Modulation of multifunctional N,O,P ligands for enantioselective copper-catalyzed conjugate addition of diethylzinc and trapping of the zinc enolate

Article abstract of DOI:10.1002/asia.201300544

In this work, we have successfully synthesized a new family of chiral Schiff base-phosphine ligands derived from chiral binaphthol (BINOL) and chiral primary amine. The controllable synthesis of a novel hexadentate and tetradentate N,O,P ligand that contains both axial and sp³-central chirality from axial BINOL and sp³-central primary amine led to the establishment of an efficient multifunctional N,O,P ligand for copper-catalyzed conjugate addition of an organozinc reagent. In the asymmetric conjugate reaction of organozinc reagents to enones, the polymer-like bimetallic multinuclear Cu-Zn complex constructed in situ was found to be substrate-selective and a highly excellent catalyst for diethylzinc reagents in terms of enantioselectivity (up to >99 % ee). More importantly, the chirality matching between different chiral sources, C₂-axial binaphthol and sp³-central chiral phosphine, was crucial to the enantioselective induction in this reaction. The experimental results indicated that our chiral ligand (R,S,S)-L1- and (R,S)-L4-based bimetallic complex catalyst system exhibited the highest catalytic performance to date in terms of enantioselectivity and conversion even in the presence of 0.005 mol % of catalyst (S/C=20 000, turnover number (TON)=17 600). We also studied the tandem silylation or acylation of enantiomerically enriched zinc enolates that formed in situ from copper-L4-complex-catalyzed conjugate addition, which resulted in the high-yield synthesis of chiral silyl enol ethers and enoacetates, respectively. Furthermore, the specialized structure of the present multifunctional N,O,P ligand L1 or L4, and the corresponding mechanistic study of the copper catalyst system were investigated by ³¹P NMR spectroscopy, circular dichroism (CD), and UV/Vis absorption. Match maker: The chiral bimetallic multinuclear Cu-Zn complex that contains a novel phosphine ligand and bears matching axial and sp³-central chirality from binaphthol and chiral amine was found to be a highly efficient catalyst in the enantioselective conjugate addition of an organic zinc reagent. Copyright

Full text of DOI:10.1002/asia.201300544

FULL PAPER
FULL PAPER
Asymmetric Catalysis
Fei Ye, Zhan-Jiang Zheng,
Wen-Hui Deng, Long-Sheng Zheng,
Yuan Deng, Chun-Gu Xia,
Li-Wen Xu*
&&&& — &&&&
Modulation of Multifunctional N,O,P
Ligands for Enantioselective Copper-
Catalyzed Conjugate Addition of
Diethylzinc and Trapping of the Zinc
Enolate
Match maker: The chiral bimetallic
multinuclear Cu Zn complex that con-
tains a novel phosphine ligand and
bears matching axial and sp3-central
chirality from binaphthol and chiral
amine was found to be a highly effi-
cient catalyst in the enantioselective
conjugate addition of an organic zinc
reagent.
À
1
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
L.-W. Xu et al.
DOI: 10.1002/asia.201300544
Modulation of Multifunctional N,O,P Ligands for Enantioselective Copper-
Catalyzed Conjugate Addition of Diethylzinc and Trapping of the Zinc
Enolate
Fei Ye,[a] Zhan-Jiang Zheng,[a] Wen-Hui Deng,[a] Long-Sheng Zheng,[a] Yuan Deng,[a]
Chun-Gu Xia,[b] and Li-Wen Xu*[a, b]
Abstract: In this work, we have suc-
cessfully synthesized a new family of
chiral Schiff base–phosphine ligands
strate-selective and a highly excellent
catalyst for diethylzinc reagents in
terms of enantioselectivity (up to
>99% ee). More importantly, the chir-
ality matching between different chiral
sources, C2-axial binaphthol and sp3-
central chiral phosphine, was crucial to
the enantioselective induction in this
reaction. The experimental results indi-
cated that our chiral ligand (R,S,S)-L1-
and (R,S)-L4-based bimetallic complex
catalyst system exhibited the highest
catalytic performance to date in terms
of enantioselectivity and conversion
even in the presence of 0.005 mol% of
catalyst (S/C=20000, turnover number
(TON)=17600). We also studied the
tandem silylation or acylation of enan-
tiomerically enriched zinc enolates that
formed in situ from copper-L4-com-
plex-catalyzed conjugate addition,
which resulted in the high-yield synthe-
sis of chiral silyl enol ethers and enoa-
cetates, respectively. Furthermore, the
specialized structure of the present
multifunctional N,O,P ligand L1 or L4,
and the corresponding mechanistic
study of the copper catalyst system
were investigated by 31P NMR spec-
troscopy, circular dichroism (CD), and
UV/Vis absorption.
derived
from
chiral
binaphthol
(BINOL) and chiral primary amine.
The controllable synthesis of a novel
hexadentate and tetradentate N,O,P
ligand that contains both axial and sp3-
central chirality from axial BINOL and
sp3-central primary amine led to the es-
tablishment of an efficient multifunc-
tional N,O,P ligand for copper-cata-
lyzed conjugate addition of an organo-
zinc reagent. In the asymmetric conju-
gate reaction of organozinc reagents to
enones, the polymer-like bimetallic
Keywords: asymmetric catalysis
·
conjugate addition · copper · N
ligands · zinc
À
multinuclear Cu Zn complex con-
structed in situ was found to be sub-
Introduction
tronic properties of chiral molecules.[2] In other words,
subtle modification and linking of modular ligands can
easily lead to the dramatic formation of highly efficient li-
gands with excellent enantioselectivity and reactivity.[3]
Inherent in many metal-based asymmetric catalyst systems
is the design and synthesis of versatile chiral ligands because
it has a pivotal influence on catalytic activity and its ability
to impact stereocontrol.[1] The art of designing these chiral
ligands still remains quite empirical for various enantioselec-
tive transformations. In this context, a way to simplify the
design of a consummate chiral ligand is to rely on modular
structures that can take full advantage of steric and elec-
Among various chiral ligands, multifunctional chiral li-
gands are probably the most interesting chiral scaffold used
to promote enantioselective inductions in many enantiose-
lective transformations and have been used to assemble dif-
ferent metals with a coordinate functional group to guaran-
tee the achievement of high enantioselectivity and catalytic
efficiency.[4] C2-axial binaphthol (BINOL) derivatives are
often used as chiral sources for multinuclear metal-based
catalysts and offer promising possibilities for modification
and derivatives,[5] which have expanded the scope of classic
homogeneous catalysis to cooperative catalysis that arises
from the synergistic and cooperative activation of natural
enzyme biocatalysis.[6] In this regard, Endo and Shibata
et al. have recently reported that a BINOL-based tetraden-
tate phosphine ligand was of crucial importance for a bimet-
allic copper–zinc catalyst system in the activation of the car-
bonyl of chalcones, in which the catalytic performance ach-
ieved was much higher than that of previous systems in the
copper-catalyzed asymmetric conjugate addition of organo-
zinc reagents to chalcones.[7] Although enormous research
[a] F. Ye,+ Dr. Z.-J. Zheng,+ W.-H. Deng, L.-S. Zheng, Dr. Y. Deng,
Prof. Dr. L.-W. Xu
Key Laboratory of Organosilicon Chemistry and
Material Technology of Ministry of Education
Hangzhou Normal University, Hangzhou 310012 (P.R. China)
Fax : (+86)571-28865135
E-mail: liwenxu@hznu.edu.cn
[b] Prof. C.-G. Xia, Prof. Dr. L.-W. Xu
State Key Laboratory for Oxo Synthesis and
Selective Oxidation, Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences, Lanzhou 730000 (P.R. China)
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300544.
&
&
2
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
L.-W. Xu et al.
efforts have been devoted to the synthesis of multinuclear
Results and Discussion
metal catalysts, the development of new chiral ligands with
excellent enantioselectivity in catalytic asymmetric reactions
remains a challenge. Therefore, the design and synthesis of
multifunctional chiral ligands associated with the construc-
tion of a multinuclear bimetal catalytic system for asymmet-
ric reactions is highly desired.[8]
The question of how to develop a novel and effective
chiral phosphine ligand with multistereogenic centers
prompted us to investigate the modulation of C2-axial and
sp3-central chirality in the development of highly efficient
and multifunctional catalyst systems for enantioselective
transformations. Considering the highly successful C2-axial
binaphthol (BINOL) and 2,2’-bis(diphenylphosphino)-1,1’-
binaphthyl (BINAP) ligand in asymmetric catalysis, we hy-
pothesized that a BINOL-derived N,O,P ligand that bears
a hydroxyl and chiral amino moiety would be an ideal chiral
ligand that bears axial and sp3-central chirality to coordinate
with different metals to form multinuclear transition-metal
catalysts (Figure 1). Herein, based on the hypothesis that
Synthesis of Multidentate and Multifunctional Phosphine
Ligands
Initially, we designed a hexadentate N,O,P ligand (Figure 1,
type 1) and tetradentate N,O,P ligand (Figure 1, type 2) with
different stereochemistry; they contained a tunable chiral
environment and space around the 3,3’-position of BINOL
(Figure 1) in which one or two imine phosphine molecules
((S)-1-[2-(diphenylphosphino)phenyl]ethanamine (1)) were
linked to BINOL. The assumed multifunctional phosphine
ligand (L1) and its variations in terms of structural diversity
and the C2-axial and sp3-central chirality also needed to be
used for the next catalytic transformation.
Compound 1, which contained a chiral primary amine
motif as a building block for the hexadentate ligand, was
easily prepared from (S)-1-phenylethanamine in moderate
yield (Scheme 1).[9] Simultaneously, two different chiral alde-
Scheme 1. Synthesis of chiral primary-amine-based phosphine as a build-
ing block.
hydes, 3-hydroxy-4-(2-hydroxynaphthalen-1-yl)-2-naphthal-
dehyde and bi-2-hydroxy-3-naphthaldehyde, were prepared
from chiral BINOL in high yields (Scheme 2).[10] Then the
five similar ligands (L1–L5) that contained both axial and
sp3-central chirality were prepared by Schiff base condensa-
tion of chiral primary-amine-based phosphine ligand 1 and
different BINOL-derived aldehydes (2a or 3a, 50–62%
total isolated yield; also see the Supporting Informa-
tion).[10,11] Except for L3, these new multifunctional ligands
featured three different coordinating sites: nitrogen, phos-
phine, and bidentate hydroxyl moiety. Notably, to highlight
the importance of the phosphine center and BINOL back-
bone, the Ar-BINMOL-derived phosphine ligand L6 was
also prepared for the next asymmetric conjugate addition re-
action of organozinc reagents to enone (Scheme 3).[12]
The crystal structure of the chiral ligand L1 is shown in
Figure 2. The phosphine ligand has a large cavity and the
phosphine atoms extend outward due to steric hindrance of
two phenyl groups. This beautiful structure would be a pow-
erful chiral phosphine ligand to achieve high efficiency and
enantioselectivity in asymmetric conjugate addition of orga-
nozinc reagents to enones, which is one of the most useful
techniques for carbon–carbon formation in organic synthe-
sis.[14] Considerable progress in asymmetric copper-catalyzed
conjugate addition of dialkyl zinc reagents has been made
and has generated tremendous interest in past decades.[15] In
addition, the reaction of the organozinc reagent is an illus-
trative and model example of asymmetric multimetallic cat-
Figure 1. Working hypothesis for the construction of multinuclear poly-
metallic or bimetallic complexes: Which is better for catalytic asymmetric
reactions?
the introduction of an sp3-central chiral phosphine to the
chiral BINOL backbone is perhaps effective in the construc-
tion of a modular multinuclear polymetallic metal complex
(type 1) or bimetallic metal catalyst system (type 2) for cata-
lytic asymmetric reactions (Figure 1), we focused on the
design and synthesis of a new family of BINOL-derived
phosphine that bears two types of chiral elements, axial and
sp3-central chirality, and we demonstrate the different cata-
lytic activity of these chiral N,O,P ligands when copper-cata-
lyzed conjugate addition of organozinc reagents to enones is
used as a model reaction.
3
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
L.-W. Xu et al.
Figure 2. Crystal structure of chiral ligand (R,S,S)-L1.
Copper-Catalyzed Conjugate Addition of Et2Zn to Enones
On the basis of the hypothesis of multinuclear bimetallic
catalysis induced by a chiral source that bears both axial
and sp3-central chirality, we then examined these ligands in
the model copper-catalyzed asymmetric conjugate addition
of diethylzinc to a chalcone (Scheme 4 and Table 1). To
Scheme 2. Synthesis of various multidentate ligands containing phosphine
and phenol groups with both axial and central chirality (MOMCl=
methyl chloromethyl ether).
Scheme 4. A model conjugate addition of diethylzinc to chalcone for the
screening of ligands.
Table 1. Screening of reaction conditions for copper-catalyzed conjugate
addition of organozinc reagents to chalcone.[a]
Entry
Ligand
n
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
L4
L4
L4
L4
L4
(S)-1
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
0
À20
À20
À20
À20
À20
À20
14
12
16
12
12
12
12
48
12
12
12
10
10
10
10
10
16
40
15
trace
28
25
70
60
25
25
75
35
92
85
85
80
80
40
84
À25
nd
94
À37
71
7[d]
8
79
87
77
83
84
94
91
94
9[e]
10
11
12
13[f]
14[g]
15[h]
16[i]
17
Scheme 3. Synthesis of chiral Ph-BINMOL-based aldehyde 2c[10b] and
corresponding phosphine ligand L6: a) [1,2]-Wittig rearrangement,[12]
iBuLi, THF, À788C; b) TMSCl (TMS=trimethylsilyl), NaI; c) NaH,
MOMCl; d) nBuLi, DMF, Et2O; e) HCl, THF; and f) CH2Cl2/EtOH, at
room temperature.
50
82
14
[a] Reaction conditions: chalcone (1 mmol), CuACTHNURTGNENG(U OTf)2 (1 mol%), chiral
alysis.[13] Thus these observations inspired us with the confi-
dence to study the catalytic activity of the new binaphthyl-
modified phosphine and its analogues (L1–L6) as well as the
chiral primary-amine-based phosphine ligand (S)-1 in the
model and enantioselective copper-catalyzed asymmetric
conjugate addition of organozinc reagents to enones.
ligand (L1–L3: 1.2 mol%; L4–L6: 2.2 mol%). [b] Isolated yields. [c] The
enantiomeric excess (ee) was determined by HPLC analysis on a chiral
stationary phase (see the Supporting Information for details); nd=not
determined. [d] 0.6 mol% of (R,S,S)-L1 was employed. [e] 1,4-Dioxane
was employed as a solvent in this case. [f] Toluene was employed as a sol-
vent. [g] CuCl2 was employed as a catalyst. [h] THF was employed as
a solvent. [i] CH2Cl2 was employed as a solvent.
&
&
4
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
L.-W. Xu et al.
identify the optimal ligand structure and metal system,
a series of copper salts in combination with chiral ligands
was evaluated as enantioselective catalysts for the conjugate
addition of Et2Zn to chalcone 6a. These experiments led to
cellent enantioselectivity (Table 1, entries 4 and 12; 94% ee)
in the presence of 1.2 or 3 equiv Et2Zn, in which the latter
conditions led to better isolated yield (92%; Table 1,
entry 12). This work suggests that monophosphine L4 is
a promising ligand in this reaction. Subsequent study of the
effect of different solvents showed that the enantioselectivi-
ty was also sensitive to the solvent. On the basis of these re-
sults, with the tetradentate ligand L4, we employed Cu-
the determination of CuACHTUNTRGNEUNG(OTf)2 (OTf=trifluoromethanesul-
fonate) as the best copper source in this reaction.[16] And
then the six phosphine ligands that involved a Schiff base
with the illustrated absolute configuration were investigated
to confirm various levels of enantioselection. The represen-
(OTf)2 and Et2O at low temperature (À208C) in the follow-
tative results from the ligand survey with Cu
N
ing studies of substrate scopes, and some other choices, such
as ligand L1, might also be effective.
marized in Table 1 (entries 1–6). From this survey and com-
parison, the novel BINOL-modified phosphine L1 that con-
tains the Schiff base derived from (R)-BINOL and (S)-1-
phenylethanamine emerged as a promising multifunctional
chiral ligand (84% ee). Notably and interestingly, ligand
(S,S,S)-4a (L2) and ligand (S,S)-4c (L5) derived from (S)-
BINOL and (S)-1-phenylethanamine exhibited poor activity
in enantiomeric induction; they were incapable of achieving
good yield and high enantioselectivity (only 25 or 37% ee,
respectively; Table 1, entries 2 and 5). This result showed
that the stereochemistry of the BINOL backbone played
a crucial role in this copper-catalyzed conjugate addition.
Moreover, the mismatch between different chiral sources,
C2-axial binaphthol and sp3-central chiral phosphine, re-
vealed that the geometric orientation of BINOL-derived
phosphine was crucial to the enantioselective induction in
this reaction. It should be noted that both the phosphine
and hydroxyl moiety also proved to be very important in
this reaction because almost no desired product was detect-
ed in the presence of phosphine-group-free ligand L3
(Table 1, entry 3) and only moderate enantioselectivity and
yield was obtained with Ar-BINMOL-derived ligand L6
under the same reaction conditions (Table 1, entry 6).
With the optimized conditions and tetradentate ligand L4
in hand, the scope of the copper-catalyzed conjugate addi-
tion reaction of various chalcones was explored (Scheme 5).
Although the enantioselective induction of hexadentate
ligand L1 was not good in this reaction, further optimization
of this process showed that the reaction might be performed
with a lower amount of ligand L1 because 0.6 mol% of L1
(Cu/L1=1.7:1) was found to be enough to give better yields
(60%) and good enantioselectivity (Table 1, entry 7,
79% ee). Interestingly, a large amount of unidentified by-
products was detected when the reaction was prolonged to
48 h (Table 1, entry 8). Other solvents were also not suitable
media for this reaction; for example, low yield and de-
creased enantioselectivity of the desired product 7a was ob-
tained in 1,4-dioxane (77% ee, 25% yield; Table 1, entry 9).
Increasing the amount of Et2Zn to 3 equiv led to the im-
provement of the isolated yield (75%; Table 1, entry 10),
whereas with 1.2 equiv of Et2Zn it was found to proceed
smoothly but resulted in poor isolated yield because of
a large amount of unidentified byproducts. Interestingly, in-
creasing the reaction temperature to 08C also gave poor
yield (35%) with no change in enantioselectivity (Table 1,
entry 11). These results showed that hexadentate ligand L1
was not suitable for the copper-catalyzed conjugate addition
of diethylzinc to chalcone in terms of enantioselectivity (up
to 87% ee) and moderate yield (up to 75% isolated yield).
On a more positive note, the tetradentate ligand L4 gave ex-
Scheme 5. Asymmetric Cu/L4-catalyzed conjugate addition of a diethyl
zinc reagent to various chalcones.
In general, excellent enantiomeric excesses (90–98% ee)
and good-to-excellent isolated yields (75–97%) were ob-
served for aromatic chalcones 6a–m that bear either elec-
tron-withdrawing or electron-donating groups. Furyl and
styryl substituents did not show any adverse effect on the
conjugate addition (94% ee for 7l and 7m). As summarized
À
in Scheme 5, the present asymmetric copper L4 catalyst
system was synthetically useful and applicable to various
chalcones because all reactions were performed with only
1 mol% of copper and 2.2 mol% of chiral ligand L4.
The attempt to expand substrate scopes of various enones
in the copper-catalyzed conjugate addition was also carried
out in the presence of hexadentate ligand L1 and tetraden-
tate ligand L4. Fortunately, the substrate scope of the pres-
5
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
L.-W. Xu et al.
Table 2. Copper-catalyzed conjugate addition of Et2Zn to 4-phenylbute-
none and its analogues (8).
Scheme 6. Copper-catalyzed asymmetric conjugate addition of diethylzinc
to a,b-unsaturated acylsilane.
Entry
R1
Conditions[a]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
H
H
A
B
B
A
B
A
B
A
B
A
B
A
B
B
A
B
B
9a: 85
9a: 90
9b: 80
9c: 82
9c: 97
9d: 98
9d: 95
9e: 94
9e: 86
9 f: 90
9 f: 99
9g: 99
9g: 81
9h: 96
9i: 99
9i: 90
9j: 80
98
>99
97
99
>99
97
99
97
98
97
98
97
98
>99
97
the corresponding chiral acylsilane 11 in good enantioselec-
tivity (82% ee) and moderate isolated yield (Scheme 6, 60%
isolated yield).
On the basis of the excellent catalytic efficiency of multi-
dentate phosphine ligands in these experimental results, we
investigated the conjugate addition of Et2Zn to chalcone
(6a) or 4-phenylbutenone (8a) with low catalyst loading.
The results of the attempts to reduce catalyst loading are
summarized in Scheme 7. Initially, we found that 0.05 mol%
m-OMe
p-OMe
p-OMe
o-OMe
o-OMe
m-Br
m-Br
p-Br
p-Br
p-Cl
9
10
11
12
13
14
15[d]
16[d]
17
p-Cl
p-CF3
2-naphthyl
2-naphthyl
p-Ph
99
98
[a] Reaction conditions A: enone 8 (1 mmol), Cu
ligand L1 (1.2 mol%); conditions B: enone
ACHTUNGTRENNUNG
8
ACHTUNGTRENNUNG
(0.5 mol%), chiral ligand L5 (1.1 mol%). [b] Isolated yields. [c] The
enantiomeric excess (ee) was determined by HPLC analysis on a chiral
stationary phase. [d] The enone is (E)-4-(naphthalen-2-yl)but-3-en-2-one.
ent catalyst system has proven to be very wide, and the best
enantioselectivity was achieved with an almost optically
pure form (99% ee) with 1 mol% of copper and 1.2 mol%
of L1 (conditions A) or with 0.5 mol% of copper and
1.1 mol% of L4 (conditions B). As shown in Table 2, differ-
ent from the above findings, both ligand L1 and L4 resulted
in superior enantioselectivities (ꢀ97% ee) and excellent iso-
lated yields (up to 99%) in the conjugate addition of 4-phe-
nylbutenone and its analogues (8). Thus, the present hexa-
dentate ligand L1-derived catalyst system has a potential
substrate-selective characteristic to discriminate between the
reactivity of acyclic enones and chalcones in terms of enan-
tioselectivity. Particularly with the use of tetradentate ligand
L4 for the copper-catalyzed conjugate addition, most of the
substrates resulted in almost perfect enantioselectvities
(99% ee), and the electronic and steric properties of b-aryl
substituents did not affect the selectivity. Clearly, for these
substrates shown in Table 2, the catalytic performance in
terms of enantioselectivity achieved by the use of ligand L1
or L4 has reached a new level relative to that of previous
systems with copper catalysis.[17]
Scheme 7. A model example of highly efficient and enantioselective con-
jugate addition of ZnEt2 to 4-phenylbutenone.
of copper catalyst was good enough in terms of enantiose-
lectivity and yield for the desired product 7a in the presence
of tetradentate ligand L4. Surprisingly, when 4-phenylbut-3-
en-2-one was used as a model substrate in the copper-cata-
lyzed conjugate addition of diethylzinc reagent, even with
the hexadentate ligand L1, the reaction could also proceed
Although acylsilane is well documented to be an unstable
compound relative to that of corresponding ketones with
a similar structure,[18] the fact that a,b-unsaturated acylsilane
was used as a special enone is interesting and worthy of in-
vestigation. Herein, we found that the (E)-3-phenyl-1-(tri-
methylsilyl)prop-2-en-1-one (10) was reactive with diethyl-
zinc in the presence of ligand L4, in which the reaction gave
À
smoothly in the presence of 0.025 mol% of copper L1 com-
plex (S/C=4000). As shown in Scheme 7, the conjugate ad-
dition reactions were completed within 12 h when using
0.025–0.1 mol% catalyst to afford product 9a in good isolat-
ed yields and excellent enantioselectivities (TON=900–
&
&
6
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
L.-W. Xu et al.
3480, 87–90% isolated yields, 97–98% ee). Importantly, the
conversion and enantioselectivity remained high when the
reaction was performed with 0.01 mol% of catalyst (S/C=
10000), which gave the gram-scale product in notable 75%
yield (isolated) and 92% ee (TON=7500) with little inhibi-
tion of the catalytic activity. More importantly, the tetraden-
tate ligand L4 exhibited higher catalytic efficiency in this re-
action. To compare the catalytic activity of L4, we chose
vestigated the conjugate-addition-initiated silylation of chal-
cone 6a by using 1 mol% Cu(OTf)2 under optimal condi-
tions with tetradentate ligand L4. The reaction gave the cor-
responding product 12a with excellent enantioselectivity,
high Z selectivity, and good yield (Table 3, entry 1). Thus it
AHCTUNGTRENNUNG
Table 3. Copper-catalyzed conjugate addition–silylation.[a]
0.005 mol% of CuACHTUNGTRENNUNG(OTf)2 as a model. It is clear that ligand
L4 is highly effective in this reaction, because 98% ee and
88% yield of the desired product 9a was achieved under
these conditions (Scheme 7; the highest TON is 17600). We
Entry
R1
R1
Yield [%][b]
ee [%][c]
Z/E[d]
À
believe that the amount of catalyst system (Cu L4) could
1
2
3
4
5
6
7
8
9
H
p-Me
p-Me
H
H
H
p-Cl
H
H
H
H
12a: 75
12b: 82
12c: 83
12d: 83
12e: 70
12 f: 85
12g: 83
12h: 73
12i: 75
12j: 78
94
92
92
93
92
90
91
>99
91
90
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
be reduced to some extent. Therefore, we have succeeded in
the development of a highly efficient catalytic system for
the conjugate addition of alkyl zinc reagent to acylic enones
with the best catalytic performance to date.[19]
p-Me
p-Me
p-Br
p-Cl
H
p-F
p-CF3
H
Trapping of the Zinc Enolates: Conjugate Addition–
Silylation and Conjugate Addition–Acylation
10
p-CF3
The common feature of asymmetric copper-catalyzed conju-
gate addition of organozinc reagents is the generation of
enantiomerically enriched zinc enolates. Thus trapping of
the zinc enolate with an electrophile could be a conjugate-
addition-initiated tandem transformation, which would
quickly lead to more complex molecules.[20] In light of the
importance of silyl enol ethers for organic synthesis,[21] it
would be desirable to prepare them by trapping zinc eno-
lates with a silylating reagent in situ (Scheme 8). In addition,
[a] Reaction conditions: enone 6 (1 mmol), CuACTHNURTGNENG(U OTf)2 (1 mol%), chiral
ligand L4 (2.2 mol%), TMSCl (2 equiv). [b] Isolated yields. [c] The enan-
tiomeric excess (ee) after desilylation to the corresponding ketone was
determined by HPLC analysis on a chiral stationary phase. [d] The ratio
1
of Z/E was determined by GC-MS and H NMR spectroscopy.
is clear that a (Z)-zinc enolate intermediate was formed in
this conjugate addition of diethylzinc to chalcone. As previ-
ously observed, substituted groups on the aryl ring almost
have no negative effect on the tandem conjugate addition–
silylation reaction. Whereas we used in situ formed zinc
enolates and chlorotrimethylsilane for the initial develop-
ment of conjugate addition–silylation, purification of these
silyl enol ethers was a nontrivial task due to the hydrolysis
of the desired compounds on chromatography supports. As
shown in Table 3, the results of this reaction suggest that
various air-stable and enantiomerically enriched (Z)-silyl
enol ethers could be easily prepared by the tandem copper-
catalyzed conjugate addition–silylation of chalcones.
As a potential alternative to silylation trapping of zinc
enolates, tandem conjugate addition–acylation has been
demonstrated successfully in recent years.[23] The formation
of a more stable enolacetate derived from enantiomerically
enriched zinc enolates would thus be a special way to pre-
pare chiral esters. We therefore continued to study the pos-
sibility of acylation for the trapping of zinc enolates. With
the conditions developed above in hand, we next investigat-
ed the acylation of zinc enolates. As expected, similarly to
the copper-catalyzed conjugate–silylation reaction, the use
of acetic anhydride as an alternative electrophile to trap
zinc enolate led to the high-yield preparation of enoacetates.
As shown in Table 4, this methodology could be applied to
various chalcones. For all the substrates investigated, the
chiral enoacetates were formed in good yields over the two-
step addition/acylation sequence. After recognizing the ef-
Scheme 8. Trapping of zinc enolates with water and chlorotrimethylsilane
(TMSCl).
the selective silylation of zinc enolate intermediates might
also shed some light on the mechanism of copper-catalyzed
conjugate addition of diethylzinc reagent in the presence of
multidentate phosphine ligand L1 or L4.
Inspired by previous findings of enantioselective copper-
catalyzed conjugate addition–silylation of zinc enolates,[22]
we studied the tandem silylation of enantiomerically en-
À
riched zinc enolates that formed in situ from copper L4
complex-catalyzed conjugate addition. In the present
copper-catalyzed conjugate addition–silylation, we first in-
7
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
L.-W. Xu et al.
Table 4. Copper-catalyzed conjugate addition-acylation.[a]
Entry
R1
R1
Yield [%][b]
ee [%][c]
Z/E[d]
1
2
3
4
5
6
7
8
H
p-Me
p-Me
H
H
H
p-Cl
H
H
p-CF3
Styryl
H
H
13a: 80
13b: 80
13c: 83
13d: 77
13e: 75
13 f: 82
13g: 80
13h: 82
13i: 77
13j: 81
13k: 85
94
92
92
93
92
90
91
>99
91
90
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
p-Me
p-Me
p-Br
p-Cl
H
p-F
p-CF3
H
9
10
11
H
94
[a] Reaction conditions: enone 6 (1 mmol), CuACTHNURTGNENG(U OTf)2 (1 mol%), chiral
ligand L4 (2.2 mol%), Ac2O (2 equiv). [b] Isolated yields. [c] The enan-
tiomeric excess (ee) after deacylation to the corresponding ketone was
determined by HPLC analysis on a chiral stationary phase. [d] The ratio
1
of Z/E was determined by GC-MS and H NMR spectroscopy.
fectiveness of copper-catalyzed conjugate addition–silylation
and conjugate addition–acylation, we anticipated that the
present pathway to trap zinc enolates would feature mild
conditions, good yield, low catalyst loading, and high diaste-
reoselectivity, as well as the inherently high level of enantio-
selectivity of asymmetric conjugate addition.
Figure 3. Schematic view of the self-assembled construction of a multinu-
clear polymetallic complex of L1.
It would be interesting to confirm the formation of
a copper- and zinc-based polymetallic complex with hexa-
dentate phosphine ligand L1. General spectral analysis
would be useful for the elucidation of the present catalyst
system. However, the instability of diethylzinc in air made it
difficult to recover the polymetallic catalyst after reaction.
With such promising findings in copper-catalyzed conjugate
addition of the diethylzinc reagent to chalcone, we proposed
that hexadentate phosphine ligand L1 could work with both
copper and zinc as a multinuclear bimetallic complex to ac-
tivate chalcone in this reaction because the zinc metal
linked with two hydroxyl groups in the BINOL-derived
phosphine was important for achieving excellent catalytic
performance. Therefore the effect of a second metal linked
with a diol moiety on the enantioselectivity of copper-cata-
lyzed conjugate addition of Et2Zn to chalcone 6a in the
presence of hexadentate phosphine ligand L1 would be im-
portant. In addition, although the enantioselective activity
of L1 is not good, we expected that the impact of a second
metal salt on enhancing the chirality or weakening the enan-
tioselectivity and reactivity would also supplement our struc-
tural elucidation of the catalyst system.
Mechanistic Study of Copper-Based Bimetallic Catalyst
Systems
Although it is premature to discuss details of the mechanism
of the whole catalytic cycle induced by the copper or bimet-
À
allic copper zinc catalytic system, it is necessary to reveal
the specialized structure of the multifunctional phosphine
ligand L1 or L4 and the corresponding copper catalyst
system that involves zinc- or titanium-based coordination.
Being aware of the X-ray structure of the chiral ligand L1
shown in Figure 1, we assumed that the protracted geometry
with Schiff base linked chiral phosphine oriented toward the
vacant apical positions would be beneficial to the construc-
tion of bimetallic multinuclear or polymetallic complex de-
rived from copper and titanium or zinc.
On the basis of the above reaction results, we hypothe-
sized that the intermolecular interaction and coordination of
Schiff base–phosphine ligand L1 or L4 with copper in the
presence of the second metal (Zn or Ti) led to the in situ
formation of a polymer-like metal-based network (Figure 3).
For hexadentate ligand L4, it is reasonable to deduce that
the bimetallic complex with a large cavity or hole in this
polymetallic complex exhibited promising size-selective acti-
vation among aromatic ketone-derived chalcones (6) and
acetone-derived enones (8) as well as discrimination be-
tween enantioselectivity and reactivity during the addition
of Et2Zn to enones.
Initially, on the basis of the hypothesis that the ligation of
zinc to ligand would be crucial to the excellent enantioselec-
tivity and reactivity, we examined the effectiveness of the
second metal catalyst instead of zinc in the copper-catalyzed
asymmetric conjugate addition of organozinc reagents. In
the first screening, we investigated Ti
ACHUTNGTNERNUG(OiPr)4, AlACHTUNGTRENNUNG(OiPr)3,
InBr3, Ni(OAc)2, KOtBu, and Si(OEt)4, which could be
A
ACHTUNGTRENNUNG
treated with the BINOL moiety to form a BINOLate metal
&
&
8
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
L.-W. Xu et al.
Table 5. The effect of the second metal catalyst on copper-catalyzed con-
jugate addition of Et2Zn to chalcone.[a]
the chalcone molecule in its extended conformation does
not fit into this rigid coordination environment completely.
The large difference between enones 8 and 10 can be ration-
alized on the basis of the position of the methyl group and
bulky trimethylsilyl group that control the relative orienta-
tion between the polymetallic catalyst system and substrates.
Consistent with the schematic view in Figure 3, the self-as-
sembled construction of the possible polymer-like multinu-
clear bimetallic complexes with a particular cavity is fea-
tured along with substrate sensitivity in the conjugate addi-
tion of organozinc reagents to enones, in which the catalytic
behavior is similar to the metal–organic framework (MOF)-
based catalyst.[25,26]
Entry
x equiv
Et2Zn
R
M2
[1.5 mol%]
t
Yield
[%][b]
ee
[h]
[%][c]
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
3.0
3.0
3.0
3.0
3.0
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
–
14
18
16
48
12
18
12
12
12
12
12
40
70
50
trace
50
trace
75
90
88
85
85
84
83
53
–
55
–
83
87
55
97
98
Ti
Al
InBr3
Ni(OAc)2
Si(OEt)4
ACHTUNGTRENNUNG
U
E
To gain information on the structure of the copper and
ligand L1-based polymetallic complex, we initially carried
out a UV spectra and circular dichroism (CD) analysis of
E
–
Ti
KOtBu
Ti(OiPr)4
(OiPr)4
9
10
11
À
the chiral ligand L1 and the metal (Cu, Ti, Cu Ti) com-
A
plexes, respectively. Although we were unsuccessful in ob-
taining the X-ray structure of the exact copper/zinc- or
copper/titanium-based multinuclear metal complexes, circu-
lar dichroism (CD) was an especially powerful method to
study the orientation of the molecules within the metal com-
plex. It has been reported to be a powerful analytical tool
for the study of supramolecular recognition or complicated
metal-based macromolecular catalyst systems.[27]
–
[a] Reaction conditions: chalcone (1 mmol), CuACTHNURGTNEUNG(OTf)2 (1 mol%), the
second metal compound (M2, 1.5 mol%), chiral ligand L1 (1.2 mol%).
[b] Isolated yields. [c] The enantiomeric excess (ee) was determined by
HPLC analysis on a chiral stationary phase (see the Supporting Informa-
tion for details).
complex[24] as cocatalyst in this copper-catalyzed conjugate
addition of Et2Zn to chalcone 6a. As shown in Table 5,
these metal compounds had a promising effect on the con-
version and enantioselectivity. The results in Table 5 as well
as Table 1 also supported the notion that the combined use
of copper and zinc or titanium resulted in a novel multinu-
clear catalyst system. The superior levels of reaction effi-
The UV spectra and circular dichroism (CD) spectra of
À
the chiral ligand L1 and the metal (Cu, Ti, Cu Ti) com-
plexes are provided in Figure 4 (also see the Supporting In-
ciency observed with 1.5 mol% of TiACTHNUTRGNENUG(OiPr)4 in the presence
of 1.2 equiv Et2Zn (70 versus 40% yield; Table 5, entries 1
and 2) or 3.0 equiv Et2Zn (90 versus 75% yield and 87
versus 83% ee; Table 5, entries 7 and 8), prompted us to
consider that the ligation of Ti with the BINOL backbone
led to a better polymetallic catalyst system. Notably, as
shown in entries 10 and 11 of Table 5, the use of TiACTHUNRGTNEUNG(OiPr)4
still retained excellent enantioselectivity (97% ee) relative
to that of the titanium-free reaction conditions. During the
experiments, we observed that the titanium-based copper-
catalyst system was also found to be effective in the conju-
gate addition of various chalcones (up to 93% ee; see the
Supporting Information), which also provided an efficient
procedure to synthesize chiral ketones catalyzed by a Cu/
Zn/Ti-based multimetallic catalyst.
Figure 4. CD spectra of chiral ligand (R,S,S)-L1 and the mixture of
On the basis of these control experiments and the facts
summarized in Table 5 for the bimetallic conjugate addition
of diethylzinc to chalcone, it seems reasonable that the
ligand-linked bimetallic catalyst system did indeed exhibit
a dramatic acceleration of the conjugate addition. However,
it is difficult to explain why the reactivity is largely different
between chalcones 6 and enones 8 in the presence of hexa-
dentate phosphine ligand L1. The substrate-sensitive
copper/zinc-based bimetallic complex might result in a rigid
polymetallic material of a certain size (Figure 3), in which
(R,S,S)-L1 with Ti
ACHTNUGRTEN(UGNN OiPr)4, CuAHCUTNRTGEGNN(NU OTf)2, and the combined use of TiACHTUNGTRENNUNG(OiPr)4
and Cu(OTf)2 in CH2Cl2.
AHCTUNGTRENNUNG
formation). As expected, coordination of the chelating hexa-
dentate phosphine ligand L1 to Cu, Ti, or bimetallic Cu Ti
caused considerable changes in the CD spectra (Figure 4).
The CD spectra of ligand L1 exhibit two major signature
bands that correspond to naphthyl p–p* transitions at 225
and 257 nm for L1. For the bimetallic complex derived from
À
9
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
L.-W. Xu et al.
the combined use of titanium and copper, it allows for the
construction of a Ti-Cu-L1-based polymetallic complex
upon guest coordination, thus resulting in larger geometry
changes for the chirality moiety and giving rise to larger
changes in the CD spectra (210–250 nm; Figure 4) due to
phenyl p–p* transitions at 218 nm. The CD spectra of the
À
À
copper L1 complex and titanium L1 complex exhibited dif-
ferent signature bands at 220–238 nm owing to the different
coordination or interaction in which titanium is linked with
the oxygen atom of the BINOL backbone and copper is co-
ordinated with the phosphine or nitrogen atom of the Schiff
base moiety. Similarly, the CD spectra of the chiral ligand
À
L4 and the metal (Cu, Ti, Cu Ti) complexes (Figure 5) also
Figure 6. ESI(+)-MS for the mixture of Cu
L4.
ACHTUNGRTEN(NUNG OTf)2 with phosphine ligand
conditions. Figure 6 shows that the ESI(+)-MS data identi-
fied the chiral copper-L4 complex intermediate of m/z
1264.63. In another regard, the negative results of the MS
À
analysis of copper L1 also supported the existence of the
possible polymetallic complex (Figure 3) but not a simple
small-molecule copper complex or dimeric complex.
The possibility of a polymetallic complex was also con-
firmed by 31P NMR spectroscopy (Figure 7). 31P NMR spec-
Figure 5. CD spectra of chiral ligand (R,S)-L4 and the mixture of (R,S)-
L4 with TiACHTUNGTRENNUNG(OiPr)4 or CuACHTUNGTRENNUNG(OTf)2 in CH2Cl2.
supported the notion that the coordination of copper and
phosphine resulted in notable changes in the CD spectra.
Specifically, the most intense band maxima shift by about
16 nm (from 264 to 280 nm). Therefore, when it comes to
the catalytic asymmetric conjugate reaction with the
À
À
copper L4 or L1 system, we propose that the observed re-
action that results in this conjugate addition might be attrib-
uted to the effect of the chiral ligand L1 or L4 that contains
both axial and sp3-central chirality oriented toward the as-
sembled formation of an ordered copper-linked polymetallic
complex. We believe that the steric hindrance of the chiral
Schiff base around the dihydroxy groups in hexadentate
ligand L1 is responsible for its lack of reactivity with diethyl-
zinc, which led to the decrease of enantioselectivity and re-
activity relative to that of tetradentate ligand L4.
Figure 7. 31P NMR spectra of chiral ligand (R,S,S)-L1 and the mixture of
(R,S,S)-L1 with Ti
and Cu(OTf)2.
ACHTNUGRTEN(UGNN OiPr)4, CuAHCUTNRTGEGNN(NU OTf)2, and the combined use of TiACHTUNGTRENNUNG(OiPr)4
AHCTUNGTRENNUNG
troscopy revealed no interaction between titanium and the
phosphine center, although there was strong and competi-
tive coordination of copper with nitrogen and the phosphine
center. The 31P NMR spectra of the Ti/Cu-based catalyst
system showed unordered signals, thereby implying that the
Ti-Cu-L1 complex has a complicated structure due to the
possibility of polymetallic coordination with the phosphine
ligand. Thus, similarly to previous reports,[3–8] the novel mul-
tifunctional chiral phosphine was formed through noncova-
Another attempt to elucidate the Ti-Cu-L1-based poly-
metallic complex by ESI-MS and MALDI-TOF MS analysis
was unsuccessful at present owing to the probably high mo-
lecular weight, and the possible interpenetrating network of
this complex. We then performed an ESI(+)-MS analysis of
the mixture of copper and tetradentate L4 under the same
À
lent-interaction-driven assembly as well as O M (Zn or Ti)
bond-forming coordination.
&
&
10
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
L.-W. Xu et al.
Conclusion
Experimental Section
Reagents were purchased from commercial sources and were used as re-
ceived unless noted otherwise. Reactions were monitored by thin-layer
chromatography using silica gel. All the reactions that dealt with air- or
moisture-sensitive compounds were carried out in a dry reaction vessel
under positive pressure of argon. Air- and moisture-sensitive liquids and
solutions were transferred with a syringe or a stainless-steel cannula.
1H NMR spectra were recorded at 400 MHz; chemical shifts are reported
in ppm relative to tetramethylsilane (TMS) with the solvent resonance
employed as the internal standard (CDCl3 at d=7.26 ppm). 13C NMR
spectra were recorded at 100 MHz; chemical shifts are reported in ppm
from TMS with the solvent resonance as the internal standard (CDCl3 at
d=77.20 ppm). 31P NMR spectra were recorded at 162 MHz; chemical
shifts for phosphorous are reported in ppm referenced to the phospho-
rous resonance of phosphoric acid (d=0 ppm). ESI-MS analysis of the
samples was conducted using an LCQ Advantage mass spectrometer
(ThermoFisher Company, USA) equipped with an ESI ion source in the
positive-ionization mode, with data acquisition using the Xcalibur soft-
ware (Version 1.4). CH2Cl2 was dried and distilled over CaH2. THF and
Et2O were distilled from sodium benzophenone ketyl. Aldehydes and ti-
tanium tetraisopropoxide were used after distillation.
In summary, we have successfully synthesized a new family
of chiral Schiff base–phosphine ligands derived from chiral
binaphthol (BINOL) and chiral primary amine. The control-
lable synthesis of a new family of multifunctional Schiff
base–phosphine ligands (HZNU-Phos) that contain both
axial and sp3-central chirality from axial BINOL and sp3-
central primary amine led to the establishment of an effi-
cient multifunctional phosphine ligand for copper-catalyzed
conjugate addition of organozinc reagents. Thus, we have es-
tablished a highly efficient and enantioselective catalyst
system comprised of a bimetallic copper–zinc complex for
conjugate addition of organic zinc reagents to aromatic
enones. In the asymmetric conjugate reaction of organozinc
reagents to enones, the polymer-like bimetallic multinuclear
À
Cu Zn complex constructed in situ was found to be a sub-
strate-selective and excellent catalyst for the diethylzinc re-
agent in terms of enantioselectivity (up to >99% ee). More
importantly, the match in chirality between different chiral
sources, C2-axial binaphthol and sp3-central chiral phos-
phine, was crucial to the enantioselective induction in this
reaction. The experimental results indicated that our chiral
ligand (R,S,S)-L1 and (R,S)-L4-based bimetallic complex
catalyst system exhibited the highest catalytic performance
to date in terms of enantioselectivity and conversion, even
in the presence of 0.005 mol% of catalyst (S/C=20000,
TON=17600). We also studied the tandem silylation or acy-
lation of enantiomerically enriched zinc enolates that were
CCDC-913453 ((R,S,S)-L1) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif.
X-ray Diffraction
Data sets were collected using Bruker APEX DUO and Bruker APEX-
II CCD diffractometers. Programs used: For data collection Bruker
APEX2,[28a] data reduction Bruker SAINT, absorption correction multi-
scan, structure solution SHELX-97,[28b] structure refinement SHELXL-
97,[28b] and for graphics Bruker SHELXTL.[28b] The detailed procedures
for the synthesis of every chiral ligand and copper-catalyzed conjugate
addition of organozincs to enones have been provided in the Supporting
Information. In the copper-catalyzed conjugate addition of diethylzinc to
enones, both method A and method B with different N,O,P ligands led to
the same products (see the Supporting Information); their differences
are only in terms of the enantiomeric excesses. These different reaction
results have been collected in the product characterization.
À
formed in situ from copper L4-complex-catalyzed conjugate
addition, which resulted in the high-yield synthesis of chiral
silyl enol ethers and enoacetates, respectively. Furthermore,
the specialized structure of multifunctional phosphine ligand
L1 or L4 was investigated and a corresponding mechanistic
study of the copper-catalyst system was carried out by
means of 31P NMR spectroscopy, circular dichroism (CD),
and UV/Vis absorption. On the basis of the above measure-
ments, we suggest that the intermolecular interaction and
coordination of Schiff base–phosphine ligand L1 with
copper in the presence of the second metal (Zn or Ti) led to
the in situ formation of a polymer-like network and dynamic
chiral multinuclear bimetallic complex, which resulted in
highly efficient activation of enone and spectacular enantio-
selective induction. Thus it is an important complementary
method to the asymmetric synthesis of various optically
active b-ethyl ketones because a new level of catalytic per-
formance was reached relative to the previously reported
chiral phosphine ligand systems for acyclic enones, especial-
ly for 4-phenylbutenone and its analogues (with a high TON
and up to 99% ee). Further investigations into the substrate-
sensitive mechanism and the intricate structure of this poly-
metallic complex are currently underway and will be report-
ed in due course.
Representative Procedure for Copper-Catalyzed Conjugate Addition of
Et2Zn to Enones
A
flame-dried Schlenk tube was charged with CuACTHGNUTRENNU(G OTf)2 (3.6 mg,
0.01 mmol) and (R,S,S)-L1 (11.0 mg, 0.012 mmol) under an N2 atmos-
phere, and the mixture was dissolved in dry Et2O (3.0 mL). The solution
was stirred at room temperature for 30 min and then cooled to À208C.
Diethylzinc (3.0 mmol, 3.0 mL of 1m toluene solution) was added drop-
wise to the above solution. Enone (1.0 mmol) was added at once to the
clear yellow solution. The mixture was stirred at À208C for 9–12 h before
being quenched with aqueous saturated NH4Cl. The layers were separat-
ed, and the aqueous layer was extracted with ethyl acetate (5 mL twice).
The combined organic layers were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by column chromatog-
raphy on silica gel to give the addition product. The enantiomeric excess
of the product was determined by chiral HPLC. The detailed experimen-
tal procedures and characteristics of corresponding products are provided
in the Supporting Information.
Acknowledgements
This project was supported by the National Natural Science Foundation
of China (no. 21173064), the Zhejiang Provincial Natural Science Foun-
dation of China (Q12B020037), and the Program for Excellent Young
Teachers in Hangzhou Normal University (HNUEYT; JTAS 2011-01-
014). L.-W.X. thanks Professor G.-Q. Lai, Professor J.-X. Jiang, Dr. X.-Q.
Xiao, Ms. F.-E. Zhu, Dr. K.-Z. Jiang, and Dr. C.-Q. Sheng of HZNU for
11
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

www.chemasianj.org
L.-W. Xu et al.
their helpful suggestions. L.-W.X. also thanks Professor M. Shibasaki and
Professor M. Kanai (at The University of Tokyo) for their past help and
guidance in copper catalysis and multinuclear catalysis.
[8] For selected reviews, see: a) Y. H. Gao, L. W. Xu, C. G. Xia, J. Mol.
Catal. 2008, 22, 565–575; b) J. Park, S. Hong, Chem. Soc. Rev. 2012,
41, 6931–6943.
[9] The starting ligand L1 was prepared from (S)-1-phenylethanamine
according to the previous literature: J. D. Huang, X. P. Hu, Z. C.
Duan, Q. H. Zeng, S. B. Yu, J. Deng, D. Y. Wang, Z. Zheng, Org.
Lett. 2006, 8, 4367–4370.
[10] The BINOL-derived aldehydes 2a and 2b were prepared according
to previous literature: a) H. C. Zhang, W. S. Huang, L. Pu, J. Org.
Chem. 2001, 66, 481–487; the synthesis of BINMOL-derived alde-
hyde has been reported very recently: b) F. Li, Z. J. Zheng, J. Y.
Shang, K. Z. Jiang, G. Q. Lai, J. X. Jiang, L. W. Xu, Chem. Asian J.
2012, 7, 2008–2013.
[1] For recent reviews, see: a) J. Magano, J. R. Dunetz, Chem. Rev.
2011, 111, 2177–2250; b) J. H. Xie, S. F. Zhu, Q. L. Zhou, Chem.
Rev. 2011, 111, 1713–1760; c) F. A. Almeida Paz, J. Klinowski,
S. M. F. Vilela, J. P. C. Tomꢁ, J. A. S. Cavaleiro, J. Rocha, Chem. Soc.
Rev. 2012, 41, 1088–1110; d) D. Gorin, B. D. Sherry, F. D. Toste,
Chem. Rev. 2008, 108, 3351–3378; e) G. Chelucci, Chem. Soc. Rev.
2006, 35, 1230–1243.
[11] a) Y. N. Belokon, D. Chusov, D. A. Borkin, L. Yashkina, A. V. Dmi-
triev, D. Katayev, M. North, Tetrahedron: Asymmetry 2006, 17,
2328–2333; b) T. Tanaka, Y. Sano, M. Hayashi, Chem. Asian J. 2008,
3, 1465–1471; c) F. F. Guo, D. L. Chang, G. Y. Lai, T. Zhu, S. S.
Xiong, S. J. Wang, Z. Y. Wang, Chem. Eur. J. 2011, 17, 11127–11130.
[12] a) G. Gao, F.-L. Gu, J.-X. Jiang, K. Jiang, C.-Q. Sheng, G.-Q. Lai,
L.-W. Xu, Chem. Eur. J. 2011, 17, 2698–2703; b) G. Gao, X. F. Bai,
H. M. Yang, J. X. Jiang, G. Q. Lai, L. W. Xu, Eur. J. Org. Chem.
2011, 5039–5046; c) G. Gao, X. F. Bai, F. Li, L. S. Zheng, Z. J.
Zheng, G. Q. Lai, K. Jiang, F. Li, L. W. Xu, Tetrahedron Lett. 2012,
53, 2164–2166.
[13] a) Multinuclearmetallic Catalysts in Organic Synthesis (Eds.: M. Shi-
basaki, Y. Yamamoto), Wiley-VCH, Weinheim, 2004; b) A. Hajra,
N. Yoshikai, E. Nakamura, Org. Lett. 2006, 8, 4153–4155; c) D. An-
selmo, E. C. Escudero-Adan, J. Benet-Buchholz, A. W. Kleij, Dalton
Trans. 2009, 7368–7373; d) D. R. Armstrong, W. Clegg, P. Garcia-
Alvarez, M. D. McCall, L. Nuttall, A. R. Kennedy, L. Russo, E.
Hevia, Chem. Eur. J. 2011, 17, 4470–4479; e) Y. N. Cheng, H. L.
Wu, P. Y. Wu, Y. Y. Shen, B. B. Uang, Chem. Asian J. 2012, 7, 2921–
2924; f) I. D’Auria, M. Lamberti, M. Mazzeo, S. Milione, G. Roviel-
lo, C. Pellecchia, Chem. Eur. J. 2012, 18, 2349–2360.
[14] For recent examples, see: a) M. Magrez, J. Wencel-Delord, A. Alex-
akis, C. Crevisy, M. Mauduit, Org. Lett. 2012, 14, 3576–3579; b) O.
Dogan, A. Bulut, S. Polat, M. A. Tecimer, Tetrahedron: Asymmetry
2011, 22, 1601–1604; c) D. Hobuss, A. Baro, K. V. Axenov, S. La-
schat, W. Frey, Eur. J. Inorg. Chem. 2011, 384–392; d) M. Welker, S.
Woodward, L. F. Veiros, M. J. Calhorda, Chem. Eur. J. 2010, 16,
5620–5629; e) M. Sada, T. Furuyama, S. Komagawa, M. Uchiyama,
S. Matsubara, Chem. Eur. J. 2010, 16, 10474–10481; f) M. Sada, S.
Matsubara, J. Am. Chem. Soc. 2010, 132, 432–433; g) J. Wencel-
Delord, A. Alexakis, C. Crevisy, M. Mauduit, Org. Lett. 2010, 12,
4335–4337; h) A. Quintard, A. Alexakis, Adv. Synth. Catal. 2010,
352, 1856–1860; i) A. Lemire, A. Cote, M. K. Janes, A. B. Charette,
Aldrichimica Acta 2009, 42, 71–83; j) J. Wencel, M. Mouduit, H.
Henon, S. Kehrli, A. Alexakis, Aldrichimica Acta 2009, 42, 43–50.
[15] For recent examples, see: a) A. P. Xing, C. B. Bai, L. L. Wang, Tetra-
hedron 2013, 69, 455–459; b) B. H. Lipshutz, S. L. Huang, W. W. Y.
Leong, G. F. Zhong, N. A. Isley, J. Am. Chem. Soc. 2012, 134,
19985–19988; c) K. Dohi, J. Kondo, H. Yamada, R. Arakawa, S. Sa-
kaguchi, Eur. J. Org. Chem. 2012, 7143–7152; d) L. Zhang, G. Q.
Yang, C. R. Shen, S. Arghib, W. B. Zhang, Tetrahedron Lett. 2011,
52, 2375–2378; e) L. Palais, L. Babel, A. Quintard, S. Belot, A.
Alexakis, Org. Lett. 2010, 12, 1988–1991; f) S. H. Gou, Z. B. Ye,
Z. Y. Huang, Appl. Organomet. Chem. 2009, 23, 541–545; g) Y. L.
Chen, R. Frohlich, D. Hoppe, Tetrahedron: Asymmetry 2009, 20,
1144–1149; h) T. Thaler, P. Knochel, Angew. Chem. 2009, 121, 655–
658; Angew. Chem. Int. Ed. 2009, 48, 645–648; i) H. Hꢁnon, M.
Mauduit, A. Alexakis, Angew. Chem. 2008, 120, 9262–9264; Angew.
Chem. Int. Ed. 2008, 47, 9122–9124; j) K. Selim, T. Soeta, K. I.
Yamada, K. Tomioka, Chem. Asian J. 2008, 3, 342–350.
[2] For selected examples, see: a) B. M. Trost, D. L. Vanvranken, C.
Bingel, J. Am. Chem. Soc. 1992, 114, 9327–9343; b) T. M. Gierasch,
M. Chytil, M. T. Didiuk, J. Y. Park, J. J. Urban, S. P. Nolan, G. L.
Verdine, Org. Lett. 2000, 2, 3999–4002; c) F. Blume, S. Zemolka, T.
Fey, R. Kranich, H. G. Schmalz, Adv. Synth. Catal. 2002, 344, 868–
883; d) Y. Mata, O. Pꢂmies, M. Diꢁguez, Chem. Eur. J. 2007, 13,
3296–3304; e) M. Diꢁguez, O. Pꢂmies, Chem. Eur. J. 2008, 14, 3653–
3669; f) S. L. Shi, L. W. Xu, K. Oisaki, M. Kanai, M. Shibasaki, J.
Am. Chem. Soc. 2010, 132, 6638–6639; g) M. Coll, K. Ahlford, O.
Pꢂmies, H. Adlofsson, M. Diꢁguez, Adv. Synth. Catal. 2012, 354,
415–427; h) X. M. Wang, F. Y. Meng, Y. Wang, Z. B. Han, Y. J.
Chen, L. Liu, Z. Wang, K. L. Ding, Angew. Chem. 2012, 124, 9410–
9416; Angew. Chem. Int. Ed. 2012, 51, 9276–9282; i) X. F. Jia, Z.
Wang, C. G. Xia, K. L. Ding, Chem. Eur. J. 2012, 18, 15288–15295;
j) M. Coll, O. Pꢂmies, M. Diꢁguez, Adv. Synth. Catal. 2013, 355,
143–160; k) J. Mazuela, O. Pꢂmies, M. Diꢁguez, Chem. Eur. J. 2013,
19, 2416–2432.
[3] Privileged Chiral Ligands and Catalysts (Eds.: Q. L. Zhou), Wiley-
VCH, Singapore, 2011.
[4] a) M. Shibasaki, N. Yoshikawa, Chem. Rev. 2002, 102, 2187–2209;
b) K. Majima, R. Takita, A. Okada, T. Oshima, M. Shibasaki, J. Am.
Chem. Soc. 2003, 125, 15837–15845; c) S. Matsunaga, T. Yoshida, H.
Morimoto, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2004, 126,
8777–8785; d) J. M. Takacs, D. S. Reddy, S. A. Moteki, D. Wu, H.
Palencia, J. Am. Chem. Soc. 2004, 126, 4494–4495; e) M. Shibasaki,
S. Matsunaga, Chem. Soc. Rev. 2006, 35, 269–279; f) Z. Chen, H.
Morimoto, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2008,
130, 2170–2171; g) B. M. Trost, C. Muller, J. Am. Chem. Soc. 2008,
130, 2438–2439; h) Y. Du, L. W. Xu, Y. Shimizu, K. Oisaki, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2008, 130, 16146–16147;
i) M. Shibasaki, M. Kanai, S. Matsunaga, N. Kumagai, Acc. Chem.
Res. 2009, 42, 1117–1127; j) D. Mendoza-Espinosa, B. Donnadieu,
G. Bertrand, Chem. Asian J. 2011, 6, 1099–1103; k) R. Bellini, J. I.
van der Vlugt, J. N. H. Reek, Isr. J. Chem. 2012, 52, 613–629; l) S.
Matsunaga, M. Shibasaki, Synthesis 2013, 421–437.
[5] a) J. M. Brunel, Chem. Rev. 2005, 105, 4233–4274. and J. M. Brunel,
Chem. Rev. 2007, 107, PR1–45; b) M. Berthod, G. Mignani, G.
Woodward, M. Lemaire, Chem. Rev. 2005, 105, 1801–1836; c) P. Ko-
ˇ
ˇ
´
ˇ
ˇ
covsky, S. Vyskocil, M. Smrcina, Chem. Rev. 2003, 103, 3213–3245.
[6] For recent examples, see: a) S. Mouri, Z. Chen, H. Mitsunuma, M.
Furutachi, S. Matsunaga, M. Shibasaki, J. Am. Chem. Soc. 2010, 132,
1255–1257; b) R. M. Haak, S. J. Wezenberg, A. W. Kleij, Chem.
Commun. 2010, 46, 2713–2723; c) Y. Liu, J. Rawlston, A. T. Swann,
T. Takatani, C. D. Sherrill, P. J. Ludovice, M. Weck, Chem. Sci. 2011,
2, 429–438; d) J. Park, K. Lang, K. A. Abboud, S. Hong, Chem. Eur.
J. 2011, 17, 2236–2245; e) P. W. N. M. van Leeuwen, D. Rivillo, M.
Raynal, Z. Freixa, J. Am. Chem. Soc. 2011, 133, 18562–18565;
f) T. R. Ward, Acc. Chem. Res. 2011, 44, 47–57; g) P. Ballester, A.
Vidal-Ferran, P. W. N. M. Van Leeuwen, Adv. Catal. 2011, 54, 63–
126, and references therein.
[16] Other copper salts, such as Cu
screened in combination with ligand L1 and L6 and CH2Cl2 as sol-
vent, but were found to be inferior to Cu(OTf)2. For example, when
L6 was used as a ligand, the desired product 7a was obtained only
in low to moderate enantioselectivity: Cu(OAc)2, 21% ee; CuI,
ACHTUNGERTN(NUNG OAc)2, CuCl, CuI, and CuBr, were
[7] a) K. Endo, M. Ogawa, T. Shibata, Angew. Chem. 2010, 122, 2460–
2463; Angew. Chem. Int. Ed. 2010, 49, 2410–2413; b) K. Endo, D.
Hamada, S. Yakeishi, M. Ogawa, T. Shibata, Org. Lett. 2012, 14,
2342–2345; c) K. Endo, D. Hamada, S. Yakeishi, T. Shibata, Angew.
Chem. 2013, 125, 634–638; Angew. Chem. Int. Ed. 2013, 52, 606–
610.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
55% ee; CuBr, 50% ee. For ligand L1, it is also necessary to note
&
&
12
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

www.chemasianj.org
L.-W. Xu et al.
that other solvents including 1,4-dioxane, CH2Cl2, toluene, and THF
resulted in poorer enantioselectivity (up to 77% ee) and low yield
(for example, entry 9 of Table 1).
2001, 57, 2371–2378; c) M. Vuagnous-d’Augustin, A. Alexakis, Tet-
rahedron Lett. 2007, 48, 7408–7412.
[24] For selected examples of zinc-linked binolates, see: a) N. Yoshikawa,
N. Kumagai, S. Matsunaga, G. Moll, T. Ohshima, T. Suzuki, M. Shi-
basaki, J. Am. Chem. Soc. 2001, 123, 2466–2467; b) N. Kumagai, S.
Matsunaga, T. Kinoshita, S. Harada, S. Okada, S. Sakamoto, K. Ya-
maguchi, M. Shibasaki, J. Am. Chem. Soc. 2003, 125, 2169–2178; Se-
lected examples of titanium-linked binolates: c) K. Mikami, Y. Mo-
toyama, M. Terada, J. Am. Chem. Soc. 1994, 116, 2812–2820; d) H.
Hanawa, T. Hashimoto, K. Maruoka, J. Am. Chem. Soc. 2003, 125,
1708–1709; e) X. S. Wang, X. W. Wang, H. C. Guo, Z. Wang, K. L.
Ding, Chem. Eur. J. 2005, 11, 4078–4088; f) H. L. Bao, J. Zhou, Z.
Wang, Y. L. Guo, T. P. You, K. L. Ding, J. Am. Chem. Soc. 2008,
130, 10116–10127; g) D. J. Ramꢆn, M. Yus, Chem. Rev. 2006, 106,
2126–2208.
[17] a) K. Soai, S. Yokoyama, T. Hayasaka, K. Ebihara, J. Org. Chem.
1988, 53, 4148–4149; b) A. Alexakis, J. Vastra, P. Mangeney, Tetra-
hedron Lett. 1997, 38, 7745–7748; c) X. Hu, H. Chen, X. Zhang,
Angew. Chem. 1999, 111, 3720–3723; Angew. Chem. Int. Ed. 1999,
38, 3518–3521; d) H. Mizutani, S. J. Degrado, A. H. Amir, J. Am.
Chem. Soc. 2002, 124, 779–781; e) A. Alexakis, C. Benhaim, S.
Rosset, M. Humam, J. Am. Chem. Soc. 2002, 124, 5262–5263; f) R.
Shintani, G. C. Fu, Org. Lett. 2002, 4, 3699–3702; g) A. P. Duncan,
J. L. Leighton, Org. Lett. 2004, 6, 4117–4119; h) S. Brꢃse, S. Hçfen-
er, Angew. Chem. 2005, 117, 8091–8093; Angew. Chem. Int. Ed.
2005, 44, 7879–7881; i) A. Alexakis, J. E. Bꢃckvall, N. Krause, O.
Pꢂmies, M. Diꢁguez, Chem. Rev. 2008, 108, 2796–2823; j) L. Palais,
A. Alexakis, Chem. Eur. J. 2009, 15, 10473–10485; k) H. Yu, F. Xie,
Z. Ma, Y. Liu, W. Zhang, Adv. Synth. Catal. 2012, 354, 1941–1947;
l) M. Magaly, J. Wencel-Delord, C. Crꢁvisy, M. Mauduit, Tetrahe-
dron 2012, 68, 3507–3511; m) H. Yu, F. Xie, Z. Ma, Y. Liu, W.
Zhang, Org. Biomol. Chem. 2012, 10, 5137–5142.
[25] a) C. D. Wu, A. Hu, L. Zhang, W. Lin, J. Am. Chem. Soc. 2005, 127,
8940–8941; b) C. Zapilko, Y. Liang, W. Nerdal, R. Anwander,
˘
Chem. Eur. J. 2007, 13, 3169–3176; c) S. Horike, M. Dinca, K.
Tamaki, J. R. Long, J. Am. Chem. Soc. 2008, 130, 5854–5855;
d) T. B. Liao, Y. Ling, Z. X. Chen, Y. M. Zhou, L. H. Weng, Chem.
Commun. 2010, 46, 1100–1102; e) Q. R. Fang, D. Q. Yuan, J. Scul-
ley, J. R. Li, Z. B. Han, H. C. Zhou, Inorg. Chem. 2010, 49, 11637–
11642; f) H. Ohta, Y. Uozumi, Y. M. A. Yamada, Chem. Asian J.
2011, 6, 2545–2549; g) X. M. Lin, T. T. Li, Y. W. Wang, L. Zhang,
C. Y. Su, Chem. Asian J. 2012, 7, 2796–2804; h) J. M. Roberts, B. M.
Fini, A. A. Sajeant, O. K. Farha, J. T. Hupp, K. A. Scheidt, J. Am.
Chem. Soc. 2012, 134, 3334–3337; i) Y.-X. Tian, Y.-P. He, J. Zhang,
Chem. Mater. 2012, 24, 4711–4716; j) Z. J. Zhang, L. P. Zhang, L.
Wojtas, M. Eddaoudi, M. J. Zaworotko, J. Am. Chem. Soc. 2012,
134, 928–933.
[18] a) X. F. Bai, G. Gao, Z. J. Zheng, F. Li, G. Q. Lai, K. Z. Jiang, F. W.
Li, L. W. Xu, Synlett 2011, 3031–3035; b) H. Azuma, K. Okano, H.
Tokuyama, Chem. Lett. 2011, 40, 959–961; c) M. Honda, T. Nakaji-
ma, M. Okada, K. Yamaguchi, M. Suda, K. K. Kunimoto, M. Segi,
Tetrahedron Lett. 2011, 52, 3740–3742; d) M. Honda, M. Segi, J.
Synth. Org. Chem. Jpn. 2010, 68, 601–613.
[19] The reaction reported by Shibata et al. (see Ref. [7]) using
0.01 mol% of copper catalyst resulted in a promising 40% yield for
chalcone substrate 6a and using 0.05 mol% of catalyst resulted in
48% yield and 81% ee for 4-phenylbutenone 8a. The previous
method showed decreased catalytic activity in the presence of
0.1 mol% of catalyst: a) Y. Takahashi, Y. Yamamoto, K. Katagiri,
H. Danjo, K. Yamaguchi, T. Imamoto, J. Org. Chem. 2005, 70, 9009–
9012; b) K. Ito, S. Eno, B. Saito, T. Katsuki, Tetrahedron Lett. 2005,
46, 3981–3985; c) K. Kawamura, H. Fukuzawa, M. Hayashi, Org.
Lett. 2008, 10, 3509–3512.
[26] Some chiral or multifunctional ligand-derived MOFs have been
found to be size-selective catalysts in various transformations (see
Ref. [25b,h]). Unfortunately, we do not have enough evidence to
support the formation of a porous metal–organic framework in this
case. Therefore, we only discuss the formation of possible poly-
metallic catalyst systems that most likely comprise the high enantio-
selective induction and substrate-sensitive structural feature.
[27] a) Supramolecular Chemistry, 2nd ed. (Eds.: J. W. Steed, J. L.
Atwood), Wiley, New York, 2009; b) S. S. Hu, J. Y. Li, J. F. Xiang, J.
Pan, S. Z. Luo, J. P. Cheng, J. Am. Chem. Soc. 2010, 132, 7216–7228;
c) A. Milo, R. Neumann, Adv. Synth. Catal. 2010, 352, 2159–2165;
d) N. Nishiguchi, T. Kinuta, Y. Nakano, T. Harada, N. Tajima, T.
Sato, M. Fujiki, R. Kuroda, Y. Matsubara, Y. Imai, Chem. Asian J.
2011, 6, 1092–1098; e) H. M. Y. Ahmed, N. Coburn, D. Dini, J. J. D.
de Jong, C. Villani, W. R. Browne, J. G. Vos, Inorg. Chem. 2011, 50,
5861–5863; f) S. Shinoda, K. Terada, H. Tsukube, Chem. Asian J.
2012, 7, 400–405; g) L. Cheng, L. M. Zhang, S. H. Gou, Q. N. Cao,
J. Q. Wang, L. Fang, CrystEngComm 2012, 14, 3888–3893; h) W.
Yang, K.-Z. Jiang, X. Lu, H.-M. Yang, L. Li, Y. Lu, L.-W. Xu,
Chem. Asian J. 2013, 8, 1182–1190.
ˇ
ˇ
[20] a) Z. Galestokovꢄ, R. Sebesta, Eur. J. Org. Chem. 2012, 6688–6695;
b) G. K. Jarugumilli, C. Y. Zhu, S. P. Cook, Eur. J. Org. Chem. 2012,
1712–1715; c) K. Kawamura, H. Fukuzawa, M. Hayashi, Bull.
Chem. Soc. Jpn. 2011, 84, 640–647; d) G. K. Jarugumilli, S. P. Cook,
Org. Lett. 2011, 13, 1904–1907; e) K. Li, A. Alexakis, Chem. Eur. J.
2007, 13, 3765–3771.
[21] a) I. Kuwajima, E. Nakamura, Acc. Chem. Res. 1985, 18, 181–187;
b) D. Cahard, P. Duhamel, Eur. J. Org. Chem. 2001, 1023–1031;
c) “Product Subclass 16: Silyl Enol Ethers”: S. Kobayashi, K.
Manabe, H. Ishitani, J. I. Matsuo in Science of Synthesis: Houben-
Weyl Methods of Molecular Transformations, Vol. 4, 2002, pp. 317–
369; d) W. Zi, S. Yu, D. Ma, Chem. Asian J. 2011, 6, 573–579.
[22] a) J. P. Gourvꢅs, R. Ruzziconi, L. Vilarroig, J. Org. Chem. 2001, 66,
617–619; b) O. Knopff, A. Alexakis, Org. Lett. 2002, 4, 3835–3837;
c) M. D. Clift, R. J. Thomson, J. Am. Chem. Soc. 2009, 131, 14579–
14583.
[28] a) Bruker, APEX and SAINT. Bruker AXS inc., Madison, Wiscon-
sin, USA; b) G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, A64,
112.
[23] a) R. K. Boeckman, D. K. Heckendorn, R. L. Chinn, Tetrahedron
Lett. 1987, 28, 3551–3554; b) I. M. Pastor, M. Yus, Tetrahedron
Received: April 19, 2013
Published online: && &&, 0000
13
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ