Enantioselective Conjugate Addition of 2-Acetyl Azaarenes to β,β-Disubstituted Nitroalkene for the Construction of All-Carbon Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.joc.7b01014

The first highly enantioselective conjugate addition of 2-acetyl azaarenes to α-substituted-β-nitroacrylates was successfully realized under mild conditions by a Ni(II)-bisoxazoline complex, providing the desired adducts bearing an all-carbon quaternary stereocenter in high yield with excellent enantioselectivity. The products obtained in this system could be readily converted into optically active β^2,2-amino esters, succinates, lactones, and lactams.

Full text of DOI:10.1021/acs.joc.7b01014

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Article
Enantioselective Conjugate Addition of 2-Acetyl
Azaarenes to beta,beta-Disubstituted Nitroalkene for the
Construction of All-carbon Quaternary Stereocenters
Hongli Ma, Lei Xie, Zhenhua Zhang, Lin-gang Wu, Bin Fu, and Zhaohai Qin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01014 • Publication Date (Web): 30 Jun 2017
Downloaded from http://pubs.acs.org on July 1, 2017
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Enantioselective Conjugate Addition of 2ꢀAcetyl Azaarenes to β,βꢀDisubstituted
Nitroalkene for the Construction of Allꢀcarbon Quaternary Stereocenters
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Hongli Ma, Lei Xie, Zhenhua Zhang, Linꢀgang Wu, Bin Fu* and Zhaohai Qin*
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Department of Applied Chemistry, China Agricultural University, Beijing 100193, P. R. China.
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ABSTRACT: The first highly enantioselective conjugate addition of 2ꢀacetyl azaarenes to
αꢀsubstitutedꢀβꢀnitroacrylates was successfully realized under mild conditions by a Ni(II)ꢀbisoxazoline
complex, providing the desired adducts bearing an allꢀcarbon quaternary stereocenter in high yield
with excellent enantioselectivity. The products obtained in this system could be readily converted into
optically active β2,2ꢀamino esters, succinates, lactones and lactams.
O
O
NO2
Ar CO2R
NO2
10 mol% Ni(acac)2
12 mol% (S,S)ꢀPhꢀBOX
N
N
Ar
+
Ar
Ar
CO2R
rt
X
X
up to 97% yield and >99% ee
29 examples
Aromatic Nꢀheterocycles (azaarenes) including pyridine, pyrimidine, quinoline, oxazole,
thiazole, and so on, are ubiquitous structural motifs in pharmaceuticals and other biologically active
compounds.1 It has been reported that the majority of all known active pharmaceutical ingredients
(APIS) contain an aromatic Nꢀheterocycle.2 On the other hand, approximately half of all APIs are
chiral compounds. Therefore, the development of efficient methodologies for incorporating an
aromatic Nꢀheterocycle in chiral molecules is highly valuable and desirable in medicinal chemistry
and organic synthesis.
Allꢀcarbon quaternary stereocenters are widely present in a number of natural products,
therapeutic agents and other functional molecules.3 Over the past several decades, studies on the
construction of allꢀcarbon quaternary stereocenters with high levels of stereocontrol have been a
longstanding and challenging topic owing to the high steric hindrance, and hence become a research
focus in organic synthesis.4 So far, there are a plethora of methods explored for this purpose, such as
alkylation,5 allylic alkylation,6 conjugate addition,7 rearrangement,8 desymmetrization,9 and so on.10
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Among them, asymmetric conjugate addition (ACA) of carbonꢀbased nucleophiles with suitable
unsaturated carbonyl acceptors is one straightforward and efficient strategy for the construction of
quaternary carbon stereocenters. In the past few years, β, βꢀdisubstituted nitroalkene as a Michael
acceptor has received increasing attention for attaining this goal, because the resulting products could
be transformed to βꢀamino acid derivatives, lactones and related bioactive compounds bearing
quaternary carbon stereocenters.11 To date, only a few examples concerning αꢀphenyl βꢀnitroacrylate
have been reported by Xiao,12a,b Jia,12c Wennemers,12d Gong12e and other groups,12f affording
efficient approaches to the construction of heteroquaternary or allꢀcarbon quaternary stereocenters. In
addition, β,βꢀdisubstituted unsaturated carbonyl compounds bearing a βꢀCF3 group have also been
employed to the conjugate addition for the construction of trifluoromethylated allꢀcarbon quaternary
stereocenters by several groups.13 Despite these notable advances, the method for the formation of
quaternary carbon stereocenters, particularly acyclic allꢀcarbon quaternary stereocenter is still
limited,14 hence remains highly desirable and challenging.
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Scheme 1. The Strategy for the Formation of Allꢀcarbon Quaternary Stereocenters
We have recently found a highly enantioselective conjugate addition between 2ꢀacetyl azaarene
as a nucleophile and βꢀCF3ꢀβꢀdisubstituted nitroalkene by employing a Ni(acac)2ꢀBOX complex.15
Inspired by this success, we envisioned that αꢀphenylꢀβꢀnitroacrylate as a Michael acceptor could also
proceed smoothly with 2ꢀacetyl azaarene to deliver the enantioselective adducts containing an
allꢀcarbon quaternary stereocenter (Scheme 1). To the best of our knowledge, the method for
incorporating various aromatic Nꢀheterocycle and an allꢀcarbon quaternary stereocenter in organic
molecule is relatively unexplored, and of great significance in medicinal and organic chemistry.
Herein we report the first asymmetric conjugate addition of various 2ꢀacetyl azaarenes to αꢀsubstituted
βꢀnitroacrylates catalyzed by a Ni(II)ꢀbisoxazoline complex, which the resulting products could be
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readily converted into versatile optically active compounds bearing an allꢀcarbon quaternary
stereocenter such as pyrrolidine, succinate, lactone and lactams.
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Table 1. Optimization of Reaction Conditionsa
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Ph CO2R1
NO2
O
O
R1O2C
Ph
NO2
N
N
LigandꢀNi(acac)2
Solvent
3aa~3ad
2a~d: R1 = Me; Bn; iꢀPr; tꢀBu
1a
H
N
S
a. R = Ph
O
O
O
O
O
O
O
O
Ph
N
b. R = Bn
c. R = iꢀPr
d. R = tꢀBu
Ph
N
N
N
N
N
N
N
R
R
Ph
Ph
Ph
Ph
Ph
Ph
L1
L4
L2
L3
entry
1
L
R1
solvent
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
MeOH
EtOH
T (oC)
time (h) yield b (%)
ee c (%)
84
36
14
0
L1a
L1b
L1c
L1d
L2
Me
0
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24
24
24
24
24
24
24
24
24
24
24
48
12
24
48
90 (3aa)
78 (3aa)
72 (3aa)
88 (3aa)
59 (3aa)
51 (3aa)
57 (3aa)
92 (3ab)
90 (3ac)
93 (3ad)
55 (3ad)
90 (3ad)
89 (3ad)
84 (3ad)
89 (3ad)
93 (3ad)
95 (3ad)
94 (3ad)
85 (3ad)
2
Me
0
3
Me
0
4
Me
0
5
Me
0
0
6
L3
Me
0
83
2
7
L4
Me
0
8
L1a
L1a
L1a
L1a
L1a
L1a
L1a
L1a
L1a
L1a
L1a
L1a
Bn
0
97
97
98
84
95
92
97
98
99
97
96
92
9
iꢀPr
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
tꢀBu
0
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12
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17
18 d
19 e
0
0
0
CH2Cl2
Toluene
Et2O
0
0
0
iꢀPrOH
iꢀPrOH
iꢀPrOH
iꢀPrOH
ꢀ10
rt
rt
rt
a
Reaction conditions unless noted otherwise: 1a (0.20 mmol), 2 (0.30 mmol), L (0.024 mmol), Ni(acac)2
b
c
(0.020 mmol) in iꢀPrOH (2 mL) under nitrogen at 0°C for 24 h. Isolated yield. Determined by HPLC
using a chiralcel ODꢀH column. d 5 mol % catalyst loading. e 2.5 mol % catalyst loading.
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We started our study from the reaction of commercially available 2ꢀacetyl pyridine 1a with
αꢀphenylꢀβꢀnitroacrylate methyl ester 2a in iꢀPrOH at 0 oC using 10 mol% of chiral
Ni(acac)2–bisoxazoline complexes based on our previous work.15 The results are summarized in Table
1. Evans′ ligands were first screened (entries 1ꢀ4), and (S,S)ꢀPhꢀBOX (L1a) afforded the best yield
and enantioselectivity (entry 1, 90% yield and 84% ee). Other bisoxazoline ligands L2, L3, and L4
were also examined, and gave lower yields or ee values (entries 5−7). Subsequently, the effect of ester
group on the reaction was tested. When replacing methyl group of αꢀphenylꢀβꢀnitroacrylate (2a) with
more sterically hindered benzyl, isoꢀpropyl and tertꢀbutyl group, the enantioselectivity increased
gradually while high reactivity still maintained (entries 8−10), particularly 2d with a tertꢀbutyl group
afforded the highest ee value (98%). In addition, other Lewis acids including Ni(ClO4)2·6H2O,
Ni(OTf)2,Cu(OTf)2, Ni(OAc)2·4H2O, and Zn(OTf)2 were examined, and most of them didn’t promote
the reaction except that Ni(OAc)2·4H2O offered an excellent enantioselectivity but moderate yield
(entry 13, 45% yield and 98% ee, see Supporting ST1).16 A simple survey of solvent demonstrated that
high to excellent enantioselectivities were achieved for the screened solvents (entries 11−15, 84−98%
ee), however, iꢀPrOH was finally chosen as the optimal solvent in terms of the reactivity and safety.
Moreover, the effect of temperature and catalyst loading on the reaction was tested. When the reaction
proceeded at −10oC for 48 h or room temperature for 12 h, 99% ee and 97% ee values were obtained
respectively, indicating that the decreased temperature could result in a little improvement in
enantioselectivity but at the expense of the reactivity (entries 16 and 9 vs entry 17). Reducing the
catalyst loading to 5 mol% and 2.5 mol%, a longer reaction time was needed for ensuring high yields
while the enantioselectivity dropped slightly (entries 18 and 19, 96% and 92% ee). Consequently, the
reaction would be carried out in iꢀPrOH at room temperature using 10 mol% of Ni(acac)2 and 12
mol% of L1a.
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Table 2. Substrate Scope of Nitroacrylatea
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entry
1
1
R
time (h)
12
yield b (%)
97 (3ae)
95 (3af)
95 (3ag)
93 (3ah)
94 (3ai)
97 (3aj)
92 (3ak)
96 (3al)
95(3am)
90(3bd)
94(3cd)
−
ee c (%)
97
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
1a
1a
4ꢀMeC6H4 (2e)
4ꢀMeOC6H4 (2f)
4ꢀFC6H4 (2g)
4ꢀBrC6H4 (2h)
4ꢀCF3C6H4 (2i)
4ꢀNO2C6H4 (2j)
2ꢀfuryl (2k)
2ꢀthienyl (2l)
Styryl (2m)
Ph (2d)
2
12
98
3
12
98
4
12
99 (R)
97
5
12
6
12
97
7
12
95
8
12
96
9
4
95
10
11
12
13d
14d
12
93
Ph (2d)
12
98
Ph (2d)
12
−
Me (2n)
12(48)
12(48)
72
95(93) (3an)
93(89) (3ao)
84(3ap)
66(80)
43(75)
94
nꢀC7H15(2o)
cyclohexyl(2p)
15
a
Reaction conditions: unless special statement, 1 (0.20 mmol), 2 (0.30 mmol), L1a (0.024 mmol), Ni(acac)2 (0.020
mmol) in iꢀPrOH (2 mL) under nitrogen at rt. Isolated yield. Determined by HPLC using a chiral column. d The
numbers in paretheses were obtained when reactions were conducted at 0 oC.
b
c
Under optimal reaction conditions, the scope of nitroacrylate was next explored, and the results
are shown in Table 2. First, a series of different substituted phenyl βꢀnitroꢀacrylates (2e−2j) were
applied to the reaction with 2ꢀacetyl pyridine. Both the yields and enantioselectivities are generally
excellent for nitroacrylate substrates bearing either electronꢀwithdrawing or electronꢀdonating groups
on the phenyl ring (entries 1−6, 94−98% yield, 92−99% ee). Subsequently, αꢀheteroaryl substituted
βꢀnitroacrylates were used in this reaction, also afforded excellent results (entries 7 and 8, 93% yield
and 97% ee, 96% yield and 96% ee, respectively). Notably, the reaction of styryl substituted
nitroacrylate (2m) with 1a proceeded for only 4 hours to give the adduct 3am in 95% yield with 95%
ee (entry 9), exhibiting higher reactivity than αꢀarylꢀsubstituted nitroalkenes. Furthermore, different
substituted 2ꢀacetylꢀpyridine derivatives 1b, 1c, and 1d were subjected to this reaction condition.
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2ꢀacetyl 5ꢀMeꢀpyridine 1b and 2ꢀacetyl 5ꢀBrꢀpyridine 1c were well tolerant with the reaction (entries
10−11), however no reaction occurred with 2ꢀacetyl 6ꢀBrꢀpyridine 1d (entry 12). This result may be
attributed to that the key intermediate metal enolate could not be formed because the pyridine N atom
coordinating to Ni(II) center was retarded by adjacent 6ꢀBr atom. Unfortunately, methyl and nꢀheptyl
substituted substrates 2n and 2o furnished only moderate enantioselectivities (66% and 43% ee).
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o
Lowering the reaction temperature to 0 C led to an obvious improvement of the enantioselectivity
(80% ee and 75% ee) albeit with a decrease of the reactivity (entries 13−14).When using the bulky
cyclohexyl substituted nitroacrylate 2p, the reaction was prolonged to 72 h at rt, and afforded a 94%
ee of product 3ap with 84% yield (entry 15). These results suggested that steric effect could be mainly
responsible for the excellent enantioselectivity of the reaction.
Table 3. Substrate Scope of Azaarenes a
entry 1 (azaarenes)
R
time (h)
36
yield b (%)
85 (3ed)
86 (3fd)
97 (3gd)
90 (3hd)
86 (3id)
96 (3jd)
92 (3kd)
92 (3ld)
85 (3md)
85 (3lk)
88 (3ll)
ee c(%)
99
1
2ꢀPyrazinyl (1e)
Ph (2d)
Ph (2d)
Ph (2d)
Ph (2d)
Ph (2d)
Ph (2d)
Ph (2d)
Ph (2d)
2
2ꢀPyrimidinyl (1f)
2ꢀQuinolinyl (1g)
2ꢀQuinoxalinyl (1h)
2ꢀOxazolyl (1i)
48
93
3
12
99
4
12
98
5
12
98
6
2ꢀThiazolyl (1j)
12
>99
99
7
2ꢀBenzothiazolyl(1k)
NꢀMeꢀ2ꢀimidazolyl (1l)
12
8
12
>99
99
9
NꢀBnꢀ2ꢀbenzimidazolyl(1m) Ph (2d)
48
10
11
NꢀMeꢀ2ꢀimidazolyl (1n)
NꢀMeꢀ2ꢀimidazolyl (1n)
2ꢀfuryl (2k)
2ꢀthienyl(2l)
48
>99
>99
48
a
Reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol), L1a (0.024 mmol), Ni(acac)2 (0.020 mmol) in iꢀPrOH (2 mL)
under nitrogen at rt. b Isolated yield. c Determined by HPLC using a chiral column
.
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To explore the generality of the catalytic asymmetric conjugate addition, we next investigated
other available 2ꢀacetyl azaarenes. As shown in Table 3, sixꢀmembered Nꢀheterocycle containing such
as 2ꢀpyrazinyl, 2ꢀpyrimidinyl, 2ꢀquinolinyl and 2ꢀquinoxalinyl group (1e−1h) were well compatible
with the reaction, delivering the desired adducts in high yields with excellent enantioselectivities
(entries 1−4, 85−97% yield and 93−98% ee). To our excitement, in the case of fiveꢀmembered
Nꢀheterocycles containing 1i−1o, both the high yields and excellent enantioselectivities were also
achieved (entries 5−9, 86−96% yield and 98−>99% ee). It is worth noting that
Nꢀmethylꢀ2ꢀacetylimidazole 1l and Nꢀbenzylꢀ2ꢀacetyl benzimidazole were very competent substrates
in terms of the enantioselectivity (entries 8 and 9). Furthermore, when NꢀMeꢀ2ꢀacetyl imidazole
reacted with αꢀ2ꢀfuryl and 2ꢀthienyl substituted βꢀnitroacrylates (2k and 2l), a nearly perfect level of
the enantioselectivity was achieved 17 (entries 10 and 11, >99% ee values).
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To show the practicality of the present reaction, a gramꢀscale experiment was tested. As shown in
Scheme 2 (Eq. 1), the catalytic asymmetric conjugate addition of 1a with 2d was accomplished at
room temperature within 60 hours in 92% yield with 90% ee value by using only a 2.0 mol % of
catalyst loading. Optically pure 3ad (>99% ee) could be obtained in 80% yield after a single
recrystallization from methanol.
Significantly, product 3, containing multiple functional groups like NO2, C=O, and CO2R, could
be converted into many useful intermediates for the synthesis of βꢀamino ester, succinates, lactams
and other biologically active compounds, as shown in Scheme 2. For example, 3ad was treated by a
oneꢀpot procedure of reduction/ringꢀclosure process (Fe/AcOH) afforded pyrroline derivative 4 (Eq.
2).14a The reduction of product 3ad with NaBH4 in MeOH produced the diastereoisomers 5, whose
major isomer was separated by column chromatography, followed treatment with TFA led to γꢀlactone
6 (Eq. 3). Notably, acyl imidazole moiety is easily transformed into a variety of carbonylꢀcontaining
derivatives such as aldehydes, ketones, and esters.18, 17c As expected, 2ꢀacetyl imidazole 3ld was
treated sequentially with MeOTf, and then DBU in methanol in oneꢀpot to give the succinate ester 7
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bearing an allꢀcarbon quaternary stereocenter in 92% yield and >99% ee (Scheme 2, eq. 4).19
Succinates are valuable chiral building blocks for the synthesis of βꢀamino acids, peptidomimics and
other bioactive derivatives.20 To our knowledge, the approach to the succinates bearing an allꢀcarbon
quaternary stereocenter has been rarely reported.21 Subsequently, treatment of
7 with
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NaBH4/NiCl2ꢁ6H2O in EtOH to afford γꢀlactam 8; or reduction of 7 with DIBALꢀH led to δꢀnitro
alcohol 9 in 85% yield with >99% ee (Scheme 2, eq. 5). Moreover, the selective reduction of 7 and 9
would generate the corresponding amino ester 11 and amino alcohol 10 according to a literature
procedure.22 In general, these transformations could lead to many biologically active compounds
bearing an allꢀcarbon quaternary stereocenter with retention of the enantiopurity including amino
esters, succinates, γꢀlactones, γꢀlactams and others.
Scheme 2. Transformations of the Products
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Figure 1. Plausible Asymmetric Induction Model and the XꢀRay Structure of 3ah.
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The absolute configuration of 3ah was determined to be R based on Xꢀray crystallographic
analysis.23 The configurations of the other adducts were assigned by analogy. A plausible asymmetric
induction model was proposed. As shown in Figure 1, 2ꢀacetyl pyridine coordinates with Ni(II)/BOX
complex to form enolate, subsequently the enolate preferentially approaches βꢀnitroacrylate from the
Siꢀface to form the major Rꢀconfigured product 3ah because the Reꢀface attack is unfavorable due to
the steric hindrance between the phenyl group of ligand L1a and βꢀnitroacrylate. Considering that the
excellent enantioselectivities achieved by various aryl and cyclohexyl vs methyl and heptyl group
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t
i
nitroacrylates, as well as ꢀCO2 Bu vs ꢀCO2Me, CO2Bn, CO2 Pr substrates, the steric effect could play a
much more important role in the stereoselectivityꢀdetermining step. The formation of enolates was
easily confirmed by the following control experiments(Scheme 3): i) Acetophenone didn’t occur with
αꢀphenyl βꢀnitroacrylate 2d under the same condition; ii) The reaction of 2ꢀacetyl pyridine with
2ꢀphenyl nitro alkene proceed smoothly to give the desired adduct 12 bearing a tertiary stereocenter in
92% yield with 94% ee. When Eꢀnitroacrylate 2n’ was reacted with 2ꢀacetyl pyridine under the same
condition, product 3an’ with inverse configuration was afforded in 41% yield and 57% ee. The nitro
group is required in this transformation, which had been confirmed and elucidated in our previous
work.15 For example, when other substrates with ꢀCO2Et or –CN substituents were employed in this
reaction, no reaction was observed (Eq. 4 and 5). In addition, based on some reports in the
literatures,24 the counterion acacꢀ could coordinate to the Ni(II) center and form complex intermediates
in a solution, providing a wellꢀdefined chiral environment. The detailed mechanism remains to be
further studied.
Scheme 3. The control experiments.
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O
12 mol% L1a
10 mol% Ni(acac)
t
BuO C
NO
2
2
5
6
7
8
2
(Eq.1)
(Eq.2)
no reaction
+
iꢀPrOH, rt
Ph
2d
O
Ph
9
O
12 mol% L1a
10 mol% Ni(acac)
N
NO
2
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NO
N
2
2
+
iꢀPrOH
Ph
92% yield, 94% ee
12
1a
t
O
O
Me CO2 Bu
NO2
12 mol% L1a
10 mol% Ni(acac)2
NO2
Me
N
N
(Eq.3)
+
tꢀBuO2C
iꢀPrOH, 0oC
41% yield, 57% ee
3an'
1a
2n'
O
O
F3C
Ph
12 mol% L1a
10 mol% Ni(acac)2
N
+
CO2Et
CN
no reaction
(Eq.4)
(Eq.5)
1a
12 mol% L1a
10 mol% Ni(acac)2
F3C
Ph
N
+
no reaction
1a
In summary, we have developed a highly enantioselective conjugate addition of 2ꢀacetyl
azaarenes to αꢀsubstituted βꢀnitroacrylates. The reaction was conducted at room temperature using a
chiral Ni(II)ꢀBOX complex, providing a variety of aromatic Nꢀheterocycleꢀcontaining compounds
bearing an allꢀcarbon quaternary stereocenter in high yields with excellent enantioselectivities (up
to >99% ee). The method features high yield and excellent enantioselectivity, broad substrate scope,
inexpensive catalysts and mild condition. More importantly, the present method provides an easy
approach to optically active β2,2ꢀamino ester, pyrrolidine, succinate, γꢀlactam and γꢀlactone derivatives
bearing allꢀcarbon quaternary stereocenters, exhibiting versatile synthetic potentials. Further extension
of this methodology in organic synthesis is currently underway.
EXPERIMENTAL SECTION
General. H NMR spectra and were recorded on a 300 MHz spectrometer in CDCl3, and 13C NMR
1
spectra were recorded on a 75 MHz spectrometer using tetramethylsilane (TMS) as internal standard.
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HRMS data were obtained by electrospray ionization (ESI) sources with a timeꢀofꢀflight mass
analyzer. Optical rotations were measured on a PerkinꢀElmer 341 LC polarimeter. The enantiomeric
excesses of (R)ꢀ and (S)ꢀenantiomer were determined by HPLC analysis over a chiral column with a
UVꢀdetector. The absolute configuration of the major enantiomer was assigned by Xꢀray diffraction
analysis. Solvents were purified and dried by standard procedures.
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General Procedure for the Catalytic Conjugate Addition Reaction.
To a Schlenk tube ligand L1a (0.024mmol), Ni(acac)2 (0.020 mmol), and iꢀPrOH (2 mL) were added
sequentially under nitrogen atmosphere. After the solution was stirred at room temperature for 1 h,
2ꢀacetyl azaarene 1 (0.20 mmol) was added, and after stirring for 20 min, αꢀsubstitutedꢀβꢀnitroacrylate
2 (0.30 mmol) was finally added. The reaction proceeded at 0 oC or rt for 4~72 h, and then the solvent
was removed under vacuum to give the crude product, which was purified by flash column
chromatography on silica gel (eluted with ethyl acetate/petroleum ether (1/10 ~ 1/5, v/v) to yield the
desired adduct.
Procedure of the Gramꢀscale Experiment
To a Schlenk tube, ligand L1a (0.24 mmol), Ni(acac)2 (0.2 mmol), and iꢀPrOH (20 mL) were added
under nitrogen atmosphere, after the solution was stirred for 1 h at room temperature, 2ꢀacetyl
pyridine 1a (10 mmol) was added, the resulting mixture was stirred for another 30 min,
αꢀphenylꢀβꢀnitroacrylate 2d (15 mmol) was finally added, and stirred for 60 h at room temperature.
The solvent was evaporated under vacuum, H2O (30 mL) was added, and extracted with CH2Cl2 (20
mL ×3), the organic layer was combined and dried over anhydrous Na2SO4, and then concentrated to
give the crude product, which was purified by flash column chromatography on silica gel (eluted with
ethyl acetate/petroleum ether (1/10, v/v) to yield the adduct 3ad (3.40 g, 92% yield, 90% ee). After
one single recrystallization from MeOH, 3ad (2.96 g) was achieved in 80% yield with >99% ee.
(R)ꢀmethyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3aa)
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White solid, Mp: 126−127 C, 69 mg, 90% yield; [α]2D0 = +76.0 (c 1.0, CH2Cl2); 84% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
(minor) = 16.00 min, t (major) = 22.20 min]; 1H NMR (300 MHz, CDCl3) δ 8.73 (d, J = 3.3 Hz, 1H),
8.04 (d, J = 7.7 Hz, 1H), 7.85 (t, J = 7.4 Hz, 1H), 7.64 – 7.28 (m, 6H), 5.36 (ABd, J = 12.4 Hz, 1H),
5.35 (ABd, J = 12.4 Hz, 1H), 4.69 (d, J = 19.4 Hz, 1H), 4.25 (d, J = 19.3 Hz, 1H), 3.71 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 198.8, 172.1, 152.7, 149.1, 136.9, 129.1, 128.4, 127.7, 126.0, 121.8, 79.5,
53.0, 50.8, 40.3; ESIꢀHRMS Calcd for C17H17N2O5 [M + H]+: 329.1132, Found: 329.1127.
o
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(R)ꢀbenzyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ab)
Colorless oil, 74 mg, 92% yield. [α]2D0 = +56.8 (c 0.75, CH2Cl2); 97% ee, determined by HPLC
analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 85:15, 1.0 mL/min, 254 nm; t (minor) =
13.52 min, t (major) = 17.47 min]; 1H NMR (300 MHz, CDCl3) δ 8.70 (dq, J = 4.7, 0.9 Hz, 1H), 7.98
(dt, J = 7.9, 1.0 Hz, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.49 (ddd, J = 7.5, 4.8, 1.3 Hz, 1H), 7.44 –
7.30 (m, 5H), 7.26 –7.16 (m, 3H), 7.14 – 7.09 (m, 2H), 5.39 (s, 2H), 5.23 – 5.08 (m, 2H), 4.67 (d, J =
19.4 Hz, 1H), 4.30 (d, J = 19.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 198.8, 171.4, 152.7, 149.0,
136.9, 136.8, 135.0, 129.0, 128.4, 128.3, 128.1, 127.6, 126.0, 121.8, 79.5, 67.6, 51.0, 40.3;
ESIꢀHRMS Calcd for C23H21N2O5 [M + H]+: 405.1445, Found: 405.1444.
(R)ꢀ isoꢀpropyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ac)
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Colorless oil, 64 mg, 90% yield. [α]D = +69.0 (c 1.0, CH2Cl2); 97% ee, determined by HPLC
analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t (minor) =
7.79 min, t (major) = 10.08 min]; 1H NMR (300 MHz, CDCl3) δ 8.78 – 8.68 (m, 1H), 8.07 – 7.99 (m,
1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.54 – 7.42 (m, 3H), 7.42 – 7.28 (m, 3H), 5.38 (s, 2H), 5.08 (hept,
J = 6.2 Hz, 1H), 4.61 (d, J = 19.3 Hz, 1H), 4.27 (d, J = 19.3 Hz, 1H), 1.17 – 1.08 (m, 6H); 13C NMR
(75 MHz, CDCl3) δ 198.8, 170.9, 152.8, 149.1, 137.2, 136.9, 128.9, 128.2, 127.6, 125.9, 121.6, 79.6,
69.7, 50.9, 40.2, 21.3, 21.2;; ESIꢀHRMS Calcd for C19H21N2O5 [M + H]+: 357.1445, Found: 357.1444.
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(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ad)
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White solid, Mp: 88−89 oC, 70 mg, 95% yield. [α]2D0 = +76.0 (c 1.0, CH2Cl2); 97% ee, determined by
HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
(minor) = 8.24 min, t (major) = 12.69 min]; 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J = 4.4 Hz, 1H),
8.03 (d, J = 7.8 Hz, 1H), 7.82 (dd, J = 10.9, 4.5 Hz, 1H), 7.46 (d, J =7.3 Hz, 3H), 7.42–7.28 (m, 3H),
5.37 (ABd, J = 12.4 Hz, 1H), 5.33 (ABd, J = 12.4 Hz, 1H), 4.55 (d, J = 19.2 Hz, 1H), 4.25 (d, J = 19.2
Hz, 1H), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.8, 170.1, 152.8, 149.0, 137.5, 136.8, 128.8,
128.0, 127.5, 125.8, 121.5, 82.5, 79.6, 51.3, 40.2, 27.4; ESIꢀHRMS Calcd for C20H23N2O5 [M + H]+:
371.1601, Found: 371.1599.
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(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀtolylꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ae)
White solid, Mp: 104−105 oC, 75 mg, 97% yield. [α]2D0 = +84.7 (c 0.45, CH2Cl2); 97% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
1
(major) = 6.02 min, t (minor) = 8.16 min]; H NMR (300 MHz, CDCl3) δ 8.73 – 8.70 (m, 1H), 8.05
(dt, J = 7.9, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.52 – 7.48 (m, 1H), 7.39 – 7.28 (m, 2H), 7.23
–7.10 (m, 2H), 5.43 – 5.22 (m, 2H), 4.53 (d, J = 19.3 Hz, 1H), 4.22 (dd, J = 19.3, 0.7 Hz, 1H), 2.33 (s,
3H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.9, 170.4, 153.0, 149.0, 137.8, 136.9, 134.5,
129.6, 127.5, 125.7, 121.6, 82.5, 79.8, 51.1, 40.3, 27.5, 20.9; ESIꢀHRMS Calcd for C21H25N2O5 [M +
H]+: 385.1757, Found: 385.1754.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀ(pꢀmethoxylphenyl)ꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3af)
White solid, Mp: 131−132 oC, 76 mg, 95% yield. [α]2D0 = +89.0 (c 0.83, CH2Cl2); 98% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
1
(minor) = 8.26 min, t (major) = 10.26 min]; H NMR (300 MHz, CDCl3) δ 8.76 – 8.68 (m, 1H),
8.09–7.99 (m, 1H), 7.90–7.79 (m, 1H), 7.56 –7.44 (m, 1H), 7.43–7.32 (m, 2H), 6.95 –6.82 (m, 2H),
5.40 – 5.20 (m, 2H), 4.50 (d, J = 19.2 Hz, 1H), 4.21 (dd, J = 19.2, 0.7 Hz, 1H), 3.79 (d, J = 0.7 Hz,
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3H), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.9, 170.4, 159.2, 153.0, 149.1, 136.9, 129.5,
127.5, 127.1, 121.6, 114.2, 82.5, 79.8, 55.2, 50.8, 40.3, 27.5; ESIꢀHRMS Calcd for C21H25N2O6 [M +
H]+: 401.1707, Found: 401.1704.
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(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀ(pꢀfluorophenyl)ꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ag)
White solid, Mp: 101–102 oC, 74 mg, 95% yield. [α]2D0 = +66.7 (c 0.45, CH2Cl2); 98% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
(minor) = 6.35 min, t (major) = 8.08 min]; 1H NMR (300 MHz, CDCl3) δ 8.72–8.69 (m, 1H), 8.05 (dt,
J = 7.9, 1.0 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.55–7.40 (m, 3H), 7.14 – 7.01 (m, 2H), 5.40 –
5.24 (m, 2H), 4.50 (d, J = 19.2 Hz, 1H), 4.22 (dd, J = 19.2, 0.8 Hz, 1H), 1.36 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 198.6, 170.1, 162.3 (d, JCꢀF = 247.9 Hz), 152.8, 149.1, 136.9, 133.4 (d, JCꢀF = 3.4 Hz),
127.7 (d, JCꢀF = 8.2 Hz), 127.6, 121.6, 115.8 (d, JCꢀF = 21.5 Hz), 82.9, 79.4, 50.9, 40.3, 27.5;
ESIꢀHRMS Calcd for C20H22FN2O5 [M + H]+: 389.1507, Found: 389.1501.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀ(pꢀbromophenyl)ꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ah)
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White solid, Mp: 144−146 oC, 83 mg, 93% yield. [α]D = +68.5 (c 0.50, CH2Cl2); 99% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 95:5, 0.6 mL/min, 254 nm; t
(minor) = 15.42 min, t (major) = 24.64 min]; 1H NMR (300 MHz, CDCl3) δ 8.74 –8.70 (m, 1H), 8.05
(dt, J = 7.9, 1.0 Hz, 1H), 7.86 (td, J = 7.7, 1.7 Hz, 1H), 7.56 – 7.47 (m, 3H), 7.39 –7.30 (m, 2H), 5.39
– 5.23 (m, 2H), 4.48 (d, J = 19.2 Hz, 1H), 4.20 (dd, J = 19.2, 0.7 Hz, 1H), 1.36 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 198.6, 169.8, 152.8, 149.1, 137.0, 136.8, 132.1, 127.7, 127.6, 122.4, 121.7, 83.0, 79.4,
51.1, 40.2, 27.5; ESIꢀHRMS Calcd for C20H22BrN2O5 [M + H]+: 449.0707, Found: 449.0708.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀ(pꢀtrifluoromethylphenyl)ꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ai)
White solid, Mp: 138−140 oC, 82 mg, 94% yield. [α]2D0 = +63.5 (c 0.40, CH2Cl2); 97% ee, determined
by HPLC analysis [Daicel Chiralcel ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
(minor) = 8.92 min, t (major) = 11.52 min]; 1H NMR (300 MHz, CDCl3) δ 8.76 – 8.70 (m, 1H), 8.05
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(dt, J = 7.9, 1.1 Hz, 1H), 7.87 (td, J = 7.7, 1.7 Hz, 1H), 7.63 (q, J = 8.6 Hz, 4H), 7.57 –7.51 (m, 1H),
5.39 (d, J = 12.6 Hz, 1H), 5.32 (dd, J = 12.6, 0.8 Hz, 1H), 4.53 (d, J = 19.2 Hz, 1H), 4.25 (dd, J =
19.2, 0.8 Hz, 1H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.5, 169.6, 152.7, 149.1, 141.7,
137.0, 130.4 (q, JCꢀF = 32.8 Hz), 127.7, 126.5, 125.9 (q, JCꢀF = 3.6 Hz), 123.8 (q, JCꢀF = 272.1 Hz),
121.7, 83.3, 79.4, 51.4, 40.2, 27.5; ESIꢀHRMS Calcd for C21H22F3N2O5 [M + H]+: 439.1475, Found:
439.14754.
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(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀ(pꢀnitrophenyl)ꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3aj)
Yellow solid, Mp: 133−135 oC, 81 mg, 97% yield. [α]2D0 = +62.7 (c 0.70, CH2Cl2); 97% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 80:20, 1.0 mL/min, 254 nm; t
(minor) = 9.17 min, t (major) = 14.04 min]; 1H NMR (300 MHz, CDCl3) δ 8.73 (dd, J = 3.9, 0.8 Hz,
1H), 8.30 – 8.21 (m, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.88 (td, J = 7.8, 1.7 Hz, 1H), 7.72 – 7.63 (m, 2H),
7.58 – 7.51 (m, 1H), 5.37 (ABd, J = 12.7 Hz, 1H), 5.36 (ABd, J = 12.6 Hz, 1H), 4.52 (d, J = 19.2 Hz,
1H), 4.26 (d, J = 19.2 Hz, 1H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.2, 169.2, 152.6, 149.2,
147.6, 144.9, 137.0, 127.8, 127.2, 124.0, 121.8, 83.7, 79.2, 51.6, 40.3, 27.5; ESIꢀHRMS Calcd for
C20H22N3O7 [M + H]+: 416.1452, Found: 416.1449.
(S)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀ(2ꢀfuryl)ꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ak)
o
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White solid, Mp: 82−83 C, 66 mg, 92% yield. [α]D = +36.1 (c 0.98, CH2Cl2); 95% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 95:5, 0.8 mL/min, 254 nm; t
(major) = 11.21 min, t (minor) = 18.32 min]; 1H NMR (300 MHz, CDCl3) δ 8.70 (d, J = 4.6 Hz, 1H),
8.04 (d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.56 – 7.47 (m, 1H), 7.40 (d, J = 1.2 Hz, 1H),
6.45– 6.33 (m, 2H), 5.39 –5.24 (m, 2H), 4.34–4.14 (m, 2H), 1.42 (s, 9H). 13C NMR (75 MHz, CDCl3)
δ 198.1, 167.9, 152.8, 150.5, 149.1, 142.7, 136.9, 127.6, 121.7, 110.7, 108.0, 83.2, 77.2, 49.0, 39.6,
27.6; ESIꢀHRMS Calcd for C18H21N2O6 [M + H]+: 361.1394, Found: 361.1394.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀ(2ꢀthienyl)ꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3al)
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White solid, Mp: 77−79 oC, 72 mg, 96% yield. [α]2D0 = +58.5 (c 0.52, CH2Cl2); 96% ee, determined by
HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 80:20, 1.0 mL/min, 254 nm; t
(minor) = 5.90 min, t (major) = 9.15 min]; 1H NMR (300 MHz, CDCl3) δ 8.78 – 8.63 (m, 1H), 8.03 (d,
J = 7.9 Hz, 1H), 7.84 (td, J = 7.7, 1.4 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.32 – 7.22 (m, 1H), 7.13 (d, J =
3.6 Hz, 1H), 6.98 (dd, J = 4.9, 3.9 Hz, 1H), 5.39 (ABd, J = 12.4 Hz, 1H), 5.34 (ABd, J = 12.4 Hz,
1H), 4.50 (d, J = 19.2 Hz, 1H), 4.29 (d, J = 19.2 Hz, 1H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
198.3, 169.1, 152.7, 149.1, 141.1, 136.8, 127.5, 126.9, 125.4, 125.4, 121.6, 83.2, 79.7, 49.9, 41.6,
27.5; ESIꢀHRMS Calcd for C18H21N2O5S [M + H]+: 377.1166, Found: 377.1162.
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(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀstyrylꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3am)
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Light yellow solid, Mp: 82−84 C, 75 mg, 95% yield. [α]2D0 = +51.8 (c 1.0, CH2Cl2); 95% ee,
determined by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0
mL/min, 254 nm; t (minor) = 7.41 min, t (major) = 8.27 min]; 1H NMR (300 MHz, CDCl3) δ 8.70 (dd,
J = 4.7, 0.6 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.52−7.48 (m, 1H), 7.40 –
7.26 (m, 5H), 6.68 (d, J = 16.3 Hz, 1H), 6.36 (d, J = 16.3 Hz, 1H), 5.18 (ABd, J = 12.3 Hz, 2H), 5.14
(ABd, J = 12.3 Hz, 2H), 4.06 (s, 2H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.6, 169.7, 152.9,
149.0, 136.9, 136.1, 132.1, 128.6, 128.2, 127.5, 127.0, 126.6, 121.7, 82.9, 78.7, 49.7, 40.9, 27.7;
ESIꢀHRMS Calcd for C22H25N2O5 [M + H]+: 397.1757, Found: 397.1754.
(S)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀmethyl)ꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3an)
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White solid, Mp: 98−100 C, 58 mg, 95% yield. [α]20 = −10.0 (c 0.60, CH2Cl2); 66% ee, determined
D
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 95:5, 0.8 mL/min, 254 nm; t
(minor) = 9.42 min, t (major) = 10.20 min]; 1H NMR (300 MHz, CDCl3) δ 8.69 – 8.67 (m, 1H), 8.03
(dt, J = 7.9, 1.1 Hz, 1H), 7.85 (td, J = 7.7, 1.7 Hz, 1H), 7.52 – 7.46 (m, 1H), 4.97 (d, J = 11.9 Hz, 1H),
4.84 (d, J = 11.9 Hz, 1H), 3.76 (ABd, J = 11.9 Hz, 1H), 3.74 (ABd, J = 11.9 Hz, 1H), 1.45 (s, 3H),
1.44 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.7, 172.1, 152.9, 149.0, 136.9, 127.4, 121.6, 82.2, 79.8,
44.2, 42.3, 27.7, 22.2; ESIꢀHRMS Calcd for C15H21N2O5 [M + H]+: 309.1445, Found: 309.1442.
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(S)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀheptylꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ao)
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Colorless oil, 73 mg, 93% yield. [α]2D0 = −8.3 (c 1.43, CH2Cl2); 43% ee, determined by HPLC analysis
[Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 95:5, 0.8 mL/min, 254 nm; t (major) = 6.25 min,
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t (minor) = 6.82 min]; H NMR (300 MHz, CDCl3) δ 8.70 – 8.66 (m, 1H), 8.03 (dt, J = 7.9, 1.1 Hz,
1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.52 – 7.47 (m, 1H), 5.03 (ABd, J = 11.9 Hz, 1H), 4.94 (ABd, J =
11.9 Hz, 1H), 3.77 (ABd, J = 19.3 Hz, 1H), 3.71 (ABd, J = 19.4 Hz, 1H), 1.80 – 1.64 (m, 2H), 1.45 (s,
9H), 1.27 (s, 10H), 0.87 (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 198.9, 171.4, 153.0., 149.0,
136.8, 127.4, 121.6, 82.2, 47.6, 41.5, 35.6, 31.6, 29.5, 28.8, 27.8, 23.5, 22.5, 14.0; ESIꢀHRMS Calcd
for C21H33N2O5 [M + H]+: 393.2384, Found: 393.2384.
(S)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀcyclohexylꢀ4ꢀ(pyridinꢀ2ꢀyl) butanoate (3ap)
White solid, mp: 78–80 oC, 63 mg, 84% yield; [α]D = –25.2 (c 0.65, CH2Cl2), 94% ee, determined by
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HPLC analysis [Daicel Chiralcel ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, 0.5 mL/min, 254 nm; t
(minor) = 9.31 min, t (major) = 13.3 min]; 1H NMR (300 MHz, CDCl3) δ 8.68 (d, J = 4.1 Hz, 1H),
8.02 (d, J = 7.8 Hz, 1H), 7.83 (td, J = 7.7, 1.7 Hz, 1H), 7.51 – 7.41 (m, 1H), 5.06 (s, 2H), 3.96 – 3.71
(m, 2H), 2.02 – 1.63 (m, 6H), 1.46 (s, 9H), 1.30 – 1.00 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 199.5,
170.4, 153.2, 148.9, 136.8, 127.3, 121.6, 82.3, 75.8, 50.8, 42.7, 39.4, 27.9, 27.9, 27.8, 26.8, 26.2;
ESIꢀHRMS Calcd for C20H28N2O5 [M + H]+: 377.2071, Found: 377.2068.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(5ꢀmethylpyridinꢀ2ꢀyl) butanoate (3bd)
White solid, Mp: 119−121 oC, 69 mg, 90% yield. [α]2D0 = +62.3 (c 0.53, CH2Cl2); 93% ee, determined
by HPLC analysis [Daicel Chiralcel ADꢀH column, nꢀhexane/iꢀPrOH = 80:20, 0.8 mL/min, 254 nm; t
(minor) = 9.47 min, t (major) = 11.18 min]; 1H NMR (300 MHz, CDCl3) δ 8.58 – 8.49 (m, 1H), 7.96
(d, J = 7.9 Hz, 1H), 7.69 – 7.59 (m, 1H), 7.51 –7.28 (m, 5H), 5.38 – 5.27 (m, 2H), 4.51 (d, J = 19.2
Hz, 1H), 4.21 (d, J = 19.1 Hz, 1H), 2.44 (s, 3H), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.6,
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170.3, 150.8, 149.5, 138.0, 137.7, 137.2, 128.9, 128.1, 125.9, 121.4, 82.6, 79.8, 51.4, 40.2, 27.5, 18.7;
ESIꢀHRMS Calcd for C21H25N2O5 [M + H]+: 385.1758, Found: 385.1755.
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(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(5ꢀbromopyridinꢀ2ꢀyl) butanoate (3cd)
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Colorless crystal, Mp: 136−137 C, 84 mg, 94% yield. [α]2D0 = +47.1 (c 0.24, CH2Cl2); 98% ee,
determined by HPLC analysis [Daicel Chiralcel ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0
mL/min, 254 nm; t (minor) = 10.57 min, t (major) = 11.37 min]; 1H NMR (300 MHz, CDCl3) δ 8.77
(d, J = 1.5 Hz, 1H), 7.97 (dt, J = 18.2, 5.2 Hz, 2H), 7.50 –7.30 (m, 5H), 5.42 –5.23 (m, 2H), 4.50 (d, J
= 19.3 Hz, 1H), 4.17 (d, J = 19.2 Hz, 1H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.0, 170.1,
151.2, 150.3, 139.7, 137.4, 128.9, 128.2, 125.8, 122.9, 82.8, 79.6, 51.3, 40.2, 27.5; ESIꢀHRMS Calcd
for C20H22BrN2O5 [M + H]+: 449.0707, Found: 449.0705.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(2ꢀpyrazinyl) butanoate (3ed)
White solid, Mp: 75–76 oC, 63 mg, 85% yield. [α]2D0 = +18.0 (c 1.23, CH2Cl2); 99% ee, determined by
HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
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(major) = 9.39 min, t (minor) = 16.88 min]; H NMR (300 MHz, CDCl3) δ 9.24 (d, J = 1.4 Hz, 1H),
8.80 (d, J = 2.4 Hz, 1H), 8.68 (dd, J = 2.4, 1.5 Hz, 1H), 7.49 – 7.29 (m, 5H), 5.36 (d, J = 12.5 Hz, 2H),
4.52 (d, J = 19.3 Hz, 1H), 4.17 (d, J = 19.3 Hz, 1H), 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
198.4, 169.9, 148.2, 147.2, 143.6, 143.4, 137.3, 129.0, 128.3, 125.7, 83.5, 79.4, 51.3, 40.3, 27.5;
ESIꢀHRMS Calcd for C19H22N3O5 [M + H]+: 372.1554, Found: 372.1550.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(pyrimidinꢀ2ꢀyl) butanoate (3fd)
Colorless oil, 64 mg, 86% yield. [α]2D0 = +69.1 (c 0.55, CH2Cl2); 93% ee, determined by HPLC
analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 80:20, 1.0 mL/min, 254 nm; t (minor)=
14.26 min, t (major) = 18.86 min]; 1H NMR (300 MHz, CDCl3) δ 9.00 – 8.92 (m, 2H), 7.55 – 7.27 (m,
7H), 5.35 (s, 2H), 4.58 (d, J = 19.4 Hz, 1H), 4.24 (d, J = 19.3 Hz, 1H), 1.42 (s, 9H); 13C NMR (75
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MHz, CDCl3) δ 196.5, 169.8, 159.5, 157.6, 137.3, 128.9, 128.2, 125.7, 123.3, 83.1, 79.3, 51.4, 41.5,
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Colorless oil, 82 mg, 97% yield. [α]2D0 = +36.4 (c 0.55, CH2Cl2); 99% ee, determined by HPLC
analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t (minor) =
6.86 min, t (major) = 8.39 min]; 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz, 2H), 8.11 (d, J =
8.5 Hz, 1H), 7.88–7.76 (m, 2H), 7.70 – 7.59 (m, 1H), 7.58–7.48 (m, 2H), 7.45–7.30 (m, 3H), 5.43
(ABd, J = 12.4 Hz, 1H), 5.40 (ABd, J = 12.5 Hz, 1H), 4.77 (d, J =19.2 Hz, 1H), 4.41 (d, J = 19.2 Hz,
1H), 1.38 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 199.2, 170.3, 152.5, 147.1, 137.7, 137.0, 130.7,
130.1, 129.7, 128.9, 128.7, 128.1, 127.6, 125.9, 117.8, 82.7, 79.7, 51.6, 40.0, 27.5; ESIꢀHRMS Calcd
for C24H25N2O5 [M + H]+: 421.1758, Found: 421.1755.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(2ꢀquinoxalinyl) butanoate (3hd)
Light yellow oil, 76 mg, 90% yield. [α]2D0 = +41.2 (c 0.89, CH2Cl2); 98% ee, determined by HPLC
analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t (minor)=
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8.72 min, t (major) = 20.90 min]; H NMR (300 MHz, CDCl3) δ 9.49 (s, 1H), 8.40 – 8.06 (m, 2H),
8.05–7.77 (m, 2H), 7.53 –7.29 (m, 5H), 5.40 (s, 2H), 4.71 (d, J = 19.2 Hz, 1H), 4.31 (d, J = 19.2 Hz,
1H), 1.41 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 198.6, 170.0, 145.9, 144.1, 142.7, 140.9, 137.4,
132.4, 130.8, 130.5, 129.4, 129.0, 128.2, 125.8, 83.0, 79.4, 51.4, 40.1, 27.5; ESIꢀHRMS Calcd for
C23H23N3NaO5 [M + Na]+: 444.1530, Found: 444.1534.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(2ꢀoxazolyl) butanoate (3id)
White solid, Mp: 85−86 oC, 62 mg, 86% yield. [α]2D0 = +66.2 (c 0.60, CH2Cl2); 98% ee, determined by
HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 80:20, 1.0 mL/min, 254 nm; t
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(minor) = 7.83 min, t (major) = 12.16 min]; H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 0.5 Hz, 1H),
7.43 – 7.29 (m, 6H), 5.39 – 5.25 (m, 2H), 4.38 (d, J = 18.9 Hz, 1H), 4.09 (d, J = 18.9 Hz, 1H), 1.40 (s,
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9H); 13C NMR (75 MHz, CDCl3) δ 185.2, 169.5, 157.5, 142.0, 136.8, 129.3, 129.0, 128.4, 125.6, 83.3,
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Light yellow solid, Mp: 58−60 C, 72 mg, 96% yield. [α]2D0 = +140.2 (c 0.55, CH2Cl2); >99% ee,
determined by HPLC analysis [Daicel Chiralcel ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0
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mL/min, 254 nm; t (major) = 11.66 min, t (minor) = 13.27 min]; H NMR (300 MHz, CDCl3) δ 8.03
(d, J = 3.0 Hz, 1H), 7.71 (d, J = 3.0 Hz, 1H), 7.45–7.26 (m, 5H), 5.35 (s, 2H), 4.47 (d, J = 18.9 Hz,
1H), 4.20 (d, J = 18.9 Hz, 1H), 1.38 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 190.9, 169.7, 166.1, 144.9,
137.1, 1289.0, 128.3, 126.6, 125.7, 125.6, 83.1, 79.4, 51.3, 40.7, 27.5; ESIꢀHRMS Calcd for
C18H21N2O5S [M + H]+: 377.1166, Found: 377.1164.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(2ꢀbenzothiazolyl) butanoate (3kd)
White solid, Mp: 90–91 oC, 79 mg, 92% yield. [α]2D0 = +42.0 (c 0.75, CH2Cl2); 99% ee, determined by
HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254nm; t
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(minor) = 6.80 min, t (major) = 8.19 min]; H NMR (300 MHz, CDCl3) δ 8.26–8.19 (m, 1H), 8.01
–7.94 (m, 1H), 7.63 – 7.50 (m, 2H), 7.50 –7.43 (m, 2H), 7.43 – 7.29 (m, 3H), 5.38 (s, 2H), 4.61 (d, J =
19.0 Hz, 1H), 4.31 (d, J = 19.0 Hz, 1H), 1.39 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 192.5, 169.7,
165.4, 153.4, 137.3, 137.1, 129.0, 128.3, 127.9, 127.1, 125.8, 125.6, 122.4, 83.2, 79.4, 51.5, 41.0, 27.5;
ESIꢀHRMS Calcd for C22H23N2O5S [M + H]+: 427.1322, Found: 427.1319.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(Nꢀmethylꢀ2ꢀimidazolyl) butanoate (3ld)
White solid, Mp: 120−121 oC, 69 mg, 92% yield. [α]2D0 = +77.6 (c 0.41, CH2Cl2); >99% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
(minor) = 10.35 min, t (major) = 13.18 min]; 1H NMR (300 MHz, CDCl3) δ 7.45 – 7.27 (m, 5H), 7.17
(s, 1H), 7.05 (s, 1H), 5.32 (ABd, J = 12.3 Hz, 1H), 5.29 (ABd, J = 12.4 Hz, 1H), 4.42 (d, J = 18.7 Hz,
1H), 4.16 (d, J = 18.7 Hz, 1H), 3.98 (s, 3H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 189.4, 170.2,
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142.5, 137.3, 129.4, 128.8, 128.1, 127.3, 125.8, 82.6, 79.8, 51.3, 41.0, 36.0, 27.5; ESIꢀHRMS Calcd
for C19H24N3O5 [M + H]+: 374.1710, Found: 374.1707.
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(S)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀfurylꢀ4ꢀ(Nꢀmethylꢀ2ꢀimidazolyl) butanoate (3lk)
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White solid, Mp: 110 −111oC, 62 mg, 85% yield. [α]2D0 = +41.9 (c 0.42, CH2Cl2); >99% ee,
determined by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 80:20, 1.0
mL/min, 254 nm; t (minor) = 9.47 min, t (major) = 11.96 min]; 1H NMR (300 MHz, CDCl3) δ 7.39 (d,
J = 1.2 Hz, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 6.47 – 6.24 (m, 2H), 5.32 (ABd, J = 12.3 Hz, 1H), 5.26
(ABd, J = 12.3 Hz, 1H), 4.12 (d, J = 1.5 Hz, 2H), 3.99 (s, 3H), 1.42 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ 188.6, 167.9, 150.2, 142.6, 142.3, 129.4, 127.3, 110.7, 108.0, 83.1, 77.4, 49.0, 40.4, 36.1,
27.6; ESIꢀHRMS Calcd for C17H22N3O6 [M + H]+: 364.1501, Found: 364.1501.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀthienylꢀ4ꢀ(Nꢀmethylꢀ2ꢀimidazolyl) butanoate (3ll)
White solid, Mp: 109−110 oC, 67 mg, 88% yield. [α]2D0 = +49.4 (c 0.5, CH2Cl2); >99% ee, determined
by HPLC analysis [Daicel Chiralcel ASꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t
(minor) = 14.04 min, t (major) = 15.84 min]; 1H NMR (300 MHz, CDCl3) δ 7.28 (dd, J = 5.2, 1.1 Hz,
1H), 7.19 (d, J = 0.8 Hz, 1H), 7.11 (dd, J = 3.7, 1.2 Hz, 1H), 7.07 (s, 1H), 6.98 (dd, J = 5.1, 3.7 Hz,
1H), 5.44 – 5.22 (m, 2H), 4.38 (d, J = 18.7 Hz, 1H), 4.21 (d, J = 18.6 Hz, 1H), 3.99 (s, 3H), 1.42 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 188.8, 169.1, 142.4, 140.8, 129.5, 127.3, 126.9, 125.5, 125.4, 83.2,
79.8, 49.9, 42.4, 36.1, 27.5; ESIꢀHRMS Calcd for C17H22N3O5S [M + H]+: 380.1275, Found:
380.1271.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀoxoꢀ2ꢀphenylꢀ4ꢀ(NꢀBnꢀ2ꢀbenzimidazolyl) butanoate (3md)
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White solid, Mp: 119−120 oC, 85 mg, 85% yield. [α]D = +45.6 (c 0.35, CH2Cl2); 99% ee, determined
by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 80:20, 1.0 mL/min, 254 nm; t
(minor) = 8.46 min, t (major) = 15.77 min]; 1H NMR (300 MHz, CDCl3) δ 8.02 – 7.91 (m, 1H), 7.50 –
7.28 (m, 8H), 7.26 – 7.18 (m, 3H), 7.07 (d, J = 6.0 Hz, 2H), 5.92 (ABd, J = 15.8 Hz, 1H), 5.81 (ABd,
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J = 15.8 Hz, 1H), 5.26 (s, 2H), 4.65 (d, J = 19.2 Hz, 1H), 4.37 (d, J = 19.0 Hz, 1H), 1.26 (s, 9H). 13
C
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NMR (75 MHz, CDCl3) δ 192.3, 170.0, 145.1, 141.8, 137.1, 136.7, 136.4, 128.9, 128.7, 128.2, 127.7,
126.5, 125.9, 124.1, 122.2, 111.1, 82.8, 79.8, 51.3, 48.6, 42.2, 27.4; ESIꢀHRMS Calcd for C29H30N3O5
[M + H]+: 500.2180, Found: 500.2179.
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(R)ꢀ5ꢀ(2ꢀpyridinyl)ꢀ3ꢀphenylꢀ3ꢀ(tꢀbutyloxy carbonyl)ꢀ3, 4ꢀdihydroꢀ2Hꢀpyrrole (4)
To the dry roundꢀbottom flask was added 3ad (60 mg, 0.16 mmol, 97% ee), THF (2 mL), MeOH (1
mL), AcOH (144 ꢂL, 16 equiv), Fe powder (403 mg, 45 equiv.) successively at room temperature, and
the resulting mixture was refluxed for 12 h under nitrogen atmosphere. After cooling to room
temperature, a solution of saturated NaHCO3 (aq. 10 mL) was added and stirred for another 30 min at
room temperature, the reaction mixture was filtrated through Celite, washed with ethyl acetate (20
mL). The water layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were
dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (petroleum/ethyl acetate = 95/5) to give (R)ꢀ4 (37.1 mg, 71% yield).
Light yellow oil, [α]2D0 = −10.9 (c 0.38 CH2Cl2); 98% ee, determined by HPLC analysis [Daicel
Chiralcel ADꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t (minor) = 7.63 min, t
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(major) = 12.27 min]; H NMR (300 MHz, CDCl3) δ 8.67 – 8.64 (m, 1H), 8.13 (dt, J = 7.9, 1.0 Hz,
1H), 7.73 (td, J = 7.7, 1.8 Hz, 1H), 7.37–7.28 (m, 5H), 7.27–7.18 (m, 1H), 5.02 (dt, J = 16.6, 1.5 Hz,
1H), 4.43 (dt, J = 16.7, 1.9 Hz, 1H), 4.27 – 4.10 (m, 1H), 3.51 (dt, J = 17.9, 1.9 Hz, 1H), 1.35 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 173.6, 173.4, 152.6, 149.0, 142.4, 136.2, 128.4, 126.8, 126.3, 124.7,
121.6, 81.3, 70.5, 58.5, 45.0, 27.6; ESIꢀHRMS Calcd for C20H23N2O2 [M + H]+: 323.1754, Found:
323.1752.
(R)ꢀ tertꢀbutyl 2ꢀnitromethylꢀ4ꢀhydroxyꢀ2ꢀphenylꢀ4ꢀ(2ꢀpyridinyl) butanoate (5)
To a stirred solution of 3ad (148 mg, 0.4 mmol) in anhydrous MeOH (5 mL) was added NaBH4 (16
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mg, 0.4 mmol) in portions at 0 C, and stirred for another 15 min. The reaction mixture was treated
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with a saturated aqueous NH4Cl solution at 0 C. The two phases were separated and the aqueous
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phase was extracted with ethyl acetate (10 mL×3). The combined organic phases were dried over
Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography
to afford the pure βꢀnitroacrylic esters 5. Colorless oil, 144 mg, 94% yield (the ratio of diastereomers,
1.4:1), 40% isolated yield for major isomer. [α]2D0 = −24.6 (c 1.0, CH2Cl2, major isomer). 97% ee,
determined by HPLC analysis [Daicel Chiralcel ASꢀH column, nꢀhexane/iꢀPrOH = 88:22, 1.0
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mL/min, 254 nm; t (minor) = 7.77 min, t (major) = 9.12 min]. (major isomer) H NMR (300 MHz,
CDCl3) δ 8.46 (d, J = 4.5 Hz, 1H), 7.62 (td, J = 7.7, 1.2 Hz, 1H), 7.48 –7.27 (m, 5H), 7.22 – 6.96 (m,
2H), 5.84 (d, J = 14.4 Hz, 1H), 5.37 (d, J =14.4 Hz, 1H), 4.67 (s, 1H), 4.43 (d, J = 10.4 Hz, 1H), 2.66
(d, J = 14.8 Hz, 1H), 2.44 (dd, J = 15.0, 11.0 Hz, 1H), 1.38 (s, 9H); (major isomer) 13C NMR (75
MHz, CDCl3) δ 171.1, 160.9, 147.9, 138.0, 136.7, 129.0, 127.3, 125.7, 122.4, 120.0, 82.2, 78.0, 68.9,
52.8, 42.7, 27.4; ESIꢀHRMS Calcd for C20H25N2O5 [M + H]+: 373.1758, Found: 373.1754.
(3R, 5S)ꢀ5ꢀ(2ꢀpyridinyl)ꢀ3ꢀnitromethylꢀ3ꢀphenylꢀdihydrofuranꢀ2ꢀone (6)
To a 25 mL roundꢀbottom flask was added βꢀnitroacrylic esters 5 (major isomer, 80 mg, 0.21 mmol),
10 mL of CH2Cl2 and 2 mL of TFA at room temperature. The reaction mixture was stirred for 24 h at
30oC, and then concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel (petroleum/ethyl acetate, 1:2，(v/v)) to give the lactone 6 (52 mg, 81%
o
yield). White solid, Mp: 58–59 C, [α]2D0 = +8.7 (c 0.31, CH2Cl2); 99% ee, determined by HPLC
analysis [Daicel Chiralcel ASꢀH column, nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 254 nm; t (minor) =
37.24 min, t (major) = 55.44 min]. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 4.5 Hz, 1H), 7.43 (td, J
= 7.8, 1.6 Hz, 1H), 7.28 (dd, J = 6.7, 3.0 Hz, 2H), 7.19 (dd, J = 9.6, 5.7 Hz, 3H), 7.13 –7.02 (m, 2H),
5.75 (dd, J = 8.9, 3.0 Hz, 1H), 4.94 (d, J = 14.2 Hz, 1H), 4.79 (d, J = 14.2 Hz, 1H), 3.51 (dd, J =13.8,
3.2 Hz, 1H), 3.28 (dd, J = 13.8, 9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 175.3, 157.8, 149.1, 136.4,
134.5, 128.9, 128.5, 126.3, 122.6, 119.8, 80.7, 77.4, 50.6, 37.0. ESIꢀHRMS Calcd for C16H15N2O4
[M+H]+: 299.1026, Found: 299.1024.
(R)ꢀtertꢀbutyl 4ꢀmethyl 2ꢀ(nitromethyl)ꢀ2ꢀphenylsuccinate (7)
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To a 25 mL ovenꢀdried vial under N2 atmosphere was added 3ld (93 mg, 0.25 mmol), 30 mg 4Å MS,
and 2.0 mL acetonitrile. After stirring for 10 minutes, MeOTf (45 mg, 0.275 mmol) was added. The
reaction mixture was stirred for 12 h at room temperature before MeOH (1.0 mL) and DBU (0.1mL)
were added. The reaction was stirred for another 1 h at room temperature, then the resulting mixture
was separated with water, and the aqueous phase was extracted with CH2Cl2 (10 mL×3). The
combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (petroleum/ethyl/acetate, 1/10 (v/v))
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to give the succinate 7 (74 mg, 92% yield). White solid, Mp: 80−81 C, [α]2D0 = −62.4 (c 0.50,
CH2Cl2); >99% ee, determined by HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH
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= 90:10, 1.0 mL/min, 210 nm; t (minor) = 6.31 min, t (major) = 7.45 min]; H NMR (300 MHz,
CDCl3) δ 7.40 –7.26 (m, 5H), 5.34 (q, J = 13.1 Hz, 2H), 3.68 (s, 3H), 3.44 (ABd, J = 17.2 Hz, 1H),
3.29 (ABd, J = 17.3 Hz, 1H), 1.40 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 171.2, 169.6, 136.9, 129.0,
128.3, 125.5, 83.1, 78.8, 51.8, 51.4, 36.9, 27.5; ESIꢀHRMS Calcd for C16H21NNaO6 [M + Na]+:
346.1261, Found: 346.1263.
(R)ꢀtertꢀbutyl 5ꢀoxoꢀ3ꢀphenylpyrrolidineꢀ3ꢀcarboxylate (8)
To a suspension of succinate 7 (40 mg, 0.12 mmol, major isomer) and NiCl2•6H2O (43 mg, 0.18
mmol) in ethanol (2 mL) was added NaBH4 (68 mg, 1.8mmol) at 0 °C and the mixture was stirred for
9 h at room temperature. Then, the reaction mixture was quenched with a solution of saturated
aqueous NH4Cl and extracted with CH2Cl2(10 mL×3). The organic layers were washed with brine and
dried over Na2SO4, concentrated under vacuum. The crude product was purified with flash
chromatography on silica gel (ethyl acetate/petroleum ether, 1:1 (v/v)) to afford the lactam 8 (31 mg,
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89%yield). White solid, Mp: 122−124 C, 99.2% ee. [α]2D0 = −8.6 (c 0.62, CH2Cl2); determined by
HPLC analysis [Daicel Chiralcel ODꢀH column, nꢀhexane/iꢀPrOH = 80:20, 1.0 mL/min, 210 nm; t
(minor) = 6.82 min, t (major) = 8.30 min]; 1H NMR (300 MHz, CDCl3) δ 7.40–7.22 (m, 5H), 6.33 (s,
1H), 4.32 (d, J = 9.8 Hz, 1H), 3.61(d, J = 9.8 Hz, 1H), 3.27 (d, J = 16.7 Hz, 1H), 2.75 (d, J =16.7 Hz,
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1H), 1.36 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 176.4, 172.0, 140.3, 128.5, 127.3, 125.8, 81.9, 55.0,
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50.6, 39.9, 27.4. ESIꢀHRMS Calcd for C15H20NO3 [M+H]+: 262.1438, Found: 262.1436.
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(R)ꢀtertꢀbutyl 4ꢀhydroxyꢀ2ꢀ(nitromethyl)ꢀ2ꢀphenylbutanoate (9)
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To a roundꢀbottom flask was added succinate 7 (72 mg, 0.22 mmol), anhydrous THF (5 mL) under
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nitrogen atmosphere, and followed by addition of DIBALꢀH (0.48 mL in THF, 0.48 mmol) at 0 C.
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The reaction mixture was stirred for another 24 h at 0 C. H2O (10 mL) was added to the reaction
mixture, and extracted with CH2Cl2(10 mL×3). The organic layer was dried over Na2SO4, filtered and
concentrated under vacuum, the crude product was purified with flash chromatography on silica gel
(ethyl acetate/petroleum ether, 1:5 (v/v)) to afford the product 9. Colorless oil, 55 mg, 85% yield. [α]2D0
= +5.0 (c 0.18, CH2Cl2); 99.5% ee, determined by HPLC analysis [Daicel Chiralcel ODꢀH column,
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nꢀhexane/iꢀPrOH = 90:10, 1.0 mL/min, 210 nm; t (major)=11.70 min, t (minor) = 14.96 min]; H
NMR (300 MHz, CDCl3) δ 7.41 – 7.27 (m, 3H), 7.24 (dd, J = 6.8, 1.7 Hz, 2H), 5.33 – 5.10 (m, 2H),
3.67 (dd, J = 11.1, 5.5 Hz, 1H), 3.49 (s, 1H), 2.60 – 2.28 (m, 2H), 1.97 (s, 1H), 1.42 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 171.3, 137.8, 128.9, 127.9, 125.8, 82.8, 79.5, 58.9, 53.0, 36.4, 27.6; ESIꢀHRMS
Calcd for C15H22NO5 [M + H]+: 296.1492, Found: 296.1485.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (No. 21172255) and the Ministry of
Science and Technology of China (No. 2015BAK45B01) for the financial support.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
The Xꢀray data for compound 3ah, HPLC data, and 1H and 13C NMR spectra(PDF)
Crystallographic data for 3ah(CIF)
AUTHOR INFORMATION
Corresponding Author *
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E-mail: fubinchem@cau.edu.cn; qinzhaohai@263.net.
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Notes
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The authors declare no competing financial interest.
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