Table 1. Cooperative Effects of Catalytic Asymmetric Aldol (1) (Entries 1-10) and Henry (2) (Entries 11-20) Reaction
entry
catalyst
L2:ZnEt2
yield %a
ee %b
entry
catalyst
L1:ZnEt2
yield %a
ee %b
1
2
3
4
5
6
7
8
9
1% L2
1% L2
1% L2
1% L2
1% L2
1% L2
1% L2
1% L2
2% L2
3% L2
1:0.5
1:1.0
1:1.5
1:2.0
1:2.5
1:3.0
1:3.5
1:4.0
1:1.0
1:1.0
36
57
72
86
94
95
95
95
68
74
25
39
57
86
92
94
95
95
42
41
11
12
13
14
15
16
17
18
19
20
1% L1
1% L1
1% L1
1% L1
1% L1
1% L1
1% L1
1% L1
2% L1
3% L1
1:0.5
1:1.0
1:1.5
1:2.0
1:2.5
1:3.0
1:3.5
1:4.0
1:10
28
44
51
67
80
84
86
89
52
63
29
42
65
84
90
92
92
92
43
45
1
0
1:1.0
a
Isolated after column chromatography. b Enantionmeric excess determined by chiral column.
excess of up to 94%. The use of more than three portions of
ZnEt had little effect on the ee. In justifying the synergistic
The availability of the structurally defined chiral ligands
and their metal complexes have made possible the direct
observation of a cooperative effect in a catalytic asymmetric
reaction. Initially, a series of (R,R)-L2-Zn(II)n (n denotes
the ratio of Zn(II) to the ligand, n ) 1-3) complexes were
investigated as mimics of a class II zinc-containing aldolase.
2
effect, the catalytic efficiency of 2 and 3 mol % mononuclear
catalysts (entries 9 and 10) was tested. The enantioselectivity
of 3 mol % mononuclear catalyst is much lower than that of
1 mol % trinuclear catalyst, thus clearly demonstrating the
existence of an intramolecular cooperativity between the
metallic centers. The cooperative phenomenon was further
proved by investigating a nitroaldol (Henry) reaction using
9
This study received impetus from the success of Trost’s and
Shibasaki’s10 catalysts. In comparison with those catalysts,
3
(R,R)-L2-Zn (II) contains three totally equal subunits in a
unique chemical and steric environment. The simple adjust-
ment of the n value allows for the direct observation of an
intramolecular cooperative effect. By employing the optimal
the (R,R)-L1-Zn
3
(II) system. As indicated in Table 1 (entries
11-20), the dinuclear and trinuclear Zn(II) complexes
display dramatically enhanced reactivity and enantioselec-
tivity when compared with the mononuclear counterpart,
which is lacking in intramolecular cooperation.
7
reaction conditions derived from our former investigation,
3
(R,R)-L2-Zn (II) was found to effectively promote the direct
aldol reaction of 4-nitrobenzaldehyde with acetone. As is
shown in Table 1, increasing the ratio of diethylzinc to (R,R)-
L2 (0.5-3.0) resulted in an increased conversion and ee
within the same time period (entries 1-6). Using 1 mol %
In summary, we report a class of new chiral macrocyclic
ligands. An enantioselective synergism has been observed
in several catalytic asymmetric reactions. Modification of
2 2 2 2 2 2
the macrocyclic donor set from N O to N P or N S may
(R,R)-L2 and 3 mol % Et
2
Zn, the product was obtained in
be expected to bind to more active metal centers. Additional
studies on the synthesis and application of these ligands are
under way in our laboratories. It is believed that chiral
multinuclear complex catalysts will be of use in future
catalytic investigation.
high yield (up to 95%), as well as an excellent enantiomeric
(
5) For enantioselective Henry reaction using heterobimetallic catalysts,
see: (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. 1997,
6, 1236. (b) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am.
Chem. Soc. 1992, 114, 4418.
6) (a) Menif, R.; Martell, A. E.; Squattrito, P. J.; Clearfield, A. Inorg.
Chem. 1990, 29, 4723. (b) Jurek, P. E.; Martell, A. E. Inorg. Chem. 2000,
3
(
Acknowledgment. This work was supported by Welch
Foundation (Grants A-0259 and A-084).
3
2
9, 1016. (c) Gao, J.; Reibenspies, J.; Martell, A. E. Inorg. Chim. Acta
002, 338, 157. (d) Gao, J.; Reibenspies, J.; Martell, A. E. Inorg. Chim.
Acta 2003, 346, 67.
7) (a) Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 2795. (b)
Gao, J.; Martell, A. E. Org. Biomol. Chem. 2003, 1, 2801.
(
Supporting Information Available: Detailed experi-
(
8) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691;
mental procedures, full characterization of the compound
(9) (a) Trost, B. M.; Silcoff, E. R.; Ito, H. Org. Lett. 2001, 3, 2497. (b)
1
-3 and CIF files for 1 and 3. This material is available
Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 5.
10) Kumagai, N.; Matsunaga, S.; Kinoshita, T.; Harada, S.; Okada, S.;
Sakamoto, S.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125,
169.
(
free of charge via the Internet at http://pubs.acs.org.
2
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