Highly enantioselective tandem double Michael reactions catalyzed by Ni(acac)2/(+)-MINBOL complex

Article abstract of DOI:10.1016/j.tetasy.2015.10.012

An in situ prepared complex of chiral ligand (+)-MINBOL 1 and Ni(acac)₂ (12.5 mol % and 0.5 mol % respectively) can efficiently catalyze enantioselective tandem double Michael reactions. In this reaction, aryl or alkyl nitroalkenes were employed as electrophiles. The corresponding tandem adducts were obtained in good yields and with high enantioselectivities (up to 97% ee).

Full text of DOI:10.1016/j.tetasy.2015.10.012

Tetrahedron: Asymmetry 26 (2015) 1369–1374
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Highly enantioselective tandem double Michael reactions catalyzed
by Ni(acac)2/(+)-MINBOL complex
⇑
Yu-Ming Hung, Chih-Hao Tseng, Biing-Jiun Uang
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
An in situ prepared complex of chiral ligand (+)-MINBOL 1 and Ni(acac)2 (12.5 mol % and 0.5 mol %
respectively) can efficiently catalyze enantioselective tandem double Michael reactions. In this reaction,
aryl or alkyl nitroalkenes were employed as electrophiles. The corresponding tandem adducts were
obtained in good yields and with high enantioselectivities (up to 97% ee).
Received 29 August 2015
Accepted 12 October 2015
Available online 2 November 2015
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
2. Result and discussion
Asymmetric tandem transformations are considered as useful
tools for the preparation of chiral compounds with multiple stere-
ogenic centres. The noteworthy feature of tandem reactions is the
access to complex molecules without any purification of possible
intermediates. As such, considerable efforts have been focused on
the development of asymmetric tandem reactions.1 The Michael
At first, we investigated the temperature effect on the elec-
trophilic trapping reaction of the chiral zinc enolate that was
formed in the Ni(acac)2/(+)-MINBOL 1 complex catalyzed asym-
metric conjugate addition of Et2Zn to chalcone 2a at ꢀ50 °C. When
chalcone 2a was completely transformed into the corresponding
chiral zinc enolate, as judged by TLC analysis, one equivalent of
trans-b-nitrostyrene 3a was added to the reaction mixture for the
second Michael addition. After the addition of trans-b-nitrostyrene
addition of carbon nucleophiles to a,b-unsaturated carbonyl com-
pounds is one of the most powerful carbon–carbon bond forming
reactions. Over the past few decades, enantioselective metal-cat-
alyzed conjugate additions of dialkyl zinc reagents to Michael
acceptors have been studied extensively.2 The crucial characteristic
of these reactions is the generation of optically active zinc enolates.
These enolates can further react with various electrophilic
reagents and generate a wide range of products with complex
functionalities.3,4
Nitro compounds have been extensively utilized in organic
synthesis due to their synthetic versatility.5 Moreover, nitroolefins
are good Michael accepters because they are easily accessible and
the resulting products can be further elaborated upon to give
important synthetic intermediates or natural products.6 Previ-
ously, we reported that enantioselective conjugate addition of
3a, the reaction temperature was set at ꢀ30 °C.
c-Nitro ketone 4a
was obtained after 48 h in 65% yield and with 92% ee (Table 1,
entry 1). Moreover, only one of four possible diastereomers was
detected (>20:1 dr, determined by crude 1H NMR). With this
encouraging result, we decided to further screen for the optimal
conditions. When the reaction temperature was increased from
ꢀ30 °C to 0 °C, the electrophilic trapping reaction time shortened
from 48 h to 3 h with a gradual improvement of yield (65–82%)
(Table 1, entries 1–4) and enantioselectivities (92–95%) (Table 1,
entries 1–4). However, it showed no significant improvement in
yield when the reaction temperature was increased to 10 °C
(Table 1, entry 5). The control experiment was also investigated
as illustrated in Figure 1.3o The b-ethylated Michael adduct 5 was
converted into the corresponding enolate by using LDA. After the
addition of nitroalkene 3a, the enolate was captured without Ni
(acac)2 and (+)-MINBOL 1. The double Michael product 4a was
obtained in relatively poor yield with the same enantioselectivity
as the starting material 5 but moderate diastereoselectivity (dr
6:1). On the other hand, the lithium enolate was reacted with
nitroalkene 3a in the presence of a chiral complex to provide the
dialkylzincs to acylic a,b-unsaturated enones could be successfully
catalyzed by the chiral ligand (+)-MINBOL 1 and Ni(acac)2.7,8
Nitroalkenes were therefore selected as electrophiles to extend
the scope of this methodology. Herein, we report highly diastereos-
elective and enantioselective tandem double Michael reactions
catalyzed by (+)-MINBOL 1 and Ni(acac)2.
c-nitro ketone 4a in 50% yield with the similar stereoselectivity
as the previous one. These results were then compared with
those obtained from the catalytic system. It was suggested that
⇑
Corresponding author.
E-mail address: bjuang@mx.nthu.edu.tw (B.-J. Uang).
http://dx.doi.org/10.1016/j.tetasy.2015.10.012
0957-4166/Ó 2015 Elsevier Ltd. All rights reserved.

1370
Y.-M. Hung et al. / Tetrahedron: Asymmetry 26 (2015) 1369–1374
Table 1
Temperature effects on the electrophilic trapping reaction
OH
N
O
1
(+)-MINBOL
O
H
H
O
NO2
(+)-MINBOL 1 (12.5 mol%)
Ni(acac)2 (0.5 mol%)
Ph
Ph
Ph
3a
oC, time
+
1.5 eq. Et2Zn
NO2
propionitrile, -50 oC
Ph
T
4a
2a
Entry
T (°C)
Time (h)
Yielda (%)
eeb (%)
1
2
3
4
5
ꢀ30
ꢀ20
ꢀ10
0
48
24
10
3
65
70
79
82
82
92
95
95
95
88
10
2
a
Isolated yield.
b
Determined by chiral HPLC using Chiralcel AD-H column.
O
O
H
1. LDA (1.1 eq.), THF, -78 oC, 1h
Ph
Ph
H
2. 3a (1.0 eq.), 0 oC, 24h
NO2
Ph
5, 93% ee
4a, 30% yield
93% ee for major isomer, dr 6:1
O
H
O
1. LDA (1.1 eq.), THF, -78 oC, 1h
Ph
Ph
H
2. 3a (1.0 eq.), (+)-MINBOL (12.5 mol%),
NO2
Ph
Ni(acac)2 (0.5 mol%), 0 oC, 24h
5, 92% ee
4a, 50% yield
92% ee for major isomer, dr 7:1
Figure 1. The control experiment of tandem double Michael reaction.
the zinc enolate was critical for chelating with the in situ prepared
chiral complex from Ni(acac)2 and (+)-MINBOL 1 and that the
complex promotes the second Michael addition.
applied the reaction to several substituted chalcones 2. Moder-
ate yields and high enantioselectivities were observed regard-
less of the various chalcones
2 (Table 2, entries 12–17).
The optimized condition (Table 1, entry 4) was adopted for
studying the substrate scope. At first, trans-b-nitrostyrenes 3
with electron-donating or electron-withdrawing groups at the
para- or meta-position of the b-phenyl group of the aromatic
nitroolefins were subjected to the catalytic system. The results
are summarized in Table 2. The substituents at the para- or
meta-position of the b-phenyl group of the nitroolefin did not
significantly affect the reactivity, diastereoselectivity or enan-
tioselectivity. The corresponding adducts were all obtained in
good yields and with excellent enantioselectivities (Table 2,
entries 1–9). Notably, the branched aliphatic nitroalkene 3j
and unbranched aliphatic nitroalkene 3k were examined and
both provided the corresponding product in satisfactory yields
with high enantioselectivities (Table 2, entries 10 and 11). To
further explore the scope of the catalytic system, we also
However, the reaction time of the electrophilic trapping step
required 6 h to consume the trans-b-nitrostyrenes 3 completely,
probably due to the electronic effect of the substituted chal-
cones. It is worthwhile noting that all of the corresponding
adducts were determined as nearly a single diastereomer from
crude 1H NMR studies. In order to determine the absolute con-
figuration of the adduct, we prepared the bromo-containing
adduct 4q (Table 2, entry 17). We were able to obtain single
crystals of compound 4q. The absolute configuration of tandem
adduct 4q was confirmed unambiguously to be (2S,3S,20R) by
X-ray crystallography (Fig. 2)9 given the known configuration
of (S)-5.8 The relative configuration within the other adducts
was assigned by the correlation of their 1H NMR splitting pat-
terns with those in 4q and the absolute configuration assigned
by analogy.

Y.-M. Hung et al. / Tetrahedron: Asymmetry 26 (2015) 1369–1374
1371
Table 2
The scope of the selected substrates
OH
N
O
1
(+)-MINBOL
O
H
H
(+)-MINBOL 1 (12.5 mol%)
Ni(acac)2 (0.5 mol%)
NO2
R3
O
Ar1
R3
Ar2
3
+ 1.5 eq. Et2Zn
Ar1
Ar2
NO2
propionitrile, -50 oC
0
oC, 3h
4
2
Entry
Ar1
Ar2
Ar3
Ph
4-MePh
4-BrPh
4-MeOPh
4-ClPh
3-CF3Ph
3-ClPh
3-BrPh
3-MeOPh
iPr
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeOPh
4-MePh
4-ClPh
3-ClPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a, 82
4b, 78
4c, 79
4d, 76
4e, 84
4f, 76
4g, 83
4h, 74
4i, 68
4j, 70
4k, 75
4l, 73
4m, 73
4n, 70
4o, 67
4p, 66
4q, 84
95
95
96
97
97
96
94
96
97
97
97
96
96
93
93
95
91
9
10
11
12c
13c
14c
15c
16c
17c
nPr
Ph
Ph
Ph
Ph
Ph
4-BrPh
4-ClPh
Ph
4-MeOPh
a
b
c
Isolated yield.
Determined by chiral HPLC using Chiralcel AD-H column.
The electrophilic trapping reaction required 6 h to complete the reaction.
3. Conclusion
We have demonstrated that the in situ prepared catalytic
system from the Ni(acac)2/(+)-MINBOL 1 complex could catalyze
the asymmetric tandem double Michael reactions effectively. This
Br
NO2
H
O
2'
H
reaction leads to the synthesis of
c-nitro ketones with three
3
2
contiguous stereogenic centres. The tandem adducts were
obtained in good yields and with 91–97% ee, which could be fur-
ther elaborated to enantioenriched pyrrolidines through reported
methods.3p,q These results encourage us to further investigate
their application in the synthesis of chiral intermediates for
biologically active molecules or natural products.
H
O
4q
Figure 2. X-ray crystallography of 4q.
4. Experimental
4.1. General
In order to further demonstrate the synthetic utility of this
methodology, we successfully conducted the gram-scaled reaction
by using 1 g of trans-chalcone 2a as the starting material. The
tandem adduct 4a was readily obtained after 3 h in 66% yield
and with 97% ee (Fig. 3).
All reactions were performed in flame-dried apparatus under an
argon atmosphere. All chemicals were purchased from commercial
O
H
O
NO2
(+)-MINBOL 1 (12.5 mol%)
Ni(acac)2 (0.5 mol%)
Ph
Ph
Ph
3a
H
+
1.5 eq. Et2Zn
NO2
Ph
propionitrile, -50 oC
0 oC, 3h
4a
2a
66%, 97% ee
1g, 5 mmol
Figure 3. Gram-scale reaction.

1372
Y.-M. Hung et al. / Tetrahedron: Asymmetry 26 (2015) 1369–1374
suppliers and used as received. Propionitrile was distilled under an
argon atmosphere from CaH2 before use. Column chromatography
was performed on silica gel with the indicated eluent. 1H and 13C
NMR spectra were recorded at 400 MHz and 100 MHz with Bru-
ker-400 MHz spectrometer. Abbreviations for 1H NMR: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet. High resolution
mass analyses were recorded on Bruker Impact HD. Optical rota-
tions were determined by using a JASCO DIP-100 polarimeter.
UV 254 nm; t(major) = 11.6 min, t(minor) = 13.7 min; 96% ee.
[a]
22.8 = ꢀ30.2 (c 1.0, CH2Cl2).
D
4.1.1.4. (2S,3S)-2-((R)-1-(4-Methoxyphenyl)-2-nitroethyl)-1,3-
diphenyl-pentan-1-one 4d3o,p 1H NMR (400 MHz, CDCl3):
.
d = 0.56 (t, J = 7.2 Hz, 3H), 1.37–1.55 (m, 2H), 2.90 (td, J = 3.2 Hz,
10.4 Hz, 10.4 Hz, 1H), 3.55–3.60 (m, 1H), 3.65 (s, 3H), 4.10 (dd,
J = 4.8 Hz, J = 9.6 Hz, 1H), 4.87 (dd, J = 3.6 Hz, J = 13.2 Hz, 1H),
4.92–4.98 (m, 1H), 6.64 (d, J = 8.4, 2H), 6.87 (d, J = 8.4 Hz,
2H), 7.21–7.30 (m, 5H), 7.36 (t, J = 7.2 Hz, 2H), 7.43 (t, J = 7.2 Hz,
1H), 7.49 ppm (d, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d = 12.1, 26.7, 43.4, 49.3, 55.1, 56.0, 75.7, 114.1, 127.2, 127.9,
128.1, 128.4, 128.9, 129.9, 133.2, 138.6, 140.9, 158.8, 204.1 ppm.
HPLC analysis: Chiralcel AD-H, 2-propanol/hexane (5:95), 1.0 mL/
min, UV 254 nm; t(minor) = 13.0 min, t(major) = 15.5 min; 97%
4.1.1. General procedure for the enantioselective tandem
double Michael reactions
To a flask were added chiral ligand (+)-MINBOL 1 (0.028 g,
0.125 mmol), Ni(acac)2 (0.0013 g, 0.005 mmol) and propionitrile
(1.0 mL). The mixture was refluxed for 1 h, then cooled to room
temperature followed by the addition of trans-chalcone 2a
(0.209 g, 1 mmol) in propionitrile (1.0 mL). The resulting mixture
was stirred for 15 min. at room temperature then cooled to
ꢀ50 °C. A diethylzinc solution (1.0 M in hexane, 1.5 mmol) was
added dropwise to the above mixture. After complete conversion
of the enone to the zinc enolate, which was confirmed by TLC,
trans-b-nitrostyrene 3a (0.150 g, 1 mmol) in 2.0 mL of propionitrile
was added and the corresponding mixture was further stirred at
0 °C for an additional 3 h. The reaction was quenched by 1 M
HCl(aq). The mixture was extracted with ether (10 mL for three
times), and the combined organic layer was dried over anhydrous
Na2SO4, and concentrated to give the crude product. The desired
product was obtained after column chromatography on silica gel
(ethyl acetate/hexane = 1:20). The dr ratio was determined by 1H
NMR. The ee values were determined by HPLC on a chiralcel AD-
H column.
ee. [
a]
D
22.8 = ꢀ23.7 (c 1.0, CH2Cl2).
4.1.1.5.
(2S,3S)-2-((R)-1-(4-Chlorophenyl)-2-nitroethyl)-1,3-
1H NMR (400 MHz, CDCl3):
diphenyl-pentan-1-one 4e3o,p
.
d = 0.56 (t, J = 7.2 Hz, 3H), 1.41–1.52 (m, 2H), 2.90 (td, J = 3.6 Hz,
10.4 Hz, 10.4 Hz, 1H), 3.53–3.58 (m, 1H), 4.08 (dd, J = 4.4 Hz,
J = 10.0 Hz), 4.89 (dd, J = 4.0 Hz, J = 13.6 Hz, 1H), 4.93–4.99 (m,
1H), 6.87 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 7.22–7.31 (m,
5H), 7.36–7.40 (m, 2H), 7.45–7.51 ppm (m, 3H). 13C NMR
(100 MHz, CDCl3): d = 12.1, 27.0, 43.6, 49.4, 55.7, 75.2, 127.4,
127.9, 128.1, 128.5, 128.7, 128.9, 129.1, 133.4, 133.48, 136.7,
138.4, 140.7, 203.6 ppm. HPLC analysis: Chiralcel AD-H, 2-propa-
nol/hexane (5:95), 1.0 mL/min, UV 254 nm; t(major) = 10.3 min,
t(major) = 11.8 min; 97% ee. [
a
]
D
22.8 = ꢀ29.9 (c 1.0, CH2Cl2).
4.1.1.6.
(2S,3S)-2-((R)-2-Nitro-1-(3-(trifluoromethyl)phenyl)
1H NMR (400 MHz,
4.1.1.1. (2S,3S)-2-((R)-2-Nitro-1-phenylethyl)-1,3-diphenylpen-
ethyl)-1,3-diphenylpentan-1-one 4f.
tan-1-one 4a3o,p
.
1H NMR (400 MHz, CDCl3): d = 0.56 (t,
CDCl3): d = 0.58 (t, J = 7.2 Hz, 3H), 1.39–1.52 (m, 2H), 2.94 (td,
J = 4.0 Hz, 10.4 Hz, 10.4 Hz, 1H), 3.60–3.65 (m, 1H), 4.11 (dd,
J = 4.8 Hz, J = 10.4 Hz, 1H), 4.93 (dd, J = 4.0 Hz, J = 14.0 Hz, 1H),
4.99–5.05 (m, 1H), 7.09–7.14 (m, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.26
(d, J = 6.8 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 7.39–7.46 (m, 3H),
7.50 ppm (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): d = 12.1,
27.5, 43.9, 49.4, 55.5, 74.7, 124.2, 124.5, 127.5, 127.9, 128.0,
128.3, 128.5, 129.2, 129.3, 130.7, 130.9, 133.6, 138.2, 139.2,
140.5, 203.3 ppm. HRMS (ESI) calcd for C26H24F3NNaO3 [M+Na]:
478.1600, found 478.1611. HPLC analysis: Chiralcel AD-H, 2-propa-
nol/hexane (5:95), 1.0 mL/min, UV 254 nm; t(minor) = 6.7 min,
J = 7.2 Hz, 3H), 1.38–1.53 (m, 2H), 2.90 (td, J = 3.2 Hz, 10.4 Hz,
10.4 Hz, 1H), 3.60 (m, 1H), 4.1 (dd, J = 4.8 Hz, J = 10.0 Hz, 1H),
4.90 (dd, J = 3.6 Hz, J = 13.6, 1H), 5.02 (t, J = 11.6 Hz, 1H), 6.95 (m,
2H), 7.07–7.13 (m, 3H), 7.22–7.31 (m, 5H), 7.36–7.46 ppm (m,
5H). 13C NMR (100 MHz, CDCl3): d = 12.1, 27.0, 44.0, 49.4, 56.0,
75.2, 127.3, 127.6, 128.0, 128.3, 128.8, 129.1, 133.2, 138.1, 138.6,
140.9, 204.0 ppm. HPLC analysis: Chiralcel AD-H, 2-propanol/hex-
ane (5:95), 1.0 mL/min, UV 254 nm; t(minor) = 10.9 min, t(major)
= 17.4 min; 95% ee. [
a
]
22.4 = ꢀ26.9 (c 1.0, CH2Cl2).
D
4.1.1.2. (2S,3S)-2-((R)-2-Nitro-1-p-tolylethyl)-1,3-diphenylpen-
tan-1-one 4b3o 1H NMR (400 MHz, CDCl3): d = 0.56 (t,
t(major) = 11.4 min; 96% ee. [
a
]
D
22.9 = ꢀ17.9 (c 1.0, CH2Cl2).
.
J = 7.2 Hz, 3H), 1.41–1.53 (m, 2H), 2.17 (s, 3H), 2.89 (td, J = 3.2 Hz,
10.4 Hz, 10.4 Hz, 1H), 3.57 (m, 1H), 4.10 (dd, J = 4.8 Hz, J = 10.6,
1H), 4.86 (dd, J = 3.6 Hz, J = 13.6 Hz, 1H), 4.96 (t, J = 12.4 Hz, 1H),
6.84 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0, 2H), 7.20–7.29 (m, 5H),
7.34–7.47 ppm (m, 5H). 13C NMR (100 MHz, CDCl3): d = 12.1,
20.9, 26.7, 43.8, 49.4, 56.0, 75.6, 127.2, 127.3, 128.0, 128.3, 129.0,
129.5, 133.1, 135.0, 137.3, 138.7, 141.0, 204.1 ppm. HPLC analysis:
Chiralcel AD-H, 2-propanol/hexane (5:95), 1.0 mL/min, UV
254 nm; t(minor) = 10.8 min, t(major) = 13.3 min; 95% ee.
4.1.1.7.
(2S,3S)-2-((R)-1-(3-Chlorophenyl)-2-nitroethyl)-1,3-
1H NMR (400 MHz, CDCl3):
diphenyl-pentan-1-one 4g3o
.
d = 0.57 (t, J = 7.2 Hz, 3H), 1.40–1.52 (m, 2H), 2.92 (td, J = 3.6 Hz,
10.4 Hz, 10.4 Hz, 1H), 3.51–3.55 (m, 1H), 4.08 (dd, J = 4.8 Hz,
J = 10.4 Hz, 1H), 4.90 (dd, J = 3.6 Hz, J = 13.6 Hz, 1H), 4.95–5.00
(m, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 6.97–7.05 (m, 2H),
7.26–7.33 (m, 3H), 7.39 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.2 Hz, 1H),
7.52 ppm (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3): d = 12.1,
27.2, 43.7, 49.4, 55.5, 74.8, 125.2, 127.4, 127.7, 127.8, 127.9,
128.0, 128.5, 129.2, 129.9, 133.4, 134.6, 138.4, 140.2, 140.6,
203.5 ppm. HPLC analysis: Chiralcel AD-H, 2-propanol/hexane
(5:95), 1.0 mL/min, UV 254 nm; t(minor) = 9.1 min, t(major)
[a
]
D
22.6 = ꢀ27.0 (c 1.0, CH2Cl2).
4.1.1.3.
(2S,3S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)-1,3-
1H NMR (400 MHz, CDCl3):
diphenyl-pentan-1-one 4c3o,p
.
= 20.7 min; 94% ee. [
a
]
D
22.9 = ꢀ24.3 (c 1.0, CH2Cl2).
d = 0.56 (t, J = 7.2 Hz, 3H), 1.41–1.52 (m, 2H), 2.90 (td, J = 3.6 Hz,
10.4 Hz, 10.4 Hz, 1H), 3.51–3.56 (m, 1H), 4.07 (dd, J = 4.8 Hz,
J = 10.0 Hz, 1H), 4.89 (dd, J = 4.4 Hz, J = 14 Hz, 1H), 4.92–4.99 (m,
1H), 6.81 (d, J = 8.8 Hz, 2H), 7.21–7.31 (m, 7H), 7.36–7.40 (m,
2H), 7.45–7.51 ppm (m, 3H). 13C NMR (100 MHz, CDCl3): d = 12.1,
27.0, 43.7, 49.5, 55.6, 75.2, 122.5, 127.5, 127.9, 128.1, 128.5,
129.1, 129.2, 131.9, 133.5, 137.2, 138.4, 140.1, 203.6 ppm. HPLC
analysis: Chiralcel AD-H, 2-propanol/hexane (5:95), 1.0 mL/min,
4.1.1.8.
(2S,3S)-2-((R)-1-(3-Bromophenyl)-2-nitroethyl)-1,3-
1H NMR (400 MHz, CDCl3):
diphenyl-pentan-1-one 4h.
d = 0.57 (t, J = 7.2 Hz, 3H), 1.40–1.52 (m, 2H), 2.92 (td, J = 3.6 Hz,
10.4 Hz, 10.4 Hz, 1H), 3.49–3.54 (m, 1H), 4.08 (dd, J = 4.8 Hz,
J = 10.4 Hz, 1H), 4.89 (dd, J = 3.6 Hz, J = 13.6 Hz, 1H), 4.93–4.99
(m, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.93 (t, J = 7.6 Hz, 1H), 7.06 (s,
1H), 7.19 (d, 8.0 Hz, 1H), 7.25–7.33 (m, 5H), 7.39 (d, J = 7.6 Hz,

Y.-M. Hung et al. / Tetrahedron: Asymmetry 26 (2015) 1369–1374
1373
2H), 7.46 (t, J = 7.6 Hz, 1H), 7.52 ppm (d, J = 8.0 Hz, 2H). 13C NMR
(100 MHz, CDCl3): d = 12.1, 27.3, 43.7, 49.4, 55.6, 74.8, 122.8,
125.7, 127.5, 127.9, 128.1, 129.2, 130.3, 130.7, 130.8,
133.5, 138.4, 140.5, 140.6, 203.5 ppm. HRMS (ESI) calcd for
t(minor) = 14.5 min, t(major) = 29.6 min; 96% ee. [
(c 1.0, CH2Cl2).
a
]
22.9 = ꢀ57.0
D
4.1.1.13.
(2S,3S)-2-((R)-2-Nitro-1-phenylethyl)-1-phenyl-3-p-
1H NMR (400 MHz, CDCl3):
C25H24BrNNaO3 [M+Na]: 488.0832, found 488.0835. HPLC analysis:
tolylpentan-1-one 4m3o
.
Chiralcel AD-H, 2-propanol/hexane (5:95), 1.0 mL/min, UV
d = 0.56 (t, J = 7.2 Hz, 3H), 1.37–1.49 (m, 2H), 2.36 (s, 3H), 2.88
(td, J = 3.6 Hz, 10.8 Hz, 10.8 Hz, 1H), 3.55–3.60 (m, 1H), 4.07 (dd,
J = 4.4 Hz, J = 10.4 Hz, 1H), 4.90 (dd, J = 3.6 Hz, J = 13.6 Hz, 1H),
5.01–5.07 (m, 1H), 6.94 (d, 7.6 Hz, 2H), 7.06–7.18 (m, 3H), 7.20–
7.23 (m, 3H), 7.24–7.40 (m, 3H), 7.40–7.45 ppm (m, 3H). 13C
NMR (100 MHz, CDCl3): d = 12.1, 21.1, 27.3, 43.9, 49.1, 56.2, 75.1,
127.3, 127.6, 127.8, 128.1, 128.3, 128.8, 129.8, 133.1, 136.9,
137.7, 138.2, 138.7, 204.2 ppm. HPLC analysis: Chiralcel AD-H,
2-propanol/hexane (5:95), 1.0 mL/min, UV 254 nm; t(minor)
22.9
254 nm; t(minor) = 9.3 min, t(major) = 22.0 min; 96% ee. [
a
]
D
=
ꢀ21.4 (c 1.0, CH2Cl2).
4.1.1.9. (2S,3S)-2-((R)-1-(3-Methoxyphenyl)-2-nitroethyl)-1,3-
diphenyl-pentan-1-one 4i3p 1H NMR (400 MHz, CDCl3):
.
d = 0.57 (t, J = 7.6 Hz, 3H), 1.41–1.55 (m, 2H), 2.93 (td, J = 3.2 Hz,
10.4 Hz, 10.4 Hz, 1H), 3.57 (s, 3H), 4.10 (dd, J1 = 4.8 Hz, J2 = 10 Hz,
1H), 4.89 (dd, J1 = 4.0 Hz, J2 = 13.6 Hz, 1H), 4.95–5.01 (m, 1H),
6.45 (s, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 7.01
(t, J = 8.0 Hz, 1H), 7.23–7.30 (m, 5H), 7.36–7.45 (m, 3H), 7.50 ppm
(d, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3): d = 11.9, 26.6, 43.9,
49.1, 54.6, 55.4, 75.1, 112.7, 112.9, 119.3, 127.0, 127.8, 128.1,
129.6, 132.9, 138.3, 139.5, 140.7, 159.5, 203.6 ppm. HRMS (ESI)
calcd for C26H27NNaO4 [M+Na]: 440.1832, found 440.1839. HPLC
analysis: Chiralcel AD-H, 2-propanol/hexane (5:95), 1.0 mL/min,
UV 254 nm; t(minor) = 12.1 min, t(major) = 23.3 min; 97% ee.
= 9.00 min, t(major) = 14.6 min; 96% ee. [
a]
D
22.9 = ꢀ46.8 (c 1.0,
CH2Cl2).
4.1.1.14.
(2S,3S)-3-(4-Chlorophenyl)-2-((R)-2-nitro-1-phenyl-
1H NMR (400 MHz,
ethyl)-1-phenylpentan-1-one 4n3o,p
.
CDCl3): d = 0.56 (t, J = 7.2 Hz, 3H), 1.36–1.43 (m, 1H), 1.47–1.54
(m, 1H), 2.90 (td, J = 3.2 Hz, 11.6 Hz, 11.6 Hz, 1H), 3.56–3.61 (m,
1H), 4.06 (dd, J = 5.2 Hz, J = 9.6 Hz, 1H), 4.85 (dd, J = 3.6 Hz,
J = 13.6 Hz, 1H), 4.93–4.99 (m, 1H), 6.94–6.96 (m, 2H), 7.11–7.16
(m, 5H), 7.23–7.27 (m, 3H), 7.34 (d, J = 8.4 Hz, 2H), 7.45 ppm (d,
J = 8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3): d = 12.0, 26.6, 44.1,
48.7, 55.7, 75.4, 127.3, 127.7, 128.1, 128.4, 128.9, 129.2, 129.3,
132.9, 133.3, 137.8, 138.4, 139.5, 203.5 ppm. HPLC analysis: Chiral-
cel AD-H, 2-propanol/hexane (5:95), 1.0 mL/min, UV 254 nm; t
[
a]
D
22.8 = ꢀ38.8 (c 1.0, CH2Cl2).
4.1.1.10.
phenylpropyl)pentan-1-one 4j.
(2S,3S)-4-Methyl-3-(nitromethyl)-1-phenyl-2-((S)-1-
1H NMR (400 MHz, CDCl3):
d = 0.56 (t, J = 7.6 Hz, 3H), 0.63 (d, J = 6.8 Hz, 3H), 0.70 (d,
J = 7.2 Hz, 3H), 1.43–1.54 (m, 2H), 2.18–2.24 (m, 1H), 2.85 (td,
J = 4.0 Hz, 10.8 Hz, 10.8 Hz), 4.13 (dd, J = 2.4 Hz, J = 10.4 Hz), 4.48
(dd, J = 10.4 Hz, J = 14.4 Hz), 4.99 (dd, J = 2.4 Hz, J = 14.0 Hz),
7.22–7.30 (m, 2H), 7.35–7.39 (m, 2H), 7.51–7.50 (m, 2H), 7.60–
7.64 (m, 1H), 8.04 ppm (d, J = 7.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3): d = 12.4, 19.3, 19.9, 27.9, 29.7, 44.0, 48.6, 50.4, 75.6,
127.2, 128.2, 128.3, 128.8, 128.9, 133.6, 138.7, 141.3, 204.4 ppm.
HRMS (ESI) calcd for C22H27NNaO3 [M+Na]: 376.1883, found
376.1883. HPLC analysis: Chiralcel AD-H, 2-propanol/hexane
(5:95), 0.5 mL/min, UV 254 nm; t(minor) = 14.1 min, t(major)
(minor) = 12.7 min, t(major) = 27.0 min; 93% ee.
(c 1.0, CH2Cl2).
[a
]
23.0 = ꢀ49.2
D
4.1.1.15.
(2S,3S)-3-(3-Chlorophenyl)-2-((R)-2-nitro-1-phenyl-
ethyl)-1-phenylpentan-1-one 4o3o
.
1H NMR (400 MHz,
CDCl3): d = 0.56 (t, J = 7.2 Hz, 3H), 1.38–1.52 (m, 2H), 2.88 (td,
J = 3.2 Hz, 11.2 Hz, 11.2 Hz, 1H), 3.59–3.64 (m, 1H), 4.07 (dd,
J = 5.2 Hz, J = 9.6 Hz, 1H), 4.83 (dd, J = 3.6 Hz, J = 13.2 Hz, 1H),
4.92–4.98 (m, 1H), 6.95–6.98 (m, 2H), 7.07–7.16 (m, 4H), 7.18
(s, 1H), 7.25–7.30 (m, 4H), 7.42–7.47 ppm (m, 3H). 13C NMR
(100 MHz, CDCl3): d = 12.1, 26.4, 44.2, 49.0, 55.7, 75.6, 126.6,
127.4, 127.7, 127.8, 128.1, 128.9, 130.3, 133.4, 134.9, 137.8,
138.4, 143.2, 203.3 ppm. HPLC analysis: Chiralcel AD-H, 2-propa-
nol/hexane (5:95), 1.0 mL/min, UV 254 nm; t(minor) = 10.6 min,
= 17.0 min; 97% ee. [
a]
25.8 = ꢀ138.7 (c 1.0, CH2Cl2).
D
4.1.1.11.
propyl)hexan-1-one 4k.
(2S,3S)-3-(Nitromethyl)-1-phenyl-2-((S)-1-phenyl-
1H NMR (400 MHz, CDCl3):
d = 0.56–0.62 (m, 6H), 1.05–1.30 (m, 4H), 1.47–1.52 (m, 2H),
2.14–2.19 (m, 1H), 2.90–2.96 (m, 1H), 4.09 (dd, J = 3.2 Hz,
J = 10.8 Hz, 1H), 4.20 (dd, J = 10.0 Hz, J = 12.8 Hz, 1H), 4.77 (dd,
J = 3.2 Hz, J = 13.2 Hz, 1H), 7.22–7.29 (m, 3H), 7.34–7.40 (m, 2H),
7.49–7.54(m, 2H), 7.59–7.64 (m, 1H), 8.01 ppm (d, J = 8.4 Hz, 2H).
13C NMR (100 MHz, CDCl3): d = 12.2, 13.4, 19.8, 28.3, 33.1, 37.6,
48.9, 50.9, 127.2, 128.1, 128.5, 128.9, 133.7, 138.9, 141.1,
204.3 ppm. HRMS (ESI) calcd for C22H27NNaO3 [M+Na]: 376.1883,
found 376.1886. HPLC analysis: Chiralcel AD-H, 2-propanol/hexane
(5:95), 0.5 mL/min, UV 254 nm; t(minor) = 31.1 min, t(major)
t(major) = 26.2 min; 93% ee. [
a
]
D
22.8 = ꢀ28.6 (c 1.0, CH2Cl2).
4.1.1.16.
(2S,3S)-1-(4-Chlorophenyl)-2-((R)-2-nitro-1-phenyl-
1H NMR (400 MHz,
ethyl)-3-phenylpentan-1-one 4p3o,p
.
CDCl3): d = 0.56 (t, J = 7.2 Hz, 3H), 1.36–1.50 (m, 2H), 2.89 (td,
J = 3.6 Hz, 10.4 Hz, 10.4 Hz, 1H), 3.56–3.61 (m, 1H), 4.03 (dd,
J = 4.8 Hz, J = 10.0 Hz, 1H), 4.86 (dd, J = 4.0 Hz, J = 13.6 Hz, 1H),
4.95–5.02 (m, 1H), 6.94 (d, J = 8.0 Hz, 2H), 7.10–7.15 (m, 3H),
7.19–7.23 (m, 4H), 7.28–7.32 (m, 1H), 7.35–7.40 ppm (m, 4H).
13C NMR (100 MHz, CDCl3): d = 12.1, 26.9, 43.9, 49.3, 56.2, 75.0,
127.2, 127.4, 127.9, 128.7, 129.1, 129.5, 136.9, 137.9, 139.8,
140.7, 202.8 ppm. HPLC analysis: Chiralcel AD-H, 2-propanol/hex-
ane (5:95), 1.0 mL/min, UV 254 nm; t(minor) = 12.4 min, t(major)
= 42.8 min; 97% ee. [
a
]
D
26.1 = ꢀ85.4 (c 1.0, CH2Cl2).
4.1.1.12. (2S,3S)-3-(4-Methoxyphenyl)-2-((R)-2-nitro-1-phenyl-
ethyl)-1-phenyl pentan-1-one 4l3o,p 1H NMR (400 MHz,
.
CDCl3): d = 0.56 (t, J = 7.6 Hz, 3H), 1.34–1.40 (m, 1H), 1.44–1.48
(m, 1H), 2.87 (td, J = 3.2 Hz, 10.8 Hz, 10.8 Hz, 1H), 3.57–3.62 (m,
1H), 3.82 (s, 3H), 4.04 (dd, J = 4.8 Hz, J = 10.4 Hz, 1H), 4.90 (dd,
J = 3.6 Hz, J = 13.6 Hz, 1H), 4.99–5.05 (m, 1H), 6.91–6.95 (m, 4H),
7.10, (m, 3H), 7.16 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 15.6, 2H), 7.40–
7.46 ppm (m, 3H). 13C NMR (100 MHz, CDCl3): d = 12.1, 27.2,
44.0, 48.7, 55.2, 56.3, 75.2, 114.4, 127.3, 127.6, 128.1, 128.3,
128.8, 128.9, 132.7, 133.2, 158.6, 204.2 ppm. HPLC analysis: Chiral-
cel AD-H, 2-propanol/hexane (5:95), 1.0 mL/min, UV 254 nm;
= 16.9 min; 95% ee. [
a]
22.8 = ꢀ29.8 (c 1.0, CH2Cl2).
D
4.1.1.17. (2S,3S)-2-((R)-1-(4-Bromophenyl)-2-nitroethyl)-3-(4-
methoxyphenyl)-1-phenylpentan-1-one 4q3o 1H NMR
.
(400 MHz, CDCl3): d = 0.55 (t, J = 7.2 Hz, 3H), 1.35–1.49 (m, 2H),
2.85 (td, J = 3.2 Hz, 10.4 Hz, 10.4 Hz, 1H), 3.53–3.57 (m, 1H), 3.82
(s, 3H), 4.03 (dd, J = 5.6 Hz, J = 10.4 Hz, 1H), 4.89 (dd, J = 4.0 Hz,
J = 13.6 Hz, 1H), 4.93–4.99 (m, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.91
(d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H),

1374
Y.-M. Hung et al. / Tetrahedron: Asymmetry 26 (2015) 1369–1374
7.27–7.30 (m, 2H), 7.45–7.51 ppm (m, 3H). 13C NMR (100 MHz,
CDCl3): d = 12.1, 27.3, 43.7, 48.7, 55.2, 55.9, 75.1, 114.5, 121.5,
128.1, 128.5, 128.8, 129.1, 131.9, 132.5, 133.5, 137.4, 138.4,
158.7, 203.8 ppm. HPLC analysis: Chiralcel AD-H, 2-propanol/
hexane (5:95), 1.0 mL/min, UV 254 nm; t(major) = 15.5 min,
1996, 37, 5141–5144; (d) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de
Vries, A. H. M. Angew. Chem., Int. Ed. 1997, 36, 2620–2623; (e) Keller, E.; Maurer,
J.; Naasz, R.; Schader, T.; Meetsma, A.; Feringa, B. L. Tetrahedron: Asymmetry
1998, 9, 2409–2413; (f) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa, B. L. J.
Org. Chem. 2002, 67, 7244–7254; (g) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller,
E.; Feringa, B. L. J. Am. Chem. Soc. 1999, 121, 1104–1105; (h) Mizutani, H.;
Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 779–781; (i) Alexakis,
A.; March, A. J. Org. Chem. 2002, 67, 8753–8757; (j) Knopff, O.; Alexakis, A. Org.
Lett. 2002, 4, 3835–3837; (k) Rathgeb, X.; March, S.; Alexakis, A. J. Org. Chem.
2006, 71, 5737–5742; (l) Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc.
2004, 126, 4528–4529; (m) Li, K.; Alexakis, A. Chem. Eur. J. 2007, 13, 3765–3771;
(n) Guo, S.; Xie, Y.; Hu, X.; Xia, C.; Huang, H. Angew. Chem., Int. Ed. 2010, 49,
2728–2731; (o) Guo, S.; Xie, Y.; Hu, X.; Huang, H. Org. Lett. 2011, 13, 5596–5599;
(p) Ni, C.-Y.; Kan, S.-S.; Liu, Q.-Z.; Kang, T.-R. Org. Biomol. Chem. 2011, 9, 6211–
6214; (q) Germain, N.; Guénée, L.; Mauduit, M.; Alexakis, A. Org. Lett. 2014, 16,
118–121; (r) Germain, N.; Schlaefli, D.; Chellat, M.; Rosset, S.; Alexakis, A. Org.
Lett. 2014, 16, 2006–2009; (s) Xu, Y.-J.; Liu, Q.-Z.; Dong, L. Synlett 2007, 273–277;
(t) Germain, N.; Alexakis, A. Chem. Eur. J. 2015, 21, 8597–8606.
t(minor) = 16.9 min; 91% ee. [
a]
D
22.9 = ꢀ57.8 (c 1.0, CH2Cl2).
Acknowledgements
We thank the Ministry of Science and Technology (MOST),
Taiwan, for the financial support (NSC102-2113-M007-009-MY3).
References
4. For the control of three contiguous stereocentres in acyclic systems using
asymmetric tandem catalytic reactions see: (a) Howell, G. P.; Fletcher, S. P.;
Geurts, K.; ter Horst, B.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 14977–14985;
(b) Arai, T.; Yokoyama, N. Angew. Chem., Int. Ed. 2008, 47, 4989–4992; (c)
Anderson, J. C.; Stepney, G. J.; Mills, M. R.; Horsfall, L. R.; Blake, A. J.; Lewis, W. J.
Org. Chem. 2011, 76, 1961–1971; (d) Eppe, G.; Didier, D.; Marek, I. Chem. Rev.
2015, 115, 9175–9206.
5. The Nitro Group in Organic Synthesis; Ono, N., Ed.; Wiley-VCH: New York, 2001.
6. (a) Barret, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751–762; (b) Yan, G.;
Borah, A. J.; Wang, L. Org. Biomol. Chem. 2014, 12, 6049–6058; (c) Halimehjani, A.
Z.; Namboothiri, I. N. N.; Hooshmand, S. E. RSC Adv. 2014, 4, 31261–31299; (d)
Halimehjani, A. Z.; Namboothiri, I. N. N.; Hooshmand, S. E. RSC Adv. 2014, 4,
48022–48084.
1. (a) Parsone, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195–206; (b)
Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134–7186; (c) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993–3009;
(d) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem. 2010, 2, 167–178; (e) Volla, C.
M. R.; Atodiresei, I.; Rueping, M. Chem. Rev. 2014, 114, 2390–2431.
2. For selected examples see: (a) Alexakis, A.; Frutos, J.; Mangeney, P. Tetrahedron:
Asymmetry 1993, 4, 2427–2430; (b) de Vries, A. H. M.; Meetsma, A.; Feringa, B. L.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2374–2376; (c) de Vries, A. H. M.; Feringa, B.
L. Tetrahedron: Asymmetry 1997, 8, 1377–1378; (d) Hu, X.; Chen, H.; Zhang, X.
Angew. Chem., Int. Ed. 1999, 38, 3518–3521; (e) Kanai, M.; Tomioka, K.
Tetrahedron Lett. 1995, 36, 4275–4278; (f) Spieler, J.; Huttenloch, O.;
Waldmann, H. Eur. J. Org. Chem. 2000, 3, 391–399; (g) Zhou, H.; Wang, W.-H.;
Fu, Y.; Xie, J.-H.; Shi, W.-J.; Wang, L.-X.; Zhou, Q.-L. J. Org. Chem. 2003, 68, 1582–
1584; (h) Kawamura, K.; Fukuzawa, H.; Hayashi, M. Org. Lett. 2008, 10, 3509–
3512; (i) Endo, K.; Hamada, D.; Yakeishi, S.; Ogawa, M.; Shibata, T. Org. Lett.
2012, 14, 2342–2345; (j) Ye, F.; Zheng, Z.-J.; Deng, W.-H.; Zheng, L.-S.; Deng, Y.;
Xia, C.-G.; Xu, L.-W. Chem. Asian J. 2013, 8, 2242–2253.
7. Wu, Z.-L.; Wu, H.-L.; Wu, P.-Y.; Uang, B.-J. Tetrahedron: Asymmetry 2009, 20,
1556–1560.
8. Tseng, C.-H.; Hung, Y.-M.; Uang, B.-J. Tetrahedron: Asymmetric 2012, 23, 130–
135.
9. CCDC 993020 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www. ccdc.cam.ac.uk/data_request/cif.
3. For selected reviews and articles see: (a) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int.
Ed. 2006, 45, 354–366; (b) Galeštoková, Z.; Šebesta, R. Eur. J. Org. Chem. 2012, 34,
6688–6695; (c) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron Lett.