Silica-supported l-proline organocatalysts for asymmetric aldolisation

Article abstract of DOI:10.1016/j.tetasy.2009.11.024

New heterogenised silica-based organocatalysts have been prepared via the sol-gel process from two silylated derivatives of l-proline, featuring either a carbamate or an ether linker. Co-gelification with variable amounts of TEOS was performed with and wi

Full text of DOI:10.1016/j.tetasy.2009.11.024

Tetrahedron: Asymmetry 20 (2009) 2880–2885
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Silica-supported L-proline organocatalysts for asymmetric aldolisation
Alexandra Zamboulis, Nicolas J. Rahier, Matthias Gehringer, Xavier Cattoën, Gilles Niel, Catherine Bied,
*
*
Joël J. E. Moreau , Michel Wong Chi Man
Institut Charles Gerhardt Montpellier (UMR 5253 CNRS-UM2-ENSCM-UM1), Architectures Moléculaires et Matériaux Nanostructurés, Ecole Nationale Supérieure de Chimie
de Montpellier, 8, Rue de L’école Normale, 34296-Montpellier Cedex5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
New heterogenised silica-based organocatalysts have been prepared via the sol–gel process from two
silylated derivatives of L-proline, featuring either a carbamate or an ether linker. Co-gelification with var-
iable amounts of TEOS was performed with and without porogen to yield high surface area solids. These
materials were evaluated as heterogeneous phase organocatalysts for the asymmetric aldol reaction of p-
nitrobenzaldehyde with acetone.
Received 16 November 2009
Accepted 27 November 2009
Available online 7 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
although increasingly complex derivatives18–21 are now being de-
signed to achieve better performances. The low turnover of the cat-
Hybrid organic/inorganic silicas with the combined properties
of the organic component and the solid structure of the silica net-
work,1–3 obtained from organoalkoxysilanes are very promising
materials for applications. Over the past two decades, several orga-
nosilyl precursors with specific organic motifs have been designed
and used to confer sought-after properties such as solid phase
extraction,4,5 molecular recognition,6,7 photoluminescence,8,9 or
catalysis10–12 to the resulting hybrid silica. In the latter field, the
sol–gel process has been used to produce covalently bonded cata-
lytic species. We and others have developed such solid catalysts for
different kinds of reactions including metathesis, coupling and
asymmetric reactions.
alysts and the usually high polarity of the reaction products result
in undesirable, tedious purification procedures. Immobilising
organocatalysts on an insoluble matrix represents an approach to
circumvent the latter problem.22–24 This method has the following
main advantages: easy handling and no air-sensitive catalytic sys-
tem; a facile work-up of the reaction by filtration to separate the
catalyst from the products in solution and an easy recovery of
the solid catalyst in addition to its possible recycling. Some authors
have successfully anchored organocatalysts on organic polymers
(polystyrene,25–30 polyethyleneglycol31–33); zeolithes,34,35 meso-
porous silica34–40 and iron oxide nanoparticles41 have also been
used as inorganic supports by grafting methods.
Homogeneous organometallic catalysis combines the use of an
appropriate ligand and a metallic species that is often very toxic
and harmful, which represents a serious issue in view of pharma-
ceutical applications. Moreover, the separation and recovery of
the often expensive transition metal is not always straightforward.
Anchoring organometallic catalysts on insoluble solid supports
represents a good alternative to reduce the metallic waste during
the reactions.13 However, there is still much to be done in order
to avoid metal leaching, which remains one of the major draw-
backs of these organometallic reactions.
Silica is an attractive support for the immobilisation of organo-
catalysts as a result of its thermal and mechanical stability as well
as its chemical inertness.42–44 These reasons prompted us to ex-
tend our previous work to the immobilisation of organocatalysts
by the sol–gel process. In contrast to the commonly used grafting
methods used to prepare hybrid materials, high and controlled
loading of the active fragment on the support can be achieved with
complete preservation of the organic fragment in the silica frame-
work due to the strong Si–C covalent bonding. Moreover, the sol–
gel synthesis of the hybrid material in the presence of surfac-
tants45,46 enables control of the porosity and of the specific surface
area of the resulting catalytic hybrid materials. These are impor-
tant parameters, especially for solid phase catalysis. Herein we re-
port the feasibility of immobilising asymmetric organocatalysts (in
Interestingly, organic molecules can also be used as catalysts for
organic transformations without any metallic species.14–17 Such a
process, known as organocatalysis, has remarkably been developed
over the past decade with recent major interests for asymmetric
reactions. Naturally occurring molecules as simple as
a-amino
the case of L-proline) by the sol–gel process. To the best of our
acids, and in particular
L
-proline, can be used for this purpose,
knowledge, only one example of L-prolinamide immobilized on sil-
ica by the sol–gel method has been reported.44 Herein we report
the preparation of new heterogenised organocatalysts via the
* Corresponding authors.
E-mail addresses: Joel.moreau@enscm.fr (J.J.E. Moreau), Michel.wong-chi-man@
sol–gel process incorporating the
L-proline motif and their catalytic
activities in an asymmetric aldol reaction.
enscm.fr (Michel Wong Chi Man).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.024

A. Zamboulis et al. / Tetrahedron: Asymmetry 20 (2009) 2880–2885
2881
2. Results and discussion
Two silylated compounds based on trans 4-hydroxy-
Q3
P2/10D
L-proline
with different linkers were envisaged as silica precursors, featuring
either a carbamate P138 or an ether moiety P2. The latter was syn-
thesised according to Scheme 1.
Q4
Derivative 1, obtained according to a previously described
methodology,47 was converted to its corresponding benzylic ester
2. Hydrosilylation was successfully performed at room tempera-
ture using the Karstedt catalyst to afford compound 3. Removal
of the benzylic and Cbz protecting groups was carried out by
hydrogenolysis under anhydrous conditions leading to the desired
precursor P2.
Q2
T3
T2
The catalytic materials were obtained from P1 or P2 and TEOS
under various conditions. The choice of the Px/TEOS ratio (from
1:10 to 1:40) and porogen (dodecylamine, or none) enabled the
formation of materials with various organic loadings, pore sizes
and surface areas according to Scheme 2. The different materials
are denominated as Px/y-G where Px is the molecular precursor,
y is the molar ratio of TEOS versus Px, and G is D in the case of
the dodecylamine porogen, N when the synthesis is performed
without any porogen.
0
-20
-40
-60
-80
δ (ppm)
-100
-120
-140
Figure 1. 29Si CP-MAS NMR spectrum of P2/10D.
These hybrid materials were characterized by multiple
analyses:
P2/10D
The 29Si NMR spectrum (Fig. 1) exhibits two sets of broad sig-
nals attributed to T (C–SiO3, ꢀ55 to ꢀ66 ppm) and Q (SiO4, ꢀ90
to ꢀ120 ppm) environments. The presence of the T units gives evi-
dence of the existence of C–Si covalent bonds; this covalent linkage
is further supported by a signal at ca. 9 ppm in the 13C CP-MAS
NMR spectra of P1/10D and P2/10D (Fig. 2), attributed to the
CH2–Si groups. The other 13C signals exhibit the expected chemical
B
250
200
150
100
δ (ppm)
50
0
-50
P1/10D
shifts of the L-proline fragments. In the case of materials derived
from P1, in particular the carbamate and carboxylic acid signals
are clearly observed at d 156 and 173 ppm, respectively; the latter
signal is also observed for materials derived from P2 in the 13C
NMR spectra.
A
250
200
150
100
50
0
-50
The N2 adsorption desorption (BET) was used to determine the
specific areas and textural properties of these solids. These mea-
surements are shown in Figure 3 in the case of P1/10N and P1/
δ (ppm)
Figure 2. 13C CP-MAS NMR spectra of (A): P1/10D, (B): P2/10D.
OBn
Si(OEt)3
Si(OEt)
3
cyclohexene
Pd/C
Cy
Cy
HSi(OEt)3
Karstedt cat.
N
N
H
O
O
O
O
EtOH/Δ/0.5 h
THF/RT/20h
77%
THF/RT/20 h
73%
89%
CO2H
CO2Bn
CO2Bn
CO2H
N
N
N
N
H
Cbz
1
Cbz
2
Cbz
P2
3
Scheme 1. Preparation of the precursor featuring an ether linker P2.
H2O, EtOH, G
R
Si(OEt)3 + y Si(OEt)4
O
R
SiO1.5·ySiO2
Px/y-G
Px
y = 10, 20, 40
O
N
H
O
OH
OH
P1
P2
R =
R =
N
H
N
H
O
O
Scheme 2. Preparation of the hybrid silica via the sol–gel process using P1 or P2.

2882
A. Zamboulis et al. / Tetrahedron: Asymmetry 20 (2009) 2880–2885
H
O
B
A
N
O
O
P1/10N
P1/10D
CO2H
CO2H
N
H
N
H
P'2
P'1
0
200
400
600
Figure 4. Structures of the two L
-proline derivatives P01 and P02.
Pore diameter (Å)
450
400
350
300
250
200
150
100
50
pletion was not observed. Although enantiomeric induction was
clearly observed in all cases, the values are lower than in the
homogeneous systems. It is noteworthy that for the most concen-
trated hybrids (entries 1, 2 and 7), the ee values are lower by ca.
10% compared to the more diluted ones. This trend might be ex-
plained by the closer proximity between the catalytic centres,
which would open racemic pathways.
P1/12N
P1/12D
0
0.0
0.2
0.4
0.6
0.8
1.0
(p/pº)
The recycling of the material was also performed (entries 4, 6
and 9). Slower reactions were observed with both types of catalysts.
Interestingly, the ees did not change in entries 6 and 9. We believe
that the slower activities are due to the inhibition of the catalytic
centres. This argument is supported by the 13C CP-MAS NMR spec-
trum of the material recovered from P2/10D after one run, and con-
tinuously washed with acetone for 24 h using a Soxhlet apparatus
(Fig. 5). We can clearly observe signals ascribable to nitroaromatic
groups (d 120–130, 147 ppm), without any trace of the correspond-
ing aldehyde CH@O signal (d 190 ppm), probably resulting from an
irreversible inhibition of the catalytic centre through the formation
of a C–N bond. This is corroborated by the N2 adsorption/desorption
experiment performed on the same material, showing a marked de-
crease of the surface area (from 643 to 270 m2 gꢀ1), whereas the
size of the available pores remains constant (ca. 30 Å).
Figure 3. (A) N2 adsorption/desorption isotherm of P1/12N (circles) and P1/12D
(triangles); (B) pore size distribution determined by the BJH method (desorption).
10D. In both cases, high surface areas were obtained, with a type IV
isotherm, typical of mesoporous materials. However, they strongly
differ in the textural properties: whereas P1/10D exhibits a very
sharp pore size distribution (ca. 25 Å), P1/10N shows a very broad
one, ranging from 150 to 500 Å. Moreover, both materials present a
significant microporosity contribution (about one half of the ad-
sorbed volume for P1/10D versus one quarter for P1/10N). The
overall results are summarized in Table 1. These results as a whole
show that the use of the dodecylamine allows a significant increase
in the porosity, with the formation of regular small mesopores;
higher surface areas and slightly higher pore volumes result from
increasing the Px/TEOS ratio, except for P2/40D. The textural prop-
erties are similar for materials derived from both precursors.
To gain further insight into the reaction mechanism, we per-
formed the same reaction without any solid or with a pure meso-
porous silica (SBA-15).51 In both cases, no reaction occurred,
evidencing the need of the amine functionality. According to the
commonly accepted mechanism,48,49 the reaction begins with the
Table 1
N2 adsorption/desorption: surface area and pore sizes
condensation of acetone with the amine fragment of L-proline to
Material
Surface areaa (m2 gꢀ1
)
Pore diameterb (Å)
form an enamine, which would attack the aldehyde to form, after
hydrolysis, the desired product. The enantioselection is believed
to arise from the positioning of the aldehyde by the COOH group
via H-bonding. In these materials, we suggest that the acidic silanol
groups present on the surface of the pores might interfere, compet-
ing with the carboxylic acid groups for the localisation of the alde-
hyde (Fig. 6).
P1/10N
P1/10D
P1/20D
P1/40D
P2/10D
P2/20D
P2/40D
352
698
877
989
643
900
436
88c
25
28
31
27
41
43
The related participation of the silanol groups from a hybrid sil-
ica surface has already been shown to be beneficial in the case of
Henry reactions.52
a
b
c
BET surface area.
BJH desorption average pore diameter (4 V/A).
Broad distribution of pore sizes.
The catalytic performances of these materials were evaluated in
3. Conclusion
the asymmetric aldolisation reaction between p-nitrobenzalde-
hyde and acetone (Table 2), which is typically used as a benchmark
for these reactions.48,49 Two new non-silylated homogeneous ana-
logues P01 and P02 were studied for comparison (Fig. 4) to preclude
any detrimental effect of the carbamate or ether linkers on the cat-
alytic performances. These compounds exhibit catalytic activities
A series of related new hybrid silicas containing the
motif have been prepared using the sol–gel process starting from
two kinds of silylated -proline derivatives. These materials cata-
L-proline
L
lyse the asymmetric aldolisation between p-nitrobenzaldehyde
and acetone at room temperature, though with moderate perfor-
mances. The decrease in activity was explained in terms of inhibi-
tion of the catalytic sites by the p-nitroaryl moiety, while the low
enantioselectivity can be rationalized considering the competition
of the acidic silanols with the COOH–proline moieties for the posi-
tioning of the aldehyde. Given the increasing interest in supported
catalysis and in particular in organocatalysis, this study should
lead to a better understanding of the inconveniences that may be
raised by the solid support, and to a better design of the catalytic
and enantioselectivities comparable to
xy- -proline (total conversion; ee 74%, 79%, 76%, 78%, respectively)
under standard conditions.49
L-proline or trans 4-hydro-
L
We next studied the performances of the supported catalysts
derived from P1 and P2. The results obtained are summarized in
Table 2. As previously observed, the heterogenized systems display
much slower kinetics.50 This effect is more pronounced in the case
of the materials derived from P2, where even after five days, com-

A. Zamboulis et al. / Tetrahedron: Asymmetry 20 (2009) 2880–2885
2883
Table 2
Catalytic activities of the supported organocatalysts in the asymmetric aldol reaction of p-nitrobenzaldehyde with acetone
O
OH
O
cat. 30% mol
O
+
(R)
DMSO
25 ºC
O2N
O2N
Entry
Material
Time (d)
Conversiona (%)
eeb (%)
1
2
3
4
5
6
7
8
9
P1/10N
P1/10D
P1/20D
P1/20Dc
P1/40D
P1/40Dc
P2/10D
P2/20D
P2/20Dc
P2/40D
1
1
1
1
1
1
5
5
5
5
100
100
100
66
100
48
64
51
28
32
20
25
36
25
38
37
27
37
36
35
10
a
b
c
Determined by 1H NMR.
Determined by chiral HPLC analysis.
Second run with a recovered material.
dried according to standard procedures. Commercially available
compounds were used as received without further purification.
1H, 13C and 29Si liquid NMR spectra were recorded on a Bruker
AC-400 or AC-250, with deuterated chloroform or deuterated
dimethylsulfoxide as solvents. Chemical shifts, d, were indexed in
ppm with respect to tetramethylsilane. 13C and 29Si CP-MAS solid
state NMR spectra were recorded on a Bruker FT AM 400. Mass
spectra were measured on a JEOL JMS-DX 300 mass spectrometer.
Porosimetry measurements were performed using a Micrometics
Tristar 3000 apparatus. Optical rotations were measured on a Per-
kin–Elmer polarimeter 241. HPLC analyses were carried using a
Waters 515 pump equipped with a Waters 2487 detector.
*
P2/10D-after one cycle
4.1.1. (2S,4R)-Dibenzyl 4-(allyloxy)pyrrolidine-1,2-
dicarboxylate 2
250
200
150
100
50
0
-50
A solution of 1 (1.88 g, 6.2 mmol) in dry THF (12 mL) was added
to N,N0-dicyclohexyl-O-benzylisourea (2.06 g, 6.6 mmol). The reac-
tion mixture was stirred at room temperature for 48 h. The white
precipitate was filtered off and washed with THF. The filtrate was
then concentrated under reduced pressure, and the residue was
purified by flash chromatography on silica gel with a gradient of
elution 30?90% of CH2Cl2 in pentane, affording 2 as a colorless
oil (1.97 g, 4.9 mmol, 76%). Rf 0.34 (EtOAc/pentane, 50:50); 1H
NMR (CDCl3) d 2.04–2.14 (m, 1H), 2.33–2.44 (m, 1H), 3.59–3.77
(m, 2H), 3.91–4.02 (m, 2H), 4.11–4.17 (m, 1H), 4.53 (m, 1H), 5.03
(m, 2H), 5.14–5.30 (m, 4H), 5.80–5.93 (m, 1H), 7.19–7.40 (m,
10H); 13C NMR (CDCl3) (2 conformational isomers): d 35.6 and
36.8, 51.8 and 52.1, 58.0 and 58.2, 66.9 and 67.0, 67.2 and 67.3,
70.22, 75.9 and 76.6, 117.45 and 117.50, 127.91 and 127.97,
128.0 and 128.1, 128.17 and 128.22, 128.35 and 128.43, 128.48
δ (ppm)
Figure 5. Solid state NMR of material P2/10D after one cycle of reaction and
washing with acetone. The asterisk corresponds to DMSO and the circle to the
aromatics of the p-nitroaryl group.
materials. Further studies are in progress to achieve efficient and
recoverable organocatalysts.
4. Experimental
4.1. General information
When required, experiments were carried out using standard
Schlenk techniques under a nitrogen atmosphere; solvents were
Si
Si
Si
Si
O
O
O
O
O
O
O
OH
O
OH
O
H
O
H
H
H
O
N
N
Ar
Ar
R
(R)
(S)
O
R
O
H
O H
Si
Si
H
H
O
O
Si
Si
Figure 6. Simplified representation of the competition between the silanol and COOH groups.

2884
A. Zamboulis et al. / Tetrahedron: Asymmetry 20 (2009) 2880–2885
and 128.55, 128.6, 134.3, 135.5 and 135.7, 136.4 and 136.6, 154.4
under nitrogen atmosphere and the reaction mixture was refluxed
for 1 h. The reaction mixture was then filtered through a pad of Cel-
ite and the filtrate was concentrated in vacuo to yield P01 as a yel-
low solid (0.12 g, 0.53 mmol, 35%). 1H NMR (CDCl3) d (ppm): 0.89 (t,
J = 7.3 Hz, 3H), 1.26–1.35 (m, 2H), 1.41–1.48 (m, 2H), 2.28–2.40 (m,
2H), 3.07–3.10 (m, 2H), 3.41 (br, 1H), 3.72 (br, 1H), 4.36 (br, 1H),
5.27 (br, 1H), 6.10 (br, 1H), 8.61 (br, 1H), 10.26 (br, 1H); 13C NMR
(CDCl3) d (ppm): 13.7, 19.9, 31.7, 33.9, 40.7, 51.2, 60.2, 73.0,
and 155, 172.4 and 172.6; ½a D24
¼ ꢀ38:8 (c 1.0, CHCl3); HRMS
ꢁ
(FAB+) calcd for C23H26O5N (M+H): 396.1811; found: 396.1828.
4.1.2. (2S,4R)-Dibenzyl 4-(3-
(triethoxysilyl)propoxy)pyrrolidine-1,2-dicarboxylate 3
To a mixture of triethoxysilane (1.50 g, 9.1 mmol) and 0.37 g of a
solution of Karstedt catalyst (2.4% Pt, 4.6 ꢂ 10ꢀ2 mmol) was added
a solution of 2 (1.80 g, 4.6 mmol) in dry THF (10 mL). The reaction
mixture was stirred at room temperature for 20 h. The mixture
was then concentrated, taken in dry pentane (20 mL), and the resi-
due was filtered through a pad of Celite. The filtrate was concen-
trated to afford 3 as a yellowish oil (2.46 g, 4.4 mmol, 96%). 1H
NMR (CDCl3) d 0.58–0.66 (m, 2H), 1.22 (m, 9H), 1.60–1.70 (m,
2H), 2.00–2.11 (m, 1H), 2.30–2.48 (m, 1H), 3.30–3.41 (m, 2H),
3.55–3.91 (m, 8H), 4.04–4.10 (m, 1H), 4.44–4.55 (m, 1H), 4.96–
5.26 (m, 4H), 7.18–7.38 (m, 10H); 13C NMR (CDCl3) (2 conforma-
tional isomers): d 6.6, 18.4, 23.21 and 23.23, 35.6 and 36.8, 51.9
and 52.2, 58.0 and 58.3, 58.5, 66.8 and 67.0, 67.2 and 67.3, 71.51
and 71.54, 76.4 and 77.0, 127.89 and 127.93, 128.07 and 128.09,
128.16 and 128.21, 128.3 and 128.4, 128.48 and 128.54, 128.6,
135.5 and 135.7, 136.5 and 136.6, 154.5 and 155.1, 172.5 and
155.6, 173.1; ½a D20
¼ ꢀ11:8 (c 0.01, CHCl3); HRMS (ESI+): calcd for
ꢁ
C10H19N2O4 (M+H): 231.1339; found 231.1330.
4.1.6. (2S,4R)-4-Propoxypyrrolidine-2-carboxylic acid P02
To a solution of 2 (0.065 g, 0.16 mmol) in dry EtOH (2 mL), were
added cyclohexene (0.10 mL, 0.99 mmol) and Pd/C (10% Pd,
0.067 g), under nitrogen atmosphere and the reaction mixture
was refluxed for 24 h. The reaction mixture was then filtered
through a pad of Celite and the filtrate was concentrated in vacuo
to afford P02 as a brown oil (0.024 g, 0.14 mmol, 87%). 1H NMR
(CDCl3) d (ppm): 0.86 (t, J = 7.4 Hz, 3H), 1.47–1.56 (m, 2H), 2.13
(br, 1H), 2.38 (br, 1H), 3.30–3.37 (m, 3H), 3.57–3.62 (m, 1H), 4.14
(br, 1H), 4.28 (br, 1H); 13C NMR (CDCl3) d (ppm): 10.5, 22.8, 35.0,
50.5, 59.9, 70.8, 77.3, 173.2; ½a D20
¼ ꢀ30:2 (c 0.008, CHCl3); HRMS
ꢁ
172.7; 29Si NMR (DMSO-d6) d ꢀ45.1; ½a 2D4
ꢁ
¼ ꢀ24:5 (c 1.2, CHCl3).
(ESI+): calcd for C8H16NO3 (M+H): 174.1125; found 174.1131.
4.1.3. (2S,4R)-4-(3-(Triethoxysilyl)propoxy)pyrrolidine-2-
carboxylic acid P2
4.2. General procedure for the sol–gel preparation of the hybrid
silica Px/y-G
To a solution of 3 (2.40 g, 4.29 mmol) in ethanol (35 mL) was
added cyclohexene (0.77 mL, 7.60 mmol) and Pd/C (10%, 1.21 g).
The suspension was refluxed for 35 min, cooled, then filtered
through a pad of Celite. The black residue was washed with ethanol
(3 ꢂ 20 mL), and the combined filtrates were concentrated to yield
P2 (1.26 g, 3.75 mmol, 87%) as an orange oil. 1H NMR (CDCl3) d
0.58–0.63 (m, 2H), 1.22 (m, 7.0 Hz, 9H), 1.50–1.70 (m, 2H), 2.11
(m, 1H), 2.39 (m, 1H), 3.25–3.40 (m, 2H), 3.45–3.55 (m, 1H),
3.78–3.90 (m, 8H), 4.12 (m, 1H); 13C NMR (CDCl3) d 6.7, 18.5,
23.2, 35.2, 50.3, 58.5, 60.5, 71.7, 77.7, 173.6; 29Si NMR (DMSO-d6)
A solution of the precursor (Px) in dry EtOH was added under
stirring to y equiv of TEOS. H2O was added via a microsyringe
((3 + 4 y) equivalents) together with TBAF [1 M in THF,
0.01 ꢂ (1 + y) equivalents] and dodecylamine (D/TEOS = 0 or
0.27). After 15 min, stirring was stopped and the mixture was aged
for 72 h at room temperature. The gel was air-dried, abundantly
washed with water, acetone and EtOH, then continuously washed
with EtOH using a Soxhlet apparatus for 72 h and dried under vac-
uum to give a white solid.
d ꢀ45.0; FTIR:
m ,
= 3432 cmꢀ1, 2988 cmꢀ1, 2932 cmꢀ1, 1639 cmꢀ1
1128 cmꢀ1; ½a 2D4
ꢁ
¼ ꢀ4:5 (c 0.5, CHCl3); HRMS (FAB+): calcd for
4.3. General procedure for the catalytic aldolisation
C14H30NO6Si (M+H): 336.1842; found 336.1851.
In a typical experiment, p-nitrobenzaldehyde (15 mg, 0.1 mmol)
was dissolved in acetone (0.2 mL, 2.7 mmol) and DMSO (0.8 mL).
Then the hybrid material (equivalent to 30 mol % of proline) was
added to this solution under stirring at room temperature. The pro-
gress of the reaction was monitored via 1H NMR analysis and the ee
of the aldol was determined by HPLC with a chiral stationary
phase: Daicel Chiracel OJ column, hexane/propan-2-ol: 85:15,
1 mL/min, detection at 254 nm, tR = 24.4 min (R), tR = 27.5 min (S).
4.1.4. (2S,4R)-Dibenzyl 4-(butylcarbamoyloxy)pyrrolidine-1,2-
dicarboxylate 4
To a solution of (2S,4R)-1,2-dibenzyloxycarbonyl-4-hydroxy-
pyrrolidine38 (0.95 g, 2.7 mmol) in dry CH2Cl2 (20 mL) was added
n-butyl isocyanate (0.35 mL, 3.1 mmol). The reaction mixture
was refluxed for two days, another portion of n-butyl isocyanate
(0.10 mL, 0.89 mmol) was then added and heating was maintained
for 20 more hours. The reaction mixture was diluted with CH2Cl2,
washed with water and purified by chromatography over silica
gel (pentane/ethyl acetate (2:1)) to afford 5 as a colourless oil
4.4. General proceedure for the recovery of the materials
(0.89 g, 2.0 mmol, 74%). 1H NMR (CDCl3)
d (ppm): 0.88 (t,
The materials filtered off from the reaction mixture were
washed successively with acetone (3 ꢂ 5 mL) and dichloromethane
(3 ꢂ 5 mL), then dried under high vacuum for 2 h.
J = 7.3 Hz, 3H), 1.24–1.32 (m, 2H), 1.38–1.46 (m, 2H), 2.07–2.18
(m, 1H), 2.34–2.43 (m, 1H), 3.10 (m, 2H), 3.64–3.76 (m, 2H),
4.40–4.50 (m, 1H), 4.81–4.87 (m, 1H), 4.96 (s, 1H), 5.00 (s, 1H),
5.11–5.20 (m, 3H), 7.16–7.31 (m, 10H); 13C NMR (CDCl3) (2 confor-
mational isomers) d (ppm): 13.6, 19.7, 31.7, 35.7 and 36.8, 40.5,
52.4 and 52.7, 57.6 and 57.9, 66.8 and 66.9, 67.1, 71.9 and 72.7,
127.7, 127.88, 127.90, 127.96, 128.04, 128.2, 128.27, 128.32,
128.4, 135.1 and 135.3, 136.0 and 136.1, 154.0 and 154.7, 155.25
Acknowledgements
The authors thank the Agence Nationale de la Recherche for
financial support (CP2D-MESORCAT). A.Z. thanks the Ministère de
l’Enseignement Supérieur et de la Recherche for a PhD grant. An-
drew Try (Macquarie University) is acknowledged for carefully
reading the manuscript.
and 155.29, 171.7 and 172.0; ½a D20
¼ ꢀ45:8 (c 0.01, CHCl3); HRMS
ꢁ
(ESI+): calcd for C25H31N2O6 (M+H): 455.2177; found 455.2204.
4.1.5. (2S,4R)-4-(Butylcarbamoyloxy)pyrrolidine-2-carboxylic
acid P01
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