Significant counterion effect of the In(III)-pybox complex in highly enantioselective carbonyl-ene reactions of ethyl glyoxylate

Article abstract of DOI:10.1016/j.tetlet.2010.06.066

A highly efficient enantioselective carbonyl-ene reaction of ethyl glyoxylate catalyzed by an In(III)-pybox complex, which is designed based on the counterion effect, is reported. Reactions of both aliphatic and aromatic 1,1-disubstituted olefins proceed smoothly to give enantioenriched homoallylic alcohols with excellent yields and enantioselectivities. In addition, electron-withdrawing as well as donating groups on the phenyl ring of α-methyl styrenes are tolerated in this reaction.

Full text of DOI:10.1016/j.tetlet.2010.06.066

Tetrahedron Letters 51 (2010) 5649–5652
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Tetrahedron Letters
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Significant counterion effect of the In(III)–pybox complex in highly
enantioselective carbonyl-ene reactions of ethyl glyoxylate
*
Jun-Feng Zhao, Teguh-Budiono W. Tjan, Teck-Peng Loh
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient enantioselective carbonyl-ene reaction of ethyl glyoxylate catalyzed by an In(III)–pybox
complex, which is designed based on the counterion effect, is reported. Reactions of both aliphatic and
aromatic 1,1-disubstituted olefins proceed smoothly to give enantioenriched homoallylic alcohols with
excellent yields and enantioselectivities. In addition, electron-withdrawing as well as donating groups
Received 19 March 2010
Revised 11 May 2010
Accepted 15 June 2010
Available online 17 June 2010
on the phenyl ring of
a
-methyl styrenes are tolerated in this reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
The carbonyl-ene reaction is an important reaction in C–C bond
formation.1 The asymmetric carbonyl-ene reaction has attracted
much attention as it offers convenient access to enantioenriched
homoallylic alcohols, which are the versatile building blocks and
intermediates of pharmaceutical and agricultural compounds.2
Very recently, our group developed an efficient catalytic system
for the asymmetric carbonyl-ene reaction of glyoxylates under
mild conditions.3 Under the catalysis of an In(III)–pybox complex,
formed in situ from commercially available In(OTf)3 and pybox
(+)-1, the enantioselective carbonyl-ene reactions of 1,1-disubsti-
tuted and 1,1,2-trisubstituted olefins, including aromatic and ali-
phatic olefins, proceeded smoothly to give the enantioenriched
homoallylic alcohols in good to excellent yields and enantioselec-
tivities. However, the obvious disadvantage of this methodology
is that the reaction rate is relatively slow requiring 4-6 days to
complete the reaction. Moreover, the reaction must be carried
out at 0 °C to obtain excellent and reproducible enantioselectivi-
ties. With regard to practicality, more reactive catalysts are
needed. In a parallel study of asymmetric ketone-ene reactions of
trifluoropyruvate, we developed a more powerful In(III)–pybox
complex by taking advantage of the counterion effect.4 Herein,
we report an improved version of the highly enantioselective car-
bonyl-ene reactions of ethyl glyoxylate, catalyzed by the more ac-
tive In(III)–pybox complex, at room temperature within several
hours.
a trifluoromethyl group in excellent yields and enantioselectivities
at room temperature within an acceptable reaction time. We
Table 1
Optimization studiesa
OH
5 mol% InX3
O
OEt
z mol% AgY
H
EtO
+
1
6 mol% (+)-
4 Å MS
O
O
2a
DCE, rt
4aa
3a
H
H
O
O
N
N
N
H
H
1
(+)-
Entry
InX3
AgY (mol %)
Time/h
Yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
9
In(OTf)3
InCl3
InBr3
InBr3
InCl3
InCl3
InCl3
InCl3
InCl3
InCl3
—
—
—
—
24
24
24
8
63
94
nd
nd
81
92
95
94
94
90
90
—
Trace
Trace
95
96
98
96
94
87
98
AgSbF6 (15)
AgSbF6 (15)
AgSbF6 (10)
AgSbF6 (5)
AgBF4 (10)
AgPF6 (10)
AgClO4 (10)
AgSbF6 (10)
8
15
24
30
24
24
24
The counterion effect had been demonstrated as an efficient
strategy to increase the catalytic activity of chiral metallic Lewis acid
complexes.5 It is also notable that the counterion effect of the In(III)–
pybox complex improved the catalytic efficiency of the parent com-
plex significantly.4 The new generation In(III)–pybox complex is
efficient enough to catalyze the ketone-ene reaction of trifluoro-
pyruvate to give enantioenriched homoallylic alcohols containing
10
11
—
a
Reactions were carried out on a 0.5 mmol scale with 2 equiv of a-methylstyrene
in 4.0 mL of solvent at room temperature, unless otherwise noted.
b
Isolated yield.
c
Determined by chiral-phase HPLC analysis and the absolute configuration of the
major products was R, assigned by comparison with the literature.
* Corresponding author. Fax: +65 6515 8229.
E-mail address: teckpeng@ntu.edu.sg (T.-P. Loh).
d
Reaction not complete.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.066

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J.-F. Zhao et al. / Tetrahedron Letters 51 (2010) 5649–5652
Table 2
In(III)–pybox complex-catalyzed asymmetric carbonyl-ene reactions of ethyl glyoxylate with various olefinsa
5 mol% InCl3
R2 OH
O
R2
10 mol% AgSbF6
R1
OEt
H
EtO
+
R1
R3
6 mol% (+)-1
4 Å MS, DCE, rt
R3
O
O
3a-p
2a
4aa-ap
Entry
1
Product
Time (h)
15
Yieldb (%)
98
eec (%)
95
OH
OEt
OEt
O
4aa
4ab
OH
2
3
4
16
16
16
97
98
98
91
93
89
O
OH
OEt
O
4ac
OH
OEt
O
4ad
OH
OEt
5
6
16
16
88
98
93
92
O
Cl
4ae
4af
OH
OEt
O
Br
OMe
OH
OEt
7
8
16
16
96
97
95
96
O
4ag
OH
MeO
MeO
OEt
O
4ah
OH
OEt
9
16
92
90
O
4ai
OH
OEt
10
11
12
16
16
16
98
89
98
92
90
90
O
4aj
OH
OEt
O
4ak
4al
OH
OEt
O
O
13d
14
20
20
72
62
99
93
OEt
Ph OH
F
4am
OH
OEt
O
4an

J.-F. Zhao et al. / Tetrahedron Letters 51 (2010) 5649–5652
5651
Table 2 (continued)
Entry
Product
Time (h)
Yieldb (%)
73
eec (%)
OH
F
OEt
15
20
93
93
O
4ao
OH
OEt
16
16
98
O
F
4ap
a
Reactions were carried out on 0.5 mmol scale with 2 equiv of the olefin in 4.0 mL of DCE at room temperature.
Isolated yield.
Determined by chiral-phase HPLC analysis or GC; the absolute (R)-configuration of the major products was assigned by comparison with the literature.
b
c
d
Diastereoselectivity was >99:1.
attempted to use this strategy to improve the efficiency of the
In(III)–pybox complex-catalyzed carbonyl-ene reaction of glyoxy-
lates, which exhibited sluggish reaction rates previously (Table 1,
entry 1).3 The asymmetric carbonyl-ene reaction of ethyl glyoxylate
Compared to the previous case,3 the new version has many advan-
tages including: (1) the reaction rate was increased significantly
while retaining the excellent yields and enantioselectivities; (2)
the reaction can be carried out at room temperature rather than
at 0 °C making it more practical, convenient, and energy efficient;
(3) the increased tolerance toward the strong electron-withdraw-
ing and donating groups expands the substrate scope of this sys-
tem; (4) this reaction could be carried out on a large scale (up to
5 mmol). All of these features should make this method more
attractive for the preparation of enantioenriched homoallylic alco-
hols in industrial applications as well as basic research.
(2a) and a-methylstyrene (3a) was chosen as a model reaction to
evaluate the counterion effect of the In(III)–pybox complex. To the
chiral In(III)–pybox complex, formed in situ from 6 mol % of pybox
(+)-1 and 5 mol % of InCl3 in 1,2-dichloroethane (DCE), was added
15 mol % of AgSbF6 in one portion. After stirring for 30 min at room
temperature, ethyl glyoxylate and
a-methylstyrene were added
sequentially. The reaction mixture was stirred at room temperature
and monitored by thin layer chromatography (TLC). The results
summarized in Table 1 show that the reaction efficiency is related
to the species as well as the scale of the counter anion of the
In(III)–pybox complex. We were delighted to find that the newly
formed In(III)–pybox complexes, based on the counterion effect,
were more efficient than the parent complexes in catalyzing the
asymmetric carbonyl-ene reactions of ethyl glyoxylate (Table 1, en-
tries 4–10). The reaction rate was increased significantly, and excel-
lent yields and enantioselectivities were obtained. The combination
of 5 mol % of InCl3, 6 mol % of pybox (+)-1, and 10 mol % of AgSbF6
provided the best results in terms of yield, reaction time, and enanti-
oselectivity (Table 1, entry 6).
Acknowledgment
We gratefully acknowledge the Nanyang Technological Univer-
sity and the Ministry of Education Academic Research Fund Tier 2
(No. T207B1220RS) for funding this research.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.06.066.
To test the generality of this methodology, various 1,1-disubsti-
tuted and 1,1,2-trisubstituted olefins and ethyl glyoxylate were re-
acted under the optimized conditions and the results are listed in
Table 2. In most cases, the new generation In(III)–pybox complex
afforded better yields and enantioselectivities than the parent
In(III)–pybox complex (Table 2). Notably, compared to the long
reaction times (4–6 days) reported previously at 0 °C,3 the reaction
time was decreased significantly to 15–20 h at room temperature
with the new generation In(III)–pybox complex. Both aromatic
and aliphatic olefins afforded the expected enantioenriched homo-
allylic alcohols in better or comparable yields and enantioselectiv-
ities compared to the previous results. Unlike in the previous case,3
and in the case of trifluoromethyl pyruvate,4 in which significant
electronic effects had been demonstrated, electronic discrimina-
tion in the asymmetric carbonyl-ene reaction decreased when
the new generation In(III)–pybox complex was used as the catalyst.
In addition, the counterion effects were amplified when electron-
withdrawing groups were present on the olefins (Table 2, entries
5, 6 and 14–16). In contrast to the previous case,3 in which the
presence of a methoxy group, a strong electron-donating group,
at either ortho or para positions led to very poor yields and
enantioselectivities, in this case a methoxy group at the ortho or
para position had no detrimental effect on the reaction efficiency
(Table 2, entries 7–9).
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enantioselective carbonyl-ene reaction catalyzed by an In(III)–py-
box complex, which is designed based on the counterion effect.

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