The synthesis of chiral isotetronic acids with amphiphilic imidazole/pyrrolidine catalysts assembled in oil-in-water emulsion droplets

Article abstract of DOI:10.1002/anie.201206438

We have synthesized a class of novel amphiphilic organocatalysts for the cascade reaction of aketoacids to aldehydes using water as the solvent. Under the optimized reaction conditions, various functionalized isotetronic acids were obtained with high yields (up to 94%) and excellent ee values (up to 99%). Both water and emulsion states were found to be crucial for achieving the high reactivity and stereoselectivity. It was also determined that the catalyst molecules are distributed mainly on the surface of the emulsion droplets according to the direct fluorescence image of the reaction system.

Full text of DOI:10.1002/anie.201206438

Angewandte
Chemie
DOI: 10.1002/anie.201206438
Asymmetric Catalysis
The Synthesis of Chiral Isotetronic Acids with Amphiphilic Imidazole/
Pyrrolidine Catalysts Assembled in Oil-in-Water Emulsion Droplets**
Boyu Zhang, Zongxuan Jiang, Xin Zhou, Shengmei Lu, Jun Li, Yan Liu,* and Can Li*
Isotetronic acids are important five-membered lactones,
which have been isolated from a variety of natural sources.[1]
This structural motif was found in a number of bioactive
natural products, including compounds with antiumor[2a,b] and
aldose reductase inhibitory[2c,d] activities. Functionalized iso-
tetronic acids are also significant for the synthesis of natural
products.[3] Many synthetic strategies have been devised to
achieve the synthesis of this type of compound.[4] However, so
far there have been only a few asymmetric methods reported
to obtain enantiomerically enriched isotetronic acids, and
most of these approaches relied heavily on the ex-chiral pool
or chiral auxiliaries[5] to control the stereoselectivities.
Bisoxazoline/copper(II) and proline have been utilized as
a catalyst to realize the enantioselective homo-aldol reaction
of pyruvates.[6] In 2007, an elegant asymmetric organocata-
lytic cascade reaction of a-ketoacids to aldehydes, thus
providing a straightforward and atom economical entry to
chiral isotetronic acids, was developed by Landais and co-
workers.[7] However, this method is still plagued by drawbacks
of relatively low efficiency and limited scope. Thus, the
development of catalytic protocols for efficient synthesis of
enantiomerically enriched isotetronic acids remains a distinct
challenge.
Emulsions are thermodynamically unstable two-phase
mixtures of oil, water, and surfactants, and are usually used as
reaction media to overcome the reactant incompatibility
problem.[8] Indeed, emulsion droplets, which have a uniform
microenvironment, were found to act as a nano-macroreactor
to induce the regioselectivities of organic reactions[9] and
accelerate the reaction rates.[10] The importance of the
isotetronic acids structural motif coupled with our ongoing
interest in developing catalytic emulsion systems[11] prompted
our investigation into the cascade reaction of a-ketoacids with
aldehydes in an oil-in-water (O/W) emulsion system. Firstly,
we anticipated that the strong acidity of the hydrated ion
generated from an a-ketoacid in water would accelerate the
proton transfer to the aldehyde and increase the reactivity.[12]
Secondly, an emulsion system can supply a much larger
interfacial area and overcome the incompatibility between a-
ketoacids in water with aldehydes. Importantly, the tunable
emulsion droplets on the nano- to macroscale could supply
a different interfacial microenvironment[13] for the reaction
and might exhibit some special effect to improve the
stereoselectivity (Scheme 1).
Scheme 1. Asymmetric catalytic cascade reaction for synthesis of
enantiopure isotetronic acids. ’emulsion catalysis strategy’
Herein, we report a new amphiphilic proline-derived
imidazole organocatalyst, which forms an emulsion system in
the reaction mixture through self-assembly. This catalytic
system can promote a high yielding and enantioselective (up
to 99% ee) cascade reaction of a-ketoacids with aldehydes
using water as the solvent for the synthesis of isotetronic acids,
and the state of the emulsions are essential for the high
activity and enantioselectivity. Furthermore, based on a direct
fluorescence image of the reaction system, we found that
catalyst molecules are mainly distributed on the surface of the
emulsion droplets.
With the concept of adjusting an interfacial microenviron-
ment of emulsion droplets, through changing the amphiphi-
licity of the catalyst in mind, a series of proline-based
organocatalysts[14] having a bezoimidazole motif (1; for
structure see Table 1) bearing hydrophobic alkyl chains with
different lengths were designed and synthesized by a three- or
four-step reaction sequence (see the Supporting Informa-
tion). In terms of the stronger basicity of imidazole, a series of
pyrolidine/imidazole organocatalysts (2) were also synthe-
sized with different synthetic routes from 1 (see the Support-
ing Information).
With these catalysts in hand, we began our investigation
on the asymmetric reaction of a-ketobutyric acid (3a) to
benzaldehyde (4a) in water[15] by using a 10 mol% catalyst
loading at room temperature. As can be seen from the results
summarized in Table 1, the catalyst 1a displayed low activity
and poor enantioselectivity (entry 1). We were glad to find
that catalysts 1b–e, bearing hydrophobic alkyl chains with
different lengths, exhibited higher reactivities and the con-
version was as high as 79% after 12 hours (entries 2–5). It is
[*] B. Zhang, Dr. Z. Jiang, Dr. X. Zhou, Dr. S. Lu, Dr. J. Li, Dr. Y. Liu,
Prof. C. Li
State Key Laboratory of Catalysis, Dalian Institute of Chemical
Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian, 116023 (China)
E-mail: yanliu503@dicp.ac.cn
canli@dicp.ac.cn
Homepage: http://www.canli.dicp.ac.cn
[**] This work was financially supported by the Natural Science
Foundation of China (20921092, 21002100) and National Basic
Research Program of China (2010CB833300).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201206438.
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Table 1: The cascade reaction of 3a and 4a catalyzed by 1 and 2.[a]
proceeded rapidly to give the corresponding isotetronic acid
with a notable improvement of the ee value of up to 94%
(entry 11). A further enhanced result (91% conversion, 95%
ee) was obtained by using the catalyst 2g having an even
longer alkyl chain (C22, entry 12). By prolonging the reaction
time to 24 hours, 2g afforded a conversion of 95% and
enantioselectivity of 94% (entry 13). By lowering the reac-
tion temperature to 58C, the 2g-catalyzed reaction of 3a to 4a
generated the corresponding product in 98% ee (entry 15). To
further explore the efficiency of the catalyst 2g, the model
reaction was carried out with a reduced catalyst loading
(1 mol%), thereby affording 5a with a 52% conversion with
the enantioselectivity as high as 95% (entry 17).
After optimizing the reaction conditions, we explored the
generality of the catalytic emulsion system for the asymmetric
cascade reaction. We were pleased to find that the high
efficiency of 2g could be extended to the reaction of a-
ketoacids with different aldehydes under emulsion conditions.
As listed in Table 2, variation of the substituent at different
Entry
Catalyst
t [h]
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
2 f
2g
2g
2g
2g
2g[f]
2g[g]
12
12
12
12
12
144
12
12
12
12
12
12
24
12
12
12
12
20
49
55
61
79
8
30
29
27
2
60
64
41
89
89
85
94
95
94
97
98
96
95
7
81
76
86
86
91
95
77
65
77
52
9
Table 2: The cascade reaction of 3 and 4 catalyzed by 2g.[a]
10
11
12
13
14[d]
15[e]
16
17
Entry
R
R’
Yield [%][b]
ee [%][c]
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
86
91
80
83
85
86
92
94
94
83
75
82
87
90
82
95 (5a)
97 (5b)
98 (5c)
95 (5d)
96 (5e)
95 (5 f)
97 (5g)
98 (5h)
95[d] (5i)
93 (5j)
98 (5k)
99 (5l)
89( 5m)
95 (5n)
93 (5o)
2[e]
3
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
4-CF3C6H4
4-NO2C6H4
4-CH3C6H4
2-thiophenyl
cyclohexyl
iPr
[a] Unless otherwise noted, the reaction was conducted with 0.75 mmol
of benzaldehyde and 0.25 mmol of a-ketobutyric acid in 0.5 mL water at
258C. [b] Conversion was determined by 1H NMR spectroscopy. [c] The
ee value was determined by HPLC analysis (see the Supporting
Information). [d] Reaction performed at 158C. [e] 58C. [f] Reaction
performed using 5 mol% of 2g. [g] 1 mol% of 2g.
4[e]
5[e,f]
6
7
8[e]
9[f]
10[f]
11[f]
12[f]
13
14
15[f]
worth noting that the reaction systems catalyzed by 1c–e are
in metastable emulsion states. The obviously different enan-
tioselectivities achieved by 1c–e implied that the catalysts
bearing hydrophobic tails of different lengths might supply
a different microenvironment on the surface of the emulsion
droplets for the reactions and strongly affect the stereoselec-
tivity. The primary results encouraged us to test the series of
catalyst 2a–g, having an imidazole motif, for the title reaction.
The reaction was sluggish using 2a, as only 8% substrate
conversion was achieved after six days, however the corre-
sponding product was obtained with moderate enantioselec-
tivity (entry 6). The catalyst 2b having a C4 hydrophobic tail
also displayed unsatisfactory reactivity and enantioselectivity
(entry 7). Gratifyingly, the amphiphilic catalyst 2c carrying
a C8 alkyl chain exhibited good catalytic performance, thus
affording an 81% conversion and 89% ee in 12 hours
(entry 8). Furthermore, an O/W emulsion emerged in the
reaction system after the reactants and the catalyst were
added and stirred in water. Encouraged by this result, the
catalysts with longer alkyl side chains (2d–g) were also
investigated in the reaction of 3a and 4a. In these cases, the
emulsions were always formed in the reaction systems and the
reactions proceeded smoothly. To our great delight, the
asymmetric reaction catalyzed by 2 f bearing a C18 alkyl chain
3-ClC6H4
4-CF3C6H4
iPr
Et
Ph
[a] Unless noted otherwise, the reaction was conducted with 3 mmol of 4
and 1.0 mmol of 3 in 2 mL water at 258C. [b] Yield of product isolated
after the one-step protection by tBuMe2SiCl (see the Supporting
Information), because 5 is unstable to column chromatography and
results in a loss of yield. [c] The ee value was determined by HPLC
analysis (see the Supporting Information). [d] Absolute configuration of
5i was determined to be S; for details, see the Supporting Information.
[e] 5 mmol CHCl3 were added to dissolve the solid aldehydes. [f] Reac-
tion time: 24 h.
positions of the phenyl moiety of the aldehyde has little
impact on the enantioselectivity of the reaction (entries 1–3).
Various substituted benzaldehydes (4e–i) reacted with a-
ketobutyric acid using the catalyst 2g, and all show high
enantioselectivities (95–99% ee; entries 5–9). Moreover, the
reaction of a-ketobutyric acid with thiophene-2-carbaldehyde
also provides 5j with satisfactory results (entry 10). To our
delight, aliphatic aldehydes were also amenable to the
reaction protocol, thus giving rise to desired products with
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enantioselectivities up to 99% ee (entries 11 and 12). Notably,
the reaction could also be realized by using different donors.
For examples, both a-ketopentanoic acid and a-ketophenyl-
propanoic acid could be employed in the reaction, to provide
the products 5n and 5o, respectively, with high yields and
ee values (entries 13–15).
To demonstrate the synthetic potential of the method, the
reaction of 3a and 4l was carried out on a gram scale in water
under optimized reaction conditions with 2g. The corre-
sponding product 5l, a food flavoring agent,[1e] was obtained
in 75% yield and with 99% ee (Scheme 2).
Figure 1. Fluorescence microscope images of a) reaction mixtures of
4a (0.75 mmol) and 3a (0.25 mmol) in 2 mL H2O with 0.025 mmol
2a, b) 2g (0.025 mmol) combined with a-ketobutyric acid 3a
(0.25 mmol) dispersed in water, c) 4a (0.75 mmol) added to system
b). d) Enlarged images of emulsion droplets and the emulsion reaction
model.
Scheme 2. Asymmetric catalytic synthesis of food flavoring agent on
the gram scale using an emulsion catalyst.
2a in combination with a-ketobutyric acid (3a) is water-
soluble, and the stained aqueous phase is observed in the
reaction medium. In contrast to 2a, 2g in combination with 3a
generated an ion pair which can be dispersed in water in an
aggregated state at the micron scale (Figure 1b). When
benzaldehyde was added into the above mixture and stirred
for a few minutes, the emulsion was formed and bright-blue,
circular-shaped fluorescent domains, emitted from amphi-
philic catalyst 2g, are clearly detected by fluorescence
microscopy, thus indicating that the catalyst is mainly
distributed at the interface of the emulsion droplets. Accord-
ingly, it is proposed that the active sites of this asymmetric
reaction might be on the surface of emulsion droplets
(Figures 1c–d).
In terms of the control experiment and fluorescence
imaging of the emulsion droplet, a possible reaction model is
proposed. As shown in Figure 1d, at the surface of emulsion
droplets the nucleophile a-ketoacid was activated by the
amphiphilic catalyst through enamine formation[16] and acid–
base interactions,[17] while the interfacial hydrated ion gen-
erated from a-ketoacids in water activated the aldehyde
electrophile. Presumably, the microenvironment of the emul-
sion droplets allows a more efficient activation of the
electrophile by the aqueous phase, while exposing the
reactive ends of the amine catalyst to the aqueous phase.
This leads to an effectively higher concentration of the
reactants, which could explain the observed improvements in
both yield as well as the enantioselectivity of the reactions.
In summary, we have synthesized a class of novel
amphiphilic organocatalysts for the cascade reaction of a-
ketoacids to aldehydes using water as the solvent. Under the
optimized reaction conditions, various functionalized isote-
tronic acids were obtained with high yields (up to 94%) and
excellent ee values (up to 99%). Both water and emulsion
states were found to be crucial for achieving the high
reactivity and stereoselectivity. It was also determined that
the catalyst molecules are distributed mainly on the surface of
the emulsion droplets according to the direct fluorescence
image of the reaction system.
To determine the role water plays in the reaction, control
experiments were performed for the reactions of 3a and 4a
with 2g using dry chloroform as the solvent or solvent-free
conditions. Both cases gave much lower reactivities and
enantioselectivities compared to using water as the solvent,
thus suggesting that hydrated ions generated from a-ketoacid
in water is crucial for both the reactivity and stereoselectivity
of the reaction. To further study the effect of water, the
reactions were performed using chloroform with small
amount of water (5 equiv to 3a). The fact that the enantio-
selectivity is significantly improved suggests that water plays
an important role in inducing enantioselectivity. As increasing
the proportion of water, emulsion state can be formed and the
activity and stereoselectivity are enhanced significantly. The
reactions using methanol or a methanol/water mixture as
solvents were also performed (Scheme 3 and see Table S1 in
the Supporting Information). Similarly, the highest reactivity
and stereoselectivity were provided in the emulsion state.
To confirm that the reaction takes place on the surface of
the emulsion droplets, the catalysts 2a and 2g in the reaction
solution were imaged by fluorescence spectroscopy (see the
Supporting Information). As shown in Figure 1, the catalyst
Scheme 3. The cascade reaction of 3a and 4a catalyzed by 2g in
different solvents.
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Received: August 10, 2012
Revised: September 21, 2012
Published online: November 14, 2012
Keywords: asymmetric catalysis · emulsions · micelles ·
.
organocatalysis · synthetic methods
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