tions, chiral indium(III) complexes are water-tolerant cata-
lysts. However, existing chiral indium(III) complexes are not
reactive enough, and their applications are limited. Therefore,
one of the major challenges in this field is to design more
reactive chiral indium(III) complexes which can substantially
expand their utility. In this paper, we showed that the chiral
In(III)-pybox complex designed based on counterion effect
is much more reactive than the corresponding parent
complex. With the catalysis of this more powerful chiral
indium(III) complex, the less reactive asymmetric ketone-
ene reactions6 of trifluoropyruvates proceeded smoothly
under mild conditions to afford the biologically important
enantioenriched tertiary homoallylic alcohols with excellent
enantioselectivities and yields.
We have recently demonstrated that the indium(III)-pybox
complex is an effective catalyst for asymmetric carbonyl-
ene reactions of glyoxylates.4a Unfortunately, long reaction
times (4-6 days) were required for completing the reactions.
Furthermore, this catalyst system is too mild to catalyze the
less reactive ketone-ene reaction (Table 1, entry 1). Coun-
anion will lead to a more reactive indium(III)-pybox
complex which derived from a main group metal.
To test this idea, we started with the highly electronegative
-
“noncoordinating” anion SbF6 , which is usually used.
Initially, the ketone-ene reaction of methyl trifluoropyruvate
and R-methylstyrene was carried out in the presence of chiral
indium(III) complex, which was formed in situ from 12 mol
% pybox 1 and 10 mol % InCl3. There was only a trace
amount of product formed after stirring at room temper-
ature for two days (monitored by TLC). When 30 mol %
of silver hexafluoroantimonate (AgSbF6) was added in one
portion, the reaction was completed after 3 h and furnished
the ketone-ene product quantitatively with excellent enan-
tioselectivity (92% ee). Encouraged by this result, we
investigated the counterion effect systematically, and the
results are summarized in Table 1. The corresponding
cationic indium(III)-pybox complexes with various coun-
teranions were prepared by treatment of chloro or bromo
indium(III)-pybox complex with the corresponding silver
salts. A significant counterion effect was observed in the
indium(III)-pybox complex, and the catalyst efficiency is
positively correlated to the acidity of the conjugated acid of
these counteranions (Table 1, entries 4, 7, 8, and 9). Interest-
ingly, the catalytic efficiency was also affected by the amount
of silver salt (Table 1, entries 4-6). Control experiments
indicated that the chiral indium complex is the real catalyst
(Table 1, entry 12). Finally, we found that in the presence of 4
Å molecular sieves 10 mol % InCl3, 12 mol % pybox (+)-1,
and 20 mol % AgSbF6 provided the best results in terms of
yield, reaction time, and enantioselectivity (Table 1, entry 4).
The catalyst loading could be lowered to 5 mol % with no
detrimental effect on yield and enantioselectivity, albeit a longer
reaction time was required (Table 1, entry 11).
Table 1. Optimization Studiesa
entry
InX3
AgY (mol %)
time (h) yieldb (%) eec (%)
(4) (a) Zhao, J. F.; Tsui, H. Y.; Wu, P. J.; Loh, T. P. J. Am. Chem. Soc.
2008, 130, 16492–16493. (b) Lu, J.; Hong, M. L.; Ji, S. J.; Loh, T. P. Chem.
Commun. 2005, 1010–1012. (c) Lu, J.; Hong, M. L.; Ji, S. J.; Teo, Y. C.;
Loh, T. P. Chem. Commun. 2005, 4217–4218. (d) Lu, J.; Ji, S. J.; Teo,
Y. C.; Loh, T. P. Org. Lett. 2005, 7, 159–161. (e) Teo, Y. C.; Tan, K. T.;
Loh, T. P. Chem. Commun. 2005, 318–1320. (f) Fu, F.; Teo, Y. C.; Loh,
T. P. Tetrahedron Lett. 2006, 47, 4267–4269. (g) Teo, Y. C.; Loh, T. P.
Org. Lett. 2005, 7, 2539–2541. (h) Teo, Y. C.; Goh, J. D.; Loh, T. P. Org.
Lett. 2005, 7, 2743–2745.
1
2
3
4
5
6
7
8
In(OTf)3
In(OTf)3 AgSbF6 (20%)
-
144
18
3
3
22
3
48
48
48
3
48
24
33
63
94
99
99
93
80
59
53
95
92
-
8
57
95
95
92
92
62
90
85
95
94
-
InBr3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
-
AgSbF6 (20%)
AgSbF6 (20%)
AgSbF6 (10%)
AgSbF6 (30%)
AgPF6 (20%)
AgBF4 (20%)
AgClO4 (20%)
AgSbF6 (20%)
AgSbF6 (10%)
AgSbF6 (20%)
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M. S.; Feng, X. M. Angew. Chem., Int. Ed. Engl. 2008, 47, 1308–1311. (c)
Zhang, X.; Chen, D. H.; Liu, X. H.; Feng, X. M. J. Org. Chem. 2007, 72,
5227–5233.
9
10d
11e
12
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a Reactions were carried out on a 0.5 mmol scale with 2 equiv of
trifluoropyruvate in 4.0 mL of 1,2-dichloroethane (DCE) at room temper-
ature, unless noted otherwise. b Isolated yield. c The ee values were
determined by chiral-phase HPLC analysis, and the absolute configuration
of the major products was R, assigned by comparing HPLC with the
literature.6e d Ethyl trifluoropyruvate was used. e 5 mol % of InCl3 and 6
mol % of (+)-1 were used.
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6810. (b) Evans, D. A.; Murry, J. A.; Matt, P.; Norcross, R. D.; Miller,
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terion effects had been shown as an efficient strategy for
improving the catalytic efficiency of chiral metallic Lewis
acid complexes.7 However, most of these successful ex-
amples are focused on transition metal complexes. We
hypothesized that replacing the counteranion of the parent
indium(III)-pybox complex with a stronger electronegative
Org. Lett., Vol. 11, No. 24, 2009
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