Direct catalytic asymmetric vinylogous michael reaction of α,β-unsaturated γ-butyrolactam under dinuclear nickel schiff base catalysis

Article abstract of DOI:10.3987/COM-12-S(N)58

Direct catalytic asymmetric vinylogous Michael reaction is described. 2.5 mol % of homobimetallic (S)-Ni₂-Schiff base complex efficiently catalyzed the addition of α,β-unsaturated γ-butyrolactam to nitroalkenes under simple proton transfer cond

Full text of DOI:10.3987/COM-12-S(N)58

HETEROCYCLES, Vol. 86, No. 1, 2012
611
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 611 - 622. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 26th June, 2012, Accepted, 27th July, 2012, Published online, 30th July, 2012
DOI: 10.3987/COM-12-S(N)58
ꢀ
DIRECT CATALYTIC ASYMMETRIC VINYLOGOUS MICHAEL
REACTION OF !,"-UNSATURATED #-BUTYROLACTAM UNDER
DINUCLEAR NICKEL SCHIFF BASE CATALYSIS
Hirooki Tanabe,a Yingjie Xu,a Bo Sun,a Shigeki Matsunaga,a* and Masakatsu
Shibasakib*
aGraduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo
b
7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. Institute of Microbial Chemistry,
Tokyo, Kamiosaki 3-14-23, Shinagawa-ku, Tokyo, 141-0021, Japan
smatsuna@mol.f.u-tokyo.ac.jp; mshibasa@bikaken.or.jp
This paper is dedicated to Professor Ei-ichi Negishi on the occasion of his 77th
birthday.
Abstract – Direct catalytic asymmetric vinylogous Michael reaction is described.
2.5 mol % of homobimetallic (S)-Ni2-Schiff base complex efficiently catalyzed
the addition of !,"-unsaturated #-butyrolactam to nitroalkenes under simple
proton transfer conditions, giving vinylogous Michael products in 83-99% yield,
16:1->30:1 dr, and 96-99% ee.
INTRODUCTION
Chiral butyrolactams are ubiquitous heterocyclic structural motifs found in many natural products and
biologically active compounds, e.g. lactacystin,1 a proteasome inhibitor, and A-315675,2 an anti-influenza
agent. The synthetic utility of these compounds has led to the development of various methods to
synthesize chiral butyrolactams.3 Catalytic asymmetric vinylogous reactions of !,"-unsaturated
#-butyrolactams can be a very powerful and straightforward method for stereoselective synthesis of
versatile building blocks towards functionalized chiral butyrolactams. In contrast to related
#-butenolides,4 however, catalytic asymmetric vinylogous reactions using !,"-unsaturated
#-butyrolactams remained unexplored until Suga and Kekehi‘s pioneering work in 2007.5 Suga and
Kekehi used preformed 2-siloxypyrroles as latent enolates to establish a Lewis acid-catalyzed
enantioselective vinylogous Mukaiyama-type Michael reaction. Casiraghi, Zanardi, and Curti et al. also
recently reported efficient Lewis base- and Lewis acid-catalyzed highly enantioselective vinylogous

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HETEROCYCLES, Vol. 86, No. 1, 2012
reactions.6 In terms of atom-economy, however, a direct vinylogous addition of !,"-unsaturated
#-butyrolactams under simple proton transfer conditions would be more favorable. To address this issue,
we and others recently reported bifunctional metal- and organo-catalyzed enantioselective vinylogous
Michael and Mannich-type reactions.7,8 In this article, we describe the full details of our work on a direct
catalytic asymmetric vinylogous Michael reaction of nitroalkenes under bimetallic Schiff base 1 catalysis
(Figure 1).
OH
OH
O
O
O
Ac
O
N
N
OH
OH
N
N
O
O
N
N
O
O
Ni
Ni
M
M OAc
O
(S)-Ni2-1 complex
M = Co(III): (S)-Co2-1 cat.
M = Mn(III): (S)-Mn2-1 cat.
(S)-Schiff base 1-H4
Figure 1. Structures of dinucleating Schiff base (R)-1-H4, and bimetallic Schiff base complexes
RESULTS AND DISCUSSION
The direct vinylogous reaction with !,"-unsaturated #-butyrolactam 2 first requires the chemoselective
activation of 2 as a donor. Electrophilic activation of the !,"-unsaturated #-butyrolactam unit in both 2
and the vinylogous Michael products leads to undesirable side reaction such as polymerization, and must
therefore be avoided. Chemoselective deprotonation from pro-nucleophile 2 while suppressing
undesirable deprotonation from vinylogous Michael products is also important because epimerization of
the products decreases the diastereoselectivity. These points must be carefully considered, in addition to
kinetic control of the enantioselectivity, diastereoselectivity, and !/#-selectivity of the metal dienolate.
Among acid/base bifunctional catalysts developed in our group,9 bimetallic Schiff base 1 catalysts,10-14
used for catalytic deprotonation of the !-proton in carbonyl donors, showed promising results in the
present vinylogous Michael reactions. Optimization studies using !,"-unsaturated #-butyrolactam 2 and
nitroalkene 3a are summarized in Table 1 and Table 2.
To select a suitable catalyst for the vinylogous reaction of 2, we screened several metals as shown in
Table 1. We first utilized dinuclear Co2-110 and Mn2-111 complexes, which have been used for Michael
reactions to nitroalkenes with "-keto esters and N-Boc oxindoles as donors. Use of the Co2-1 and Mn2-1
complexes (entries 1-2) resulted in good diastereoselectivity, but the yield and enantioselectivity were
only moderate. On the other hand, the use of a dinuclear Ni2-1 complex12 gave promising results,
affording product 4a in 64% yield, 30:1 dr, and 91% ee in THF at 25 °C (entry 3). No !-adduct was

HETEROCYCLES, Vol. 86, No. 1, 2012
613
detected in entry 3. Other bimetallic catalysts, such as Zn2-1, and Cu2-1 complexes resulted in poor
reactivity (entries 4-5).
Table 1. Metal Effects
Ph
(S)-M2-1
(10 mol %)
NO2
4a
NO2
N
+
Boc
Ph
H
THF, 25 °C, 20 h
N
O
2
3a
Boc
O
dra
syn:anti
% eeb
entry
cat.
% yielda
28
1
2
3
4
5
20:1
8:1
47
50
Co2-1
Mn2-1
Ni2-1
28
64
30:1
N.D.
N.D.
91
trace
trace
N.D.
N.D.
Cu2-1
Zn2-1
1
b
Footnotea Determined by H NMR analysis of crude mixture. Determined by chiral stationary-phase
HPLC analysis using CHIRALPAK IC.
To further improve the reactivity and enantioselectivity, we further optimized the reaction conditions
using Ni2-1 catalysts, as summarized in Table 2. Among the solvents screened (entries 1-7), 1,4-dioxane
gave the best diastereoselectivity and enantioselectivity (entry 3). Other solvents resulted in less
satisfactory reactivity and/or selectivity. Increasing the amount of donor 2 improved the yield to some
extent (entries 8-9). With 2 equiv of donor 2, catalyst loading was reduced to 2.5 mol %, giving the
product 4a in 85% yield, >30:1 dr, and 95% ee after 20 h (entry 10). To accelerate the reaction, molecular
sieves were added in entries 11-12,15 but this resulted in less satisfactory reactivity and selectivity.
Raising the reaction temperature to 50 °C improved the reactivity, and product 4a was obtained in
quantitative conversion after 13 h (entry 13, 98% isolated yield). It is noteworthy that high
enantioselectivity was maintained even at an elevated temperature (entry 9: 95% ee vs entry 13: 97% ee).
When catalyst loading was further reduced to 1.0 mol %, the reaction did not complete even when the
reaction time was prolonged (36 h), and the stereoselectivity was slightly decreased (entry 14). Thus, we
selected the conditions in entry 13 as optimum.

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HETEROCYCLES, Vol. 86, No. 1, 2012
Table 2. Optimization of Reaction Conditions
Ph
(S)-Ni2-1
(x mol %)
NO2
4a
NO2
N
+
Boc
Ph
conditions, 20 h
H
N
O
2
(y equiv)
3a
Boc
O
cat.
(x mol %)
2
(y equiv)
% yielda
temp time
dra
syn:anti
solvent
THF
additive
% eeb
entry
(°C)
25
25
25
25
25
25
25
25
25
25
25
25
50
50
(h)
20
20
20
20
20
20
20
20
20
20
20
20
13
36
1
2
none
none
none
none
none
none
none
none
none
none
MS 4Å
MS 5Å
none
none
64
44
30:1
>30:1
>30:1
N. D.
8:1
91
92
96
60
70
69
88
96
95
95
94
92
97
93
10
10
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
2.0
2.0
2.0
2.0
2.0
2.0
Et
2O
3
1,4-dioxane
iPr2O
64
10
4
trace
7
10
5
MeCN
10
6
toluene
30
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
29:1
10
7
CH2Cl2
10
10
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
75
10
9
88
10
10
11
12
13
14
85
2.5
2.5
2.5
2.5
1.0
66
58
98c
84c
1
b
Footnotea Determined by H NMR analysis of crude mixture. Determined by chiral stationary-phase
HPLC analysis using CHIRALPAK IC. c Isolated yield after purification by column chromatography.
The substrate scope of the reaction under optimized reaction conditions with homodinuclear (S)-Ni2-1 is
summarized in Table 3. !-Aryl-substituted nitroalkenes with either an electron-withdrawing group or an
electron-donating group gave the products in high yield with high stereoselectivity (entries 2-4). Notably,
sterically-hindered 2-bromo-substituted nitroalkene 3c also showed good reactivity and enantioselectivity,
although the diastereoselectivity was somewhat decreased (entry 3, 16:1 dr). !-Heteroaryl-substituted
nitroalkenes 3e and 3f also gave comparably high reactivity and selectivity (entries 5-6). As for
!-alkyl-substituted nitroalkenes, both linear and branched nitroalkenes 3g and 3h gave the products in
good yield and with high selectivity, although a slightly longer reaction time (24 h) was required (entries
7-8). Nitrodiene 3i was also applicable, giving predominantly the 1,4-adduct in 83% yield, 25:1 dr, and
99% ee (entry 9). The absolute and relative configurations of product 4b were unequivocally determined
by X-ray crystallographic analysis (Figure 2),16 and those of other products were assigned by analogy.

HETEROCYCLES, Vol. 86, No. 1, 2012
615
Table 3. Direct Catalytic Asymmetric Vinylogous Michael Reaction of an ",!-Unsaturated
#-Butyrolactam to Nitroalkenesa
R
(S)-Ni2-1
(2.5 mol %)
NO2
NO2
N
+
Boc
R
H
1,4-dioxane
50 °C
N
O
Boc
O
2 (2 equiv)
R: 3
3
4
cat
(x mol %)
time
(h)
%
%
entry
drc
yieldb
4
eed
1
2
3
4
5
6
7
8
9
3a
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
13
12
11
25
11
15
24
24
16
4a
4b
4c
4d
4e
4f
98
96
98
98
98
99
89
97
83
>30:1
29:1
97
99
98
98
98
98
96
99
99
Ph-
3b
3c
3d
3e
3f
4-Br-C6H4-
2-Br-C6H4-
4-MeO-C6H4-
2-furyl
16:1
>30:1
>30:1
>30:1
26:1
2-thienyl
3g
3h
3i
4g
4h
4i
PhCH2CH2-
i-propyl
>30:1
25:1
(E)-Ph-CH=CH-
a
b
Footnote Reaction was run using 2 equiv of 3 in 1,4-dioxane (0.15 M) at 50 °C. Isolated yield after
c
1
Determined by H NMR analysis of crude mixture.
d
purification by column chromatography.
Determined by HPLC using chiral column IC, IB or AD-H. See experimental section for detail.
Figure 2. ORTEP plot of product 4b (50% probability thermal ellipsoids).
The postulated catalytic cycle of the reaction under dinuclear nickel catalysis is shown in Figure 3. Based
on previous studies of dinuclear Ni-catalysis,12 we speculate that one of the Ni-O bonds in the outer O2O2

616
HETEROCYCLES, Vol. 86, No. 1, 2012
cavity works as a Brønsted base to deprotonate 2 and generate Ni-vinylogous enolate in situ. The other Ni
in the inner N2O2 cavity functions as a Lewis acid to control the position of nitroalkenes 3, similar to
conventional metal-salen Lewis acid catalysis. The C-C bond-formation, followed by protonation, affords
product 4 and regenerates the Ni2-1 catalyst. The high diastereoselectivity observed in Table 2 suggests
that negligible undesired epimerization of the products occurred via deprotonation. A control experiment
using #-Me-substituted ",!-unsaturated #-butyrolactam under the present Ni2-1 catalysis did not proceed,
suggesting that the steric hindrance suppressed the epimerization by the Ni2-1 catalyst.ꢀ
O
Lewis acid
N
H
Boc
N
N
deprotonation
Ni
O
O
O
O
Ni
O
N
N
N
O
Ni
Ni
H
OtBu
O
O
O
O
Brønsted base
O
addition-
protonation
N+
R
activation of
nitroalkene
N
Ni
O
O!
O
N
R
O
O
Ni
O
NO2
N
O
H
N
Boc
H
OtBu
H
O
Figure 3. Postulated catalytic cycle of vinylogous Michael reaction under dinuclear Schiff base catalysis
In summary, we developed a highly enantio- and diastereoselective catalytic asymmetric vinylogous
Michael reaction of ",!-unsaturated #-butyrolactam to nitroalkenes. A homodinuclear Ni2-Schiff base 1
complex was suitable for the reaction and vinylogous Michael adducts were obtained in 83-99% yield,
16:1->30:1 dr, and 96-99% ee.
EXPERIMENTAL
General: Infrared (IR) spectra were recorded on a JASCO FT/IR 410 Fourier transform infrared
spectrophotometer. NMR spectra were recorded on JEOL ECX500 spectrometers, operating at 500 MHz
for 1H NMR and 125.65 MHz for 13C NMR. Chemical shifts in CDCl3 were reported in the scale relative

HETEROCYCLES, Vol. 86, No. 1, 2012
617
1
13
to tetramethylsilane (0 ppm) for H NMR. For C NMR, chemical shifts were reported in the scale
relative to CHCl3 (77.0 ppm) as an internal reference. Column chromatography was performed with silica
gel Merck 60 (230-400 mesh ASTM). Optical rotations were measured on a JASCO P-1010 polarimeter.
ESI mass spectra were measured on Waters micromass ZQ (for LRMS) and ESI mass spectra for HRMS
were measured on a JEOL JMS-T100LC AccuTOF spectrometer. The enantiomeric excess (ee) was
determined by HPLC analysis. HPLC was performed on JASCO HPLC systems consisting of the
following: pump, PU-2080 plus; detector, UV-2075 plus, measured at 254 nm; column, DAICEL
CHIRALPAK IC, IB or AD-H; mobile phase, hexane-iPrOH.
General Procedure for Direct Catalytic Asymmetric Vinylogous Michael Reaction of
",!-Unsaturated #-Butyrolactam 2:
To a stirred solution of (S)-Ni2-Schiff base 1 catalyst (4.8 mg, 7.5 µmol, 2.5 mol %) in 1,4-dioxane (2.0
mL) at room temperature were added successively ",!-unsaturated #-butylolactam 2 (0.6 mmol) and
nitroalkene 3 (0.3 mmol). The resulting mixture was stirred at 50 ºC for indicated time in Table 3. After
cooling down to room temperature, silica gel (ca. 30 mg) suspension in EtOAc was added. The resulting
suspension was stirred at room temperature for 15 min. Then, the mixture was filtrated to remove silica
gel and the catalyst. The filtrate was concentrated under reduced pressure, and the residue was purified by
silica gel flash column chromatography (hexane/ethyl acetate = 10/1 to 2/1) to give product 4.
(S)-tert-Butyl 2-((S)-2-nitro-1-phenylethyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (4a):
Colorless solid; IR (KBr) $ 3097, 2979, 1775, 1696, 1556, 1362, 1274 cm-1; 1H NMR (CDCl3) % 1.66 (s,
9H), 4.48-4.56 (m, 1H), 4.64-4.74 (m, 2H), 4.87-4.90 (m, 1H), 6.18 (dd, J = 1.9, 6.1 Hz 1H), 7.03 (dd, J =
2.2, 6.1 Hz 1H), 7.27-7.45 (m, 5H); 13C NMR (CDCl3) % 28.0, 43.8, 65.0, 73.2, 84.1, 127.6, 128.5, 128.6,
129.2, 134.8, 146.1, 149.2, 168.2; LRMS (ESI): m/z 355 [M+Na]+; HRMS (ESI): m/z calculated for
24.0
C17H20N2O5Na+ [M+Na]+: 355.1264, found: 355.1258; ["]D –155 (c 0.93, CHCl3); HPLC (DAICEL
CHIRALPAK IC, EtOH, flow rate: 0.7 mL/min, detection at 254 nm) tR 9.4 min (minor) and 13.8 min
(major).
(S)-tert-Butyl 2-((S)-1-(4-bromophenyl)-2-nitroethyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate
(4b): Colorless solid; IR (KBr) $ 3103, 2979, 2933, 1759, 1555, 1489, 1368, 1298, 1253, 1157, 1048,
1009, 822 cm-1; 1H NMR (CDCl3, 500 MHz) % 1.63 (s, 9H), 4.52 (dd, J = 4.7, 12.6 Hz, 1H), 4.56-4.60 (m,
1H), 4.66 (dd, J = 9.5, 12.6 Hz, 1H), 4.83-4.86 (m, 1H), 6.16 (dd, J = 1.7, 6.2 Hz, 1H), 7.00 (dd, J = 2.1,
6.2 Hz, 1H), 7.12-7.15 (m, 2H), 7.51-7.54 (m, 2H); 13C NMR (CDCl3, 125 MHz) % 28.1, 43.5, 64.6, 73.3,
84.4, 122.6, 128.9, 129.3, 132.5, 133.8, 145.8, 149.5, 167.8; LRMS (ESI): m/z 433, 435 [M+Na]+; HRMS

618
HETEROCYCLES, Vol. 86, No. 1, 2012
(FAB): m/z calculated for C17H19Br81N2O5Na+ [M+Na]+: 435.0355, found: 435.0350; HPLC (chiral
column: DAICEL CHIRALPAK IC, ethanol, flow rate: 0.4 mL/min, detection: at 254 nm): tR = 15.1 min
(R,R) and 24.1 min (S,S); ["]D29.7 = –114 (c 0.50, CHCl3).
(S)-tert-Butyl 2-((S)-1-(2-bromophenyl)-2-nitroethyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate
(4c): Colorless solid; IR (KBr) $ 3105, 2982, 2949, 1766, 1558, 1474, 1368, 1288, 1159, 1046, 829, 772,
1
729 cm--1; H NMR (CDCl3) % 1.65 (s, 9H), 4.66-4.75 (m, 2H), 5.10-5.16 (m, 2H), 6.10 (dd, J =1.6, 6.3
Hz, 1H), 6.98-7.01(m, 1 H), 7.10 (dd, J = 3.0, 6.3 Hz, 1H), 7.19-7.23 (m, 1H), 7.33-7.37 (m, 1H),
13
7.63-7.67(m,1H); C NMR (CDCl3) % 28.1, 43.1, 62.1, 74.0, 84.4, 125.4, 128.0, 128.3, 130.0, 133.7,
134.1, 146.7, 149.7, 168.3; LRMS (ESI): m/z 433, 435 [M+Na]+; HRMS (FAB): m/z calculated for
C17H19Br81N2O5Na+ [M+Na]+: 435.0355, found: 435.0349; ["]D24.0 –127 (c 0.99, CHCl3), HPLC (DAICEL
CHIRALPAK IC, ethanol, flow rate: 0.4 mL/min, detection at 254 nm) tR 18.6 min (minor) and 27.0 min
(major).
(S)-tert-Butyl 2-((S)-1-(4-methoxyphenyl)-2-nitroethyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate
(4d): Colorless oil; IR (neat) $ 2979, 2839, 1783, 1612, 1557, 1514, 1368, 1255, 1157, 1103, 1034, 824,
753 cm-1; 1H NMR (CDCl3, 500 MHz) % 1.65 (s, 9H), 3.80 (s, 3H), 4.49 (dd, J = 4.3, 12.5 Hz, 1H),
4.56-4.60 (m, 1H), 4.64 (dd, J = 9.6, 12.5 Hz, 1H), 4.83-4.86 (m, 1H), 6.16 (dd, J = 1.9, 6.1 Hz, 1H),
6.90-6.93 (m, 2H), 7.04 (dd, J = 2.1, 6.1 Hz, 1H), 7.15-7.19 (m, 2H); 13C NMR (CDCl3, 125 MHz) % 28.1,
43.3, 55.3, 65.2, 73.7, 84.2, 144.7, 126.5, 128.6, 128.8, 146.4, 149.5, 159.6, 168.2; LRMS (ESI): m/z 385
[M+Na]+; HRMS (FAB): m/z calculated for C18H22NaN2O6+ [M+Na]+: 385.1370, found: 385.1364; HPLC
(chiral column: DAICEL CHIRALPAK IC, ethanol, flow rate: 0.4 mL/min, detection: at 254 nm): tR =
20.2 min (minor) and 29.7 min (major); ["]D24.9 = –94.7 (c 0.90, CHCl3).
(S)-tert-Butyl 2-((S)-1-(furan-2-yl)-2-nitroethyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (4e):
Colorless solid; IR (KBr) 2969, 1789, 1698, 1552, 1369, 1288, 1254, 1162, 1051, 916, 848, 795, 755
1
cm-1; H NMR (CDCl3) % 1.62 (s, 9H), 4.34 (dd, J = 4.3, 13.5 Hz, 1H), 4.54 (dd, J = 9.8, 13.5 Hz ,1H),
4.76 (ddd, J = 4.3, 4.3, 9.8 Hz, 1H), 4.97 (ddd, J = 1.7, 2.1, 4.3 Hz, 1H), 6.22 (dd, J = 1.7, 6.2 Hz, 1H),
6.31 (brd, J = 3.4 Hz, 1H), 6.38 (dd, J = 1.9, 3.4 Hz, 1H), 7.19 (dd, J = 2.1, 6.2 Hz, 1H), 7.44 (dd, J = 0.7,
13
1.9 Hz,, 1H); C NMR (CDCl3) % 28.0, 38.1, 63.4, 72.5, 84.2, 108.8, 110.7, 128.6, 143.1, 146.8, 148.9,
149.0, 168.1 ; LRMS (ESI): m/z 345 [M+Na]+; HRMS (ESI): m/z calculated for C15H18N2O6Na+ [M+Na]+:
24.0
345.1057, found: 345.1053; ["]D –179 (c 1.11, CHCl3), HPLC (DAICEL CHIRALPAK IC, ethanol,
flow rate: 0.7 mL/min, detection at 254 nm) tR 8.6 min (minor) and 10.4 min (major).

HETEROCYCLES, Vol. 86, No. 1, 2012
619
(S)-tert-Butyl
2-((S)-2-nitro-1-(thiophen-2-yl)ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate
(4f): Colorless solid; IR (KBr) $ 3099, 2981, 1782, 1693, 1556, 1358. 1277, 1152, 1107, 1032, 835, 714
cm-1; 1H NMR (CDCl3) % 1.64 (s, 9H), 4.50 (dd, J = 4.8, 13.4 Hz, 1H), 4.57 (dd, J = 9.5, 13.4 Hz, 1H),
4.89 (ddd, J = 4.8, 4.8, 9.5, 1H), 4.94-4.96 (m, 1H), 6.20 (dd, J = 1.5, 6.1 Hz, 1H), 6.97 (d, J = 3.4 Hz,
1H), 7.01 (dd, J = 3.4, 5.2 Hz, 1H), 7.16 (dd, J = 2.1, 6.1 Hz, 1H), 7.30 (d, J = 5.2 Hz, 1H);13C NMR
(CDCl3) % 28.0, 39.8, 64.8, 74.9, 84.3, 125.7, 126.3, 127.4, 128.8, 137.2, 146.3, 149.1, 168.1; LRMS
(ESI): m/z 361 [M+Na]+; HRMS (ESI): m/z calculated for C15H18N2O5SNa+ [M+Na]+: 361.0829, found:
24.0
362.0826; ["]D –184 (c 1.03, CHCl3), HPLC (DAICEL CHIRALPAK IC, ethanol, flow rate: 0.4
mL/min, detection at 254 nm) tR 18.3 min (minor) and 27.1 min (major).
(S)-tert-Butyl 2-((S)-1-nitro-4-phenylbutan-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (4g):
Colorless oil; IR (neat) $ 3022, 2980, 2932, 1778, 1555, 1456, 1370, 1314, 1158, 1105, 1049, 825, 753,
700 cm-1;1H NMR (CDCl3, 500 MHz) % 1.49 (s, 9H), 1.77-1.82 (m, 2H), 2.72-2.75 (m, 2H), 3.27-3.33 (m,
1H), 4.04 (dd, J = 7.3, 13.1 Hz, 1H), 4.14 (dd, J = 5.2, 13.1 Hz, 1H), 4.78-4.80 (m, 1H), 6.17 (dd, J = 1.5,
6.2 Hz, 1H), 7.06 (dd, J = 1.7, 6.2 Hz, 1H), 7.13-7.27 (m, 5H); 13C NMR (CDCl3, 125 MHz) % 27.9, 31.8,
33.3, 37.9, 63.1, 75.1, 84.0, 126.5, 128.1, 128.7, 129.2, 140.1, 145.8, 149.2, 168.2; LRMS (ESI): m/z 383
[M+Na]+; HRMS (FAB): m/z calculated for C19H24NaN2O5+ [M+Cs]+: 383.1577, found: 383.1574; HPLC
(chiral column: DAICEL CHIRALPAK AD-H, solvent: hexane/2-propanol = 9/1, flow rate: 0.5 mL/min,
detection: at 254 nm): tR = 31.9 min (minor) and 36.5 min (major); ["]D 29.7 = –113.6 (c = 0.70, CHCl3).
(S)-tert-Butyl 2-((S)-3-methyl-1-nitrobutan-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (4h):
Colorless solid; IR (KBr) $ 3090, 2973, 1787, 1708, 1552, 1474, 1366, 1281, 1162, 1047, 848, 825, 752
cm-1; 1H NMR (CDCl3, 500 MHz) % 1.07 (d, J = 6.7 Hz, 3H), 1.15 (d, J = 6.7 Hz, 3H), 1.57 (s, 9H),
1.77-1.84 (m, 1H), 3.11-3.16 (m, 1H), 3.92 (dd, J = 4.4, 13.8 Hz, 1H), 4.13 (dd, J = 6.9, 13.8 Hz, 1H),
4.93-4.94 (m, 1H), 6.21 (dd, J = 1.4, 6.2 Hz, 1H), 7.10 (dd, J = 1.9, 6.2 Hz, 1H); 13C NMR (CDCl3, 125
MHz) % 20.5, 20.6, 28.0, 29.5, 43.9, 62.0, 73.6, 83.9, 129.3, 146.1, 149.0, 168.2; LRMS (ESI): m/z 321
[M+Na]+; HRMS (ESI): m/z calculated for C14H22NaN2O5+ [M+Na]+: 321.1421, found: 321.1427; HPLC
(chiral column: DAICEL CHIRALPAK IC, solvent: ethanol, flow rate: 0.4 mL/min, detection: at 254
nm): tR = 14.8 min (minor) and 21.9 min (major); ["]D29.7 = –177 (c = 1.0, CHCl3).
(S)-tert-Butyl 2-((S,E)-1-nitro-4-phenylbut-3-en-2-yl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate
(4i): Colorless oil; IR (neat) $ 2980, 1780, 1742, 1555, 1369, 1315, 1157, 1105, 1049, 969, 824, 751, 693
cm-1; 1H NMR (CDCl3, 500 MHz) % 1.53 (s, 9H), 4.00-4.05 (m, 1H), 4.20 (dd, J = 9.9, 12.9 Hz, 1H), 4.27
(dd, J = 4.6, 12.9 Hz, 1H), 4.77-4.79 (m, 1H), 5.95 (dd, J = 8.6, 15.9 Hz, 1H), 6.13 (dd, J = 1.3, 6.1 Hz,

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1H), 6.58 (d, J = 15.9 Hz, 1H), 7.12 (dd, J = 1.2, 6.1 Hz, 1H), 7.17-7.28 (m, 5H); 13C NMR (CDCl3, 125
MHz) % 28.0, 42.5, 64.1, 74.9, 84.3, 122.2, 126.6, 128.6, 128.7, 128.8, 135.5, 136.3, 146.4, 149.5, 168.1;
+
LRMS (ESI): m/z 381 [M+Na]+; HRMS (ESI): m/z calculated for C19H22NaN2O5 [M+Na]+: 381.1421,
found: 381.1419; HPLC (chiral column: DAICEL CHIRALPAK IB, solvent: hexane/2-propanol = 4/1,
flow rate: 1.0 mL/min, detection: at 254 nm): tR = 75.2 min (minor) and 89.5 min (major); ["]D29.7 = –169
(c = 0.90, CHCl3).
ACKNOWLEDGEMENTS
This work was supported in part by Scientific Research on Innovative Areas “Molecular Activation
Directed toward Straightforward Synthesis” from MEXT, Grant-in-aid for Young Scientist (A) from
JSPS, the Naito Foundation, Takeda Science Foundation, and the Noguchi Institute. We thank prof. M.
Kanai at the University of Tokyo for his fruitful discussion and unlimited access to analytical facilities in
his lab.
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16. CCDC 786778 contains the supplementary crystallographic data for 4b. The data can be obtained
free
of
charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.