An unexpected inversion of enantioselectivity in direct asymmetric aldol reactions on a unique L-proline/γ-Al2O3 catalyst

Article abstract of DOI:10.1016/j.jcat.2006.07.025

L-proline adsorbed on γ-Al₂O₃ unexpectedly switches the enantioselectivity of the direct asymmetric aldol reaction of acetone with p-nitrobenzaldehyde from 68% ee (R configuration for free L-proline catalyst) with 80% yield to 21% ee (S configuration) with 78% yield. The inversion of enantioselectivity was also observed in the direct asymmetric aldol reactions of acetone with several other aromatic aldehydes catalyzed by the L-proline adsorbed on γ-Al₂O₃. This inversion phenomenon is found to be general for different types of amino acids adsorbed on γ-Al₂O₃. The hydroxyl groups on γ-Al₂O₃ are found to be involved in the inversion induction of enantioselectivity in these direct asymmetric aldol reactions.

Full text of DOI:10.1016/j.jcat.2006.07.025

Journal of Catalysis 243 (2006) 442–445
www.elsevier.com/locate/jcat
Research Note
An unexpected inversion of enantioselectivity in direct asymmetric aldol
reactions on a unique L-proline/γ -Al2O3 catalyst
Lin Zhong a, Jianliang Xiao a,b, Can Li a,∗
a
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, PR China
b
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Received 27 May 2006; revised 24 July 2006; accepted 26 July 2006
Abstract
L-proline adsorbed on γ -Al O unexpectedly switches the enantioselectivity of the direct asymmetric aldol reaction of acetone with p-nitro-
2
3
benzaldehyde from 68% ee (R configuration for free L-proline catalyst) with 80% yield to 21% ee (S configuration) with 78% yield. The inversion
of enantioselectivity was also observed in the direct asymmetric aldol reactions of acetone with several other aromatic aldehydes catalyzed by the
L-proline adsorbed on γ -Al O . This inversion phenomenon is found to be general for different types of amino acids adsorbed on γ -Al O . The
2
3
2 3
hydroxyl groups on γ -Al O are found to be involved in the inversion induction of enantioselectivity in these direct asymmetric aldol reactions.
2
3
© 2006 Elsevier Inc. All rights reserved.
Keywords: Asymmetric catalysis; Aldol reactions; L-Proline/γ -Al O catalyst; Inversion; Enantioselectivity
2
3
1. Introduction
aldol reaction, proline and its derivatives have been covalently
immobilized on solid supports [13–16]. Compared with cova-
lent immobilization, adsorption of a chiral molecule onto a solid
surface could be a more simple and promising means for het-
erogenizing chiral catalysts [17–21]. An attractive feature of
this method is that the major enantiomer can be reversed under
certain conditions [19,20,22–27]. The extensive studies on this
chiral inversion on a solid surface help clarify the adsorption
mode of modifier and its interaction with reactant and hence
are helpful in explaining the origin of the reaction enantioselec-
tion.
Some attempts to immobilize L-proline on silica by sim-
ple adsorption for direct asymmetric aldol reactions have been
reported [8], and lower chemical and optical yields were ob-
tained compared with those obtained using free L-proline as
catalyst. However, an inversion phenomenon was not observed.
Herein, we report that a novel catalyst for direct asymmetric
aldol reactions is formed on the adsorption of L-proline on γ -
Al2O3, which unexpectedly affords products with the absolute
configuration opposite to that obtained with free L-proline as
the catalyst. Our finding may generate a new opportunity for
understanding and designing organo-inorganic hybrid catalysts
for chiral synthesis.
The aldol reaction is one of the most important transforma-
tions in organic synthesis due to its usefulness in construct-
ing stereochemically complex natural and nonnatural products
[1,2]. Over the past decades, asymmetric methodologies for this
reaction have been developed, of which preformed enolate is
an unavoidable necessity in most cases [3]. In 1997, Yamada
et al. reported the first direct asymmetric aldol reactions of
aldehydes with unmodified ketones catalyzed by heterobimetal-
lic bifunctional transition-metal complexes [4]. Recently, List
et al. [5] reinvestigated the Hajos–Eder–Sauer–Wiechert reac-
tion [6,7] and found that the amino acid proline is an effective
organocatalyst for intermolecular direct asymmetric aldol re-
actions. However, 20–30 mol% proline was required, and only
modest enantioselectivity was obtained for most of the aldol
reactions [5,8]. Several proline derivatives and their structural
analogues have been synthesized, with the aim of improving
catalyst activity and enantioselectivity [9–12]. To further im-
prove and recycle the amino acid catalyst for direct asymmetric
*
Corresponding author. Fax: +86 411 84694447.
E-mail address: canli@dicp.ac.cn (C. Li).
0021-9517/$ – see front matter © 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.jcat.2006.07.025

L. Zhong et al. / Journal of Catalysis 243 (2006) 442–445
443
2. Experimental
Chiralpak AD-H column. Enantioselectivity is expressed as ee
(%) = 100 × |R − S|/(R + S).
Chemicals and γ -Al2O3 (Sasol, BET: 209 m2/g) were com-
mercially obtained. NMR spectra were recorded on a Bruker
DRX 400 spectrometer. Chemical shifts are given in δ relative
to TMS, and coupling constants J are given in Hz. Infrared
spectra were recorded on a Nicolet Nexus 470 spectrometer.
HPLC was performed on an HPLC 1100 device using Chiralpak
AD-H (5 µm, 4.6 × 250 mm, Daicel Chemical Industries, Ltd.)
and Hypersil ODS (5 µm, 4.6 × 100 mm, Agilent) columns.
UV-Raman spectra were recorded at room temperature using a
Jobin–Yvon T64000 triple-stage spectrograph with a spectral
resolution of 2 cm−1. The 244-nm line from a Coherent Innova
300 Fred laser was used as excitation source, and the power of
the laser at the sample was <1.0 mW.
γ -Al2O3 was silylated as described previously [28,29]. The
γ -Al2O3 was preheated at 150 ◦C for 3 h under vacuum. After
1 g of γ -Al2O3 was dispersed in 20 ml of toluene, 5 ml of
the silylating agent chlorotrimethylsilane (TMSCl) was added
to the mixture. The suspension was refluxed for 12 h under N2
atmosphere, and then the sample was filtered, washed several
times with ethanol, and dried in vacuo (60 ◦C) overnight.
To a mixture of acetone (2 ml) and γ -Al2O3 (129 mg),
L-proline (17.2 mg, 0.15 mmol) was added, followed by the
corresponding aldehyde (0.5 mmol). The resulting mixture was
stirred at room temperature for 5.5–48 h. The reaction mix-
ture was treated with saturated ammonium chloride solution,
and then γ -Al2O3 was filtered off. The aqueous layer was
extracted several times with ethyl acetate, and the combined
organic layers were dried with anhydrous MgSO4 and evapo-
rated. Purification by silica gel column chromatography gave
the pure aldol product. Ee was determined by HPLC on a
3. Results and discussion
Initially, we investigated the model aldol reaction of ace-
tone with p-nitrobenzaldehyde catalyzed by L-proline in the
presence of γ -Al2O3 (Table 1). The L-proline-catalyzed aldol
reaction gave the aldol product 1 with R configuration and
68% ee, whereas racemic 1 was observed for the γ -Al2O3-
catalyzed aldol reaction (Table 1, entries 1 and 2). When γ -
Al2O3 was added to the aldol reaction mixture (0.5 mmol p-
nitrobenzaldehyde, 2 ml acetone, and 30 mol% L-proline) at
room temperature, the ee value of 1 was reduced, and the reac-
tion became racemic when the ratio of L-proline and γ -Al2O3
reached 6.0 (Table 1, entries 3–5). When the concentration of γ -
Al2O3 was increased further, 1 was unexpectedly obtained with
an S configuration, and its ee values increased from 4 to 21%
(Table 1, entries 6–8). The L-proline/γ -Al2O3 catalyst, pre-
pared by a simple adsorption of L-proline on γ -Al2O3, showed
the S configuration again and approximately the same enantios-
electivity as that for the mixture of L-proline and γ -Al2O3 at a
ratio of 3.3 (Table 1, entries 7 and 9). These results suggest that
a unique catalyst is formed on the adsorption of L-proline on
γ -Al2O3.
To investigate the adsorption of L-proline on γ -Al2O3, UV-
Raman spectra of L-proline in solid form and on γ -Al2O3 were
obtained (Fig. 1). The band at 1380 cm−1 corresponding to the
symmetric stretching vibration of the carboxylate group of free
L-proline shifted to 1390 cm−1 after L-proline was adsorbed
on γ -Al2O3. The Raman bands of L-proline became broad,
and some characteristic bands disappeared for the adsorbed L-
Table 1
Aldol reaction of acetone with p-nitrobenzaldehyde catalyzed by L-proline in the presence of γ -Al O
2
3
a
Entry
L-Prolin: γ -Al O
(molecules/nm )
Reaction time (h)
Yield (%)
Ee (%)
Config.
2
3
2
b
1
2
3
4
5
6
7
8
9
0
48
8
68
80
67
61
68
80
78
80
65
60
62
78
0
68
52
22
0
Rac.
R
No γ -Al O
2
3
25.0
7.2
6.0
5.0
3.3
2.5
3.3
3.3
3.3
3.3
5.5
5.5
5.5
5.5
5.5
5.5
5.5
5.5
5.5
27
R
R
Rac.
S
4
21
18
20
0
64
64
S
S
c
S
d
10
11
12
Rac.
R
e
f
R
a
Isolated yield after separation by silica gel.
b
c
d
e
f
γ -Al O as catalyst.
2
3
The as-synthesized catalyst.
γ -Al O was preadsorbed by pyridine as described in Ref. [30].
2
3
2
α-Al O , BET: 4 m /g.
2
3
Silylated γ -Al O .
2
3

444
L. Zhong et al. / Journal of Catalysis 243 (2006) 442–445
proline. These changes indicate that L-proline strongly interacts
with γ -Al2O3 and that the carboxylate groups are involved in
the interaction [31–33]. The L-proline/γ -Al2O3 preadsorbed
with pyridine resulted in the aldol product 1 with a dramati-
cally reduced ee value, clearly showing that the acidic sites on
γ -Al2O3 play an important role in the aldol reaction, because
the preadsorbed pyridine can occupy these sites (Table 1, entry
10). To further clarify the roles of the surface sites in the asym-
metric aldol reaction, α-Al2O3 and silylated γ -Al2O3 (both
of which have much less surface hydroxyl groups and hence
are less likely to interact with proline) were used as supports;
they both gave results similar to those obtained with the free
L-proline (Table 1, entries 11 and 12). These results suggest
that the surface hydroxyl groups on γ -Al2O3 are essential to in-
duce the inversion of enantioselectivity. It is also interesting that
the inversion of enantioselectivity occurred for a L-proline/γ -
Al2O3 ratio of about 3–5 molecules/nm2 (Table 1, entries 6–9).
This value is in accordance with the surface hydroxy concen-
tration of γ -Al2O3 (about 4 molecules/nm2) [34], suggesting
that the new catalyst is formed only when L-proline interacts
with surface hydroxyl group. The chiral inversion phenomenon
was also observed for other natural amino acids adsorbed on γ -
Al2O3. Fig. 2 shows that seven other natural amino acids, when
adsorbed on γ -Al2O3, can induce the inversion of enantioselec-
tivity and give aldol product 1 with an S configuration and ee
values of 3–16%.
The aldol reactions of acetone with several other aldehydes
catalyzed by L-proline/ γ -Al2O3 were also examined (Table 2).
The results demonstrate that the aldol reactions of all the aro-
matic aldehydes with acetone can be catalyzed by L-proline/
γ -Al2O3 to give the corresponding aldol products 1–4 with a
reversed S configuration, except for the aliphatic isobutylalde-
hyde (Table 2). Therefore, it seems that the inversion phenom-
enon is quite general—namely, the coupling of L-proline with
Fig. 1. UV-Raman spectra of (a) L-proline adsorbed on γ -Al O , (b) L-proline
2
3
in solid form, and (c) γ -Al O .
2
3
Table 2
Cross aldol reactions of acetone with aldehydes catalyzed by free L-proline and L-proline adsorbed on γ -Al O
2
3
a
Aldehyde acceptor
Product
Catalyst
Reaction time (h)
Yield
Ee (%)
Config.
L-proline
L-proline/γ -Al O
8
5.5
80
78
68
21
R
S
2
3
3
L-proline
L-proline/γ -Al O
40
31
78
38
4
19
R
S
2
L-proline
L-proline/γ -Al O
29
23
78
27
65
14
R
S
2
3
3
L-proline
L-proline/γ -Al O
48
40
52
18
60
8
R
S
2
L-proline
L-proline/γ -Al O
24
18
85
57
83
9
R
R
2
3
a
Isolated yield after separation by silica gel.

L. Zhong et al. / Journal of Catalysis 243 (2006) 442–445
445
edged. The authors thank Changsheng Wang for helpful dis-
cussions, and Yanbao Dong and Zhimin Liu for measuring the
Raman and IR spectra.
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ꢀ
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2
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activates acetone, and the hydroxyl group on γ -Al2O3 activates
the carbonyl of p-nitrobenzaldehyde through hydrogen bond-
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attacked by the enamine on γ -Al2O3, resulting in formation of
the product with an S configuration.
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the L-proline/γ -Al2O3 catalyst give products with configura-
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asymmetric aldol reactions. Although improvement of enan-
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Acknowledgments
The financial support from the National Natural Science
Foundation of China (grant 20321303) is gratefully acknowl-