Silica-supported l -proline organocatalysts for asymmetric aldolisation

Tetrahedron: Asymmetry 20 (2009) 2880–2885

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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

Article history: Received 16 November 2009 Accepted 27 November 2009 Available online 7 January 2010

a b s t r a c t 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 without porogen to yield high surface area solids. These materials were evaluated as heterogeneous phase organocatalysts for the asymmetric aldol reaction of pnitrobenzaldehyde with acetone. Ó 2009 Elsevier Ltd. All rights reserved.

1. Introduction Hybrid organic/inorganic silicas with the combined properties of the organic component and the solid structure of the silica network,1–3 obtained from organoalkoxysilanes are very promising materials for applications. Over the past two decades, several organosilyl 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 catalytic species. We and others have developed such solid catalysts for different kinds of reactions including metathesis, coupling and asymmetric reactions. 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 pharmaceutical 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 drawbacks of these organometallic reactions. 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 acids, and in particular L-proline, can be used for this purpose, * Corresponding authors. E-mail addresses: [email protected] (J.J.E. Moreau), Michel.wong-chi-man@ 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

although increasingly complex derivatives18–21 are now being designed to achieve better performances. The low turnover of the catalysts 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 system; 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 mesoporous silica34–40 and iron oxide nanoparticles41 have also been used as inorganic supports by grafting methods. Silica is an attractive support for the immobilisation of organocatalysts as a result of its thermal and mechanical stability as well as its chemical inertness.42–44 These reasons prompted us to extend 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 framework due to the strong Si–C covalent bonding. Moreover, the sol– gel synthesis of the hybrid material in the presence of surfactants45,46 enables control of the porosity and of the specific surface area of the resulting catalytic hybrid materials. These are important parameters, especially for solid phase catalysis. Herein we report the feasibility of immobilising asymmetric organocatalysts (in the case of L-proline) by the sol–gel process. To the best of our knowledge, only one example of L-prolinamide immobilized on silica by the sol–gel method has been reported.44 Herein we report the preparation of new heterogenised organocatalysts via the sol–gel process incorporating the L-proline motif and their catalytic activities in an asymmetric aldol reaction.

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2. Results and discussion

Q3

Two silylated compounds based on trans 4-hydroxy-L-proline with different linkers were envisaged as silica precursors, featuring either a carbamate P138 or an ether moiety P2. The latter was synthesised according to Scheme 1. Derivative 1, obtained according to a previously described methodology,47 was converted to its corresponding benzylic ester 2. Hydrosilylation was successfully performed at room temperature 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. 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. These hybrid materials were characterized by multiple analyses: The 29Si NMR spectrum (Fig. 1) exhibits two sets of broad signals attributed to T (C–SiO3, 55 to 66 ppm) and Q (SiO4, 90 to 120 ppm) environments. The presence of the T units gives evidence 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 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. The N2 adsorption desorption (BET) was used to determine the specific areas and textural properties of these solids. These measurements are shown in Figure 3 in the case of P1/10N and P1/

P2/10D

Q4

T2

0

-20

-40

Q2

T3

-60

-80

-100

-120

-140

δ (ppm) Figure 1.

29

Si CP-MAS NMR spectrum of P2/10D.

P2/10D

B 250

200

150

100 δ (ppm)

50

0

-50 P1/10D

A 250

200

Figure 2.

150

13

100 δ (ppm)

50

0

-50

C CP-MAS NMR spectra of (A): P1/10D, (B): P2/10D.

OBn Cy O

N

CO2H

N

N H

Cy

HSi(OEt) 3 Karstedt cat.

O

THF/RT/20 h 73%

CO2Bn

N

Cbz 1

Si(OEt)3

cyclohexene Pd/C

O

THF/RT/20h 77%

CO 2Bn

N

Cbz 2

EtOH/Δ/0.5 h 89%

Cbz

Si(OEt) 3

+ y Si(OEt)4

H2O, EtOH, G

R

SiO1.5·ySiO2

Px

Px/y-G y = 10, 20, 40

O N H

O

O OH

P1 R = N H

O

P2

CO 2 H

N H P2

3

Scheme 1. Preparation of the precursor featuring an ether linker P2.

R

Si(OEt)3 O

OH

R= N H

O

Scheme 2. Preparation of the hybrid silica via the sol–gel process using P1 or P2.

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B

H N

dV/dlog(D)

O

O

O P1/10N P1/10D

N H P'1

-1

Quantity adsorbed (cm³.g )

0 450 400 350 300 250 200 150 100 50 0

200

400

0.2

0.4

0.6

0.8

1.0

(p/pº) 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 adsorbed 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 properties are similar for materials derived from both precursors. Table 1 N2 adsorption/desorption: surface area and pore sizes

a b c

CO2H

P'2

Figure 4. Structures of the two L-proline derivatives P0 1 and P0 2.

P1/12N P1/12D

0.0

N H

600

Pore diameter (Å)

A

CO2H

Material

Surface areaa (m2 g1)

Pore diameterb (Å)

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

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 the asymmetric aldolisation reaction between p-nitrobenzaldehyde and acetone (Table 2), which is typically used as a benchmark for these reactions.48,49 Two new non-silylated homogeneous analogues P0 1 and P0 2 were studied for comparison (Fig. 4) to preclude any detrimental effect of the carbamate or ether linkers on the catalytic performances. These compounds exhibit catalytic activities and enantioselectivities comparable to L-proline or trans 4-hydroxy-L-proline (total conversion; ee 74%, 79%, 76%, 78%, respectively) under standard conditions.49 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-

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 concentrated hybrids (entries 1, 2 and 7), the ee values are lower by ca. 10% compared to the more diluted ones. This trend might be explained by the closer proximity between the catalytic centres, which would open racemic pathways. 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 spectrum of the material recovered from P2/10D after one run, and continuously 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 corresponding 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 decrease of the surface area (from 643 to 270 m2 g1), whereas the size of the available pores remains constant (ca. 30 Å). To gain further insight into the reaction mechanism, we performed the same reaction without any solid or with a pure mesoporous 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 condensation of acetone with the amine fragment of L-proline to 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, competing with the carboxylic acid groups for the localisation of the aldehyde (Fig. 6). The related participation of the silanol groups from a hybrid silica surface has already been shown to be beneficial in the case of Henry reactions.52 3. Conclusion A series of related new hybrid silicas containing the L-proline motif have been prepared using the sol–gel process starting from two kinds of silylated L-proline derivatives. These materials catalyse the asymmetric aldolisation between p-nitrobenzaldehyde and acetone at room temperature, though with moderate performances. The decrease in activity was explained in terms of inhibition 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 positioning 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

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O

OH +

a

c

(R)

DMSO 25 ºC

O2N

b

O

cat. 30% mol

O

O2N

Entry

Material

Time (d)

Conversiona (%)

1 2 3 4 5 6 7 8 9 10

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

eeb (%) 20 25 36 25 38 37 27 37 36 35

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. 1 H, 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 Perkin–Elmer polarimeter 241. HPLC analyses were carried using a Waters 515 pump equipped with a Waters 2487 detector.

* P2/10D-after one cycle

250

200

150

100

50

0

-50

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 O

O N

H

Si

Si O

O

4.1.1. (2S,4R)-Dibenzyl 4-(allyloxy)pyrrolidine-1,2dicarboxylate 2 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 reaction 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

H

O

O

H

R O Si

O N

Ar (R)

Si O H

O

O

OH

Si O H

O

H

O

OH

H R O H

O Si

Figure 6. Simplified representation of the competition between the silanol and COOH groups.

Ar (S)

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and 128.55, 128.6, 134.3, 135.5 and 135.7, 136.4 and 136.6, 154.4 and 155, 172.4 and 172.6; ½a24 D 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  102 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 residue was filtered through a pad of Celite. The filtrate was concentrated 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 conformational 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 172.7; 29Si NMR (DMSO-d6) d 45.1; ½a24 D ¼ 24:5 (c 1.2, CHCl3). 4.1.3. (2S,4R)-4-(3-(Triethoxysilyl)propoxy)pyrrolidine-2carboxylic acid P2 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  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) d 45.0; FTIR: m = 3432 cm1, 2988 cm1, 2932 cm1, 1639 cm1, 1128 cm1; ½a24 D ¼ 4:5 (c 0.5, CHCl3); HRMS (FAB+): calcd for C14H30NO6Si (M+H): 336.1842; found 336.1851. 4.1.4. (2S,4R)-Dibenzyl 4-(butylcarbamoyloxy)pyrrolidine-1,2dicarboxylate 4 To a solution of (2S,4R)-1,2-dibenzyloxycarbonyl-4-hydroxypyrrolidine38 (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 (0.89 g, 2.0 mmol, 74%). 1H NMR (CDCl3) d (ppm): 0.88 (t, 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 conformational 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 and 155.29, 171.7 and 172.0; ½a20 D 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 P0 1 To a solution of 4 (0.68 g, 1.5 mmol) in dry EtOH (12 mL), was added cyclohexene (0.30 mL, 3.0 mmol) and Pd/C (10% Pd, 0.45 g),

under nitrogen atmosphere and the reaction mixture was refluxed for 1 h. The reaction mixture was then filtered through a pad of Celite and the filtrate was concentrated in vacuo to yield P0 1 as a yellow 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, 155.6, 173.1; ½a20 D 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 P0 2 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 P0 2 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; ½a20 D ¼ 30:2 (c 0.008, CHCl3); HRMS (ESI+): calcd for C8H16NO3 (M+H): 174.1125; found 174.1131. 4.2. General procedure for the sol–gel preparation of the hybrid silica Px/y-G 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  (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 vacuum to give a white solid. 4.3. General procedure for the catalytic aldolisation 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 progress 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). 4.4. General proceedure for the recovery of the materials The materials filtered off from the reaction mixture were washed successively with acetone (3  5 mL) and dichloromethane (3  5 mL), then dried under high vacuum for 2 h. 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. Andrew Try (Macquarie University) is acknowledged for carefully reading the manuscript. References 1. Sanchez, C. J. Mater. Chem. 2005, 15, 3541–3988. 2. Jaroniec, M.; Schüth, F. Chem. Mater. 2008, 20, 599–1190.

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