Copper-catalyzed enantioselective 1,4-conjugate addition of dialkylzinc reagents to α,β- and α,β,γ,δ-unsaturated ketones

Article abstract of DOI:10.1016/j.tet.2019.05.029

An enantioselective Cu(II)-catalyzed conjugate addition of dialkylzinc reagents to α,β- or α,β,γ,δ-unsaturated ketones with chiral cyclohexane-based amidophosphine ligands was developed. With 2 mol% of Cu(OAc)₂·H₂O/L5, the conjugate

Full text of DOI:10.1016/j.tet.2019.05.029

Accepted Manuscript
Copper-catalyzed enantioselective 1,4-conjugate addition of dialkylzinc reagents to
α,β- and α,β,γ,δ-unsaturated ketones
Rukeya Rexiti, Jian Lu, Feng Sha, Xin-Yan Wu
PII:
S0040-4020(19)30568-X
https://doi.org/10.1016/j.tet.2019.05.029
TET 30350
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 20 February 2019
Revised Date: 5 May 2019
Accepted Date: 13 May 2019
Please cite this article as: Rexiti R, Lu J, Sha F, Wu X-Y, Copper-catalyzed enantioselective 1,4-
conjugate addition of dialkylzinc reagents to α,β- and α,β,γ,δ-unsaturated ketones, Tetrahedron (2019),
doi: https://doi.org/10.1016/j.tet.2019.05.029.
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Copper-catalyzed enantioselective 1,4-
conjugate addition of dialkylzinc reagents to
α,β- and α,β,γ,δ-unsaturated ketones
Leave this area blank for abstract info.
Rukeya Rexiti, Jian Lu, Feng Sha, Xin-Yan Wu*
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and
Technology, Shanghai 200237, P. R. China

1
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Tetrahedron
journal homepage: www.elsevier.com
Copper-catalyzed enantioselective 1,4-conjugate addition of dialkylzinc reagents to
α,β- and α,β,γ,δ-unsaturated ketones
Rukeya Rexiti, Jian Lu, Feng Sha, Xin-Yan Wu*
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, Shanghai 200237, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An enantioselective Cu(II)-catalyzed conjugate addition of dialkylzinc reagents to α,β- or
α,β,γ,δ-unsaturated ketones with chiral cyclohexane-based amidophosphine ligands was
developed. With 2 mol% of Cu(OAc)2·H2O/L5, the conjugate addition of diethylzinc to α,β-
unsaturated ketones was achieved in good-to-excellent yields (up to 98%) and high
enantioselectivities (up to 92% ee). This catalytic system was shown to be efficient for the 1,4-
conjugate addition of Et2Zn to (2E,4E)-1,5-diphenylpenta-2,4-dien-1-one with 85% yield and
90% ee. Moreover, with 1 mol% of Cu(OTf)2/L11, the conjugate addition of α,β,γ,δ-unsaturated
ketones was accomplished with 1,4-regioselectivity, good yields (79—86%) and excellent
enantioselectivities (up to 97% ee).
Available online
Keywords:
Asymmetric catalysis
Conjugate addition
Copper
2016 Elsevier Ltd. All rights reserved.
Enone
Phosphine
1. Introduction
asymmetric reactions. Very recently, we have developed chiral
hexane-based P,N-ligands for the copper-catalyzed asymmetric
C-C bond-forming reactions.6 We envision that these chiral
ligands would also be effective for the copper-catalyzed
conjugate addition of organozinc to unsaturated carbonyl
compounds. Herein, we report an efficient copper-catalyzed
enantioselective 1,4-conjugate addition of a dialkylzinc reagent
to both α,β- and α,β,γ,δ-unsaturated ketones.
Copper-catalyzed asymmetric conjugate addition of carbon
nucleophiles to α,β-unsaturated compounds is one of the most
important asymmetric C-C bond-forming reactions in organic
synthesis. Over the past two decades, a variety of chiral ligands
as well as organometallic reagents (such as RMgX, RLi, and
R2Zn) with chiral CuI or CuII complexes have been developed to
promote such transformations.[1] However, the developed ligands
are mainly based on binaphthol-derived phosphine ligands,
amino acid-derived Schiff bases and N-heterocyclic carbenes.
The use of organozinc reagents[1c,2] and extended Michael
acceptors[3] for the highly enantioselective 1,4-conjugate addition
to acyclic enones still remains a challenging task. Although a
number of chiral copper catalytic systems have been developed to
promote 1,4-conjugate additions of dialkylzinc to structurally
diverse enones, only a limited number of reports involving chiral
P,N-ligands as the Michael acceptor have demonstrated high
enantioselectivity (≥ 90% ee) for acyclic enones.[4] There are few
ligands with broad applicability. To the best of our knowledge,
the use of chiral P,N-ligands to promote enantioselective 1,4-
conjugate addition of organozinc to α,β,γ,δ-unsaturated carbonyl
compounds remains vacant.
2. Results and Discussion
2.1. Enantioselective 1,4-conjugate addition of α,β-unsaturated
ketones
To begin with, the conjugate addition of diethylzinc to
chalcone 1a was carried out using 2 mol% of Cu(OAc)2·H2O and
o
2 mol% of chiral ligands in dichloromethane at 0 C. A number
of chiral hexane-based P,N-ligands were screened (Figure 1), and
the results are summarized in Table 1. The results suggest that
the ligand plays an important role for the catalytic activity and
stereocontrol. Tridentate amidophosphine ligands L3-L6
produced higher yields than the bidentate aminophosphine L1
and amidophosphine L2 and the tridentate iminophosphine L7
and aminophosphine L8 (entries 3-6 vs entries 1, 2, 7 and 8). The
lower chemical yields of the tridentate ligands might be the result
Comparing to asymmetric 1,4-conjugate addition, conjugate
addition to extended Michael acceptors requires an additional
control of regioselectivity (1,4- vs 1,6-selectivity). In previous
reports, only chiral BINAP5a,5b and tert-leucine-base N-
heterocyclic carbene5c have been proven to be capable of
producing good 1,4-regioselectivity for the conjugate addition of
organozinc to α,β,γ,δ-unsaturated carbonyl compounds. Chiral
ligands inarguably play an important role for catalytic
of
a
low conversion. To improve the yields, more
amidophosphine ligands with an additional chiral group were
screened (entries 9-12). However, the enantioselectivity did not
exceed ligand L5. Among all the amidophosphine ligands
screened, L3 and L5 led to the highest yield and
enantioselectivity, respectively (entries 3 and 5). Moreover, there
might exist
a matched relationship between the chiral

2
Tetrahedron
ACCEPTED MANUSCRIPT
cyclohexane backbone and the amino acid scaffold in the
(entries 9-11 vs entries 1 and 4). In order to improve
ligands (entry 5 vs entry 6, entry 11 vs entry 12). Product 2a was
assigned as the R-configuration by referring to the optical
rotation and HPLC spectra in the previous reports.[4h,4j,7] In terms
of the enantioselectivity, ligand L5 was selected for further
study.
enantioselectivity of the model reaction, the catalyst loading of
Cu(OAc)2·H2O/L5 and Cu(HCO2)2·4H2O/L5 was increased to 5
mol%. The results showed that both the chemical yield and
enantioselectivity were improved (entries 12 and 13). Based on
the results shown in Table 2, Cu(OAc)2·H2O was chosen as the
copper source for subsequent reactions.
Table 2. Screening of copper salts for the enantioselective
1,4-conjugate addition of chalconea
Entry
1
2
3
4
5
6
7
8
Cu salt
Cu(OAc)2·H2O
Cu(OAc)2
Cu(acac)2
Cu(HCO2)2·4H2O
Cu(OTf)2
CuSO4
CuSO4·5H2O
CuBr2
Time (h)
Yield (%)b
Ee (%)c
70
69
61
71
-41
3
3
36
66
6
6
4
6
2
36
36
36
6
6
6
78
73
87
78
86
18
22
28
69
91
87
91
87
9
CuI
Figure 1. The structures of the chiral hexane-based P,N-
ligands
10
11
12d
13d
Cu(CH3CN)4BF4
Cu(CH3CN)4ClO4
Cu(OAc)2·H2O
Cu(HCO2)2·4H2O
-48
-27
75
2
2
76
Table 1. Screening of the chiral ligands for the
a
Unless noted otherwise, the reaction was carried out with chalcone 1a (0.5
enantioselective 1,4-conjugate addition of chalconea
mmol), diethylzinc (0.75 mL of 1 M hexane solution, 1.5 eq), 2 mol% copper
salt and 2 mol% chiral ligand L5 in 3 mL of dichloromethane at 0 oC.
b Isolated yields.
c The ee values were determined by HPLC using a Chiralpak AD-H column.
d Using 5 mol% of copper salt and 5 mol% of chiral ligand L5.
Table 3. The solvent survey for the enantioselective 1,4-
conjugate addition of chalconea
Entry
1
2
3
4
5
6
7
8
Ligand
L1
L2
L3
L4
L5
L6
L7
L8
T (h)
36
36
2
2
6
6
8
24
48
48
8
Yield (%)b
Ee (%)c
-3
-27
64
2
70
-64
49
14
32
20
20
31
94
92
78
86
51
28
42
21
80
82
Entry
1
2
3
4
5
6
7
8
Solvent
hexane
toluene
CH2Cl2
CHCl3
Time (h)
Yield (%)b
Ee (%)c
39
85
75
35
-1
88
88
-36
60
36
2
2
24
24
0.5
0.5
24
1
37
96
91
33
32
97
94
57
92
89
22
14
94
9
L9
10
11
12
L10
L11
L12
62
-58
ClCH2CH2Cl
Et2O
8
a
The reactions were carried out with chalcone 1a (0.5 mmol), diethylzinc
MTBE
THF
1,4-dioxane
EtOAc
CH3CN
DMF
(0.75 mL of 1 M hexane solution, 1.5 eq.), 2 mol% Cu(OAc)2·H2O and 2
mol% chiral ligand in 3 mL of dichloromethane at 0 oC.
b Isolated yields.
9
10
11
12
13
6
52
54
20
88
c The ee values were determined by HPLC using a Chiralpak AD-H column.
48
24
1.5
Next, our attention was turned to the screening of copper salts
(Table 2). The results suggest that the conjugate reaction is
sensitive to the copper salts. With Cu(OAc)2 as the precatalyst,
similar results as using Cu(OAc)2·H2O were obtained (entries 1
and 2). When divalent copper salts such as Cu(acac)2,
Cu(HCO2)2·4H2O and Cu(OTf)2 were used as the precatalyst,
higher chemical yields were obtained than using Cu(OAc)2·H2O
(entries 3-5 vs entry 1). Use of Cu(HCO2)2·4H2O gave a slightly
higher enantioselectivity than that of Cu(OAc)2·H2O (entry 4).
When divalent copper salts such as CuSO4, CuBr2 and
CuSO4·5H2O were used, the reaction rate was sluggish, leading
to poor chemical yields and enantioselectivities (entries 6-8).
When monovalent copper salts such as CuI, Cu(CH3CN)4ClO4
and Cu(CH3CN)4BF4 were used as precatalyst, although good
chemical yields were achieved, their entioselectivities were lower
than using Cu(OAc)2·H2O or Cu(HCO2)2·4H2O as prcatalyst
1:1
CH2Cl2/MTBE
Et2O
14d
15e
16f
48
1
4
trace
96
90
-
Et2O
Et2O
-82
80
a Unless noted otherwise, the reactions were carried out with chalcone 1a (0.5
mmol), diethylzinc (0.75 mL of 1 M hexane solution, 1.5 eq), 5 mol%
Cu(OAc)2·H2O and 5 mol% chiral ligand L5 in 3 mL of solvent at 0 oC.
b Isolated yields.
c The ee values were determined by HPLC using a Chiralpak AD-H column.
d Ligand L3 was used instead of ligand L5.
e Ligand L6 was used instead of ligand L5.
f Ligand L11 was used instead of ligand L5.
Encouraged by the preliminary results, the solvent effect was
investigated and the results are summarized in Table 3. The
results show that, with hexane as solvent, the model reaction was
very slow and led to poor yield and low enantioselectivity (entry

3
5
2
1
1
1
30
96
92
86
88
85
81
1). The conjuate reaction in toluene was achieved in 96% yield
ACCEPTED MANUSCRIPT
with 85% ee in 2 hours (entry 2). Halohydrocarbon solvents such
as CHCl3 and ClCH2CH2Cl led to a slow reaction rate and poor
enantioselectivity, which is different from that in CH2Cl2 (entries
3-5). Acyclic ethers such as Et2O and MTBE (methyl tert-butyl
ether) gave better results than cyclic ethers such as THF and 1,4-
dioxane, and the former solvents produced excellent yields and
high enantioselectivities (entries 6 and 7 vs entries 8 and 9). In
EtOAc, the model reaction was achieved in 89% yield in 6 hours,
but the enantioselectivity was unsatisfactory (entry 10). In
stronger coordinating solvents including DMF and CH3CN, the
conjugate reaction was sluggish, leading to poor chemical yields
and enantioselectivities (entries 11 and 12). The solvent effect
observed agreed with the conclusion drawn in Alexakis’s
review.1b A mixing solvent such as CH2Cl2 and MTBE in 1:1
volume ratio was also examined, and the results were similar to
that with MTBE as solvent (entry 13 vs entry 7). The solvent
survey suggests that diethyl ether is the most suitable solvent for
this asymmetric transform. Moreover, the results in Table 1
indicated that ligand L3, L6 and L11 provided higher chemical
yields and a litter lower enantioselectivities than ligand L5, so
these ligands were also examined using ether as solvent (Table 3,
entries 14-16). Ligand L3 was ineffective for the sake of its
insolubility in ether. Although using ligand L6 and L11 in ether
could improve the enantioselectivity, ligand L5 was still the
optimal one.
6
7
1
60
0.5
240
a
The reactions were carried out with chalcone 1a (0.5 mmol), diethylzinc
(0.75 mL of 1 M hexane solution, 1.5 eq) in 4 mL ether at 0 oC.
b Isolated yields.
c The ee values were determined by HPLC using a Chiralpak AD-H column.
After surveying the solvent, we turned our attention to other
conditions such as the substrate concentration, ratio of ligand to
copper salt, catalyst loading and reaction temperature. The results
are summarized in Table 4 and Table 5. The results shown in
Table 4 shows that within a certain range of chalcone
concentration (0.1 M~0.25 M with respect to the volume of
o
ether) at 0 C, no influence on the reaction rate, the chemical
yield and the enantioselectivity was observed (entries 1-4). The
o
o
reaction temperature varying from -30 C to 10 C affected the
reaction rate rather than yield and enantioselectivity, and a higher
temperature led to a faster reaction rate (entries 3 and 5-8).
However, when the reaction temperature was raised to 25 oC, the
enantioselectivity was decreased evidently (entry 9).
The effect of the molar ratio of ligand L5 to Cu(OAc)2·H2O
was listed in Table 5. With an increment of chiral ligand loading,
a
decrement of reaction rate, chemical yield and
enantioselectivity was observed (entries 1-3). The presence of
excess copper salt led to a similar effect (entry 4). The loading
amount of Cu(OAc)2·H2O/L5 could be reduced to 2 mol% with a
retained reaction efficiency (entry 5 vs entry 1). A subsequent
reduction of catalyst loading resulted in a longer reaction time,
and the chemical yield and enantioselectivity decreased
obviously (entries 6 and 7). However, 86% yield and 81% ee
could be accomplished with 0.5 mol% of chiral catalyst (entry 7).
Table 4. Effects of substrate concentration and reaction
temperature on the enantioselective 1,4-conjugate addition of
chalconea
Based on the results shown in Table 4 and Table 5, the
optimal reaction condition was established to be 2 mol%
Cu(OAc)2·H2O and 2 mol% L5 in ether (0.125 M) at 0 oC.
Entry
Conc. (M)b
Temp
(oC)
0
Time
(min)
30
Yield (%)c
Ee (%)d
Table 6. Substrate scope of the enantioselective 1,4-conjugate
addition of α,β-unsaturated ketonesa
1
2
3
4
5
6
7
8
0.25
0.167
0.125
0.1
95
97
99
95
98
97
94
96
96
88
88
88
88
88
86
84
84
63
0
30
0
30
0
30
0.125
0.125
0.125
0.125
0.125
-10
-20
-30
10
25
50
60
180
20
Entry
Ar
R
Time
(h)
Yield
(%)b
Ee
(%)c
9
10
1
2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-ClC6H4
0.5
1
96 (2a)
76 (2b)
82 (2c)
86 (2d)
81 (2e)
98 (2f)
84 (2g)
93 (2h)
92 (2i)
81 (2j)
72 (2k)
93 (2l)
82(2m)
88 (2n)
88
79
85
86
78
38
83
88
85
62
72
65
87
73
a
The reactions were carried out with chalcone 1a (0.5 mmol), diethylzinc
(0.75 mL of 1 M hexane solution), 5 mol% Cu(OAc)2·H2O and 5 mol% chiral
ligand L5 in ether.
4-CF3C6H4
4-BrC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-FC6H4
b The concentration of substrate 1a with respect to the volume of ether.
c Isolated yields.
3
0.5
0.5
0.5
1
4
d The ee values were determined by HPLC using a Chiralpak AD-H column.
5
Table 5. Effects of the loading amount of Cu(OAc)2·H2O and
chiral ligand L5a
6
7
1
8
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
1-Naphthyl
2- Naphthyl
C6H5
0.5
0.5
12
4
9
10
11
12
13d
14
Entry
x
L5/Cu
1
Time (min)
Yield (%)b
Ee (%)c
88
1
2
3
4
5
30
99
94
92
87
3
5
1.5
2
40
85
2
5
60
83
1
10
0.5
180
85

4
Tetrahedron
ACCEPTED MANUSCRIPT
15
16
17
18
19
20
21
C6H5
C6H5
4-MeC6H4
4-MeOC6H4
4-MeC6H4
2-Thienyl
Me
1
6
92 (2o)
89
regioselectivity (Scheme 2). To further improve the results, the
reaction conditions for the conjugate addition of dienone 4a were
re-optimized, including the choice of chiral ligand, copper salt,
solvent and substrate.
70 (2p)
92 (2q)
66 (2r)
72 (2s)
62 (2t)
56 (2u)
91
90
91
92
90
78
4-MeC6H4
C6H5
1
0.5
0.5
8
C6H5
C6H5
Et
C6H5
i-Pr
24
a Unless noted otherwise, the reaction was carried out with substrate 1 (0.5
mmol), diethylzinc (0.75 mL of 1 M hexane solution, 1.5 eq), 2 mol%
Cu(OAc)2·H2O and 2 mol% chiral ligand L5 in 4 mL ether at 0 oC.
b Isolated yields.
Scheme 2. The conjugate addition of diethylzinc to dienone
4a
c The ee values were determined by HPLC using chiral column.
d The solvent was toluene.
Initially, chiral hexane-based P,N-ligands L1-L7 and L9-L12
were screened (Table 7, entries 1-11). CH2Cl2 was used as
solvent, as a result of the solubility of these chiral ligands. The
results suggest that ligand L11 gave better results than other
ligands. However, both chemical yield and enantioselectivity
were unsatisfied (48% yield and 50% ee, entry 10). GC-MS
analysis of the crude products suggests that no 1,6-regioisomer
was formed in this process. To improve the catalytic system,
chiral ligand L11 was selected for further studies. Product 5a was
assigned as R-configuration by referring to the optical rotation
direction in the previous report.[8]
Under the optimized reaction conditions, the substrate scope
of α,β-unsaturated ketones was investigated (Table 5). For
chalcones, except for 4-CF3 and 4-MeO substituted substrates
(entries 2, 11 and 16), other chalcones examined provided good
yields (81-96%, entries 3-10, 12-15 and 17). The
enantioselectivities of the diverse chalcones varied largely (38-
91% ee). The presence of both electron-withdrawing and
donating groups at the ortho-position in the β-aryl of α,β-
unsaturated ketones appeared to be disadvantageous to the
conjugate addition. Both the reaction rate and enantioselectivity
were lower than those of the para- or meta-substituted analogues
(entry 6 vs entries 4 and 5, entry 10 vs entries 8 and 9, entry 12
vs entry 13). Note that the solubility of 2-naphthyl chalcone is
poor in ether. As a result, toluene was used as the solvent,
leading to a good yield and enantioselectivity (entry 13). When
(E)-1,3-di-p-tolylprop-2-en-1-one was used as Michael acceptor,
92% yield with 90% ee was accomplished in one hour (entry 17).
Heteroaromatic-containing enone was also examined. However,
the use of (E)-3-phenyl-1-(thiophen-2-yl)prop-2-en-1-one gave
high enantioselectivity but moderate chemical yield (entry 18),
and the low chemical yield was resulted from the
Michael/Michael tandem side reaction. Moreover, the catalytic
system is suitable for alkyl enones (entries 19-21). However, β-
alkyl α,β-unsaturated ketones such as (E)-1-phenylbut-2-en-1-
one were unreactive under the typical reaction conditions.
Table 7. Screening of copper salts and chiral ligands for the
enantioselective 1,4-conjugate addition of dienone 4aa
Entry
Cu salt
Ligand
Yield (%)b
Ee (%)c
1
2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2
L1
L2
6
-15
-14
26
6
45
49
41
45
45
13
45
42
48
46
44
34
47
45
64
40
50
35
3
L3
4
L4
5
L5
45
24
34
42
45
50
34
60
57
82
87
94
48
73
81
6
L6
7
L7
Under the typical reaction conditions, dimethylzinc was used
as a nucleophile instead of diethylzinc for the conjugate reaction
(Scheme 1). The results indicated that the reaction was slow, and
side reactions occurred. Although the chemical yield was only
33% in 24 hours, the desired product was achieved in higher
enantioselectivity (96% ee) than the 1,4-adducts of diethylzinc.
Dibutylzinc and diphenylzinc were also examined as nucleophile.
The addition reaction with dibutylzinc was complicated, and
diphenylzinc was not reactive.
8
L9
9
L10
L11
L12
L11
L11
L11
L11
L11
L11
L11
L11
10
11
12
13
14
15
16
17
18
19
Cu(acac)2
Cu(HCOO)2·4H2O
Cu(HCOO)2
Cu(OTf)2
CuCl2
CuI
Cu(CH3CN)4BF4
a The reaction were carried out with substrate 4a (0.2 mmol), diethylzinc (0.3
mL of 1 M hexane solution, 1.5 eq), 5 mol% copper salt and 5 mol% chiral
ligand in 2 mL CH2Cl2 at 0 oC for 48 hours.
Scheme 1. The conjugate addition of dimethylzinc to
chalcone 1a
b Isolated yields.
c The ee values were determined by HPLC using a Chiralcel OD-H column.
Table 8. Solvent survey of the enantioselective 1,4-conjugate
addition of dienone 4aa
2.2 Enantioselective 1,4-conjugate addition of α,β,γ,δ-
unsaturated ketones
Under the above-mentioned reaction conditions, the conjugate
addition of diethylzinc to acyclic α,β,γ,δ-unsaturated ketone 4a
was examined. To our delight, 85% yield and 90% ee were
obtained, and the conjugate addition reaction showed 1,4-

5
i The reaction was performed in 2.5 mmol scale.
Entry
1
Solvent
toluene
Time (h)
24
Yield (%)b
Ee (%)c
ACCEPTED MANUSCRIPT
j 4 mL 1:1 CH2Cl2/MTBE was used as solvent.
k 1 mL 1:1 CH2Cl2/MTBE was used as solvent.
62
64
87
94
90
90
87
89
88
-
2
CH2Cl2
24
Reaction conditions including the loading amount of ligand,
the reaction temperature, the molar ratio of chiral ligand to
copper, the chiral catalyst, and the reaction concentration were
further optimized (Table 9). At lower temperature, a longer
reaction time was required for the conjugate reaction, and a
3
ClCH2CH2Cl
Et2O
24
70
4
12
78
5
MTBE
12
84
6
THF
24
58
7
EtOAc
48
64
o
temperature of 0 C was showed to be optimal (entries 1-3).
8
CH3CN
48
trace
47
Increasing the molar ratio of ligand L11 to Cu(OTf)2 from 1:1 to
2:1 led to similar results (entries 2, 4 and 5). These results were
different from that observed for chalcone with Cu(OAc)2·H2O/L5
as chiral catalyst (Table 5). When the amount of Et2Zn was
reduced to 1.1 equivalent, the chemical yield decreased
dramatically (entry 6). Varying the chiral catalyst loading from 5
mol% to 0.5 mol% led to similar results (entries 8-10 vs entry 2).
Further reducing the catalyst amount to 0.1 mol% compromised
the conjugate addition since the reaction did not complete even
after 5 days (entry 11). The change of substrate concentration had
minimal influence on this reaction (entries 9, 13 and 14). Based
on the results mentioned above, the optimal reaction condition
was established to be 1 mol% Cu(OTf)2 and 1 mol% L11 in 1:1
CH2Cl2/MTBE (0.1 M concentration of unsaturated ketone
respect to CH2Cl2/MTBE) at 0 oC (entries 9 and 13 in Table 9).
9
DMF
48
82
90
89
88
10
11
12
1:1 CH2Cl2/MTBE
2:1 CH2Cl2/MTBE
4:1 CH2Cl2/MTBE
24
80
24
80
24
82
a The reaction were carried out with substrate 4a (0.2 mmol), diethylzinc (0.3
mL of 1 M hexane solution, 1.5 eq), 5 mol% Cu(OTf)2 and 5 mol% chiral
ligand L11 in 2 mL solvent at 0 oC.
b Isolated yields.
c The ee values were determined by HPLC using a Chiralcel OD-H column.
The effect of copper salts on the conjugate addition between
Et2Zn and dienone 4a was summarized in Table 7 (entries 10 and
12-19). Different from chalcone as Michael acceptor, the copper
precatalyst containing crystal water affected both the chemical
yield and enantioselectivity (Table 7, entry 10 vs entry 12, entry
14 vs entry 15). When Cu(OTf)2 was used as precatalyst, the 1,4-
adduct 5a was obtained in the highest chemical yield and
enantioselectivity (64% yield with 94% ee, entry 16).
Under the optimized reaction conditions, the substrate scope
of α,β,γ,δ-unsaturated ketones was investigated (Table 10). The
asymmetric catalytic system tolerated a variety of substrate. The
1,4-adducts 5 were obtained in good yields (79-86%) for all the
dienones examined. For all substrates except that shown in entry
8, excellent enantioselectivities were achieved (89-97% ee). The
substituent at phenyl group of substrates 4 played an irregular
role in the control of stereoselectivity.
The solvent survey indicated that CH2Cl2 provided the highest
enantioselectivity among the solvents screened (entry 2, Table 8),
while MTBE gave the highest chemical yield (entry 5, Table 8).
Therefore, a solvent mixture of CH2Cl2 and MTBE was
examined. The results suggested that the volume ratio of CH2Cl2
to MTBE had a slight effect on the asymmetric conjugate
addition (entries 10-12). Considering both the chemical yield and
enantioselectivity, 1:1 CH2Cl2/MTBE was selected as the solvent
for further optimization of the reaction conditions.
Table 10. Substrate scope of the enantioselective 1,4-
conjugate addition of α,β,γ,δ-unsaturated ketonesa
Table 9. Further optimization of the reaction conditionsa
Entry
Ar
R
Time (h)
Yield
(%)b
Ee
(%)c
94
92
90
93
89
93
91
78
93
95
97
Entry
1
x
5
Temp (oC)
Time (h)
6
Yield (%)b
Ee (%)c
92
1
2
C6H5
4-BrC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
4-MeOC6H4
C6H5
C6H5
C6H5
24
24
24
24
24
24
24
24
24
18
24
84 (5a)
79 (5b)
80 (5c)
84 (5d)
82 (5e)
81 (5f)
84 (5g)
85 (5h)
86 (5i)
84 (5j)
82 (5k)
25
0
62
80
61
80
81
61
80
82
84
83
45
83
84
78
2
5
24
90
3
C6H5
3
5
-20
0
72
75
4
C6H5
4d
5
24
90
5
C6H5
5e
5
0
24
89
6
C6H5
6f
5
0
24
90
7
4-BrC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
4-MeOC6H4
7g
5
0
24
90
8
C6H5
8
9h
2.5
1
0
24
94
9
C6H5
0
24
94
10
11
C6H5
10h
11i
12h
13h,j
14h,k
0.5
0.1
5
0
36
91
C6H5
0
120
24
87
a
The reactions were carried out with substrate 4 (0.5 mmol), diethylzinc
0
90
(0.75 mL of 1 M hexane solution, 1.5 eq), 1 mol% Cu(OTf)2 and 1 mol%
chiral ligand L11 in 5 mL 1:1 CH2Cl2/MTBE at 0 oC.
b Isolated yields.
1
0
24
93
1
0
18
93
c The ee values were determined by chiral HPLC analysis.
a Unless stated otherwise, the reaction were carried out with substrate 4a (0.2
mmol), diethylzinc (0.3 mL of 1 M hexane solution, 1.5 eq), x mol%
Cu(OTf)2 and x mol% chiral ligand L11 in 2 mL 1:1 CH2Cl2/MTBE at 0 oC.
b Isolated yields.
3. Conclusion
In conclusion, we have developed
a Cu(II)-catalyzed
c The ee values were determined by HPLC using a Chiralcel OD-H column.
d The amount of chiral ligand L11 was 7.5 mol%.
enantioselective 1,4-conjugate addition of dialkylzinc reagent to
enones and dienones. With 2 mol% of chiral amidophosphine
ligand L5 and Cu(OAc)2·H2O, 1,4-adducts of α-aryl enone, α-
alkyl enones and dienes were obtained in excellent yields (up to
e The amount of chiral ligand L11 was 10 mol%.
f The amount of diethylzinc was 1.1 equivalent.
g The amount of diethylzinc was 2 equivalent.
h The reaction was performed in 0.5 mmol scale.

6
Tetrahedron
ACCEPTED MANUSCRIPT
98%) with high enantioselectivities (up to 96% ee).
7.51 (m, 3H), 7.42 (t, J = 7.6 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H),
Furthermore, a more efficient catalytic system was extended for
the 1,4-conjugate addition of diethylzinc reagent to α,β,γ,δ-
unsaturated ketones. With 1 mol% of chiral amidophosphine
ligand L11 and Cu(OTf)2, the 1,4-adducts were afforded in good
yields (79-86% yield) and excellent enantioselectivities (up to
97% ee).
3.37-3.26 (m, 3H), 1.86-1.76 (m, 1H), 1.73-1.60 (m, 1H), 0.81 (t,
J = 7.2 Hz, 3H); HPLC (AD-H column, λ = 240 nm, eluent: n-
hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR = 8.39 min
(minor), 10.43 min (major).
4.2.3 (R)-3-(4-bromophenyl)-1-phenylpentan-1-one (2c):
Yellow oil, 82% yield, 85% ee, [α]D27+9.1 (c 0.91, CHCl3); H
1
NMR (CDCl3, 400 MHz): δ 7.89 (d, J = 7.6 Hz, 2H), 7.52 (t, J =
7.6 Hz, 1H), 7.44-7.38 (m, 4H), 7.10 (d, J = 8.0 Hz, 2H), 3.27-
3.18 (m, 3H), 1.82-1.72 (m, 1H), 1.65-1.54 (m, 1H), 0.79 (t, J =
7.2 Hz, 3H); HPLC (AD-H column, λ = 240 nm, eluent: n-
hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR = 10.35
min (minor), 13.78 min (major).
4. Experimental
4.1. General methods
All reactions were carried out under N2 atmosphere using
standard Schlenk techniques with magnetic stirring. Anhydrous
solvents were distilled from CaH2 (dichloromethane, chloroform,
ClCH2CH2Cl, ethyl acetate, acetonitrile), sodium-benzophenone
(hexane, toluene, ether, MTBE, THF). Anhydrous DMF was
dried over CaH2 and distilled under reduced pressure. Thin-layer
chromatography (TLC) was performed on Silicycle 10-40 ꢀm
silica gel plates. Column chromatography was performed using
silica gel (300-400 mesh) eluting with petroleum ether and ethyl
acetate.
4.2.4 (R)-3-(4-chlorophenyl)-1-phenylpentan-1-one (2d):
1
Yellow oil, 86% yield, 86% ee, [α]D27+13.8 (c 0.79, CHCl3); H
NMR (CDCl3, 400 MHz): δ 7.81-7.79 (m, 2H), 7.44 (t, J = 7.2
Hz, 1H), 7.35-7.31 (m, 2H), 7.16-7.13 (m, 2H), 7.08-7.06 (m,
2H), 3.19-3.10 (m, 3H), 1.73-1.64 (m, 1H), 1.57-1.46 (m, 1H),
0.71 (t, J = 7.6 Hz, 3H); HPLC (AD-H column, λ = 240 nm,
eluent: n-hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR =
10.10 min (minor), 13.14 min (major).
Optical rotations were measured on a WZZ-2A digital
polarimeter at the wavelength of the sodium D-line (589 nm).
The NMR spectra were recorded on Bruker 400 spectrometer.
The chemical shifts of 1H NMR were referenced to
tetramethylsilane (δ 0.00) using CDCl3 as solvent, and the 13C
NMR spectra was referenced to solvent carbons (77.0 ppm for
CDCl3). High Resolution Mass spectra (HRMS) were recorded
on Micromass GCT spectrometer with Electron Spray Ionization
(ESI-TOF) resource. HPLC analysis was performed on Waters
equipment using Daicel Chiralpak AD-H column, Chiralcel OD-
H column and OJ-H column.
4.2.5 (R)-3-(3-chlorophenyl)-1-phenylpentan-1-one (2e):
1
Yellow oil, 81% yield, 78% ee, [α]D27+18.5 (c 0.82, CHCl3); H
NMR (CDCl3, 400 MHz): δ 7.82-7.80 (m, 2H), 7.45 (t, J = 7.2
Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.13-7.02 (m, 4H), 3.20-3.11
(m, 3H), 1.74-1.64 (m, 1H), 1.58-1.47 (m, 1H), 0.72 (t, J = 7.6
Hz, 3H); HPLC (AD-H column, λ = 240 nm, eluent: n-hexane/i-
propanol = 90/10, flow rate: 0.6 mL/min): tR = 10.02 min (minor),
11.02 min (major).
4.2.6 (R)-3-(2-chlorophenyl)-1-phenylpentan-1-one (2f):
1
Yellow oil, 98% yield, 38% ee, [α]D27+15.2 (c 0.88, CHCl3); H
Chiral ligands were prepared according to literature
procedures.[6a,6c,9]
NMR (CDCl3, 400 MHz): δ 7.85-7.83 (m, 2H), 7.44 (t, J = 7.2
Hz, 1H), 7.35-7.32 (m, 2H), 7.26 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz,
1H), 7.17 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 7.12 (td, J1 = 8.0 Hz,
J2 = 1.2 Hz, 1H,), 7.02 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H,), 3.82-
3.75 (m, 1H), 3.23 (dd, J1 = 16.8 Hz, J2 = 6.0 Hz, 1H), 3.15 (dd,
J1 = 16.8 Hz, J2 = 8.0 Hz, 1H), 1.78-1.68 (m, 1H), 1.66-1.55 (m,
1H), 0.73 (t, J = 7.2 Hz, 3H); HPLC (AD-H column, λ = 240 nm,
eluent: n-hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR =
9.60 min (minor), 11.57 min (major).
4.2. General procedure for the enantioselective 1,4-conjugate
addition of α,β-unsaturated ketones
A flame-dried Schlenk tube was charged with chiral ligand L5
(2 mol%, 0.01 mmol) in dry toluene (4 mL), Cu(OAc)2·H2O (2
mol%, 0.01 mmol) was added and the mixture was stirred at 25
oC under N2 atmosphere for 30 min. Then the mixture was cooled
down to 0 °C. The α,β-unsaturated ketone 1 (0.5 mmol) was
added at 0 °C, followed by adding diethylzinc (0.75 mL, 1 M in
hexane, 1.5 eq) dropwise via a syringe. After the reaction was
completed (monitored by TLC), 2 mL of 1 M HCl were added
slowly. The resulting mixture was stirred for 0.5 hour, then
extracted with ether (10 mL × 3). The combined organic phase
was washed with saturated aqueous Na2CO3 and brine,
respectively. After drying over anhydrous sodium sulfate, the
solvent was removed under reduced pressure. The resulting
residue was purified by chromatography on silica gel to afford
the desired product 2. Chiral HPLC chromatography was used to
determine the enantiomeric excesses.
4.2.7 (R)-3-(4-fluorophenyl)-1-phenylpentan-1-one (2g):
1
Yellow oil, 84% yield, 83% ee, [α]D27+10.1 (c 0.80, CHCl3); H
NMR (CDCl3, 400 MHz): δ 7.80-7.78 (m, 2H), 7.42 (t, J = 7.2
Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.10-7.06 (m, 2H), 6.88-6.83
(m, 2H), 3.17-3.10 (m, 3H), 1.73-1.63 (m, 1H), 1.56-1.45 (m,
1H), 0.70 (t, J = 7.2 Hz, 3H); HPLC (AD-H column, λ = 240 nm,
eluent: n-hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR =
10.13 min (minor), 12.27 min (major).
4.2.8 (R)-1-phenyl-3-(p-tolyl)pentan-1-one (2h): Yellow oil,
93% yield, 88% ee, [α]D27-5.1 (c 2.00, CHCl3); 1H NMR (CDCl3,
400 MHz): δ 7.78 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 7.2 Hz, 1H),
7.28 (t, J = 7.6 Hz, 2H), 7.01-6.96 (m, 4H), 3.18-3.08 (m, 3H),
2.17 (s, 3H), 1.68-1.63 (m, 1H), 1.53-1.47 (m, 1H), 0.71-0.67 (m,
3H); HPLC (AD-H column, λ = 240 nm, eluent: n-hexane/i-
propanol = 90/10, flow rate: 0.6 mL/min): tR = 9.04 min (minor),
11.59 min (major).
4.2.1 (R)-1,3-diphenylpentan-1-one (2a): Yellow oil, 96%
1
yield, 88% ee, [α]D27-1.9 (c 2.00, CHCl3); H NMR (CDCl3, 400
MHz): δ 7.82 (d, J = 8.0 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.35 (t,
J = 7.6 Hz, 2H), 7.23-7.09 (m, 5H), 3.25-3.13 (m, 3H), 1.76-1.67
(m, 1H), 1.60-1.52 (m, 1H), 0.73 (t, J = 7.6 Hz, 3H); HPLC (AD-
H column, λ = 240 nm, eluent: n-hexane/i-propanol = 90/10, flow
rate: 0.6 mL/min): tR = 9.48 min (minor), 11.12 min (major).
4.2.9 (R)-1-phenyl-3-(m-tolyl)pentan-1-one (2i): Yellow oil,
92% yield, 85% ee, [α]D27-0.6 (c 1.00, CHCl3); 1H NMR (CDCl3,
400 MHz): δ 7.82 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.2 Hz, 1H),
7.32 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.2 Hz, 1H), 6.95-6.89 (m,
3H), 3.19-3.08 (m, 3H), 2.23 (s, 3H), 1.73-1.62 (m, 1H), 1.59-
1.48 (m, 1H), 0.71 (t, J = 7.2 Hz, 3H); HPLC (AD-H column, λ =
4.2.2 (R)-1-phenyl-3-(4-(trifluoromethyl)phenyl)pentan-1-one
(2b): Yellow oil, 76% yield, 79% ee, [α]D27+17.1 (c 0.81, CHCl3);
1H NMR (CDCl3, 400 MHz): δ 7.90 (d, J = 7.6 Hz, 2H), 7.54-

7
240 nm, eluent: n-hexane/i-propanol = 90/10, flow rate: 0.6
mL/min): tR = 11.08 min (minor), 12.36 min (major).
flow rate: 0.6 mL/min): tR = 11.44 min (minor), 18.20 min
(major).
ACCEPTED MANUSCRIPT
4.2.10 (R)-1-phenyl-3-(o-tolyl)pentan-1-one (2j): Yellow oil,
81% yield, 62% ee, [α]D27+31.7 (c 0.66, CHCl3); 1H NMR
(CDCl3, 400 MHz): δ 7.83-7.81 (m, 2H), 7.44 (t, J = 7.2 Hz, 1H),
7.36-7.32 (m, 2H), 7.13-6.97 (m, 4H), 3.55-3.47 (m, 1H), 3.22-
3.12 (m, 2H), 2.30 (s, 3H), 1.75-1.65 (m, 1H), 1.62-1.51 (m, 1H),
0.73 (t, J = 7.2 Hz, 3H); HPLC (AD-H column, λ = 240 nm,
eluent: n-hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR =
10.60 min (minor), 12.46 min (major).
4.2.18
(R)-3-phenyl-1-(thiophen-2-yl)pentan-1-one
(2r):
1
Yellow oil, 66% yield, 91% ee, [α]D27-11.2 (c 2.00, CHCl3); H
NMR (CDCl3, 400 MHz): δ 7.54 (dd, J1 = 3.6 Hz, J2 = 0.8 Hz,
1H), 7.47 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1H), 7.21-7.07 (m, 5H),
6.97 (dd, J1 = 4.8 Hz, J2 = 3.6 Hz, 1H), 3.18-3.03 (m, 3H), 1.75-
1.65 (m, 1H), 1.62-1.51 (m, 1H), 0.71 (t, J = 7.2 Hz, 3H); HPLC
(AD-H column, λ = 240 nm, eluent: n-hexane/i-propanol = 90/10,
flow rate: 0.6 mL/min): tR = 10.15 min (minor), 12.11 min
(major).
4.2.11 (R)-3-(4-methoxyphenyl)-1-phenylpentan-1-one (2k):
1
Yellow oil, 72% yield, 72% ee, [α]D27-4.5 (c 2.00, CHCl3); H
4.2.19 (R)-4-phenylhexan-2-one (2s): Yellow oil, 72% yield,
92% ee, [α]D27-26.1 (c 1.00, CHCl3); 1H NMR (CDCl3, 400 MHz):
δ 7.23-7.18 (m, 2H), 7.13-7.08 (m, 3H), 2.99-2.92 (m, 1H), 2.65
(d, J = 7.2 Hz, 2H), 1.94 (s, 3H), 1.65-1.55 (m, 1H), 1.54 -1.43
(m, 1H), 0.70 (t, J = 7.2 Hz, 3H); HPLC (OJ-H column, λ = 220
nm, eluent: n-hexane/i-propanol = 90/10, flow rate: 0.9 mL/min):
tR = 13.03 min (minor), 14.55 min (major).
NMR (CDCl3, 400 MHz): δ 7.81-7.79 (m, 2H), 7.42 (t, J = 7.6
Hz, 1H), 7.31 (t, J = 7.6 Hz, 2H), 7.06-7.03 (m, 2H), 6.75-6.71
(m, 2H), 3.66 (s, 3H), 3.17-3.06 (m, 3H), 1.72-1.62 (m, 1H),
1.56-1.45 (m, 1H), 0.70 (t, J = 7.2 Hz, 3H); HPLC (AD-H
column, λ = 240 nm, eluent: n-hexane/i-propanol = 90/10, flow
rate: 0.6 mL/min): tR = 12.15 min (minor), 16.82 min (major).
4.2.12 (R)-3-(naphthalen-1-yl)-1-phenylpentan-1-one (2l):
4.2.20 (R)-5-phenylheptan-3-one (2t): Yellow oil, 62% yield,
1
1
Yellow oil, 93% yield, 65% ee, [α]D27+60.7 (c 0.99, CHCl3); H
90% ee, [α]D27+11.1 (c 0.76, CHCl3); H NMR (CDCl3, 400
NMR (CDCl3, 400 MHz): δ 8.14 (d, J = 8.4 Hz, 1H), 7.79 (d, J =
7.6 Hz, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.61-7.56 (m, 1H), 7.39-
7.24 (m, 7H), 4.23-4.09 (m, 1H), 3.32-3.19 (m, 2H), 1.87-1.69
(m, 2H), 0.73 (t, J = 7.2 Hz, 3H); HPLC (AD-H column, λ = 240
nm, eluent: n-hexane/i-propanol = 90/10, flow rate: 0.6 mL/min):
tR = 14.61 min (minor), 16.16 min (major).
MHz): δ 7.21-7.18 (m, 2H), 7.11-7.08 (m, 3H), 3.00-2.93 (m,
1H), 2.61 (d, J = 7.2 Hz, 2H), 2.29-2.08 (m, 2H), 1.64-1.43 (m,
2H), 0.86 (t, J = 7.2 Hz, 3H), 0.69 (t, J = 7.2 Hz, 3H); HPLC (OJ-
H column, λ = 220 nm, eluent: n-hexane/i-propanol = 90/10, flow
rate: 0.9 mL/min): tR = 7.05 min (minor), 8.34 min (major).
4.2.21 (R)-2-methyl-5-phenylheptan-3-one (2u): Yellow oil,
56% yield, 78% ee, [α]D27-10.5 (c 0.80, CHCl3); 1H NMR (CDCl3,
400 MHz): δ 7.21-7.18 (m, 2H), 7.11-7.08 (m, 3H), 3.03-2.96 (m,
1H), 2.71-2.60 (m, 2H), 2.41-2.31 (m, 1H), 1.63-1.45 (m, 2H),
0.93 (d, J = 7.2 Hz, 3H), 0.85 (d, J = 7.2 Hz, 3H), 0.70 (t, J = 7.2
Hz, 3H); HPLC (OJ-H column, λ = 220 nm, eluent: n-hexane/i-
propanol = 90/10, flow rate: 0.9 mL/min): tR = 8.02 min (minor),
9.00 min (major).
4.2.13 (R)-3-(naphthalen-2-yl)-1-phenylpentan-1-one (2m):
1
Yellow oil, 82% yield, 87% ee, [α]D27+15.8 (c 0.95, CHCl3); H
NMR (CDCl3, 400 MHz): δ 7.87 (d, J = 7.6 Hz, 2H), 7.75 (d, J =
8.4 Hz, 3H), 7.65 (s, 1H), 7.45-7.32 (m, 6H), 3.45-3.25 (m, 3H),
1.89-1.79 (m, 1H), 1.77-1.66 (m, 1H), 0.81 (t, J = 7.2 Hz, 3H);
HPLC (AD-H column, λ = 240 nm, eluent: n-hexane/i-propanol
= 90/10, flow rate: 0.6 mL/min): tR = 12.00 min (minor), 14.22
min (major).
4.2.22 (R)-1,3-diphenylbutan-1-one (3): Dimethylzinc was used
instead of diethylzinc. 33% yield, 96% ee, [α]D27-2.8 (c 1.00,
CHCl3); 1H NMR (CDCl3, 400 MHz): δ 7.85 (d, J = 7.2 Hz, 2H),
7.46 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.24-7.17 (m,
4H), 7.14-7.11 (m, 1H), 3.47-3.39 (m, 1H), 3.22 (dd, J1 = 16.4
Hz, J2 = 5.6 Hz, 1H), 3.11 (dd, J1 = 16.4 Hz, J2 = 8.4 Hz, 1H),
1.26 (d, J = 6.8 Hz, 3H); HPLC (AD-H column, λ = 240 nm,
eluent: n-hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR =
9.65 min (minor), 10.78 min (major).
4.2.14 (R)-1-(4-chlorophenyl)-3-phenylpentan-1-one (2n):
1
Yellow oil, 88% yield, 73% ee, [α]D27+12.0 (c 0.65, CHCl3); H
NMR (CDCl3, 400 MHz): δ 7.71 (d, J = 8.4 Hz, 2H), 7.26 (d, J =
8.8 Hz, 2H), 7.19-7.07 (m, 5H), 3.16-3.08 (m, 3H), 1.73-1.63 (m,
1H), 1.59-1.49 (m, 1H), 0.70 (t, J = 7.2 Hz, 3H); HPLC (AD-H
column, λ = 240 nm, eluent: n-hexane/i-propanol = 90/10, flow
rate: 0.6 mL/min): tR = 11.35 min (minor), 13.91 min (major).
4.2.15 (R)-3-phenyl-1-(p-tolyl)pentan-1-one (2o): Yellow oil,
92% yield, 89% ee, [α]D27+12.9 (c 0.78, CHCl3); 1H NMR
(CDCl3, 400 MHz): δ 7.70 (d, J = 8.0 Hz, 2H), 7.19-7.05 (m, 7H),
3.16-3.09 (m, 3H), 2.26 (s, 3H), 1.74-1.62 (m, 1H), 1.58-1.48 (m,
1H), 0.70 (t, J = 7.2 Hz, 3H); HPLC (AD-H column, λ = 240 nm,
eluent: n-hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR =
11.67 min (minor), 16.03 min (major).
4.3. General procedure for the enantioselective 1,4-conjugate
addition of α,β,γ,δ-unsaturated ketones
To a flame-dried Schlenk tube charged with chiral ligand L11
(1 mol%, 0.005 mmol) and 5 mL CH2Cl2/MTBE (1:1 v/v),
Cu(OTf)2 (1 mol%, 0.005 mmol) was added and the mixture was
o
stirred at 25 C under N2 atmosphere for an hour. Then mixture
o
4.2.16 (R)-1-(4-methoxyphenyl)-3-phenylpentan-1-one (2p):
was cooled to 0 C. The α,β,γ,δ-unsaturated ketone 4 (0.5 mmol)
1
Yellow oil, 70% yield, 91% ee, [α]D27+4.9 (c 2.00, CHCl3); H
was added at 0 °C, followed by adding diethylzinc (0.75 mL, 1 M
in hexane, 1.5 eq) dropwise via a syringe. After the reaction was
completed (monitored by TLC), 5 mL of an aqueous solution of
NH4Cl were added slowly. The resulting mixture was stirred for
15 minutes, then extracted with dichloromethane (10 mL × 3)
and washed with brine. The organic phase was dried over
anhydrous sodium sulfate, and then concentrated. The resulting
residue was purified by chromatography on silica gel to afford
the desired product 5. Chiral HPLC chromatography was used to
determine the enantiomeric excesses.
NMR (CDCl3, 400 MHz): δ 7.91-7.87 (m, 2H), 7.30-7.26 (m,
2H), 7.24-7.16 (m, 3H), 6.92-6.88 (m, 2H), 3.85 (s, 3H), 3.26-
3.15 (m, 3H), 1.81-1.73 (m, 1H), 1.69-1.60 (m, 1H), 0.80 (t, J =
7.2 Hz, 3H); HPLC (AD-H column, λ = 240 nm, eluent: n-
hexane/i-propanol = 90/10, flow rate: 0.6 mL/min): tR = 18.79
min (minor), 28.76 min (major).
4.2.17 (R)-1,3-di-p-tolylpentan-1-one (2q): Yellow oil, 92%
yield, 90% ee, [α]D27+9.7 (c 0.94, CHCl3); 1H NMR (CDCl3, 400
MHz): δ 7.70 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 7.02-
6.96 (m, 4H), 3.13-3.06 (m, 3H), 2.25 (s, 3H), 2.18 (s, 3H), 1.71-
1.61 (m, 1H), 1.55-1.44 (m, 1H), 0.69 (t, J = 7.2 Hz, 3H); HPLC
(AD-H column, λ = 240 nm, eluent: n-hexane/i-propanol = 90/10,
4.3.1 (R,E)-3-ethyl-1,5-diphenylpent-4-en-1-one (5a): White
o
solid, 84% yield, 94% ee, mp 86.0-87.7 C, [α]D25-93.7 (c 0.48,

8
Tetrahedron
ACCEPTED MANUSCRIPT
1
MeOH); H NMR (CDCl3, 400 MHz): δ 7.95 (d, J = 7.6 Hz,
(OD-H column, λ = 254 nm, eluent: n-hexane/i-propanol = 90/10,
flow rate: 0.9 mL/min): tR = 6.13 min (minor), 6.91 min (major).
2H), 7.55 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.32 - 7.26
(m, 4H), 7.18 (t, J = 7.2 Hz, 1H), 6.39 (d, J = 16.0 Hz, 1H), 6.07
(dd, J = 16.0, 8.4 Hz, 1H), 3.08 (d, J = 6.4 Hz, 2H), 2.89 - 2.80
(m, 1H), 1.66 - 1.58 (m, 1H), 1.52 - 1.41 (m, 1H), 0.94 (t, J = 7.6
Hz, 3H); HPLC (OD-H column, λ = 254 nm, eluent: n-hexane/i-
propanol = 90/10, flow rate: 0.9 mL/min): tR = 7.48 min (minor),
8.99 min (major).
4.3.6 (R,E)-3-ethyl-5-(4-methoxyphenyl)-1-phenylpent-4-en-1-
one (5f): Semi-solid, 81% yield, 93% ee, [α]D20-54.3 (c 2.75,
CH2Cl2); 1H NMR (CDCl3, 400 MHz): δ 7.95 - 7.92 (m, 2H),
7.55 - 7.51 (m, 1H), 7.46 -7.42 (m, 2H), 7.24 (dt, J = 8.8, 2.0 Hz,
2H), 6.81 (dt, J = 8.8, 2.0 Hz, 2H), 6.33 (d, J = 16.0 Hz, 1H),
5.92 (dd, J = 16.0, 8.8 Hz, 1H), 3.77 (s, 3H), 3.05 (d, J = 7.6 Hz.
2H), 2.85 - 2.76 (m, 1H), 1.64 - 1.55 (m, 1H), 1.50 -1.39 (m, 1H),
0.93 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 199.5,
158.7, 137.4, 132.8, 131.0, 130.3, 129.6, 128.5, 128.1 127.1,
113.8, 55.2, 44.1, 40.7, 27.9, 11.7; IR (KBr, cm-1): ν 3026, 2962,
2927, 1686, 1601, 1515, 1446, 1250, 1172, 1035, 967, 822, 753,
685, 608; HRMS (ESI) calcd for C20H23O2 ([M+H]+): 295.1693,
found 295.1690. HPLC (OD-H column, λ = 254 nm, eluent: n-
hexane/i-propanol = 90/10, flow rate: 0.9 mL/min): tR = 8.94 min
(major), 10.49 min (minor).
4.3.2 (R,E)-5-(4-bromophenyl)-3-ethyl-1-phenylpent-4-en-1-
one (5b): Colorless oil, 79% yield, 92% ee, [α]D20-40.8 (c 3.65,
CH2Cl2); H NMR (CDCl3, 400 MHz): δ 7.94 - 7.92 (m, 2H),
1
7.55 - 7.51 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.37 (dt, J = 8.4, 1.2
Hz, 2H), 7.17 - 7.14 (m, 2H), 6.32 (d, J = 16.0 Hz, 1H), 6.05 (dd,
J = 15.6, 8.4 Hz, 1H), 3.06 (d, J = 6.8 Hz, 2H), 2.87 - 2.78 (m,
1H), 1.66 - 1.56 (m, 1H), 1.52 - 1.41 (m, 1H), 0.93 (t, J = 7.6 Hz,
3H); 13C NMR (CDCl3, 100 MHz): δ 199.1, 137.2, 136.3, 134.1,
132.9, 131.4, 129.2, 128.5, 128.0, 127.6, 120.6, 43.7, 40.6, 27.8,
11.7; IR (KBr, cm-1): ν 3029 2964, 2926, 1684, 1596, 1491, 1447,
1367, 1217, 1130, 1068, 1012, 969, 776, 689; HRMS (ESI) calcd
for C19H19BrNaO ([M+Na]+): 365.0511, found 365.0517. HPLC
(AD-H column, λ = 254 nm, eluent: n-hexane/i-propanol = 90/10,
flow rate: 0.9 mL/min): tR = 8.56 min (minor), 9.56 min (major).
4.3.7 (R,E)-1-(4-bromophenyl)-3-ethyl-5-phenylpent-4-en-1-
one (5g): Colorless oil, 84% yield, 91% ee, [α]D20-38.1 (c 5.52,
CH2Cl2); 1H NMR (CDCl3, 400 MHz): δ 7.78 (dt, J = 8.8, 2.0 Hz,
2H), 7.56 (dt, J = 8.4, 2.0 Hz, 2H), 7.31 - 7.24 (m, 4H), 7.20 -
7.15 (m, 1H), 6.38 (d, J = 15.6 Hz, 1H), 6.04 (dd, J = 15.6, 8.8
Hz, 1H), 3.01 (d, J = 6.8 Hz, 2H), 2.85 - 2.76 (m, 1H), 1.65 -
1.55 (m, 1H), 1.50 - 1.39 (m, 1H), 0.93 (t, J = 7.6 Hz, 3H); 13C
NMR (CDCl3, 100 MHz): δ 198.2, 137.2, 135.9, 132.9, 131.8,
130.4, 129.6, 128.4, 128.0, 127.0, 126.0, 43.8, 40.6, 27.8, 11.7;
IR (KBr, cm-1): ν 3012, 3022, 2966, 1687, 1584, 1497, 1394,
1260, 1070, 1008, 962, 813, 773, 690, 495; HRMS (ESI) calcd
for C19H19BrKO ([M+K]+): 381.0251, found 381.0254. HPLC
(OD-H column, λ = 254 nm, eluent: n-hexane/i-propanol = 90/10,
flow rate: 0.9 mL/min): tR = 7.96 min (minor), 17.83 min (major).
4.3.3 (R,E)-5-(4-chlorophenyl)-3-ethyl-1-phenylpent-4-en-1-
one (5c): Colorless oil, 80% yield, 90% ee, [α]D20-46.3 (c 3.21,
CH2Cl2); 1H NMR (CDCl3, 400 MHz): δ 7.94-7.92 (m, 2H), 7.55
-7.51 (m, 1H), 7.46 -7.42 (m, 2H), 7.21 (s, 4H), 6.34 (d, J = 16.0
Hz, 1H), 6.04 (dd, J = 16.0, 8.8 Hz, 1H), 3.06 (d, J = 6.4 Hz, 2H),
2.88 - 2.79 (m, 1H), 1.67 - 1.56 (m, 1H), 1.52 - 1.41 (m, 1H),
0.93 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 199.2,
137.2, 135.9, 133.9, 132.9, 132.5, 129.1, 128.5, 128.5, 128.0,
127.2, 43.7, 40.6, 27.8, 11.7; IR (KBr, cm-1): ν 3028, 2969, 2926,
1683, 1591, 1491, 1447, 1367, 1273, 1217, 1137, 1094, 963, 771,
689; HRMS (ESI) calcd for C19H20ClO ([M+H]+): 299.1197,
found 299.1204. HPLC (AD-H column, λ = 254 nm, eluent: n-
hexane/i-propanol = 90/10, flow rate: 0.9 mL/min): tR = 7.99 min
(minor), 8.97 min (major).
4.3.8 (R,E)-1-(4-chlorophenyl)-3-ethyl-5-phenylpent-4-en-1-
one (5h): Colorless oil, 85% yield, 78% ee, [α]D20-35.0 (c 4.43,
CH2Cl2); 1H NMR (CDCl3, 400 MHz): δ 7.86 (d, J = 8.4 Hz, 2H),
7.40 (d, J = 8.8 Hz, 2H), 7.32 - 7.23 (m, 4H), 7.18 (t, J = 7.2 Hz,
1H), 6.38 (d, J = 16.0 Hz, 1H), 6.04 (dd, J = 15.6, 8.8 Hz, 1H),
3.02 (d, J = 6.8 Hz, 2H), 2.86 - 2.77 (m, 1H), 1.66 - 1.55 (m, 1H),
1.51 - 1.40 (m, 1H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
100 MHz): δ 198.0, 139.3, 137.3, 135.6, 132.9, 130.4, 129.5,
128.8, 128.4, 127.0, 126.0, 43.9, 40.7, 27.8, 11.7; IR (KBr, cm-1):
ν 3011, 3028, 2962, 1687, 1590, 1492, 1399, 1266, 1090, 1008,
962, 813, 746, 695, 525; HRMS (ESI) calcd for C19H20ClO
([M+H]+): 299.1197, found 299.1182. HPLC (OD-H column, λ =
254 nm, eluent: n-hexane/i-propanol = 90/10, flow rate: 0.9
mL/min): tR = 7.31 min (minor), 14.65 min (major).
4.3.4 (R,E)-3-ethyl-5-(4-fluorophenyl)-1-phenylpent-4-en-1-
one (5d): Colorless oil, 84% yield, 93% ee, [α]D20-39.9 (c 2.97,
CH2Cl2); 1H NMR (CDCl3, 400 MHz): δ 7.95-7.93 (m, 2H), 7.53
(t, J = 7.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.28 - 7.23 (m, 2H),
6.97 - 6.91 (m, 2H), 6.35 (d, J = 16.0 Hz, 1H), 5 (dd, J = 16.0,
8.8 Hz, 1H), 3.06 (d, J = 6.4 Hz, 2H), 2.87 - 2.78 (m, 1H), 1.66 -
1.56 (m, 1H), 1.52 - 1.40 (m, 1H), 0.94 (t, J = 7.6 Hz, 3H); 13C
NMR (CDCl3, 100 MHz): δ 199.3, 161.9 (d, J = 245.0 Hz), 137.3,
133.6 (d, J = 2.9 Hz), 132.9 (d, J = 2.2 Hz), 132.9, 129.1, 128.5,
128.0, 127.5 (d, J = 8.0 Hz), 115.2 (d, J = 21.2 Hz), 43.9, 40.6,
27.8, 11.7; IR (KBr, cm-1): ν 3027, 3043, 2963, 1683, 1596, 1447,
1360, 1217, 1155, 1086, 969, 856, 814, 771, 696; HRMS (ESI)
calcd for C19H20FO ([M+H]+): 283.1493, found 283.1488. HPLC
(OD-H column, λ = 254 nm, eluent: n-hexane/i-propanol = 90/10,
flow rate: 0.9 mL/min): tR = 7.30 min (minor), 8.28 min (major).
4.3.9 (R,E)-3-ethyl-1-(4-fluorophenyl)-5-phenylpent-4-en-1-
one (5i): Colorless oil, 86% yield, 93% ee, [α]D20-49.0 (c 4.76,
1
CH2Cl2); H NMR (CDCl3, 400 MHz): δ 7.98 - 7.93 (m, 2H),
7.32 - 7.30 (m, 2H), 7.28 - 7.22 (m, 2H), 7.19 - 7.15 (m, 1H),
7.12 - 7.06 (m, 2H), 6.39 (d, J = 16.0 Hz, 1H), 6.05 (dd, J = 16.0,
8.4 Hz, 1H), 3.03 (d, J = 6.0 Hz, 1H), 2.86 - 2.77 (m, 1H), 1.66 -
1.56 (m, 1H), 1.51 - 1.40 (m, 1H), 0.94 (t, J = 7.6 Hz, 3H); 13C
NMR (CDCl3, 100 MHz): δ 197.6, 165.5 (d, J = 252.3 Hz), 137.3,
133.7 (d, J = 2.9 Hz), 133.0, 130.7 (d, J = 8.8 Hz), 130.4, 128.4,
127.0, 126.0, 115.5 (d, J = 21.2 Hz), 43.8, 40.7, 27.8, 11.7; IR
(KBr, cm-1): ν 3002, 3028, 2961, 1687, 1594, 1507, 1410, 1235,
1157, 968, 833, 773, 690, 598, 489; HRMS (ESI) calcd for
C19H20FO ([M+H]+): 283.1493, found 283.1491. HPLC (OD-H
column, λ = 254 nm, eluent: n-hexane/i-propanol = 90/10, flow
rate: 0.9 mL/min): tR = 6.72 min (minor), 10.97 min (major).
4.3.5 (R,E)-3-ethyl-1-phenyl-5-(p-tolyl)pent-4-en-1-one (5e):
1
Semi-solid, 82% yield, 89% ee, [α]D20-39.5 (c 3.97, CH2Cl2); H
NMR (CDCl3, 400 MHz): δ 7.94 - 7.91 (m, 2H), 7.53 - 7.49 (m,
1H), 7.42 (t, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.06 (d, J
= 8.0 Hz, 2H), 6.35 (d, J = 15.6 Hz, 1H), 6.00 (dd, J = 16.0, 8.8
Hz, 1H), 3.04 (d, J = 6.0 Hz, 2H), 2.86 - 2.77 (m, 1H), 2.29 (s,
3H), 1.66 - 1.55 (m, 1H), 1.50 - 1.39 (m, 1H), 0.93 (t, J = 7.6 Hz,
3H); 13C NMR (CDCl3, 100 MHz): δ 199.4, 137.3, 136.6, 134.6,
132.8, 132.1, 130.1, 129.0, 128.5, 128.0, 125.9, 44.0, 40.7, 27.8,
21.0, 11.7; IR (KBr, cm-1): ν 3025, 3022, 2966, 1687, 1594, 1506,
1446, 1361, 1268, 1224, 1070, 968, 771, 684, 608; HRMS (ESI)
calcd for C20H23O ([M+H]+): 279.1743, found 279.1738. HPLC
4.3.10 (R,E)-3-ethyl-5-phenyl-1-(p-tolyl)pent-4-en-1-one (5j):
1
Semi-solid, 84% yield, 95% ee, [α]D20-52.5 (c 4.24, CH2Cl2); H
NMR (CDCl3, 400 MHz): δ 7.84 (d, J = 8.0 Hz, 2H), 7.32 - 7.22

9
Ye, J. Chin. J. Org. Chem. 2015, 35, 1414-1427; (k) Hayashi,
M.; Matsubara, R. Tetrahedron Lett. 2017, 58, 1793-1805.
(m, 6H), 7.19 - 7.15 (m, 1H), 6.39 (d, J = 16.0 Hz, 1H), 6.06 (dd,
J = 16.0, 8.4 Hz, 1H), 3.03 (d, J = 6.8 Hz, 2H), 2.87 - 2.78 (m,
1H), 2.39 (s, 3H), 1.66 - 1.56 (m, 1H), 1.51 - 1.39 (m, 1H), 0.93
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 199.0, 143.6,
137.5, 134.9, 133.3, 130.2, 129.2, 128.4, 128.2, 126.9, 126.0,
43.8, 40.7, 27.8, 21.5, 11.7; IR (KBr, cm-1): ν 3003, 3022, 2962,
1681, 1610, 1450, 1266, 1183, 1019, 968, 803, 746, 690, 571,
464; HRMS (ESI) calcd for C20H22O ([M+H]+): 279.1743, found
279.1740. HPLC (OD-H column, λ = 254 nm, eluent: n-hexane/i-
propanol = 90/10, flow rate: 0.9 mL/min): tR = 6.36 min (minor),
8.44 min (major).
ACCEPTED MANUSCRIPT
2. For early work on the asymmetric conjugate addition of
organometallic reagents, 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.
1996, 35, 2374-2376.
3. For review, see: (a) Csaky, A. G.; Herran, G. D. L.; Murcia, M. C.
Chem. Soc. Rev. 2010, 39, 4080-4102; (b) Silva, E. M. P.; Silva,
A. M. S. Synthesis 2012, 44, 3109-3128; (c) Schmid, T. E.; Drissi-
Amraoui, S.; Crévisy, C.; Baslé, O.; Mauduit, M. Beilstein J. Org.
Chem. 2015, 11, 2418-2434.
4. For examples, see: (a) Hu, X.; Chen, H.; Zhang, X. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 3518-3521; (b) Shintani, R.; Fu, G. C.
Org. Lett. 2002, 4 , 3699-3702; (c) Hu, Y.; Liang, X.; Wang, J.;
Zheng, Z.; Hu, X. J. Org. Chem. 2003, 68, 4542-4545; (d) Liang,
Y.-X.; Gao, S.; Wan, H.-H.; Hu, Y.-C.; Chen, H.-L.; Zheng, Z.;
Hu, X.-Q. Tetrahedron: Asymmetry 2003, 14, 3211-3217; (e) Liu,
L.-T.; Wang, M.-C.; Zhao, W.-X.; Zhou, Y.-L.; Wang, X.-D.
Tetrahedron: Asymmetry 2006, 17, 136-141; (f) Roma, A. D.;
Ruffo, F.; Woodward, S. Chem. Commun. 2008, 5384-5386; (g)
Xie, Y.-J.; Huang, H.-M.; Mo, W.-M.; Fan, X.-Q.; Shen, Z.-Q.;
Shen, Z.-L.; Sun, N.; Hu, B.-X.; Hu, X.-Q. Tetrahedron:
Asymmetry 2009, 20, 1425-1432; (h) Magrez, M.; Wencel-Delord,
J.; Crevisy, C.; Mauduit, M. Tetrahedron 2012, 68, 3507-3511; (i)
Lega, M.; Margalef, J.; Ruffo, F.; Pàmies, O.; Diéguez, M.
Tetrahedron: Asymmetry 2013, 24, 995-1000; (j) Endo, K.;
Takayama, R.; Shibata, T. B. Synlett 2013, 24, 1155-1159.
5. For copper-catalyzed enantioselective 1,4-conjugate addition of
organozinc reagents to α,β,γ,δ-unsaturated carbonyl compounds,
see: (a) Magrez-Chiquet,M.; Morin, M. S. T. ; Wencel-Delord, J.;
Amraoui, S. D.; Baslé, O.; Alexakis, A.; Crévisy, C.; Mauduit, M.
Chem. Eur. J. 2013, 19, 13663-13667; (b) Morin, M. S. T.; Vives,
T.; Baslé, O.; Crévisy, C.; Ratovelomanana-Vidal, V.; Mauduit,
M. Synthesis 2015, 47, 2570-2577; (c) Drissi-Amraoui, S.; Morin,
M. S. T; Crévisy, C.; Baslé, O.; de Figueiredo, R. M.; Mauduit,
M.; Campagne, J.-M. Angew. Chem. Int. Ed. 2015, 54, 11830-
11834.
4.3.11 (R,E)-3-ethyl-1-(4-methoxyphenyl)-5-phenylpent-4-en-
1-one (5k): Semi-solid, 82% yield, 97% ee, [α]D20-48.3 (c 4.19,
CH2Cl2); 1H NMR (CDCl3, 400 MHz): δ 7.93 (dt, J = 9.2, 2.4 Hz,
2H), 7.31 (d, J = 7.2 Hz, 2H), 7.26 (t, J = 7.6 Hz, 2H), 7.19 - 7.14
(m, 1H), 6.91 (dt, J = 8.8, 2.0 Hz, 2H), 6.39 (d, J = 16.0 Hz, 1H),
6.07 (dd, J = 15.6, 8.4 Hz, 1H), 3.82 (s, 3H), 3.01 (d, J = 7.2 Hz,
2H), 2.87 - 2.78 (m, 1H), 1.66 - 1.56 (m, 1H), 1.50 - 1.39 (m, 1H),
0.93 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ 197.9,
163.3, 137.4, 133.3, 130.4, 130.3, 130.1, 128.4, 126.9, 126.0,
113.6, 55.3, 43.6, 40.8, 27.8, 11.7; IR (KBr, cm-1): ν 3013, 3028,
2956, 1677, 1599, 1512, 1255, 1168, 1029, 962, 829, 746, 695,
602, 510; HRMS (ESI) calcd for C20H23O2 ([M+H]+): 295.1693,
found 295.1691. HPLC (OD-H column, λ = 254 nm, eluent: n-
hexane/i-propanol = 90/10, flow rate: 0.9 mL/min): tR = 9.67 min
(minor), 17.71 min (major).
Acknowledgments
We are grateful for the financial support from Science and
Technology
Commission
of
Shanghai
Municipality
(15ZR1409200), and the Fundamental Research Funds for the
Central Universities.
6. (a) Rexiti, R.; Lu, J.; Wang, G.; Sha, F.; Wu, X.-Y. Tetrahedron:
Asymmetry 2016, 27, 923-929; (b) Xu, N.; Gu, D.-W.; Zi, J.; Wu,
X.-Y.; Guo, X.-X. Org. Lett. 2016, 18, 2439-2442; (c) Rexiti, R.;
Zhang, Z.-G.; Lu, J.; Sha, F.; Wu, X.-Y. J. Org. Chem. DOI:
10.1021/acs.joc.8b02798.
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Supplementary data
Copies of HPLC spectra and NMR spectra associated with this
article can be found in the Supporting Information.