Asymmetric aldol reaction catalyzed by the self-Assembled nanostructures of L-Proline containing amphiphilic dipeptide: A morphological dependence

Article abstract of DOI:10.1246/cl.2012.1349

An L-proline containing amphiphilic dipeptide was found to self-assemble into nanosphere and nanofiber structures. These nanostructures could catalyze an asymmetric aldol reaction in water. Good reactivity and enantiomeric selectivity was observed for the

Full text of DOI:10.1246/cl.2012.1349

doi:10.1246/cl.2012.1349
Published on the web October 20, 2012
1349
Asymmetric Aldol Reaction Catalyzed by the Self-assembled Nanostructures
of L-Proline Containing Amphiphilic Dipeptide: A Morphological Dependence
Mingzhe Shao, Qingxian Jin, Li Zhang,* and Minghua Liu*
Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
(Received May 14, 2012; CL-120619; E-mail: liumh@iccas.ac.cn, zhangli@iccas.ac.cn)
An L-proline containing amphiphilic dipeptide was found to
self-assemble into nanosphere and nanofiber structures. These
nanostructures could catalyze an asymmetric aldol reaction
in water. Good reactivity and enantiomeric selectivity was
observed for the nanosphere structure. Although the reaction
could be catalyzed by the nanofiber structure, its enantioselec-
tivity was remarkably decreased. It was suggested that the
appropriate packing of the chiral assemblies can selectively
control the access of the reactants and thus lead to a higher
enantioselectivity in the chirality matched structures.
The potential of using water as a reaction medium for
Figure 1. Asymmetric aldol reaction of cyclohexanone with p-
asymmetric catalytic reaction has been increasingly realized,1-3
nitrobenzaldehyde in water and the structures of catalysts.
because water is a green solvent, providing an environmentally
benign, safe, and low-cost reaction medium. In this context,
micelles, vesicles, or emulsions have emerged as a powerful
approach to achieve efficient asymmetric reaction in water, due
to the generally increased local concentration of reactants and
further providing favorable microenvironment for the catalytic
reaction.3
In recent years, asymmetric aldol reactions catalyzed by
proline derivatives have been reported to be useful C-C bond-
forming reactions and aldol products with excellent enantio-
selectivity are obtained.4 Generally, the aldol reactions are
performed in organic solvents such as DMSO, DMF, and
toluene, while the water as solvent often causes both low yield
and enantioselectivity. However, considering that water is a
desirable green solvent, more and more efforts have been
devoted to the development of the asymmetric aldol reaction in
water.
Figure 2. (A) Particle size distribution of (a) PTC12 assemblies in
Previous studies have shown that proline derivatives with
hydrophobic chains could directly catalyze asymmetric aldol
reaction of cyclohexanone and p-nitrobenzaldehyde in water.5
Proline-based compounds were also shown to be catalysts in
water with the aid of polymer or surfactant.6,7 In addition,
polystyrene (PS)-supported proline was reported to show stereo-
chemical control of direct aldol reaction in water8 and so on.9 In
this paper, we designed amphiphilic proline-tryptophan dipep-
tides and studied their effectiveness as a catalyst for aldol
reaction in water. We have found that the dipeptide derivatives
can self-assemble in water or form supramolecular gels in a
mixture of DMSO and water, producing nanosphere and
nanofiber structures, respectively. Interestingly, when these
two nanostructures were used as catalyst, different enantiose-
lectivity were observed.
water; (b) after addition of cyclohexanone and p-nitrobenzaldehyde;
(c) after 8 h reaction. (B), (C) SEM image of PTC12 assemblies in
water. (D) SEM image of PTC12 xerogel obtained in DMSO/water
(1:2). Inset is the photo of the PTC12 supramolecular gel.
dynamic light scattering (DLS). The DLS measurements
exhibited some particles with diameter about 115 « 45 nm
(Figure 2A), which were subsequently observed by SEM. In
SEM observation, the assemblies showed spherical nanoparti-
cles with diameters of 90-150 nm (Figures 2B and 2C),
indicating that the proline-tryptophan amphiphiles spontane-
ously assembled into nanosphere structures. On the other hand,
when the dipeptide formed supramolecular gels in a mixture of
DMSO and water (1:2 v/v), nanofiber structures were obtained,
as shown in Figure 2D. The SEM revealed that the widths of the
entangled fibers were 100-150 nm in diameter and the length
extended to micrometer, typical of the nanofiber structures for
physical gels.10,11
The molecular structures of the proline-tryptophan amphi-
philes are shown in Figure 1. The self-assembly of PTC12 in
water in the presence of trifluoroacetic acid (TFA) was
characterized by scanning electron microscopy (SEM) and
Chem. Lett. 2012, 41, 1349-1350
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1350
Table 1. Screening of catalysts in the direct asymmetric aldol
reaction of cyclohexanone with p-nitrobenzaldehyde in water
Entry Catalyst
Additive
Solvent
Yield/%a
ee/%b
1
2
3
4
5
6
7
Proline
PT
TFA
TFA
TFA
TFA
TFA
TFA
TFA
H2O
H2O
H2O
H2O
H2O
H2O
H2O
0
0
®
®
83
27
90
80
20
PTC10
PT2 C10
PTC12
PTC14
PTC12 gel
83
50
87
79
80
Figure 3. (A) The nanosphere structures formed by PTC12 in water.
(B) The scheme of PTC12 supramolecular gels.
aIsolated yield. bBy Chiral-HPLC (Daicel Chiracel-AD column, cyclo-
hexane/i-PrOH = 0.48:0.02, 0.5 mL min¹1); TFA is 20% (mol %) of
aldehyde.
some spaces for the reactants to access. While in the nanofiber
structures, the neighboring aromatic rings packed so closely that
the reactants are difficult to access. In addition, the curvature of
nanosphere structures probably contributes to the high enantio-
meric selectivity.12-14
The aldol reaction of cyclohexanone and p-nitrobenzalde-
hyde was carried out in a water dispersion of amphiphilic
dipeptide. In a typical experiment, 2 equiv of cyclohexanone to
the aldehyde were used, and the concentration of catalyst was
kept at 10% (mol %) of aldehyde. As for the reaction catalyzed
by supramolecular gels, the supramolecular PTC12 gels were
dispersed in the aqueous reaction system. After 8 h at room
temperature in water, the reaction was complete. We then
analyzed the yield and the enantiomeric excess of the product.
The results are shown in Table 1.
In summary, the amphiphilic proline based dipeptide has
been synthesized and its self-assembled nanospheres have been
proven to be an efficient catalyst for the direct asymmetric aldol
reactions in water. The hydrophobicity of proline derivatives has
a profound effect on the reaction stereoselectivity. In addition,
the proline dipeptide can form supramolecular gels in the mixed
solvent of DMSO and water. The enantiomeric selectivity was
found to be related to the assembly of catalyst molecules. The
enantiomeric selectivity of aldol reaction catalyzed by PTC12
gels with nanofiber structures was found to be lower than that
catalyzed by nanosphere structures. It is expected that the
supramolecular catalyst obtained through the self-assembly can
contribute to green chemistry.
It is reported that aldol reactions are typically performed in
organic solvents, such as DMSO, DMF, or chloroform. It is
difficult to obtain desirable yield and ee value in water without
modifying the proline, as observed in Entry 1. The dipeptide of
proline and tryptophan also cannot catalyze the reaction in water,
indicating that the tryptophan moiety does not contribute to
enantiomeric selectivity. When the amphiphilic dipeptides were
used as catalysts, great enhancement of yield and enantiomeric
selectivity was achieved, as shown in Entries 3-6. It was noted
that the hydrophobic chains affected the ee value of the product.
With the hydrophobicity increased, especially when two hydro-
phobic chains were adopted, the yield and ee value of product
decreased remarkably. The particle size distribution was
monitored by DLS measurement during reaction. It was obvious
that the particle size increased upon addition of the reactant
to the aqueous system, which changed from 115 to 150 nm,
indicating that the reactant existed in the aggregates instead of
the bulk water. The particle was stable enough that the reaction
did not destroy the structure of the assemblies, which was
characterized by the DLS measurements after the reaction
finished. The particle diameter remained at 150 nm, only with a
little increase in multidispersity. As we mentioned above, the
reactant of cyclohexanone and p-nitrobenzaldehyde existed in
the assembly of PTC12, not only increasing its solubility in
water, but being isolated to interact with bulk water directly.
This attributed to the enhancement of enantiomeric selectivity.
As for the reaction catalyzed by PTC12 supramolecular gels,
moderate yield was obtained, suggesting that the reactivity was
kept via the ordered assemblies. However, the ee value is much
lower than that catalyzed by nanosphere structures, as shown in
Entry 7. We suppose that the hydrogen bonding between amide
moieties, which drive PTC12 to form supramolecular gels, made
the proline moieties so close that the enantioselectivity was
decreased. Figure 3 illustrates the packing difference of the
functional groups of the nanospheres and nanofibers. In the
nanosphere structure, the neighboring functional groups have
This work was supported by the Basic Research Develop-
ment Program (Nos. 2010CB833305 and 2009CB930802), the
National Natural Science Foundation of China (Nos. 91027042
and 21021003), and the Fund of the Chinese Academy of
Sciences.
Paper based on a presentation made at the International
Association of Colloid and Interface Scientists, Conference
(IACIS2012), Sendai, Japan, May 13-18, 2012.
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© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/