Multinuclear catalyst for copper-catalyzed asymmetric conjugate addition of organozinc reagents

Article abstract of DOI:10.1002/anie.200906839

(Figure Presented) A whole lot o' metal: An efficient copper-catalyzed asymmetric conjugate addition was achieved using a binol-derived ligand. The catalytic system has a turnover number of 2000, and the excellent cata-lytic performance could be attributed to the generation of a multinuclear complex such as 1. binol = 2, 2'-dihydroxy-l, 1'-binaphthyl.

Full text of DOI:10.1002/anie.200906839

Communications
DOI: 10.1002/anie.200906839
Multinuclear Catalyst
Multinuclear Catalyst for Copper-Catalyzed Asymmetric Conjugate
Addition of Organozinc Reagents**
Kohei Endo,* Mika Ogawa, and Takanori Shibata*
Recent progress in metal catalysis has arisen from dramatic
improvements in catalytic performance using multinuclear
complexes. There has been great interest in controlling the
synergistic and cooperative effects between the metal centers
in such complexes; however, the complicated nature and
restriction of the ligand framework make it difficult to design
tri-, tetra-, and multinuclear complexes.[1] For example, there
are excellent reports concerning rhodium- or ruthenium-
linked oligomeric complexes for heterogeneous asymmetric
hydrogenation; the improvement of catalytic activity and
stereoselectivity remains untouched.[2] Therefore, the design
of ligand architectures and the demonstration of excellent
catalytic activity using multinuclear complexes, including
oligomeric complexes, are the next challenge in organic
chemistry. We describe herein the dramatic effect of a
multinuclear complex, having both copper and zinc centers,
upon catalytic performance. 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 acyclic enones. Our working hypothesis is
shown in Scheme 1. The deprotonation reaction of the
phosphorus ligand 1, which bears a hydroxy moiety, by an
organometallic reagent generates metal-linked ligand 2, the
phosphorus moieties of which coordinate to transition-metal
centers to form the tetranuclear complex 3. Such a pliable
ligand scaffold as 1 makes it possible to tune the structural
and electronic features.
The metal-linked scaffold prompted us to examine the
copper-catalyzed asymmetric conjugate addition of organo-
zinc reagents to enones using (R)-3,3’-bis(diphenylphos-
phino)-[1,1’-binaphthalene]-2,2’-diol (L1).[3] To identify the
optimal ligand structure, binol derivatives L1–L3 were
examined (Table 1). The reaction of Et2Zn and (E)-chalcone
(4a) was conducted in the presence of CuCl2·2H2O and the
ligand in THF at either 08C or À208C.[4,5] The reaction using
simple (R)-binol (binol = 1,1’-binaphthol) at 08C was exam-
ined but it did not proceed at all (Table 1, entry 1). In contrast,
the reaction using Et2Zn (1.5 equiv) in the presence of L1 was
complete in 1 hour at 08C to give the product 5a in 67% yield
with 92% ee (Table 1, entry 2). The mixture of CuCl2·2H2O
and L1 in THF gave a white suspension, and when this was
treated with Et2Zn a homogeneous solution resulted. How-
Table 1: Screening of reaction conditions.[a]
Scheme 1. Working hypothesis for the formation of multinuclear com-
plexes.
Entry L (mol%)
R (equiv) T [8C] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
(R)-binol (5)
L1 (5)
L1 (10)
L2 (5)
L1 (5)
L1 (5)
Et (1.5)
Et (1.5)
Et (1.5)
Et (1.5)
Et (3.0)
Et (3.0)
Et (3.0)
Et (3.0)
0
0
0
0
0
24
1
48
72
0.5
0.5
24
24
16
–
67
23
12
96
>98
21
30
89
68
–
92
68
10
91
94
65
71
<1
95
87
[*] Prof. Dr. K. Endo, M. Ogawa, Prof. Dr. T. Shibata
Department of Chemistry and Biochemistry
School of Advanced Science and Engineering, Waseda University
Okubo, Shinjuku, Tokyo 169-8555 (Japan)
Fax: (+81)3-5286-8098
À20
À20
À20
À20
L3 (5)
E-mail: kendo@aoni.waseda.jp
tshibata@waseda.jp
Homepage: http://www.chem.waseda.ac.jp/shibata/
L3 (10)
9
10
11
(R)-binol (5)[d] Et (3.0)
L1 (5)
L1 (5)
Me (3.0)
nBu (3.0) À20
RT 16
[**] K.E. is the recipient of the Teijin Pharma Award in Synthetic Organic
Chemical Society (Japan). This work was supported financially by a
Grant-in-Aid for Young Scientists (B) (No. 21750108) from the
Japan Society for the Promotion of Science and by a Waseda
University Grant for Special Research Projects.
16
93
[a] CuCl2·2H2O (5 mol%) used in all cases. [b] Yields determined based
on NMR spectra. [c] The enantiomeric excess (ee) was determined by
HPLC analysis on a chiral stationary phase (see the Supporting
Information for details). [d] PPh3 (10 mol%) was employed. MOM=
methoxymethyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200906839.
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ever, the use of twice the amount of L1 (10 mol%) relative to
CuCl2·2H2O resulted in a clear yellow solution and a
dramatically decreased reaction rate; the reaction was
quenched after 48 hours and gave the product 5a in 23%
yield with 68% ee (Table 1, entry 3). The reaction using
MOM-protected L2, bearing diphenylphosphino moieties at
the 3,3’-positions, gave a notable result: CuCl2·2H2O and L2
generated an oligomeric gel in THF, and the addition of
diethylzinc did not give soluble complexes. The subsequent
addition of (E)-chalcone (4a) gave an insoluble gel, and the
desired product 5a was obtained in 12% yield and 10% ee
along with large amounts of unknown by-products after
72 hours (Table 1, entry 4). The reaction with L1 using
diethylzinc (3 equiv) at 08C improved the yield to 96% with
91% ee (Table 1, entry 5). The same reaction at À208C gave
better results, and product 5a was obtained in greater than
98% yield with 94% ee (Table 1, entry 6). In contrast, the
monophosphine ligand L3 decreased the reaction rate
(homogeneous solution) and the reaction was not complete
within 24 hours, but the product 5a was produced in low
yields with moderate ee values (Table 1, entries 7 and 8).
These results are similar to those of the reaction using
10 mol% L1 (Table 1, entry 3). Accordingly, the phosphorus
moiety at the 3’-position in L1 is important for the generation
of the multicopper complex as the dramatic increase in
catalytic activity and enantioselectivity relative to L3 is
notable. These findings clarified that the metal centers of
the Cu/Zn/L1 catalyst provided unique catalytic activity
which was not present for the monocopper complex. As
shown in entry 9 of Table 1, the reaction in the presence of
PPh3 (10 mol%) and (R)-binol (5 mol%) gave the product 5a
after 16 hours in 89% yield with less than 1% ee, thereby
indicating that the phosphine and the (R)-binol moieties must
be part of the same molecule to achieve selectivity in the
conjugate addition reaction. The use of other dialkylzincs,
such as Me2Zn and nBu2Zn, gave the products 6a and 7a,
respectively, in high yield with high enantioselectivity
(Table 1, entries 10 and 11). Surprisingly, the reaction pro-
ceeded in the presence of 0.05 mol% of the copper complex
with L1X [Eq. (1); see Table 2 for L1X structure].[6] The
reaction took place at À208C to give the product 5a in 99%
yield (isolated) with 96% ee. A previously reported catalyst
system requires 1 mol% to achieve greater than 80% yield
and greater than 80% ee in the copper-catalyzed asymmetric
conjugate addition of organozinc reagents to acyclic enones,
since the organocopper intermediates are generally unstable
at lower temperatures for a long period of time.[7a,b] Therefore,
we have succeeded in achieving the highest catalytic con-
jugate addition of alkylzinc reagents to acyclic enones to
date.[7a,b]
Additional investigations showed that L1X gave the best
catalytic performance and achieved the highest catalytic
activity (Table 2). The L1X ligand can be used under two
different sets of reaction conditions to promote the asym-
metric conjugate addition of diethylzinc to enones 4a–p. The
results of chalcones bearing electron-donating or electron-
withdrawing groups showed high to excellent yields and
excellent ee values under reaction conditions A (Table 2),
which is superior to existing catalyst systems. Literature
precedent has stated that the electronic nature of the
substituents dramatically affects the catalysis and decreases
the reaction rate.[7c] Modest catalytic performance when
electron-rich chalcones are used is a typical disadvantage of
Table 2: Asymmetric conjugate addition to various enones.[a]
Entry Enone, R
5
Conditions A
Conditions B
Yield ee
Yield
ee
[%][b]
[%][c]
[%][b] [%][c]
1
2
3
4
5
6
7
8
4a, C6H5
5a 91
5b 95
5c 99
5d 97
5e 94
5 f 93
5g 98
>98 (S) 99
98 (+) 93
98 (S) 88
96 (S) 91
>98 (+) 90
98 (À) 90
>98 (S) 82
>98 (À) 91
>98 (À) 90
98 (+) 82
89 (R) 52
96 (+) 91
93 (S) 48
92 (+) 91
96 (S)[d]
94 (+)
93 (S)
90 (S)
95 (+)
94 (À)
94 (S)
97 (À)
96 (À)
91 (+)
72 (R)
97 (+)
81 (S)
81 (+)
4b, 4-FC6H4
4c, 4-ClC6H4
4d, 4-F3CC6H4
4e, 4-MeC6H4
4 f, 4-PhC6H4
4g, 4-MeOC6H4
4h, naphthalene-2-yl 5h 99
9
4i, furan-2-yl
4j, thiophen-2-yl
4k, cyclohexyl
4l, n-C5H11
4m
5i
5j
97
93
10
11
12
13
14
15
5k 91
5l 85
5m 94
4n
5n 92
4o
5o (90)
5p 67 (88)
86 (R) (60) 13 (R)
97 (S)
16[e] 4p
–
–
[a] Reaction conditions A: enone (0.5 mmol), CuCl2·2H2O (0.5 mol%),
L1X (0.5 mol%); reaction conditions B: enone (0.5 mmol), CuCl2·2H2O
(0.05 mol%), L1X (0.05 mol%). [b] Yields of the isolated products. NMR
yields are given within the parentheses. [c] The ee values were deter-
mined by HPLC analysis or GC analysis on chiral stationary phases (see
the Supporting Information for details). The absolute configuration was
determined by comparing the reported specific rotation data or retention
time from HPLC analyses. The + or À signs refer to the optical rotation.
[d] (E)-Chalcone (5 mmol) was used. [e] CuBr·SMe2 (12 mol%) and L1X
(12 mol%) in toluene. Bn=benzyl.
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Communications
the copper-catalyzed asymmetric conjugate addi-
tion of organozinc reagents. In contrast, the
present catalysis using binol derivatives provides
versatile catalytic performance to give the desired
products, even in the presence of 0.5 mol%
catalyst. A notable characteristic of the present
catalysis is that 0.05 mol% catalyst (S/Cu = 2000,
conditions B) is enough to efficiently catalyze the
reaction without any inhibition of the catalytic
activity. These results suggest that additional
modification of the diol architecture and phos-
phorus substituents could improve the catalysis.
The reaction of 4k bearing a cyclohexyl moiety
required 18 hours to give the product 5k in 91%
yield with 89% ee (Table 2, entry 11; condi-
tions A). The reaction of 4k under reaction
conditions B unfortunately delivered the product
5k in 52% yield with 72% ee. The less hindered
enone 4l, bearing an alkyl chain, gave the product
5l in 85% yield with 96% ee after 3 hours
(Table 2, entry 12; conditions A). To date, these
results for 4k and 4l are the best reported thus far
Scheme 2. Proposed structures of the multinuclear complexes.
with respect to the yield and enantioselectivity. Furthermore,
the reaction of 4l under conditions B for 24 hours delivered 5l
in 91% yield with 97% ee (Table 2, entry 12; conditions B).
The reaction using (E)-4-phenylbut-3-en-2-one (4m) under
reaction conditions A gave the desired product 5m in 94%
yield with 93% ee, and under reaction conditions B, 5m was
isolated in 48% yield with 81% ee (Table 2, entry 13).
Furthermore, the use of the dialkyl-substituted enone (E)-
oct-3-en-2-one (4n) resulted in 92% yield of the product
having a 92% ee (Table 2, entry 14; conditions A). The lower
catalyst loading could afford the corresponding product 5n in
91% yield with 81% ee (Table 2, entry 14; conditions B). The
reaction of cyclohex-2-enone (4o) gave the product 5o in
90% yield and 86% ee (Table 2, entry 15; conditions A).
Under the reaction conditions B 4o yielded product with a
dramatically decreased enantioselectivity. The reaction of 4p
using L1X gave 5p, which was isolated in 67% yield, with
superior stereoselectivity; this is the highest enantioselectivity
of 5p reported to date (Table 2, entry 16). Previously
developed ligands can typically not facilitate high catalytic
performance for both cyclic and acyclic enones; for example,
the phosphoramidite ligand generally gives much higher
stereoselectivity in reactions of cyclic enones than in those of
acyclic enones.[5] Consequently, the present ligand system has
a potential advantage of providing the generality for the
asymmetric conjugate addition of organozinc reagents to a
variety of acyclic enones, which might be attributed to the
effect of the multinuclear system.
of complex B with an additional copper center to give a
complex such as D is important for achieving excellent
catalytic performance. We propose that the active catalyst is
formed upon generation of complex D.
The ESI MS analyses of D showed the presence of [D-
(CuBr)2Zn2 + SMe2 + H]+ (m/z 1784.5, 100%) and [B-
(CuBr)Zn2 + SMe2 + H]+ (m/z 1640.8, 22%) as major frag-
ments of the complexes formed in solution (see the Support-
ing Information for details).[9] Although the ESI MS analyses
did not indicate oligomeric complexes, their formation cannot
be ruled out. This data suggest that multinuclear complexes
serve as the predominant species in the described catalysis.
In conclusion, we discovered and demonstrated the
promising behavior of binol derivatives, which established
the efficient copper-catalyzed asymmetric conjugate addition
of organozinc reagents to enones. The highest catalytic
performance was achieved relative to the previously devel-
oped ligand systems for acyclic enones. The experimental
results indicated that the L3–Cu complex was not suitable for
the high catalytic performance; therefore, the L1-type scaf-
folds coordinated to multiple metal centers result in effective
chiral catalysts. We are now investigating the utility of the
present catalyst system for various types of catalytic reactions,
as well as studying the mechanism. The influence of the
combined copper and zinc centers, and the exact structure of
complex in both the solid and liquid states will be disclosed in
due course.
Received: December 4, 2009
Published online: February 23, 2010
The MOM-protected L2 showed poor catalytic perfor-
mance (Table 1, entry 4), which suggests that complexes
derived form L2-type ligands, such as complexes A and C
(Scheme 2), are not active catalysts.[8] Since L3 showed poor
catalytic performance (Table 1, entries 7 and 8), and a 1:2
ratio of CuCl2·2H2O and L1 gave a similarly poor catalytic
performance, it appears that the formed complexes, for
example B, bearing uncoordinated phosphorus moieties are
probably not the active catalysts. Therefore, the coordination
Keywords: alkylation · synthetic methods · copper ·
.
Michael addition · zinc
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