Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to α,β-unsaturated ketones followed by trapping with nitroolefins

Article abstract of DOI:10.1016/j.tet.2019.06.032

A copper catalyzed asymmetric tandem double Michael addition of diethylzinc to α,β-unsaturated ketones followed by trapping with nitroolefins has been developed using chiral P,N-ligands. The tandem products were obtained in good yields and excellent enantioselectivities with three contiguous stereocenters.

Full text of DOI:10.1016/j.tet.2019.06.032

Tetrahedron xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-catalyzed asymmetric tandem double Michael reactions of
diethylzinc to a,b-unsaturated ketones followed by trapping with
nitroolefins
,
, **
Qiang Wang a, Shuang Li a, Chuan-Jin Hou a *, Ting-Ting Chu a, Xiang-Ping Hu b
a School of Light Industry and Chemical Engineering, Dalian Polytechnic University, Dalian, 116034, China
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper catalyzed asymmetric tandem double Michael addition of diethylzinc to a,b-unsaturated ke-
Received 6 April 2019
Received in revised form
4 June 2019
Accepted 18 June 2019
Available online xxx
tones followed by trapping with nitroolefins has been developed using chiral P,N-ligands. The tandem
products were obtained in good yields and excellent enantioselectivities with three contiguous
stereocenters.
© 2019 Elsevier Ltd. All rights reserved.
Keywords:
Chiral P,N-ligands
Asymmetric tandem reactions
Double Michael reactions
Enolate trapping
Nitroolefins
1. Introduction
workers [4] reported the first asymmetric tandem reaction of
organozinc reagents with 2-cyclohexanone and aldehydes. Since
Asymmetric tandem reactions have been proven efficient for the
preparation of chiral compounds. Compared with the general
stepwise sequences of reactions, asymmetric tandem reactions can
be used to form several bonds and two or more contiguous chiral
centres by using a single catalyst in one pot without a need to
isolate the intermediates. More importantly, tandem reactions can
save time and energy and produce minimal waste. As a result,
considerable efforts have been exerted to develop new asymmetric
tandem reactions [1].
this pioneering work, various electrophiles such as aldehydes [5],
ketones [6], acyl halides [7], epoxides [8], oxocarbenium ions [9],
ally halides or ally acetates [10], nitrosos [11], alkyl halides or
tosylates [12] and bromine or NFSI (N-fluorobenzenesulfonimide)
[13] have been developed for trapping zinc enolate through an
asymmetric tandem process. Despite these achievements, the
scope of substrates in these reactions is generally limited to cyclic
enones, while very few of acyclic
a,b-unsaturated ketones are
adopted. Moreover, few reports are available on application of
a,b-
Over the past few decades, the metal-catalyzed conjugated
addition of organozinc reagents to a,b-unsaturated carbonyl com-
unsaturated systems as electrophiles to trap chiral zinc enolate. In
2010, Huang [14] succeeded in performing the copper-catalyzed
asymmetric conjugate addition of diethylzinc to chalcones, fol-
lowed by enolate trapping with N-tosyl aldimine with chiral
phosphite-pyridine amide ligands (S,S)-L1 (Scheme 1a). Subse-
quently, Huang [15] demonstrated a similar enolate trapping with
nitroolefins using the same ligands (Scheme 1b). In 2011, Liu [16]
described the asymmetric trapping of zinc enolate using nitro-
olefins as electrophiles with phosphoramidites ligands (S)-L2
(Scheme 1b). In 2015, Uang [17] developed a nickel-catalyzed
tandem reaction by the trapping of zinc enolate with nitroolefins
electrophiles using MINBOL L3 as ligand (Scheme 1b). Given the
pounds has been extensively studied [2]. One of the characteristic
features of these reactions is the in situ formation of an interme-
diate zinc enolate. Thus, if an appropriate electrophile is added to
the reaction system, the zinc enolate can then be trapped and the
tandem reaction can be realized [3]. In 1997, Feringa and co-
* Corresponding author.
** Corresponding author.
E-mail addresses: houcj@dlpu.edu.cn (C.-J. Hou), xiangping@dicp.ac.cn
(X.-P. Hu).
https://doi.org/10.1016/j.tet.2019.06.032
0040-4020/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Q. Wang et al., Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.032

2
Q. Wang et al. / Tetrahedron xxx (xxxx) xxx
Scheme 1. Metal-catalyzed asymmetric tandem reactions of the enolate trapping with a,b-unsaturated electrophiles.
importance of the resulting chiral
g
-nitro ketones and related
screen the optimal reaction conditions. The first investigation on
copper salts modified with ligand (R)-L4b showed that the copper
sources significantly affected yield and stereoselectivity (Table 1,
entries 3e8). Among the copper salts tested, CuCl proved to be the
best choice and gave the corresponding product with 77% yield and
88% ee (Table 1, entry 3). Other copper salts, such as CuI,
Cu(OAc)2$H2O, Cu(OTf)2, Cu(OTf)$(C6H6)0.5 and Cu(CH3CN)4BF4,
produced poor results with respect to both yield and stereo-
selectivity (Table 1, entries 4e8). Subsequent solvents screening
indicated that toluene and CH2Cl2 were suitable in terms of reac-
tivity and stereoselectivity (Table 1, entries 9e11). Furthermore, the
temperature also significantly influenced the reactivity and ster-
eoselectivity of the reaction. When the reaction temperature
increased from ꢀ20 ꢁC to 0 ꢁC, an obviously improvement of yield
and enantioselectivity was observed (Table 1, entries 12e13).
However, almost no reaction occurred when the temperature was
lowered to ꢀ40 ꢁC (Table 1, entries 14e15).
compounds, the development of new catalytic system for this
asymmetric tandem reaction is still in high demand. Herein, we
would like to report our investigations on copper-catalyzed
asymmetric tandem double Michael reactions of diethylzinc to
a,b-unsaturated ketones followed by trapping with nitroolefins
using chiral P,N-ligands L4 (Scheme 1c).
2. Result and discussion
In 1999, Zhang [18] reported the synthesis of chiral P,N-ligands
L4 from NOBIN and successfully demonstrated its application in the
copper-catalyzed asymmetric conjugate addition of diethylzinc to
enones. We envisioned that the zinc enolate intermediate gener-
ated in the reaction system can be trapped by
electrophiles such as nitroolefins and subsequently realize the
a,b-unsaturated
asymmetric tandem double Michael reaction. We started our
investigation by using chalcone 1a, Et2Zn and trans-b-nitrostyrene
Having established the optimal reaction conditions of CuCl/(R)-
L4b/toluene/0 ꢁC/12 h, we first explored various chalcones 1 to
evaluate the substrate scope. Scheme 2 summarized the results.
The steric and electronic properties of the aromatic substituent
group in chalcones had little effect on the reactivity and stereo-
selectivity of this transformation. Substrates with different substi-
tution patterns (ortho-, meta- or para-) and different electronic
properties (electron-donating or electron-withdrawing) at the
2a as the reactants, and the reaction was performed at ꢀ20 ꢁC in
toluene for 12 h in the presence of 2 mol% catalyst generated in situ
with CuBr and chiral P,N-ligand (R)-L4a. To our delight, high yield
with excellent diastereoselectivity (>20:1) and good enantiose-
lectivity were observed (Table 1, entry 1). The sterically more hin-
dered chiral P,N-ligand (R)-L4b produced a better result of 86% ee
(Table 1, entry 2). Given this encouraging result, we decided to
Please cite this article as: Q. Wang et al., Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.032

Q. Wang et al. / Tetrahedron xxx (xxxx) xxx
3
Table 1
phenyl group of chalcones were all tolerated under the reaction
conditions, thereby affording the corresponding products with
good yields and excellent enantioselectivities (3a-3h and 3l-3q).
Heteroaromatic aldehydes such as furyl and thienyl aldehyde
derived chalcones were also suitable for this reaction and gener-
ated products with 93% and 95% ee, respectively (3i and 3j). 1-
Naphthyl and 2-naphthyl substrates also proceeded efficiently
with 94% and 91% ee (3k and 3r). It is also worth noting that all of
the corresponding products were determined as a single diaste-
reomer from the 1HNMR spectrum.
Optimized reaction conditions for the tandem double Michael reaction.a
Entry Ligand Copper salt
Solvent Temperature Yield (%)b Ee (%)c
1
2
3
4
5
6
7
8
L4a
L4b
L4b
L4b
L4b
L4b
L4b
L4b
L4b
L4b
L4b
L4b
L4b
L4b
L4b
CuBr
CuBr
CuCl
CuI
toluene ꢀ20 ꢁ
toluene ꢀ20 ꢁ
toluene ꢀ20 ꢁ
toluene ꢀ20 ꢁ
toluene ꢀ20 ꢁ
toluene ꢀ20 ꢁ
toluene ꢀ20 ꢁ
C
C
C
C
C
C
C
C
C
C
C
80
77
77
30
60
<10
20
<10
45
15
75
85
82
<10
<10
75
86
88
53
73
ndd
59
nd
78
64
91
94
92
nd
nd
To further demonstrate the generality of the current tandem
double Michael reaction, we evaluated the substrate scope with
regard to nitroolefins. Scheme 3 summarized the results. A series of
nitroolefins substituted with electron-donating and electron-
withdrawing groups in the phenyl moiety reacted smoothly, and
the corresponding products were obtained with good yields and
excellent enantioselectivities (4a-4f and 4k). The furyl and thienyl
substituted nitroolefins also worked well and generated the prod-
ucts with 93% and 95% ee, respectively (4g and 4h). 1-naphthyl
derived nitroolefin was also a suitable substrate that entailed a
corresponding product with 93% ee (4i). Notably, the aliphatic
nitroolefin 2j is examined and provided the corresponding product
4j with moderate yield and high enantioselectivity. To determine
the absolute configuration of the products, we obtained a single
crystal of compound 4k and the absolute configuration was
confirmed unambiguously to be (2R,3R,10S) through X-ray crystal-
lography19 (Fig. 1).
Cu(OAc)2$H2O
Cu(OTf)2
Cu(CH3CN)4BF4
Cu(OTf)$(C6H6)0.5 toluene ꢀ20 ꢁ
9
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Et2O
THF
ꢀ20 ꢁ
ꢀ20 ꢁ
10
11
12
13
14
15
CH2Cl2 ꢀ20 ꢁ
toluene 0 ꢁ
CH2Cl2 0 ꢁ
toluene ꢀ40 ꢁ
C
C
C
C
CH2Cl2 ꢀ40 ꢁ
a
The reaction was carried out with 1a (0.4 mmol), Et2Zn (0.5 mmol), 2a
(0.5 mmol), [Cu] (0.008 mmol, 2 mol%), (R)-L4 (0.01 mmol, 2.5 mol%) in 3 mL of
solvent for 12 h.
b
Isolated yields.
The ee value was determined by HPLC.
nd ¼ Not determined.
c
d
Scheme 2. Substrate scope of chalcones 1. Reaction conditions: 1 (0.4 mmol), Et2Zn (0.5 mmol), 2a (0.5 mmol), CuCl (0.008 mmol, 2 mol%), (R)-L4b (0.01 mmol, 2.5 mol%), toluene
(3 mL), 0 ꢁC, 12 h. The dr were over 20:1 in all cases.
Please cite this article as: Q. Wang et al., Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.032

4
Q. Wang et al. / Tetrahedron xxx (xxxx) xxx
Scheme 3. Substrate scope of nitroolefins 2. Reaction conditions: 1 (0.4 mmol), Et2Zn (0.5 mmol), 2 (0.5 mmol), CuCl (0.008 mmol, 2 mol%), (R)-L4b (0.01 mmol, 2.5 mol%), toluene
(3 mL), 0 ꢁC, 12 h. The dr were over 20:1 in all cases.
4. Experimental section
4.1. General method
All reactions were carried out under N2 atmosphere. Solvents
were purified by standard procedure. Commercial reagents were
used without further purification. The chiral P,N-ligands [18] and
substares of chalcones [15] and nitroolefins [15] were prepared
according to the reported procedure. 1HNMR spectra were recorded
Fig. 1. X-ray crystallography of compound 4k.
on a Bruker 400 MHz spectrometer. Chemical shifts are expressed
in
d value (ppm) using tetramethylsilane (TMS) as an internal
standard. HPLC analysis was performed on an Agilent 1260 series
instrument with a chiralpak AS-H, chiralcel OD-H, chiralcel AD-H or
chiralcel OJ-H column.
4.2. General procedure for asymmetric tandem double Michael
reactions
Scheme 4. Gram-scale experiment.
The chiral P,N-ligand (R)-L4b (5.70 mg, 0.01 mmol), CuCl
(0.80 mg, 0.008 mmol) and dry toluene (1 mL) was added to a
Schlenk tube under nitrogen. After stirring for 1 h at room tem-
perature, a solution of the chalcone substrate 1 (0.4 mmol) in 1 mL
of toluene was added. The reaction mixture was stirred at room
temperature for 10 min and then cooled to 0 ꢁC. Et2Zn (1.0 M in
hexane, 0.5 mL, 0.5 mmol, 1.25 eq) was added slowly. After the
To further demonstrate the practicality of the current method-
ology, the scale-up experiment was carried out at the gram scale. To
our delight, the desired product was obtained with 77% yield and
92% ee without noticeable loss of activity and enantioselectivity
(Scheme 4).
mixture was stirred for 2 h at 0 ꢁC, nitroolefin substrate
2
3. Conclusion
(0.5 mmol, 1.25 eq) was added and the resulting mixture was
further stirred for 12 h at 0 ꢁC. The solution was diluted with diethyl
ether and washed successively with 1 N HCl and brine. The organic
layer was dried over anhydrous Na2SO4. The solvent was removed
to give the crude product which was purified by flash column
chromatography to give the corresponding product. The dr values
were determined by 1HNMR spectroscopy as more than 20:1 and
the enantiomeric excesses were determined by HPLC on a Chiralcel
column.
In conclusion, we developed a copper-catalyzed asymmetric
tandem double Michael reaction of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins using chiral P,N-li-
gands. In this reaction, a wide range of chalcones substrates, as well
as nitroolefins, can be tolerable, thereby affording the corre-
sponding tandem products with three contiguous stereocenters
with good yields and high enantioselectivities.
Please cite this article as: Q. Wang et al., Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.032

Q. Wang et al. / Tetrahedron xxx (xxxx) xxx
5
4.2.1. (2R,3R)-2-((S)-2-nitro-1-phenylethyl)-1,3-diphenylpentan-1-
4.2.6. (2R,3R)-3-(4-bromophenyl)-2-((S)-2-nitro-1-phenylethyl)-1-
one (3a). [15e17]
phenylpentan-1-one (3f). [15,16]
The title compound was prepared according to the General
Procedure in 85% yield and 94% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.5 min, t (minor) ¼ 7.6 min]. 1H NMR
The title compound was prepared according to the General
Procedure in 78% yield and 93% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 7.7 min, t (minor) ¼ 9.9 min]. 1H NMR
(400 MHz, CDCl3)
d
7.47 (d, J ¼ 7.5 Hz, 2H), 7.43e7.33 (m, 3H),
(400 MHz, CDCl3) d 7.55e7.45 (m, 5H), 7.31e7.27 (m, 2H), 7.18e7.11
7.32e7.18 (m, 5H), 7.13e7.02 (m, 3H), 7.01e6.92 (m, 2H), 5.08e4.99
(m, 1H), 4.93 (dd, J ¼ 13.6, 3.6 Hz, 1H), 4.13 (dd, J ¼ 9.9, 4.8 Hz, 1H),
3.63 (dt, J ¼ 11.3, 4.0 Hz, 1H), 2.94 (td, J ¼ 10.6, 3.3 Hz, 1H), 1.58e1.38
(m, 2H), 0.57 (t, J ¼ 7.2 Hz, 3H).
(m, 5H), 7.01e6.96 (m, 2H), 5.00 (dd, J ¼ 13.4, 11.4 Hz, 1H), 4.88 (dd,
J ¼ 13.5, 3.7 Hz, 1H), 4.10 (dd, J ¼ 9.8, 5.1 Hz, 1H), 3.63 (dt, J ¼ 11.6,
4.0 Hz, 1H), 2.92 (td, J ¼ 11.0, 3.3 Hz, 1H), 1.57e1.51 (m, 1H),
1.46e1.36 (m, 1H), 0.59 (t, J ¼ 7.3 Hz, 3H).
4.2.7. (2R,3R)-2-((S)-2-nitro-1-phenylethyl)-1-phenyl-3-(p-tolyl)
pentan-1-one (3g). [15,17]
4.2.2. (2R,3R)-3-(2-chlorophenyl)-2-((S)-2-nitro-1-phenylethyl)-1-
phenylpentan-1-one (3b)
The title compound was prepared according to the General
Procedure in 82% yield and 94% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 99/1, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.5 min, t (minor) ¼ 7.3 min]. 1H NMR
The title compound was prepared according to the General
Procedure in 72% yield and 91% ee [Determined by HPLC with a
Chiralcel AD-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 8.4 min, t (minor) ¼ 9.3 min]. 1H NMR
(400 MHz, CDCl3) d 7.51e7.43 (m, 3H), 7.30e7.28 (m, 2H), 7.24e7.21
(400 MHz, CDCl3) d 7.54e7.42 (m, 4H), 7.28e7.24 (m, 3H), 7.23e7.15
(m, 2H), 7.19e7.09 (m, 5H), 7.00e6.95 (m, 2H), 5.07 (dd, J ¼ 13.6,
11.7 Hz, 1H), 4.95 (dd, J ¼ 13.6, 3.7 Hz, 1H), 4.12 (dd, J ¼ 10.3, 4.6 Hz,
1H), 3.62 (dt, J ¼ 11.6, 4.0 Hz, 1H), 2.92 (td, J ¼ 10.7, 3.5 Hz, 1H), 2.40
(s, 3H), 1.54e1.37 (m, 2H), 0.60 (t, J ¼ 7.3 Hz, 3H).
(m, 4H), 7.11e7.04 (m, 3H), 4.98 (d, J ¼ 7.6 Hz, 2H), 4.20 (dd, J ¼ 9.3,
5.8 Hz, 1H), 3.73 (dd, J ¼ 13.5, 7.5 Hz, 1H), 3.69e3.62 (m, 1H),
1.74e1.63 (m, 1H), 1.56e1.45 (m, 1H), 0.61 (t, J ¼ 7.3 Hz, 3H). 13C
NMR (100 MHz, CDCl3)
d 203.2, 138.7, 138.6, 137.7, 135.4, 133.3,
130.1, 128.9, 128.4, 128.3, 128.1, 127.9, 127.6, 127.5, 76.3, 54.6, 44.4,
43.8, 26.0, 11.4. HRMS cacld for C25H28ClN2O3 [M þ NH4]þ:
439.1783, found: 439.1779.
4.2.8. (2R,3R)-3-(4-methoxyphenyl)-2-((S)-2-nitro-1-phenylethyl)-
1-phenylpentan-1-one (3h). [15e17]
The title compound was prepared according to the General
Procedure in 82% yield and 96% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 95/5, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 9.5 min, t (minor) ¼ 11.3 min]. 1H NMR
4.2.3. (2R,3R)-3-(3-chlorophenyl)-2-((S)-2-nitro-1-phenylethyl)-1-
phenylpentan-1-one (3c). [15,17]
The title compound was prepared according to the General
Procedure in 76% yield and 90% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 98/2, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 15.0 min, t (minor) ¼ 18.1 min]. 1H NMR
(400 MHz, CDCl3) d 7.51e7.43 (m, 3H), 7.31e7.28 (m, 2H), 7.22e7.17
(m, 2H), 7.16e7.09 (m, 3H), 7.01e6.93 (m, 4H), 5.05 (dd, J ¼ 13.5,
11.6 Hz, 1H), 4.94 (dd, J ¼ 13.6, 3.7 Hz, 1H), 4.09 (dd, J ¼ 10.1, 4.7 Hz,
1H), 3.86 (s, 3H), 3.64 (dt, J ¼ 11.4, 4.1 Hz, 1H), 2.90 (td, J ¼ 10.8,
3.4 Hz, 1H), 1.55e1.49 (m, 1H), 1.44e1.36 (m, 1H), 0.60 (t, J ¼ 7.2 Hz,
3H).
(400 MHz, CDCl3) d 7.53e7.45 (m, 3H), 7.33e7.28 (m, 4H), 7.23e7.11
(m, 5H), 7.04e6.98 (m, 2H), 4.99 (dd, J ¼ 13.4, 11.3 Hz, 1H), 4.87 (dd,
J ¼ 13.4, 3.7 Hz, 1H), 4.11 (dd, J ¼ 9.6, 5.3 Hz, 1H), 3.71e3.61 (m, 1H),
2.92 (td, J ¼ 11.2, 3.3 Hz, 1H), 1.57e1.55 (m, 1H), 1.48e1.40 (m, 1H),
0.60 (t, J ¼ 7.3 Hz, 3H).
4.2.9. (2R,3R)-3-(furan-2y-l)-2-((S)-2-nitro-1-phenylethyl)-1-
phenylpentan-1-one (3i)
The title compound was prepared according to the General
Procedure in 72% yield and 93% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.8 min, t (minor) ¼ 8.0 min]. 1H NMR
4.2.4. (2R,3R)-3-(3-methoxyphenyl)-2-((S)-2-nitro-1-phenylethyl)-
1-phenylpentan-1-one (3d). [16]
The title compound was prepared according to the General
Procedure in 72% yield and 97% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 7.5 min, t (minor) ¼ 10.8 min]. 1H NMR
(400 MHz, CDCl3) d 7.56e7.50 (m, 2H), 7.49e7.42 (m, 2H), 7.31e7.29
(m, 1H), 7.28e7.26 (m, 1H), 7.22e7.12 (m, 3H), 7.10e7.03 (m, 2H),
6.35 (dd, J ¼ 3.2,1.9 Hz,1H), 6.18 (d, J ¼ 3.1 Hz,1H), 4.98 (dd, J ¼ 13.4,
11.1 Hz, 1H), 4.90 (dd, J ¼ 13.4, 4.0 Hz, 1H), 4.24 (dd, J ¼ 9.3, 5.6 Hz,
1H), 3.69e3.59 (m, 1H), 3.07 (td, J ¼ 10.1, 4.1 Hz, 1H), 1.55e1.43 (m,
(400 MHz, CDCl3) d 7.52e7.44 (m, 3H), 7.37e7.31 (m, 2H), 7.28e7.25
(m, 1H), 7.18e7.11 (m, 3H), 7.02e6.97 (m, 2H), 6.87 (dd, J ¼ 7.9,
2.0 Hz, 2H), 6.84e6.79 (m, 1H), 5.05 (dd, J ¼ 13.5, 11.5 Hz, 1H), 4.96
(dd, J ¼ 13.6, 3.8 Hz, 1H), 4.12 (dd, J ¼ 10.0, 4.8 Hz, 1H), 3.85 (s, 3H),
3.67 (dt, J ¼ 11.6, 4.0 Hz, 1H), 2.93 (td, J ¼ 10.6, 3.5 Hz, 1H), 1.55e1.39
(m, 2H), 0.62 (t, J ¼ 7.3 Hz, 3H).
2H), 0.69 (t, J ¼ 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 203.0, 154.1,
141.9,138.3,137.8,133.3,128.9,128.6,128.4,128.1,127.8, 127.6, 110.4,
108.2, 75.8, 53.8, 44.4, 42.6, 24.6, 12.2. HRMS cacld for C23H24NO4
[MþH]þ: 378.1700, found: 378.1694.
4.2.10. (2S,3R)-2-((S)-2-nitro-1-phenylethyl)-1-phenyl-3-
(thiophen-2-yl)pentan-1-one (3j)
4.2.5. (2R,3R)-3-(4-chlorophenyl)-2-((S)-2-nitro-1-phenylethyl)-1-
phenylpentan-1-one (3e). [15e17]
The title compound was prepared according to the General
Procedure in 85% yield and 95% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 7.4 min, t (minor) ¼ 8.6 min]. 1H NMR
The title compound was prepared according to the General
Procedure in 88% yield and 96% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 98/2, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 15.3 min, t (minor) ¼ 18.9 min]. 1H NMR
(400 MHz, CDCl3)
d
7.52e7.44 (m, 3H), 7.34 (d, J ¼ 5.1 Hz, 1H),
(400 MHz, CDCl3)
d
7.51e7.45 (m, 3H), 7.40e7.36 (m, 2H), 7.33e7.28
7.31e7.29 (m, 1H), 7.28e7.26 (m, 1H), 7.18e7.09 (m, 3H), 7.06e6.97
(m, 4H), 5.05 (dd, J ¼ 13.6,11.4 Hz,1H), 4.98 (dd, J ¼ 13.6, 3.9 Hz,1H),
4.06 (dd, J ¼ 10.1, 4.6 Hz, 1H), 3.75 (dt, J ¼ 11.3, 4.2 Hz, 1H), 3.32 (td,
J ¼ 10.6, 3.2 Hz, 1H), 1.61e1.56 (m, 1H), 1.46e1.38 (m, 1H), 0.71 (t,
(m, 2H), 7.21e7.13 (m, 5H), 7.01e6.96 (m, 2H), 5.00 (dd, J ¼ 13.4,
11.4 Hz, 1H), 4.89 (dd, J ¼ 13.5, 3.7 Hz, 1H), 4.10 (dd, J ¼ 9.8, 5.0 Hz,
1H), 3.63 (dt, J ¼ 11.6, 4.0 Hz, 1H), 2.94 (td, J ¼ 11.1, 3.3 Hz, 1H),
1.58e1.55 (m, 1H), 1.46e1.37 (m, 1H), 0.59 (t, J ¼ 7.3 Hz, 3H).
J ¼ 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
d 203.5, 144.9, 138.5,
Please cite this article as: Q. Wang et al., Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.032

6
Q. Wang et al. / Tetrahedron xxx (xxxx) xxx
138.0, 133.4, 128.9, 128.5, 128.2, 127.7, 127.4, 127.1, 126.4, 124.6, 75.1,
57.4, 45.0, 44.1, 28.9, 12.2. HRMS cacld for C23H24NO3S [MþH]þ:
394.1471, found: 394.1468.
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.9 min, t (minor) ¼ 9.7 min]. 1H NMR
(400 MHz, CDCl3) d 7.45e7.39 (m, 4H), 7.36e7.30 (m, 3H), 7.28e7.24
(m, 2H), 7.19e7.13 (m, 3H), 7.01e6.96 (m, 2H), 5.02 (dd, J ¼ 13.5,
11.4 Hz, 1H), 4.91 (dd, J ¼ 13.6, 3.7 Hz, 1H), 4.07 (dd, J ¼ 10.0, 4.9 Hz,
1H), 3.63 (dt, J ¼ 11.4, 4.2 Hz, 1H), 2.94 (td, J ¼ 10.4, 3.7 Hz, 1H),
1.54e1.42 (m, 2H), 0.61 (t, J ¼ 7.3 Hz, 3H).
4.2.11. (2R,3R)-3-(naphthalen-1-yl)-2-((S)-2-nitro-1-phenylethyl)-
1-phenylpentan-1-one (3k). [16]
The title compound was prepared according to the General
Procedure in 80% yield and 94% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.9 min, t (minor) ¼ 8.7 min]. 1H NMR
4.2.16. (2R,3R)-2-((S)-2-nitro-1-phenylethyl)-3-phenyl-1-(p-tolyl)
pentan-1-one (3p)
(400 MHz, CDCl3)
d
7.93e7.86 (m, 2H), 7.72 (d, J ¼ 7.8 Hz, 1H),
The title compound was prepared according to the General
Procedure in 75% yield and 95% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.1 min, t (minor) ¼ 7.1 min]. 1H NMR
7.56e7.52 (m, 2H), 7.43e7.39 (m, 1H), 7.36e7.29 (m, 6H), 7.28e7.25
(m, 1H), 7.23e7.15 (m, 4H), 4.84 (dd, J ¼ 13.2, 11.4 Hz, 1H), 4.67 (dd,
J ¼ 13.3, 3.9 Hz, 1H), 4.27 (t, J ¼ 7.4 Hz, 1H), 3.93 (ddd, J ¼ 11.2, 7.2,
3.9 Hz, 1H), 3.80 (ddd, J ¼ 10.9, 7.5, 3.2 Hz, 1H), 2.02e1.93 (m, 1H),
1.84e1.75 (m, 1H), 0.62 (t, J ¼ 7.3 Hz, 3H).
(400 MHz, CDCl3) d 7.45e7.38 (m, 4H), 7.36e7.23 (m, 4H), 7.14e7.11
(m, 2H), 7.08 (d, J ¼ 8.0 Hz, 2H), 7.01e6.95 (m, 2H), 5.05 (dd, J ¼ 13.5,
11.6 Hz, 1H), 4.94 (dd, J ¼ 13.6, 3.7 Hz, 1H), 4.11 (dd, J ¼ 10.1, 4.7 Hz,
1H), 3.61 (dt, J ¼ 11.5, 4.1 Hz, 1H), 2.95 (td, J ¼ 10.6, 3.5 Hz, 1H), 2.35
(s, 3H), 1.57e1.39 (m, 2H), 0.60 (t, J ¼ 7.3 Hz, 3H). 13C NMR
4.2.12. (2R,3R)-2-((S)-2-nitro-1-phenylethyl)-3-phenyl-1-(m-tolyl)
pentan-1-one (3l)
The title compound was prepared according to the General
Procedure in 80% yield and 96% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 5.5 min, t (minor) ¼ 6.7 min]. 1H NMR
(100 MHz, CDCl3) d 203.5, 144.2, 141.1, 138.4, 136.4, 129.2, 129.1,
128.8,128.3,128.1,127.6,127.4,127.3, 75.4, 56.0, 49.6, 44.2, 27.1, 21.6,
12.2. HRMS cacld for
402.2058.
C
26H28NO3 [MþH]þ: 402.2064, found:
(400 MHz, CDCl3) d 7.44e7.39 (m, 2H), 7.35e7.31 (m, 1H), 7.28e7.21
(m, 5H), 7.20e7.12 (m, 4H), 7.02e6.97 (m, 2H), 5.02 (dd, J ¼ 13.5,
11.5 Hz, 1H), 4.92 (dd, J ¼ 13.6, 3.8 Hz, 1H), 4.11 (dd, J ¼ 9.9, 4.9 Hz,
1H), 3.64 (dt, J ¼ 11.5, 4.2 Hz, 1H), 2.95 (td, J ¼ 10.7, 3.5 Hz, 1H), 2.28
(s, 3H),1.55e1.41 (m, 2H), 0.61 (t, J ¼ 7.3 Hz, 3H). 13C NMR (100 MHz,
4.2.17. (2R,3R)-1-(4-methoxyphenyl)-2-((S)-2-nitro-1-
phenylethyl)-3-phenylpentan-1-one (3q). [16]
The title compound was prepared according to the General
Procedure in 70% yield and 95% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 8.4 min, t (minor) ¼ 10.8 min]. 1H NMR
CDCl3)
d 204.0, 141.1, 138.8, 138.3, 138.2, 134.0, 129.1, 128.8, 128.7,
128.2, 128.1, 127.6, 127.4, 127.3, 125.4, 75.3, 56.3, 49.5, 44.2, 26.9,
21.2, 12.2. HRMS cacld for C26H31N2O3 [M þ NH4]þ: 419.2329,
found: 419.2323.
(400 MHz, CDCl3)
d
7.50 (d, J ¼ 8.9 Hz, 2H), 7.46e7.30 (m, 5H),
7.17e7.10 (m, 3H), 7.00e6.95 (m, 2H), 6.75 (d, J ¼ 9.0 Hz, 2H), 5.03
(dd, J ¼ 13.5, 11.5 Hz, 1H), 4.93 (dd, J ¼ 13.6, 3.8 Hz, 1H), 4.07 (dd,
J ¼ 10.0, 4.7 Hz, 1H), 3.83 (s, 3H), 3.61 (dt, J ¼ 11.4, 4.1 Hz, 1H), 2.95
(td, J ¼ 10.7, 3.4 Hz, 1H), 1.57e1.43 (m, 2H), 0.60 (t, J ¼ 7.3 Hz, 3H).
4.2.13. (2R,3R)-1-(3-methoxyphenyl)-2-((S)-2-nitro-1-
phenylethyl)-3-phenylpentan-1-one (3m)
The title compound was prepared according to the General
Procedure in 72% yield and 90% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 7.7 min, t (minor) ¼ 8.9 min]. 1H NMR
4.2.18. (2R,3R)-1-(naphthalen-2-yl)-2-((S)-2-nitro-1-phenylethyl)-
3-phenylpentan-1-one (3r)
The title compound was prepared according to the General
Procedure in 80% yield and 91% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 7.1 min, t (minor) ¼ 8.6 min]. 1H NMR
(400 MHz, CDCl3) d 7.45e7.41 (m, 2H), 7.37e7.31 (m, 1H), 7.28e7.25
(m, 2H), 7.19e7.12 (m, 4H), 7.09e7.07 (m, 1H), 7.04e6.97 (m, 4H),
5.05 (dd, J ¼ 13.5, 11.6 Hz, 1H), 4.94 (dd, J ¼ 13.6, 3.7 Hz, 1H), 4.11
(dd, J ¼ 10.0, 4.8 Hz, 1H), 3.78 (s, 3H), 3.63 (dt, J ¼ 11.5, 4.1 Hz, 1H),
2.95 (td, J ¼ 10.6, 3.5 Hz, 1H), 1.56e1.41 (m, 2H), 0.61 (t, J ¼ 7.3 Hz,
(400 MHz, CDCl3)
d
7.82 (d, J ¼ 8.1 Hz, 1H), 7.79e7.68 (m, 4H),
7.62e7.56 (m, 1H), 7.53e7.48 (m, 1H), 7.47e7.41 (m, 2H), 7.36e7.30
(m, 3H), 7.17e7.12 (m, 2H), 7.11e7.02 (m, 3H), 5.09 (dd, J ¼ 13.5,
11.5 Hz, 1H), 4.99 (dd, J ¼ 13.6, 3.8 Hz, 1H), 4.27 (dd, J ¼ 10.0, 4.8 Hz,
1H), 3.71 (dt, J ¼ 11.4, 4.2 Hz, 1H), 3.02 (td, J ¼ 10.7, 3.4 Hz, 1H),
1.64e1.55 (m, 1H), 1.53e1.45 (m, 1H), 0.62 (t, J ¼ 7.3 Hz, 3H). 13C
3H). 13C NMR (100 MHz, CDCl3)
d 203.8, 159.6, 141.0, 140.1, 138.3,
129.4, 129.2, 128.9, 128.0, 127.7, 127.4, 127.3, 121.0, 120.0, 112.2, 75.3,
56.4, 55.4, 49.6, 44.2, 27.0,12.2. HRMS cacld for C26H28NO4 [MþH]þ:
418.2013, found: 418.2007.
NMR (100 MHz, CDCl3)
d 203.7, 141.1, 138.5, 136.2, 135.5, 132.2,
4.2.14. (2R,3R)-1-(4-chlorophenyl)-2-((S)-2-nitro-1-phenylethyl)-
3-phenylpentan-1-one (3n). [15e17]
130.5, 129.8, 129.1, 128.9, 128.7, 128.3, 128.1, 127.7, 127.6, 127.5, 127.4,
126.7, 123.5, 75.3, 56.6, 49.6, 44.3, 27.0, 12.2. HRMS cacld for
The title compound was prepared according to the General
Procedure in 88% yield and 94% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.7 min, t (minor) ¼ 9.8 min]. 1H NMR
C
29H28NO3 [MþH]þ: 438.2064, found: 438.2061.
4.2.19. (2R,3R)-2-((S)-1-(3-chlorophenyl)-2-nitroethyl)-1,3-
diphenylpentan-1-one (4a). [15e17]
(400 MHz, CDCl3)
d
7.46e7.38 (m, 4H), 7.36e7.31 (m, 1H), 7.28e7.22
The title compound was prepared according to the General
Procedure in 78% yield and 93% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.5 min, t (minor) ¼ 7.7 min]. 1H NMR
(m, 4H), 7.20e7.11 (m, 3H), 7.01e6.95 (m, 2H), 5.02 (dd, J ¼ 13.5,
11.5 Hz, 1H), 4.91 (dd, J ¼ 13.6, 3.7 Hz, 1H), 4.07 (dd, J ¼ 10.0, 4.9 Hz,
1H), 3.63 (dt, J ¼ 11.5, 4.1 Hz, 1H), 2.94 (td, J ¼ 10.5, 3.7 Hz, 1H),
1.54e1.40 (m, 2H), 0.60 (t, J ¼ 7.3 Hz, 3H).
(400 MHz, CDCl3) d 7.59e7.54 (m, 2H), 7.53e7.48 (m, 1H), 7.47e7.41
(m, 2H), 7.37e7.28 (m, 5H), 7.11e7.01 (m, 2H), 6.98e6.94 (m, 1H),
6.88e6.82 (m, 1H), 5.01 (dd, J ¼ 13.8, 11.3 Hz, 1H), 4.94 (dd, J ¼ 13.8,
4.0 Hz, 1H), 4.13 (dd, J ¼ 10.2, 4.7 Hz, 1H), 3.58 (dt, J ¼ 11.2, 4.2 Hz,
1H), 2.96 (td, J ¼ 10.5, 3.8 Hz, 1H), 1.56e1.44 (m, 2H), 0.62 (t,
J ¼ 7.3 Hz, 3H).
4.2.15. (2R,3R)-1-(4-bromophenyl)-2-((S)-2-nitro-1-phenylethyl)-
3-phenylpentan-1-one (3o). [15]
The title compound was prepared according to the General
Procedure in 85% yield and 90% ee [Determined by HPLC with a
Please cite this article as: Q. Wang et al., Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.032

Q. Wang et al. / Tetrahedron xxx (xxxx) xxx
7
4.2.20. (2R,3R)-2-((S)-1-(3-methoxyphenyl)-2-nitroethyl)-1,3-
4.2.25. (2R,3R)-2-((R)-1-(furan-2-yl)-2-nitroethyl)-1,3-
diphenylpentan-1-one (4b). [16,17]
diphenylpentan-1-one (4g). [15,16]
The title compound was prepared according to the General
Procedure in 72% yield and 94% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 8.1 min, t (minor) ¼ 9.3 min]. 1H NMR
The title compound was prepared according to the General
Procedure in 82% yield and 93% ee [Determined by HPLC with a
Chiralcel AD-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 8.0 min, t (minor) ¼ 11.7 min]. 1H NMR
(400 MHz, CDCl3)
d
7.57e7.52 (m, 2H), 7.51e7.45 (m, 1H), 7.44e7.39
(400 MHz, CDCl3)
d
7.75e7.64 (m, 2H), 7.53 (t, J ¼ 7.4 Hz, 1H),
(m, 2H), 7.36e7.28 (m, 4H), 7.27e7.25 (m, 1H), 7.06 (t, J ¼ 7.9 Hz,
1H), 6.68e6.62 (m, 1H), 6.57 (d, J ¼ 7.7 Hz, 1H), 6.51e6.46 (m, 1H),
5.01 (dd, J ¼ 13.6, 11.3 Hz, 1H), 4.93 (dd, J ¼ 13.6, 3.9 Hz, 1H), 4.15
(dd, J ¼ 10.1, 4.7 Hz, 1H), 3.62 (s, 3H), 3.62e3.56 (m, 1H), 2.97 (td,
J ¼ 10.6, 3.5 Hz, 1H), 1.58e1.43 (m, 2H), 0.61 (t, J ¼ 7.3 Hz, 3H).
7.44e7.36 (m, 4H), 7.35e7.29 (m, 2H), 7.28e7.26 (m, 1H), 7.15e7.11
(m, 1H), 6.08 (dd, J ¼ 3.2, 1.9 Hz, 1H), 5.95 (d, J ¼ 3.3 Hz, 1H), 4.89
(dd, J ¼ 13.6, 3.9 Hz, 1H), 4.83 (dd, J ¼ 13.6, 10.7 Hz, 1H), 4.36 (dd,
J ¼ 10.2, 4.8 Hz, 1H), 3.72 (dt, J ¼ 10.5, 4.3 Hz, 1H), 2.96 (td, J ¼ 10.3,
4.0 Hz, 1H), 1.57e1.44 (m, 2H), 0.63 (t, J ¼ 7.3 Hz, 3H).
4.2.26. (2R,3R)-2-((R)-2-nitro-1-(thiophen-2-yl)ethyl)-1,3-
diphenylpentan-1-one (4h). [16]
4.2.21. (2R,3R)-2-((S)-1-(4-chlorophenyl)-2-nitroethyl)-1,3-
diphenylpentan-1-one (4c). [15e17]
The title compound was prepared according to the General
Procedure in 76% yield and 95% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 7.3 min, t (minor) ¼ 8.3 min]. 1H NMR
The title compound was prepared according to the General
Procedure in 80% yield and 95% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.6 min, t (minor) ¼ 9.5 min]. 1H NMR
(400 MHz, CDCl3)
d
7.75e7.64 (m, 2H), 7.53 (t, J ¼ 7.4 Hz, 1H),
(400 MHz, CDCl3)
d
7.57e7.49 (m, 3H), 7.43 (t, J ¼ 7.4 Hz, 2H),
7.44e7.36 (m, 4H), 7.315e7.29 (m, 2H), 7.28e7.26 (m, 1H), 7.15e7.11
(m, 1H), 6.08 (dd, J ¼ 3.2, 1.9 Hz, 1H), 5.95 (d, J ¼ 3.3 Hz, 1H), 4.89
(dd, J ¼ 13.6, 3.9 Hz, 1H), 4.83 (dd, J ¼ 13.6, 10.7 Hz, 1H), 4.36 (dd,
J ¼ 10.2, 4.8 Hz, 1H), 3.72 (dt, J ¼ 10.5, 4.3 Hz, 1H), 2.96 (td, J ¼ 10.3,
4.0 Hz, 1H), 1.57e1.44 (m, 2H), 0.63 (t, J ¼ 7.3 Hz, 3H). 13C NMR
7.37e7.28 (m, 4H), 7.27e7.25 (m, 1H), 7.13e7.09 (m, 2H), 6.92 (d,
J ¼ 8.5 Hz, 2H), 5.00 (dd, J ¼ 13.6, 11.2 Hz, 1H), 4.94 (dd, J ¼ 13.6,
4.1 Hz, 1H), 4.12 (dd, J ¼ 10.1, 4.8 Hz, 1H), 3.60 (dt, J ¼ 11.1, 4.3 Hz,
1H), 2.94 (td, J ¼ 10.5, 3.7 Hz, 1H), 1.57e1.41 (m, 2H), 0.61 (t,
J ¼ 7.3 Hz, 3H).
(100 MHz, CDCl3)
d 203.7, 141.2, 140.6, 138.7, 133.4, 129.2, 128.5,
128.1, 128.0, 127.5, 127.0, 125.4, 124.5, 76.6, 56.5, 49.4, 39.5, 26.9,
4.2.22. (2R,3R)-2-((S)-1-(4-bromophenyl)-2-nitroethyl)-1,3-
diphenylpentan-1-one (4d). [15e17]
12.2. HRMS cacld for
394.1467.
C
23H24NO3S [MþH]þ: 394.1471, found:
The title compound was prepared according to the General
Procedure in 82% yield and 93% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 98/2, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 14.2 min, t (minor) ¼ 20.1 min]. 1H NMR
4.2.27. (2R,3R)-2-((S)-1-(naphthalen-1-yl)-2-nitroethyl)-1,3-
diphenylpentan-1-one (4i). [15,16]
The title compound was prepared according to the General
Procedure in 65% yield and 93% ee [Determined by HPLC with a
Chiralcel AD-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
(400 MHz, CDCl3)
d
7.56e7.49 (m, 3H), 7.42 (t, J ¼ 7.4 Hz, 2H),
7.36e7.31 (m, 3H), 7.27e7.25 (m, 3H), 7.15e7.04 (m, 1H), 6.85 (d,
J ¼ 8.4 Hz, 2H), 4.99 (dd, J ¼ 13.6, 11.1 Hz, 1H), 4.93 (dd, J ¼ 13.7,
4.1 Hz, 1H), 4.12 (dd, J ¼ 10.1, 4.8 Hz, 1H), 3.59 (dt, J ¼ 11.0, 4.4 Hz,
1H), 2.94 (td, J ¼ 10.5, 3.7 Hz, 1H), 1.56e1.44 (m, 2H), 0.61 (t,
J ¼ 7.3 Hz, 3H).
1
254 nm, 40 ꢁC; t (major) ¼ 8.7 min, t (minor) ¼ 15.2 min]. H NMR
(400 MHz, CDCl3) d 7.86e7.78 (m, 1H), 7.63e7.56 (m, 3H), 7.53e7.45
(m, 6H), 7.36 (t, J ¼ 7.3 Hz, 1H), 7.20 (d, J ¼ 7.4 Hz, 2H), 7.11 (t,
J ¼ 7.8 Hz, 2H), 7.06e6.99 (m, 2H), 5.39 (dd, J ¼ 13.8, 11.8 Hz, 1H),
5.25 (dd, J ¼ 14.0, 3.6 Hz, 1H), 4.46 (dt, J ¼ 11.6, 3.6 Hz, 1H), 4.22 (dd,
J ¼ 10.9, 3.7 Hz, 1H), 3.12 (td, J ¼ 10.7, 3.9 Hz, 1H), 1.53e1.40 (m, 2H),
0.63 (t, J ¼ 7.3 Hz, 3H).
4.2.23. (2R,3R)-2-((S)-2-nitro-1-(p-tolyl)ethyl)-1,3-
diphenylpentan-1-one (4e). [15e17]
The title compound was prepared according to the General
Procedure in 82% yield and 90% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 5.9 min, t (minor) ¼ 7.3 min]. 1H NMR
4.2.28. (2R,3R)-2-((R)-1-cyclohexyl-2-nitroethyl)-1,3-
diphenylpentan-1-one (4j). [15,16]
The title compound was prepared according to the General
Procedure in 60% yield and 94% ee [Determined by HPLC with a
Chiralcel AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 6.0 min, t (minor) ¼ 9.1 min]. 1H NMR
(400 MHz, CDCl3)
d
7.53e7.44 (m, 3H), 7.40 (t, J ¼ 7.4 Hz, 2H),
7.35e7.29 (m, 2H), 7.28e7.23 (m, 3H), 6.96 (d, J ¼ 7.9 Hz, 2H), 6.88
(d, J ¼ 8.1 Hz, 2H), 4.99 (dd, J ¼ 13.3, 11.4 Hz, 1H), 4.90 (dd, J ¼ 13.4,
3.8 Hz,1H), 4.13 (dd, J ¼ 9.7, 5.1 Hz,1H), 3.61 (dt, J ¼ 11.3, 4.3 Hz,1H),
2.93 (td, J ¼ 10.7, 3.4 Hz, 1H), 2.22 (s, 3H), 1.57e1.42 (m, 2H), 0.60 (t,
J ¼ 7.3 Hz, 3H).
(400 MHz, CDCl3)
d
8.08 (d, J ¼ 7.9 Hz, 2H), 7.67 (t, J ¼ 7.1 Hz, 1H),
7.57 (t, J ¼ 7.6 Hz, 2H), 7.40 (t, J ¼ 7.4 Hz, 2H), 7.32 (d, J ¼ 7.2 Hz, 1H),
7.28e7.25 (m, 2H), 4.98 (d, J ¼ 14.0 Hz, 1H), 4.55 (dd, J ¼ 14.1,
10.2 Hz, 1H), 4.19 (dd, J ¼ 10.5, 2.4 Hz, 1H), 2.89 (td, J ¼ 10.4, 4.4 Hz,
1H), 2.31e2.21 (m, 1H), 1.61e1.46 (m, 7H), 1.27e1.24 (m, 1H),
1.00e0.96 (m, 1H), 0.92e0.87 (m, 4H), 0.61 (t, J ¼ 7.2 Hz, 3H).
4.2.24. (2R,3R)-2-((S)-1-(4-methoxyphenyl)-2-nitroethyl)-1,3-
diphenylpentan-1-one (4f). [15e17]
The title compound was prepared according to the General
Procedure in 70% yield and 93% ee [Determined by HPLC with a
Chiralpak AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 8.9 min, t (minor) ¼ 10.2 min]. 1H NMR
4.2.29. (2R,3R)-2-((S)-1-(4-bromophenyl)-2-nitroethyl)-3-(4-
methoxyphenyl)-1-phenylpentan-1-one (4k). [15,17]
The title compound was prepared according to the General
Procedure in 82% yield and 95% ee [Determined by HPLC with a
Chiralcel AS-H column, hexane/isopropanol ¼ 90/10, 0.8 mL/min,
254 nm, 40 ꢁC; t (major) ¼ 7.9 min, t (minor) ¼ 11.5 min]. 1H NMR
(400 MHz, CDCl3)
d 7.56e7.51 (m, 2H), 7.50e7.45 (m, 1H), 7.41 (t,
J ¼ 7.4 Hz, 2H), 7.35e7.29 (m, 3H), 7.27e7.22 (m, 2H), 6.91 (d,
J ¼ 8.7 Hz, 2H), 6.68 (d, J ¼ 8.7 Hz, 2H), 4.97 (dd, J ¼ 13.2, 11.4 Hz,
1H), 4.90 (dd, J ¼ 13.3, 4.0 Hz, 1H), 4.13 (dd, J ¼ 9.8, 5.0 Hz, 1H), 3.70
(s, 3H), 3.60 (dt, J ¼ 11.3, 4.4 Hz, 1H), 2.93 (td, J ¼ 10.7, 3.5 Hz, 1H),
1.57e1.41 (m, 2H), 0.60 (t, J ¼ 7.3 Hz, 3H).
(400 MHz, CDCl3)
d
7.56e7.48 (m, 3H), 7.34 (t, J ¼ 7.8 Hz, 2H), 7.26
(d, J ¼ 8.4 Hz, 2H), 7.18 (d, J ¼ 8.6 Hz, 2H), 6.96 (d, J ¼ 8.6 Hz, 2H),
6.85 (d, J ¼ 8.4 Hz, 2H), 5.03e4.96 (m, 1H), 4.93 (dd, J ¼ 13.6, 4.1 Hz,
Please cite this article as: Q. Wang et al., Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.032

8
Q. Wang et al. / Tetrahedron xxx (xxxx) xxx
(c) J.H. Kim, Y.O. Ko, J. Bouffard, S. Lee, Chem. Soc. Rev. 44 (2015) 2489.
[4] B.L. Feringa, M. Pineschi, L.A. Arnold, R. Imbos, A.H.M. de Vries, Angew. Chem.
Int. Ed. 109 (1997) 2773.
[5] (a) E. Keller, J. Maurer, R. Naasz, T. Schader, A. Meetsma, B.L. Feringa, Tetra-
hedron: Asymmetry 9 (1998) 2409;
1H), 4.06 (dd, J ¼ 10.1, 4.6 Hz, 1H), 3.87 (s, 3H), 3.59 (dt, J ¼ 10.9,
4.3 Hz, 1H), 2.89 (td, J ¼ 10.6, 3.4 Hz, 1H), 1.52e1.47 (m, 1H),
1.44e1.37 (m, 1H), 0.60 (t, J ¼ 7.2 Hz, 3H).
(b) A. Mandoli, L.A. Arnold, A.H.M. de Vries, P.S. salvadori, B.L. Feringa, Tet-
rahedron: Asymmetry 12 (2001) 1929;
Acknowledgments
(c) L.A. Arnold, R. Naasz, A.J. Minnaard, B.L. Feringa, J. Am. Chem. Soc. 123
(2001) 5841;
(d) L.A. Arnold, R. Naasz, A.J. Minnaard, B.L. Feringa, J. Org. Chem. 67 (2002)
7244;
(e) I. Zelocualtecatl-Montiel, F. Garcia-Alvarez, J.R. Juarez, L. Orea, D. Gnecco,
A. Mendoza, F. Chemla, F. Ferreira, O. Jackowski, D.M. Aparicio, A. Perez-Luna,
J.L. Teran, Asian J. Org. Chem. 6 (2017) 67.
The authors are grateful for the financial support from the Na-
tional Natural Science Foundation of China (Nos. 21403022,
21572226 and 21772196), Program of Star of Dalian Youth Science
and Technology (2016RQ062), Fundamental Research Funds for the
Higher Education of Liaoning Province (2017J027), and Liaoning
BaiQianWan Talents Program (201892153).
[6] (a) K. Agapiou, D.F. Cauble, M.J. Krische, J. Am. Chem. Soc. 126 (2004) 4518;
(b) K. Oisaki, D. Zhao, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 129 (2007)
7439.
[7] S.K. Murphy, M. Zeng, S.B. Herzon, Org. Lett. 18 (2016) 4880.
[8] M. Welker, S. Woodward, A. Alexakis, Org. Lett. 12 (2010) 576.
[9] (a) A. Alexakis, G.P. Trevitt, G. Bernardinelli, J. Am. Chem. Soc. 123 (2001)
4358;
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2019.06.032.
(b) A. Alexakis, S. March, J. Org. Chem. 67 (2002) 8753;
(c) O. Knopff, A. Alexakis, Org. Lett. 4 (2002) 3835.
[10] (a) R. Naasz, L.A. Arnold, M. Pineschi, E. Keller, B.L. Feringa, J. Am. Chem. Soc.
121 (1999) 1104;
References
(b) M. Pineschi, F.D. Moro, F. Gini, A.J. Minnaard, B.L. Feringa, Chem. Commun.
(2004) 1244;
(c) E.W. Dijk, L. Panella, P. Pinho, R. Naasz, A. Meetsma, A.J. Minnaard,
B.L. Feringa, Tetrahedron 60 (2004) 9687;
(d) X. Rathgeb, S. March, A. Alexakis, J. Org. Chem. 71 (2006) 7537;
(e) G.K. Jarugumilli, S.P. Cook, Org. Lett. 13 (2011) 1904;
(f) K. Kawamura, H. Fukuzawa, M. Hayashi, Bull. Chem. Soc. Jpn. 84 (2011)
640;
[1] For some reviews, see: a) T.-L. Ho (Ed.), Tandem Organic Reactions, Wiley,
New York, 1992;
b) P.J. Parsons, C.S. Penkett, A.J. Shell, Chem. Rev. 96 (1996) 195;
c) C.J. Chapman, C.G. Frost, Synthesis (2007) 1;
d) C.M.R. Volla, L. Atodiresei, M. Rueping, Chem. Rev. 114 (2014) 2390.
[2] For some reviews, see: (a) A. Alexakis, C. Benhaim, Eur. J. Org. Chem. (2002)
3221;
(g) G.K. Jarugumilli, C. Zhu, S.P. Cook, Eur. J. Org. Chem. (2012) 1712.
[11] Y.-J. Xu, Q.-Z. Liu, L. Dong, Synlett (2007) 273.
(b) J. Christoffers, G. Koripelly, A. Rosiak, M. Rossle, Synthesis (2007) 1279;
(c) A. Alexakis, J.E. Backvall, N. Krause, O. Pamies, M. Dieguez, Chem. Rev. 108
(2008) 2796;
(d) T. Thaler, P. Knochel, Angew. Chem. Int. Ed. 48 (2009) 645;
(e) T. Jerphagnon, M.G. Pizzuti, A.J. Minnaard, B. Feringa, Chem. Soc. Rev. 38
(2009) 1039;
[12] (a) S.J. Degrado, H. Mizutani, A.H. Hoveyda, J. Am. Chem. Soc. 123 (2001) 755;
(b) H. Mizutani, S.J. Degrado, A.H. Hoveyda, J. Am. Chem. Soc. 124 (2002) 779.
[13] (a) K. Li, A. Alexakis, Tetrahedron Lett. 46 (2005) 5823;
(b) L. Wang, W. Meng, C.-L. Zhu, Y. Zheng, J. Nie, J.-A. Ma, Angew. Chem. Int.
Ed. 50 (2011) 9442.
[14] S. Guo, Y. Xie, X. Hu, C. Xia, H. Huang, Angew. Chem. Int. Ed. 49 (2010) 2728.
[15] S. Guo, Y. Xie, X. Hu, H. Huang, Org. Lett. 13 (2011) 5596.
[16] C.-Y. Ni, S.-S. Kan, Q.-Z. Liu, T.-R. Kang, Org. Biomol. Chem. 9 (2011) 6211.
[17] Y.-M. Hung, C.-H. Tseng, B.-J. Uang, Tetrahedron: Asymmetry 26 (2015) 1369.
18 X. Hu, H. Chen, X. Zhang, Angew. Chem. Int. Ed. 38 (1999) 3518.
(f) M.M. Heravi, M. Dehghani, V. Zadsirjan, Tetrahedron: Asymmetry 27
(2016) 513;
(g) M. Hayashi, R. Matsubara, Tetrahedron Lett. 58 (2017) 1793;
(h) K. Zheng, X. Liu, X. Feng, Chem. Rev. 118 (2018) 7586.
[3] For some reviews, see: (a) H.-C. Guo, J.-A. Ma, Angew. Chem. Int. Ed. 45 (2006)
354;
(b) Z. Galestokova, R. Sebesta, Eur. J. Org. Chem. (2012) 6688;
Please cite this article as: Q. Wang et al., Copper-catalyzed asymmetric tandem double Michael reactions of diethylzinc to a,b-unsaturated
ketones followed by trapping with nitroolefins, Tetrahedron, https://doi.org/10.1016/j.tet.2019.06.032