, 796, 702; HRMS (ESI)
336.1089, found: 336.1082; [
meric excess was determined by HPLC with a Chiralpak OJ-H column
a]
D
20þ39.2 (c 1.0, CH2Cl2). The enantio-
calcd for C12H13NO5 (MꢀH)ꢀ: 250.0715, found: 250.0712;
[
a
]
20þ12.5 (c 1.0, CH2Cl2). The enantiomeric excess was determined
D
(hexane/i-PrOH¼60:40,
l
¼208 nm, 0.5 mL/min), tmajor¼31.2 min,
by HPLC with a Chiralpak IC column (hexane/i-PrOH¼60:40,
tminor¼53.8 min, 88% ee; tmajor¼45.4 min, tminor¼61.7 min, 90% ee.
l
¼220 nm, 1.0 mL/min), tminor¼9.4 min, tmajor¼11.9 min, 90% ee.
4.3.4. (3R)-1-tert-Butyl 6-methyl 2-nitro-5-oxo-3-phenylhexanedioate
(3d). Prepared according to the general procedure Section 4.2 as
a colorless oil (65.4 mg, 93% yield), a mixture of two inseparable
4.5.2. (R)-Methyl 5-nitro-2-oxo-4-p-tolylpentanoate (4b). Prepared
according to the general procedure Section 4.4 as a colorless oil
(43.5 mg, 82% yield). 1H NMR (400 MHz, CDCl3)
d 7.20e7.03 (m, 4H),
diastereoisomers. 1H NMR (400 MHz, CDCl3)
d
7.38e7.26 (m, 10H),
4.63 (qd, J¼12.5, 7.4 Hz, 2H), 4.11e3.96 (m, 1H), 3.84 (s, 3H), 3.40
5.37 (d, J¼9.9,1H), 5.32 (d, J¼9.4,1H), 4.34e4.21 (m, 2H), 3.82 (s, 3H),
3.81 (s, 3H), 3.60 (dd, J¼18.5, 9.8, 1H), 3.47e3.39 (m, 2H), 3.26 (dd,
J¼18.5, 3.6, 1H), 1.47 (s, 9H), 1.23 (s, 9H); 13C NMR (100 MHz, CDCl3)
(dd, J¼18.6, 7.4 Hz,1H), 3.28 (dd, J¼18.6, 6.7 Hz,1H), 2.31 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 191.0, 160.7, 137.9, 134.9, 129.8, 127.3, 79.3,
53.2, 42.3, 38.3, 21.0; IR (thin film) n
/cmꢀ1: 1730, 1602, 1554, 1162,
d
190.2, 190.2, 162.3, 161.7, 160.6, 160.6, 137.2, 136.2, 129.0, 128.9,
1079, 948, 861, 548, 523; HRMS (ESI) calcd for C13H15NO5 (MꢀH)ꢀ:
128.7, 128.3, 128.2, 128.1, 91.8, 91.8, 85.6, 84.9, 53.1, 53.1, 41.9, 41.6,
264.0877, found: 264.0882; [
tiomeric excess was determined by HPLC with a Chiralpak IC col-
a
]
20þ17.1 (c 1.0, CH2Cl2). The enan-
D
41.2, 41.0, 27.6, 27.3; IR (thin film)
n
/cmꢀ1: 1735, 1603, 1563, 1158,
1073, 949, 861, 548, 524; HRMS (ESI) calcd for C17H21NO7 (MꢀH)ꢀ:
umn (hexane/i-PrOH¼60:40,
l
¼208 nm, 1.0 mL/min),
350.1245, found: 350.1243; [
a
]
20þ34.2 (c 1.0, CH2Cl2). The enantio-
tminor¼9.8 min, tmajor¼12.1 min, 90% ee.
D
meric excess was determined by HPLC with a Chiralpak OJ-H column
(hexane/i-PrOH¼85:15,
l
¼208 nm, 0.8 mL/min), tmajor¼26.0 min,
4.5.3. (R)-Methyl 4-(4-methoxyphenyl)-5-nitro-2-oxopentanoate
tminor¼51.3 min, 90% ee; tmajor¼45.7 min, tminor¼82.6 min, 88% ee.
(4c). Prepared according to the general procedure Section 4.4 as
a colorless oil (47.8 mg, 85% yield). 1H NMR (400 MHz, CDCl3)
d 7.15
4.3.5. (3R)-1-Benzyl 6-methyl 2-nitro-5-oxo-3-phenylhexanedioate
(3e). Prepared according to the general procedure Section 4.2 as
a white solid (77.1 mg, 91% yield), a mixture of two inseparable
diastereoisomers. Mp 85e86 ꢁC; 1H NMR (400 MHz, CDCl3)
(d, J¼8.6 Hz, 2H), 6.85 (d, J¼8.7 Hz, 2H), 4.61 (qd, J¼12.5, 7.4 Hz, 2H),
4.09e3.97 (m, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 3.38 (dd, J¼18.5, 7.5 Hz,
1H), 3.26 (dd, J¼18.5, 6.6 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 191.0,
160.7, 159.3, 129.8, 128.5, 114.5, 79.4, 55.2, 53.2, 42.4, 38.0; IR (thin
d
7.43e7.27 (m, 11H), 7.26e7.20 (m, 7H), 7.12 (d, J¼4.1 Hz, 2H), 5.50
film) n
/cmꢀ1: 1730, 1602, 1554, 1515, 1162, 1078, 948, 861, 549, 523;
(d, J¼9.5 Hz, 1H), 5.44 (d, J¼8.6 Hz, 1H), 5.23 (s, 2H), 5.02 (q,
J¼11.9 Hz, 2H), 4.40e4.23 (m, 2H), 3.80 (s, 6H), 3.62 (dd, J¼18.3,
HRMS (ESI) calcd for C13H15NO6 (MꢀH)ꢀ: 280.0827, found:
280.0822; [
a]
20þ32.3 (c 1.0, CH2Cl2). The enantiomeric excess was
D

9402
R.-jiong Lu et al. / Tetrahedron 68 (2012) 9397e9404
determined by HPLC with a Chiralpak IC column (hexane/i-
34.2; IR (thin film) n
/cmꢀ1: 2925, 1732, 1555, 1161, 1077, 948, 861,
PrOH¼60:40,
l¼220 nm, 1.0 mL/min), tminor¼11.7 min,
548, 523; HRMS (ESI) calcd for C12H12FNO5 (MꢀH)ꢀ: 268.0627,
tmajor¼14.2 min, 90% ee.
found: 268.0635; [
a
]
20þ10.2 (c 1.0, CH2Cl2). The enantiomeric ex-
D
cess was determined by HPLC with a Chiralpak IC column (hexane/
4.5.4. (R)-Methyl 4-(4-fluorophenyl)-5-nitro-2-oxopentanoate
(4d). Prepared according to the general procedure Section 4.4 as
a colorless oil (45.2 mg, 84% yield). 1H NMR (400 MHz, CDCl3)
i-PrOH¼60:40,
l
¼208 nm, 1.0 mL/min), tminor¼8.7 min,
tmajor¼10.2 min, 92% ee.
d
7.25e7.17 (m, 2H), 7.06e6.98 (m, 2H), 4.63 (ddd, J¼28.6, 12.6,
4.5.9. (R)-Methyl 4-(3-chlorophenyl)-5-nitro-2-oxopentanoate
(4i). Prepared according to the general procedure Section 4.4 as
a colorless oil (49.7 mg, 87% yield). 1H NMR (400 MHz, CDCl3)
7.4 Hz, 2H), 4.13e4.01 (m, 1H), 3.85 (s, 3H), 3.39 (dd, J¼18.7, 7.5 Hz,
1H), 3.28 (dd, J¼18.7, 6.6 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 190.7,
162.3 (d, J¼247.3 Hz), 160.6, 133.7 (d, J¼3.4 Hz), 129.2 (d, J¼8.2 Hz),
d
7.26 (dd, J¼8.2, 6.7 Hz, 3H), 7.19e7.11 (m, 1H), 4.74e4.55 (m,
116.1 (d, J¼21.6 Hz), 79.1, 53.2, 42.2, 37.9; IR (thin film)
n
/cmꢀ1
:
2H), 4.12e3.99 (m, 1H), 3.86 (s, 3H), 3.41 (dd, J¼18.9, 7.3 Hz, 1H),
2925, 1732, 1555, 1161, 1077, 948, 861, 549, 523; HRMS (ESI) calcd
3.30 (dd, J¼19.0, 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 190.5,
for C12H11FNO5 (MꢀH)ꢀ: 268.0627, found: 268.0620; [
a
]
20þ17.8 (c
160.5, 140.1, 135.0, 130.4, 128.4, 127.7, 125.8, 78.7, 53.3, 42.0, 38.2;
D
1.0, CH2Cl2). The enantiomeric excess was determined by HPLC
IR (thin film) n
/cmꢀ1: 1757, 1731, 1554, 1165, 1082, 949, 861, 549,
with a Chiralpak IC column (hexane/i-PrOH¼60:40,
l¼208 nm,
523; HRMS (ESI) calcd for C12H12ClNO5 (MꢀH)ꢀ: 284.0331, found:
1.0 mL/min), tminor¼7.9 min, tmajor¼10.1 min, 92% ee.
284.0336; [
a
]
20þ21.3 (c 1.0, CH2Cl2). The enantiomeric excess was
D
determined by HPLC with a Chiralpak IC column (hexane/i-
4.5.5. (R)-Methyl 4-(4-chlorophenyl)-5-nitro-2-oxopentanoate
PrOH¼60:40,
l
¼208 nm, 1.0 mL/min), tminor¼8.5 min,
(4e). Prepared according to the general procedure Section 4.4 as
tmajor¼10.4 min, 92% ee.
a colorless oil (46.8 mg, 84% yield). 1H NMR (400 MHz, CDCl3)
d 7.31
(d, J¼8.4 Hz, 2H), 7.19 (d, J¼8.3 Hz, 2H), 4.63 (ddd, J¼28.3, 12.7,
7.4 Hz, 2H), 4.11e4.00 (m, 1H), 3.85 (s, 3H), 3.40 (dd, J¼18.8, 7.5 Hz,
1H), 3.28 (dd, J¼18.8, 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
4.5.10. (S)-Methyl 5-nitro-2-oxo-4-(thiophen-2-yl)pentanoate (4j).
Prepared according to the general procedure Section 4.4 as a color-
less oil (41.7 mg, 81% yield). 1H NMR (400 MHz, CDCl3)
d 7.25e7.19
d
190.6,160.5,136.5,134.1,129.4,128.9, 78.9, 53.3, 42.1, 38.0; IR (thin
(m, 1H), 7.00e6.89 (m, 2H), 4.80e4.59 (m, 2H), 4.46e4.34 (m, 1H),
3.87 (s, 3H), 3.47 (dd, J¼18.8, 7.2 Hz,1H), 3.36 (dd, J¼18.9, 6.5 Hz, 1H);
film) n
/cmꢀ1: 1731, 1554, 1381, 1163, 1061, 948, 861, 549, 522; HRMS
(ESI) calcd for C12H11ClNO5 (MꢀH)ꢀ: 284.0331, found: 284.0335;
13C NMR (100 MHz, CDCl3)
d 190.5, 160.5, 140.6, 127.2, 125.9, 125.1,
[
a
]
20þ14.8 (c 1.0, CH2Cl2). The enantiomeric excess was determined
79.3, 53.3, 43.0, 34.0; IR (thin film) n
/cmꢀ1: 2958, 2925, 1758, 1724,
D
by HPLC with a Chiralpak IC column (hexane/i-PrOH¼60:40,
1562, 1546, 1382, 1263, 1173, 1042, 940, 861, 550, 522; HRMS (ESI)
l
¼208 nm, 1.0 mL/min), tminor¼8.2 min, tmajor¼10.2 min, 92% ee.
calcd for C10H11NO5S (MꢀH)ꢀ: 256.0285, found: 256.0281;
[
a
]
20þ23.1 (c 1.0, CH2Cl2). The enantiomeric excess was determined
D
4.5.6. (R)-Methyl 4-(4-bromophenyl)-5-nitro-2-oxopentanoate
(4f). Prepared according to the general procedure Section 4.4 as
a colorless oil (53.5 mg, 81% yield). 1H NMR (400 MHz, CDCl3)
by HPLC with
l
a
Chiralpak IC column (hexane/i-PrOH¼60:40,
¼208 nm, 1.0 mL/min), tminor¼9.9 min, tmajor¼12.6 min, 88% ee.
d
7.53e7.40 (m, 2H), 7.12 (d, J¼8.4 Hz, 2H), 4.63 (ddd, J¼27.3, 12.7,
4.5.11. (R)-Ethyl 5-nitro-2-oxo-4-phenylpentanoate (4k). Prepared
7.3 Hz, 2H), 4.13e3.98 (m, 1H), 3.85 (s, 3H), 3.39 (dd, J¼18.8, 7.5 Hz,
according to the general procedure Section 4.4 as a colorless oil
1H), 3.28 (dd, J¼18.8, 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
(49.9 mg, 94% yield). 1H NMR (400 MHz, CDCl3)
d 7.37e7.27 (m, 3H),
d
190.6, 160.5, 137.0, 132.3, 129.2, 122.2, 78.8, 53.3, 42.0, 38.0; IR
7.25e7.18 (m, 2H), 4.66 (qd, J¼12.6, 7.4 Hz, 2H), 4.29 (q, J¼7.0 Hz,
2H), 4.14e4.00 (m, 1H), 3.41 (dd, J¼18.6, 7.3 Hz, 1H), 3.29 (dd,
J¼18.6, 6.7 Hz, 1H), 1.34 (t, J¼7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
(thin film) n
/cmꢀ1: 1732, 1554, 1162, 1076, 949, 861, 548, 523; HRMS
(ESI) calcd for C12H11BrNO5 (MꢀH)ꢀ: 327.9826, found: 327.9825;
[
a
]
20þ10.4 (c 1.0, CH2Cl2). The enantiomeric excess was determined
d 191.3, 160.3, 138.1, 129.2, 128.1, 127.5, 79.2, 62.8, 42.2, 38.6, 13.9; IR
D
by HPLC with a Chiralpak IC column (hexane/i-PrOH¼60:40,
(thin film) n
/cmꢀ1: 2926, 2360, 1754, 1724, 1547, 1383, 1175, 939,
l
¼208 nm, 1.0 mL/min), tminor¼8.6 min, tmajor¼10.5 min, 94% ee.
870, 553, 515; HRMS (ESI) calcd for C13H14NO5 (MꢀH)ꢀ: 264.0877,
found: 264.0871; [
cess was determined by HPLC with a Chiralpak IC column (hexane/
a
]
20þ14.6 (c 1.0, CH2Cl2). The enantiomeric ex-
D
4.5.7. (R)-Methyl 5-nitro-4-(4-nitrophenyl)-2-oxopentanoate
(4g). Prepared according to the general procedure Section 4.4 as
i-PrOH¼60:40,
l
¼208 nm, 1.0 mL/min), tminor¼8.9 min,
a colorless oil (47.4 mg, 80% yield). 1H NMR (400 MHz, CDCl3)
d
8.21
tmajor¼10.2 min, 85% ee.
(d, J¼8.7 Hz, 2H), 7.46 (d, J¼8.5 Hz, 2H), 4.71 (ddd, J¼20.9, 13.0,
7.3 Hz, 2H), 4.26e4.14 (m, 1H), 3.87 (s, 3H), 3.46 (dd, J¼19.1, 7.5 Hz,
4.5.12. (R)-Allyl 5-nitro-2-oxo-4-phenylpentanoate (4l). Prepared
1H), 3.36 (dd, J¼19.1, 6.5 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 190.2,
according to the general procedure Section 4.4 as a colorless oil
(49.9 mg, 90% yield). 1H NMR (400 MHz, CDCl3)
d 7.37e7.27 (m, 3H),
160.4, 147.7, 145.3, 128.7, 124.3, 78.3, 53.4, 41.8, 38.2; IR (thin film) n/
cmꢀ1: 1732, 1604, 1555, 1437, 1348, 1176, 1049, 939, 869, 553, 516;
7.25e7.18 (m, 2H), 5.92 (ddd, J¼16.5,11.2, 6.0 Hz,1H), 5.35 (dd, J¼23.7,
13.8 Hz, 2H), 4.66 (ddd, J¼20.0, 12.9, 6.6 Hz, 4H), 4.14e4.01 (m, 1H),
3.42 (dd, J¼18.7, 7.3 Hz, 1H), 3.30 (dd, J¼18.7, 6.7 Hz, 1H); 13C NMR
HRMS (ESI) calcd for C12H12N2O7 (MꢀH)ꢀ: 295.0572, found:
295.0566; [
a
]
20þ6.7 (c 1.0, CH2Cl2). The enantiomeric excess was
D
determined by HPLC with a Chiralpak IC column (hexane/i-
(100 MHz, CDCl3) d 191.0,159.9,138.0, 130.5, 129.2,128.2, 127.5, 120.2,
79.1, 67.1, 42.2, 38.6;IR(thinfilm)n
/cmꢀ1: 2925,1756,1723,1547,1382,
PrOH¼70:30,
l
¼263 nm, 1.0 mL/min), tminor¼18.0 min,
1175, 940, 869, 552, 518; HRMS (ESI) calcd for C14H15NO5 (MꢀH)ꢀ:
tmajor¼22.2 min, 94% ee.
276.0877, found: 276.0883; [
a]
D
20þ13.8 (c 1.0, CH2Cl2). The enantio-
4.5.8. (R)-Methyl 4-(2-fluorophenyl)-5-nitro-2-oxopentanoate
(4h). Prepared according to the general procedure Section 4.4 as
a colorless oil (45.8 mg, 85% yield). 1H NMR (400 MHz, CDCl3)
meric excess was determined by HPLC with a Chiralpak IC column
(hexane/i-PrOH¼60:40,
l¼208 nm, 1.0 mL/min), tminor¼8.4 min,
tmajor¼9.5 min, 90% ee.
d
7.34e7.27 (m, 1H), 7.24 (s, 1H), 7.15e7.02 (m, 2H), 4.81e4.66 (m,
2H), 4.30e4.19 (m, 1H), 3.47 (dd, J¼19.0, 7.1 Hz, 1H), 3.38 (dd,
J¼19.0, 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 190.8, 160.8 (d,
4.5.13. (R)-Isopropyl 5-nitro-2-oxo-4-phenylpentanoate
(4m). Prepared according to the general procedure Section 4.4 as
a colorless oil (54.2 mg, 97% yield). 1H NMR (400 MHz, CDCl3)
J¼246.4 Hz), 160.6, 130.0 (d, J¼2.4 Hz), 130.0 (d, J¼6.7 Hz), 124.7 (d,
J¼3.6 Hz), 116.3, 116.1, 77.4 (d, J¼2.8 Hz), 53.2, 41.0 (d, J¼2.1 Hz),

R.-jiong Lu et al. / Tetrahedron 68 (2012) 9397e9404
9403
d
7.36e7.26 (m, 3H), 7.25e7.20 (m, 2H), 5.16e5.01 (m, 1H), 4.66 (qd,
4.6. General procedure for reductive amination
J¼12.6, 7.4 Hz, 2H), 4.06 (q, J¼7.2 Hz, 1H), 3.38 (dd, J¼18.5, 7.3 Hz,
1H), 3.27 (dd, J¼18.5, 6.8 Hz, 1H), 1.31 (dd, J¼6.2, 4.5 Hz, 6H); 13C
Compound 3a or 4a (0.200 mmol) was hydrogenated over Raney
nickel (200 mg) in methanol (4 mL) under a hydrogen atmosphere
(40 bar) at 40 ꢁC for 4 h. The mixture was cooled to room tem-
perature and filtered through a pad of Celite. Then the Celite was
washed with ethyl acetate (3 mLꢂ2). The combined filtrate was
concentrated under vacuum. The residue was purified by column
NMR (100 MHz, CDCl3) d 191.7, 159.9, 138.2, 129.1, 128.1, 127.5, 79.2,
71.2, 42.2, 38.7, 21.5; IR (thin film) n
/cmꢀ1: 2985, 1747, 1722, 1554,
1378,1162,1072, 861, 701, 549, 522; HRMS (ESI) calcd for C14H17NO5
(MꢀH)ꢀ: 278.1034, found: 278.1027; [
a
]
20þ14.1 (c 1.0, CH2Cl2). The
D
enantiomeric excess was determined by HPLC with a Chiralpak IC
column (hexane/i-PrOH¼70:30,
l
¼208 nm, 1.0 mL/min),
chromatography
acetate¼5:1).
over
silica
gel
(dichloromethane/ethyl
tminor¼9.2 min, tmajor¼9.8 min, 88% ee.
4.5.14. (R)-Ethyl 5-methyl-4-(nitromethyl)-2-oxohexanoate (4n).
4.7. Spectral data of products 6 and 7
Prepared according to the general procedure Section 4.4 as a color-
less oil (39.3 mg, 85% yield). 1H NMR (400 MHz, CDCl3)
d 4.49e4.38
4.7.1. (2S/2R,3R,5S)-2-Ethyl 5-methyl 3-phenylpyrrolidine-2,5-
dicarboxylate (6). Prepared according to the general procedure
Section 4.6 as a colorless oil (44.9 mg, 81% yield), a mixture of two
(m, 2H), 4.34 (q, J¼7.1 Hz, 2H), 3.03 (dd, J¼18.7, 5.3 Hz, 1H), 2.92 (dd,
J¼18.7, 7.5 Hz, 1H), 2.69 (dq, J¼7.1, 5.5 Hz, 1H), 1.92e1.77 (m, 1H), 1.38
(t, J¼7.1 Hz, 3H), 0.96 (dd, J¼6.8, 4.6 Hz, 6H); 13C NMR (100 MHz,
diastereoisomers. 1H NMR (400 MHz, CDCl3)
d 7.36e7.27 (m, 5H),
CDCl3)
(thin film)
d 192.6, 160.6, 76.7, 62.8, 38.4, 38.0, 28.9, 19.4, 18.9, 13.9; IR
7.25e7.17 (m, 2.7H), 4.24e3.99 (m, 3.7H), 3.86 (d, J¼7.7 Hz,1H), 3.83
(s, 1H), 3.78 (s, 3.7H), 3.63 (dd, J¼14.3, 7.1 Hz, 0.3H), 3.36 (dd,
J¼16.3, 8.1 Hz, 1H), 2.58e2.27 (m, 4H), 1.16 (t, J¼7.1 Hz, 3H), 0.78 (t,
n
/cmꢀ1: 2965, 2929, 1729, 1552, 1547, 1353, 1178, 1050,
939, 872, 553, 518; HRMS (ESI) calcd for C10H17NO5 (MꢀH)ꢀ:
20þ5.0 (c 1.0, CH2Cl2). The enantio-
J¼7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
174.6, 173.7, 173.3, 172.7,
230.1034, found: 230.1039; [
a]
D
meric excess was determined by HPLC with a Chiralpak AD-H col-
141.2, 138.6, 128.6, 128.2, 127.9, 127.4, 127.1, 126.9, 67.5, 65.6, 61.1,
umn
(hexane/i-PrOH¼99:1,
l
¼208
nm,
0.8
mL/min),
60.6, 60.0, 59.8, 52.4, 52.3, 49.0, 38.8, 35.0, 14.1, 13.5; IR (thin film) n/
cmꢀ1: 2962, 2926, 2853, 1744, 1262, 1208, 1098, 1018, 801, 702;
tminor¼21.5 min, tmajor¼23.5 min, 86% ee.
HRMS (ESI) calcd for C15H19NO4 (MþNa)þ: 300.1206, found:
300.1203; [
a
]
20ꢀ5.3 (c 1.0, CH2Cl2). The enantiomeric excess was
4.5.15. (R)-Ethyl 4-cyclohexyl-5-nitro-2-oxopentanoate (4o).
Prepared according to the general procedure Section 4.4 as
a colorless oil (47.2 mg, 87% yield). 1H NMR (400 MHz, CDCl3)
D
determined by HPLC with a Chiralpak IC column (hexane/i-
PrOH¼60:40,
l
¼208 nm, 0.8 mL/min), tmajor¼13.5 min,
d
4.44 (qd, J¼12.5, 6.5 Hz, 2H), 4.34 (q, J¼7.1 Hz, 2H), 3.06 (dd,
tminor¼16.4 min, 86% ee; tminor¼14.3 min, tmajor¼18.9 min, 80% ee.
J¼18.8, 5.4 Hz, 1H), 2.93 (dd, J¼18.8, 7.3 Hz, 1H), 2.73e2.61 (m,
1H), 1.87e1.60 (m, 6H), 1.50e1.42 (m, 1H), 1.19e1.08 (m, 2H),
4.7.2. (2S,4R)-Methyl 4-phenylpyrrolidine-2-carboxylate (7).
Prepared according to the general procedure Section 4.6 as
a colorless oil (31.6 mg, 77% yield). 1H NMR (400 MHz, CDCl3)
1.06e0.91 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
192.7, 160.6, 76.7,
62.7, 39.0, 38.4, 37.8, 29.9, 29.6, 26.2, 26.2, 26.1, 13.9; IR (thin film)
n
/cmꢀ1: 2928, 2854, 1730, 1553, 1160, 1076, 949, 861, 549, 522;
d
7.38e7.26 (m, 3H), 7.21 (dd, J¼9.7, 7.5 Hz, 2H), 4.01 (t, J¼8.1 Hz,
HRMS (ESI) calcd for C13H21NO5 (MꢀH)ꢀ: 270.1347, found:
1H), 3.77 (s, 3H), 3.46e3.29 (m, 2H), 3.07 (t, J¼8.5 Hz, 1H),
2.72e2.56 (m, 1H), 2.30 (s, 1H), 1.97 (ddd, J¼10.6, 10.0, 7.3 Hz, 1H);
270.1355; [
a
]
20þ6.2 (c 1.0, CH2Cl2). The enantiomeric excess was
D
13C NMR (100 MHz, CDCl3):
d 175.3, 141.7, 128.6, 127.2, 126.7, 60.0,
determined by HPLC with a Chiralpak IC column (hexane/i-
54.2, 52.2, 45.6, 38.0; IR (thin film) n
/cmꢀ1: 2954, 2926, 2854,
PrOH¼80:20,
l
¼208 nm, 1.0 mL/min), tmajor¼13.3 min,
tminor¼14.0 min, 86% ee.
1736, 1651, 1622, 1455, 1436, 1216, 758, 700; HRMS (ESI) calcd for
C12H15NO2 (MþH)þ: 206.1176, found: 206.1167; [
a
]
20ꢀ15.0 (c 1.0,
D
4.5.16. (4R)-Methyl 5-nitro-2-oxo-4-phenylhexanoate (4p). Prepared
CH2Cl2). The enantiomeric excess was determined by HPLC with
according to the general procedure Section 4.4 as a colorless oil
a Chiralpak IC column (hexane/i-PrOH¼80:20, ¼208 nm, 0.7 mL/
l
(38.2 mg, 72% yield). 1H NMR (400 MHz, CDCl3)
d 7.37e7.27 (m, 3H),
min), tmajor¼35.8 min, tminor¼38.7 min, 90% ee.
7.22 (dd, J¼13.2, 5.3 Hz, 2H), 4.79 (dq, J¼9.9, 6.7 Hz, 1H), 3.84e3.73
(m, 4H), 3.49 (dd, J¼18.2, 9.7 Hz, 1H), 3.09 (dd, J¼18.1, 4.0 Hz, 1H),
Acknowledgements
1.34 (d, J¼6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 190.5, 160.6,
137.4, 129.1, 128.2, 128.1, 86.9, 53.0, 44.8, 42.3, 17.8; IR (thin film) n/
Financial supports from National Natural Science Foundation of
China (Nos. 20972195, 21172270) and Guangdong Engineering Re-
search Center of Chiral Drugs are gratefully acknowledged.
cmꢀ1: 1757, 1731, 1278, 1240, 1070, 704; HRMS (ESI) calcd for
C13H15NO5 (MꢀH)ꢀ: 264.0877, found: 264.0882; [
a
]
D
20þ6.3 (c 1.0,
CH2Cl2). The enantiomeric excess was determined by HPLC with
a Chiralpak IC column (hexane/i-PrOH¼85:15,
l¼208 nm, 1.0 mL/
Supplementary data
min), tminor¼15.2 min, tmajor¼16.3 min, 90% ee.
Supplementary data related to this article can be found online at
http://dx.doi.org/10.1016/j.tet.2012.09.014.
4.5.17. (4R)-Methyl 5-nitro-2-oxo-4-phenylheptanoate(4q). Prepared
according to the general procedure Section 4.4 as a colorless oil
(36.3 mg, 65% yield). 1H NMR (400 MHz, CDCl3)
d 7.36e7.27 (m, 3H),
References and notes
7.26e7.18 (m, 2H), 4.62 (td, J¼10.5, 3.1 Hz, 1H), 3.83e3.71 (m, 4H),
3.51 (dd, J¼18.1, 10.2 Hz, 1H), 3.02 (dd, J¼18.1, 3.6 Hz, 1H), 1.87e1.76
(m, 1H), 1.53e1.45 (m, 1H), 0.85 (t, J¼7.3 Hz, 3H); 13C NMR (100 MHz,
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