Self-Assembly of Amphiphilic Dipeptide with Homo-and Heterochiral

Jul 26, 2018 - National Center for Nanoscience and Technology, Zhongguancun ... effect of two stereogenic centers in the self-assembly and catalysis...
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Article Cite This: ACS Omega 2018, 3, 8329−8336

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Self-Assembly of Amphiphilic Dipeptide with Homo- and Heterochiral Centers and Their Application in Asymmetric Aldol Reaction Sudipto Bhowmick,† Li Zhang,† Guanghui Ouyang,† and Minghua Liu*,†,‡,§

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†

Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Zhongguancun Beiyijie No. 2, Haidian, Beijing 100190, P. R. China ‡ National Center for Nanoscience and Technology, Zhongguancun Beiyitiao No. 11, Haidian, Beijing 100190, P. R. China § Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, P. R. China S Supporting Information *

ABSTRACT: Chiral self-assembly has drawn increasing interest in supramolecular chemistry. Here, we have designed amphiphilic L-Pro−L-Glu and L-Pro−D-Glu dipeptides and investigated their chiral self-assembly as well as asymmetric catalytic performance to disclose the synergistic effect of two stereogenic centers in the self-assembly and catalysis. It was found that both of the diastereomeric dipeptides can easily self-assemble into organogels with nanofibers. When these nanofibers were used as a catalyst for the asymmetric aldol reactions, enhanced enantioselectivity was obtained compared with their molecular state. Moreover, the L−L isomer assemblies showed higher enantioselectivity than the L−D isomer. It was revealed that both the supramolecular chirality of the nanofiber and the chiral catalytic site of L-proline played important roles in the asymmetric catalysis. In addition, the synergistic effect of two homochiral centers led to more efficient supramolecular catalysis that the L−L assemblies showed high yields (up to 97%), anti-diastereoselectivity (up to 99%), and excellent enantioselectivity (up to >99%).

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INTRODUCTION Recently, chiral self-assembly has drawn great interest because many of the self-assembly processes including those in biological systems involve the chirality issue.1−4 Through chiral selfassembly, various chiral nanostructures such as twists, nanotubes, nanorods, and nanocages could be obtained, which find further applications in chiroptical materials, chiral sensing, and enantioselective recognitions.5−15 Among various applications of the chiral nanostructures, the asymmetric catalysis, which tries to mimic the enzyme reaction, has been attracting great interest in recent days, whereas the development of chiral molecular catalysts for asymmetric reactions is still one of the central topic of organic synthesis and an area of immense interest. Various supramolecular chiral nanoarchitectures such as nanotubes, nanorods, nanocages, nanofibers, micelles, and vesicles have been recently employed as catalysts.16−30 Although great development has been achieved in the supramolecular catalyst, increasing the enantioselectivity and robustness of the supramolecular catalyst still remains an important issue. Here, we report a new supramolecular catalyst, which is based on the selfassembly of amphiphilic dipeptides with two chiral moieties, as shown in (Figure 1). The dipeptide was composed of L- or D© 2018 American Chemical Society

glutamide connected with the L-proline moiety. L- or Dglutamide was employed to facilitate the self-assembly because this unit was found to have a strong self-assembly capacity.31 LProline was selected because the amino acid can serve as a good catalyst for asymmetric reactions.32−39 We designed two dipeptides with homochiral (L−L) and heterochiral (L−D) centers to see the interplay of two chiral centers in the selfassembly as well as in the catalysis, which was scarcely reported before. After the pioneering work done by Hayashi and Barbas,40,41 different types of L-proline-based catalysts such as solidsupported, ionic liquid-tagged, and polymeric catalysts were developed. However, only few applications with a supramolecular nanostructure in asymmetric catalysis were reported. In 2009, Miravet and co-workers used fabricated proline-based supramolecular hydrogel for application in asymmetric aldol reactions, and they reached up to 90% enantioselectivity.42−46 Our group synthesized L-proline-containing amphiphilic dipepReceived: April 29, 2018 Accepted: July 13, 2018 Published: July 26, 2018 8329

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Figure 1. Synthesis procedures of amphiphilic gelators.

tide, which self-assembled into vesicles in water media and showed excellent enantioselectivity for the aldol reaction.47 Recently, Parquette synthesized proline−lysine-based dipeptide, which self-assembled into a supramolecular nanotube. With 10 mmol % catalyst loading, excellent enantioselectivity, in certain cases ee up to 97.5%, was realized.48 However, the reaction needed 4−5 days. Thus, a more efficient catalyst with a small amount of catalyst loading , higher reactivity, and enantioselectivity is still expected. We have found that our dipeptide can self-assemble into chiral nanofibers showing circular dichroism (CD) signals. When these nanofibers were used as a catalyst for the asymmetric aldol reaction, with low catalyst loading (2 mol %), we obtained high isolated yields (up to 97%), higher anti-diastereoselectivity (up to 99%), and enantioselectivity (ee up to >99%) in the presence of water within 1.5−8 h of reaction time at room temperature. Furthermore, it was observed that this supramolecular catalyst did not perform well in an organic medium. We have further revealed that the interplay between two chiral centers in the dipeptides played an important role both in the self-assembly and in the catalytic effect. The dipeptide with homochiral centers is more efficient in favoring the chiral self-assembly and higher enantioselectivity.

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RESULTS AND DISCUSSION Self-Assembly of the Dipeptides. We synthesized the dipeptides by the combination of radially available trans-4hydroxyproline with modified L- or D-glutamide. First, we protected the secondary amine and acid group of 4-hydroxyproline and then introduced the bulky tert-butyldimethylsilyl group, with the replacement of hydrogen of the starting material. Then, we deprotected the ester group for the coupling reaction with modified glutamide. Finally, we deprotected the boc (tertbutoxycarbonyl) group, and we got our desired product. The amphiphilic proline based L−L and L−D dipeptides can easily self-assemble into a white organogel in several organic solvents such as CH3CN, CH3CN/CHCl3, CH3CN/DCM, and CH3CN/tetrahydrofuran (THF). The gelation ability of L−L and L−D isomers in these organic solvents was investigated by the “stable to inversion in a test tube” method, as shown in Figure 2A. Scanning electron microscopy (SEM) was used to characterize the xerogels from air-dried organogels, as shown in (Figure 2E,F). It was found that one-dimensional nanofiber

Figure 2. (A) Photo pictures of L−L gel in different solvents; from left to right, CH3CN, CH3CN/CHCl3, CH3CN/DCM, and CH3CN/ THF. (B) CD spectra of L−L and L−D isomer gels in CH3CN/CHCl3. (C) XRD patterns of L−L and L−D xerogels obtained from CH3CN/ CHCl3. (D) UV−vis spectra of L−L and L−D gels in CH3CN/CHCl3. (E) SEM image of L−L xerogel formed in CH3CN/CHCl3. (F) SEM image of L−D xerogel formed in CH3CN/CHCl3.

structures with a high aspect ratio were obtained for both L−L and L−D isomers, which is typical of the supramolecular gels.49 The width of the fibers is about 0.1−0.3 μm. These numerous fibers are intertwined to form three-dimensional networks, and they immobilize solvents to form stable supramolecular gels. The organogels were further characterized by the ultraviolet− visible (UV−vis) and CD spectra. Figure 2B,D shows the CD and UV−vis spectra of the organogels. L−L and L−D isomers both showed an adsorption band at around 279 nm in the THF gel, ascribed to the proline moiety conjugated with the amide 8330

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relative strong peaks at 3460 cm−1 for the N−H stretching vibration is observed at L−L in CH2Cl2 solution, which could be ascribed to the free amide groups. Upon gel formation, a strong peak was observed at 3293 cm−1, which can be assigned to the H-bonded N−H vibrations. In addition, the amide I band at 1647 cm−1 in CH2Cl2 solution shifted to 1642 cm−1 in the gel, which also confirmed the H-bond between amide groups in the gel.51 These data indicated that the hydrogen bonding between amide moieties is the main driving force for the formation of gels. Temperature-dependent 1H NMR (Figure 3B) spectra of the L−L isomer further confirmed the hydrogen bonding attributed to the self-assembly. The protons of the amide group (−CO− NH−) shift toward the upfield with increasing temperature, supporting that hydrogen bonding between the amide group is weakened with the increase of temperature.52,53 Asymmetric Catalysis for Aldol Reaction by the Nanofibers. After the characterization of our newly synthesized supramolecular catalyst, we started to screen the applicability with the L−L isomer for the asymmetric aldol reaction in the presence of water. First, an attempt was made between 4nitrobenzaldehyde and cyclohexanone in the presence of benzoic acid (used as an additive to enhance the reaction rate) with different amounts of water (0.01−1 mL) as well as in brine. The reactions were completed within 3 h, and good yield but low-to-moderate stereoselectivity was obtained (Table 1 entries 1−4). Even though we increased the catalyst loading from 2 to 5 mol % in the presence of 0.5 mL of water, still only 70% enantioselectivity was observed (Table 1 entry 5). Another thing that we observed is that if we increase the amount of water, then both diastereoselectivity and enantioselectivity decreased. Parallel to this, we investigated the reactions with the L−D isomer in the presence of water and brine (Table 1 entries 7− 10). From these experiments, we observed that in some cases, it took more time to complete the reactions (Table 1 entries 8, 10), but enantioselectivity increased a little bit. The other parameters such as yield and diastereoselectivity are almost similar to the previous result. Thereafter, we also examined the reaction with dichloromethane (DCM) and obtained low diastereo- and enantioselectivities. Then, we tried to solve the problem with the help of supramolecular architecture. For this purpose, we prepared four different supramolecular organogels where the major solvent was acetonitrile. One organogel was prepared from pure acetonitrile, and for the other three mixtures, the major solvent was acetonitrile and cosolvents (6.6%) were chosen as DCM, THF, and chloroform. After that, we performed one reaction just by putting all substrates directly on the organogel without evaporation of the solvent. After completion of the reaction, we checked the selectivity and observed that it was almost similar to the previous result (64%), but it took almost 3 days to complete the reaction (Table 1 entry 12). Then, we evaporated the solvent from the four organogels and investigated the aldol reaction directly by putting the substrates on the xerogel under the same reaction conditions (Table 1 entries 13−17). Surprisingly it was observed that in the presence of the supramolecular nanocatalyst, diastereoselectivity as well as enantioselectivity increased significantly. Moreover, less time (only 2 h) was required to complete the reaction than the previous one (Table 1 entries 13−17). The main remarkable observation is that, for the unassembled catalyst, we found only 36% enantioselectivities (Table 1 entry 2), and whenever it changed to the form of a supramolecular catalyst, it provided us

group. The CD spectra of L−L and L−D isomers exhibited an obvious difference. As for the L−L isomer, an obvious positive Cotton effect was observed at around 270 nm, which is consistent with that of the adsorption band characterized by UV−vis spectra. On the other hand, it is almost CD silent for the L−D isomer. This result indicated that the remote chiral center of amphiphilic L-glutamide also has an important effect on the supramolecular chirality. The homochiral centers are easier for the chiral self-assembly. Figure 2C shows the X-ray diffraction (XRD) patterns of L−L and L−D isomers. L−L xerogel from CH3CN/CHCl3 showed four obvious diffraction peaks, corresponding to a layer spacing of 3.2, 1.6, 1.1, and 0.8 nm respectively, based on the Bragg’s equation. The proportion of these spacings is 1:1/2:1/3:1/4, suggesting a lamellar structure.50 L−D xerogels from CH3CN/ CHCl3 also exhibited a lamellar structure, which showed a layer spacing of 2.1 nm. The layer spacings of 3.2 and 2.1 nm obtained from the XRD patterns are greater than the L−L or L−D molecular length (CPK molecular model measured the length of the molecules to be 1.8 nm), implying that L−L or L−D selfassemblies are made from the interdigitated bilayer structures, in which alkyl chains are more densely packed or interdigitated in the L−D isomer. To further understand the driving force for self-assembled nanostructures, Fourier transform infrared (FT-IR) and temperature-variation NMR spectra of the L−L gels were investigated. Figure 3A shows characteristic infrared absorption for hydrogen bonds between N−H and CO. Two peaks were observed at the N−H vibration at around 3300−3500 cm−1. The

Figure 3. (A) FT-IR spectra of L−L xerogel obtained from CH3CN/ CHCl3 and L−L powder obtained from CH2Cl2. (B) Temperaturedependent 1H NMR spectra of the L−L isomer in the CD3CN solvent. 8331

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Table 1. Screening between the Organocatalyst and the Supramolecular Catalyst in the Aldol Reactiona

entry

solvent/gel/xerogel (mL)

time (h)

yield (%)b

drc [anti/syn]

ee (%)d [anti]

1 2 3 4 5e 6 7 8 9 10 11 12f 13g 14h 15i 16j 17

H2O (0.01) H2O (0.1) H2O (0.5) H2O (1) H2O (0.5) brine (0.5) H2O (0.1) H2O (0.5) H2O (1) brine (0.5) DCM gel xerogel xerogel xerogel xerogel xerogel

3 3 3 3 3 2 3 9 3 15 6 36 2 2 2 2 2

95 93 94 95 92 96 91 89 92 90 85 89 94 95 93 94 94

83/17 91/9 91/9 60/40 83/17 90/10 88/12 87/13 88/12 89/11 63/37 78/22 84/16 93/7 89/11 84/16 83/17

64 36 66 64 70 60 82 78 80 84 22 64 86 95 94 95 88

a

Reactions were carried out by using aldehyde (1 mmol), cyclohexanone (4 mmol), catalyst (0.02 mmol), and benzoic acid (0.02 mmol) in 0.1 mL of water at room temperature for the mentioned time. Entries 1−6 are examples with the L−L isomer of the organocatalyst, and entries 7−10 are examples with the L−D isomer of the organocatalyst. Entries 11−16 are examples in the presence of the supramolecular catalyst. bIsolated yield after purification by column chromatography. cAnti/syn diastereomeric ratios were determined by 1H NMR spectrum of the crude product mixture. d Determined by chiral HPLC analysis (chiral phases: Chiralpak OD-H, AD-H and AS-H) with hexane−IPA as an eluent. e5 mol % catalyst was used. fWithout evaporation of the solvent from the gel. gXerogel obtained from acetonitrile. hXerogel obtained from the acetonitrile/chloroform mixture. iXerogel obtained from the acetonitrile/DCM mixture. jXerogel obtained from the acetonitrile/THF mixture.

high enantioselectivities (95%) under the same reaction conditions (Table 1 entry 14). Among the four xerogels, the combination of acetonitrile/chloroform worked very well than others. Thereafter, we tried all reactions with the xerogels, which are made from acetonitrile/chloroform mixture. Then, we tried one more reaction with 1 mol % catalyst loading, but diastereoand enantioselectivities both were decreased slightly (Table 1 entry 17). From the results we can say that the supramolecular nanostructure is solely responsible for the enhancement of high enantioselectivity in this particular reaction. Inspired from this new finding, we investigated the substituent effects of various aromatic aldehydes and different ketones in the aldol reaction to identify the scope and limitations of the supramolecular catalyst under optimized conditions. The results are summarized in Table 2. From Table 2, we can see that the reaction between cyclohexanone and aromatic aldehydes containing an electronwithdrawing group led to very good yields (up to 97%), high diastereoselectivity (up to 99:1), and excellent enantioselectivities (up to 95%) within 1.5−8 h. Here, we tried to examine almost all kinds of substrates such as electron donating and electron withdrawing as well as polycyclic aromatic aldehydes and different types of ketones in the reaction. In case of the electron-donating group present in aldehyde such as 2methoxylbenzaldehyde, the product with 93% ee was obtained within 6 h. Furthermore, for a polycyclic aromatic aldehyde such as 2-naphthaldehyde, we obtained 92% ee (Table 2 entry 10). We also examined the electron-donating group such as methoxy in the 3-position as well as methyl in the 4-position of the aromatic aldehyde, and we observed good yields and enantioselectivities (Table 2 entries 11−12).

Next, we tried to broaden the substrate scope of this methodology with some unsymmetrical ketones such as tetrahydropyran-4-one, tetrahydrothiopyran-4-one, tert-butyl 4-oxopiperidine-1-carboxylate, and 4-methylcyclohexanone as donors. They provided good yield and enantioselectivities (up to 95%). We also examined with the cyclopentanone type of ketone and observed >99% ee within only 2 h of reaction. Except aliphatic aldehyde, almost all type of aromatic aldehydes as well as different kinds of ketones were examined. From Table 2, we observed very promising catalytic efficacy of the supramolecular nanocatalyst. Then, we investigated the efficiency of another L−D isomer of our supramolecular catalyst in the same reaction under optimized conditions. It showed almost parallel diastereoselectivity and somewhat lower enantioselectivities than the L−L isomer (Table 2 entries 18−21). Furthermore, in most cases, poor chemical yield (64−82%) and long reaction time (4−48 h) were observed. From the above results, we can propose a possible mechanism for the self-assembly and reaction, as illustrated in Figure 4. Both amphiphilic dipeptides can self-assemble into nanofibers through a multi-bilayer unit. In these nanofibers, the active catalytic center L-proline is located on the surface of the nanofibers. Because of accumulation of the surface of the nanofiber, the localized concentration of substrates was increased and the reaction was accelerated. On the other hand, with respect to the asymmetric reaction, not only the catalytic site by L-proline but also the collective or supramolecular chirality will significantly affect the enantioselectivity of the reaction. In the case of the L−L isomer, the compound formed a nanofiber showing a strong positive supramolecular 8332

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Table 2. Substituent Effects of Different Aromatic Aldehydes and Ketones in the Aldol Reactiona

entry

aryl

R1 R2

time (h)

yield (%)b

drc [anti/syn]

ee (%)d [anti]

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18e 19e 20e 21e

4-NO2C6H4 2-MeOC6H4 2-ClC6H4 3-CNC6H4 4-BrC6H4 2-NO2C6H4 2-FC6H4 3-FC6H4 4-CF3C6H4 2-naphthyl 3-MeOC6H4 4-MeC6H4 4-NO2C6H4 4-NO2C6H4 4-NO2C6H4 4-NO2C6H4 4-NO2C6H4 4-NO2C6H4 2-MeOC6H4 2-ClC6H4 3-CNC6H4

(CH2)3 (CH2)3 (CH2)3 (CH2)3 (CH2)3 (CH2)3 (CH2)3 (CH2)3 (CH2)3 (CH2)3 (CH2)3 (CH2)3 CH2OCH2 CH2CHMeCH2 (CH2)2 CH2SCH2 CH2NBocCH2 (CH2)3 (CH2)3 (CH2)3 (CH2)3

2 6 2 4 3 1.5 1.5 2.5 2 8 4 6 1.5 1.5 2 7 3 4 48 30 24

92 89 97 91 92 96 95 91 94 92 93 90 95 93 95 97 89 82 64 71 81

93/7 89/11 99/1 93/7 92/8 93/7 95/5 96/4 95/5 93/7 92/8 85/15 88/12 88/12 87/13 85/15 61/39 94/6 88/12 92/8 94/6

95 93 91 92 94 94 92 94 90 92 90 82 95 90 >99 80 65 85 88 87 89

a

Reactions were carried out by using aldehyde (1 mmol), cyclohexanone (4 mmol), supramolecular catalyst (0.02 mmol), and benzoic acid (0.02 mmol) in 0.1 mL of water at room temperature for the mentioned time. bIsolated yield after purification by column chromatography. c Diastereomer ratios (anti/syn) were determined by 1H NMR spectrum of the crude product mixture. dDetermined by chiral HPLC analysis (chiral phases: Chiralpak OD-H, AD-H and AS-H) with hexane−IPA as an eluent. eReaction performed with the L−D isomer.

D isomers, although the molecular chirality of the active catalyst is the same, the collective chirality of the fiber was not as efficient as those from the homochiral dipeptide. Thus, we observed the decrease of enantioselectivity. Apart from this, we also examined the same reaction in water as well as in organic media with two new catalytic systems (L−L 1 and L−D 1) prepared by substituted proline with L/D-glutamic acid diethyl ester hydrochloride to check the requirement of supramolecular self-assembly. In case of applicability, we obtained moderate diastereoselectivity and poor to average enantioselectivities (up to 76%) for all cases. That means, the long chain glutamide scaffold helps for the process of supramolecular self-assembly and also increases the H-bonding amide moiety, which is very important for the catalysis. We can now easily conclude that supramolecular chirality definitely plays a major role for obtaining higher selectivity (see the Supporting Information). It should be noted that the solvent also has an effect on the self-assembly of the amphiphile dipeptide. Whereas the organic solvent can possibly cause the disassembly of the nanofiber in the reaction media, the addition of a small amount of water will be very efficient in maintaining the nanostructure, and thus we obtained higher yield and enantioselectivity. Finally, the reusability of the catalyst is also another important parameter of the efficient catalyst. Here, we have done experiments by the following method of List and Singh.54,55 First, the aldol reaction was carried out with 4-nitrobenzaldehyde (1 mmol), cyclohexanone (4 mmol), supramolecular catalyst (0.02 mmol), and benzoic acid (0.02 mmol) in 0.1 mL of water at room temperature. The disappearance of the starting material was monitored by thin-layer chromatog-

Figure 4. Illustration of the possible mechanism for the self-assembly in asymmetric aldol reaction.

chirality. Both the supramolecular and molecular chiralities of Lproline synergistically play in catalyzing the aldol reaction, and thus a maximum 99% enantioselectivity was reached. In the L− 8333

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FE-SEM microscope. UV and CD spectra were recorded on JASCO UV-550 and JASCO J-810 CD spectrophotometers, respectively. XRD was measured on a Rigaku D/Max-2500 Xray diffractometer (Japan) with Cu Kα radiation (λ = 1.5406 Å), which was operated at 45 kV, 100 mA. TLC was performed by precoated plates (Merck Kieselgel 60 F254) and checked with UV light (254 nm) or aqueous potassium permanganate solution. Flash column chromatography was performed using 200−300 mesh silica gel, and n-hexane and ethyl acetate were used as eluents. FT-IR spectra were recorded on a spectrometer where KBr was used for the preparation of the pellets. Enantiomeric ratio was determined by chiral high-performance liquid chromatography (HPLC) with chiral columns (chiralpak AS-H column, chiralpak AD-H column, and chiralpak OD-H column), and HPLC grade isopropyl alcohol (IPA)/hexane was used as an eluent. The absolute configurations of the products were determined with comparison of the retention time from the literature.56,57 Compounds 1 and 2 were prepared by the known procedure;58 thereafter, trans-N-Boc-4-tert-butyldimethylsiloxy-L-proline 2 (56 mg, 0.16 mmol) was dissolved in DCM (4.7 mL) and cooled to 0 °C. Then, 1-hydroxybenzotrizole (0.032 g) was added to the solution, and the mixture was stirred for 5 min at the same temperature. After that, 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (0.046 g) was added to the mixture and stirred for 5 min, and finally amine 359 (78 mg, 0.16 mmol) was added. The mixture was allowed to reach room temperature and stirred for 18 h. The reaction was monitored by TLC, and after completion of the reaction, it was washed with 10% citric acid (2 × 30 mL), saturated NaHCO3 (2 × 30 mL), and brine (1 × 30 mL). The collected organic portion was dried over Na2SO4, and the solvent was removed by a rotary evaporator. Crude boc (tert-butoxycarbonyl) protected product 4 was obtained as a white solid. The crude reaction mixture was purified by flash column chromatography on silica gel (50% EtOAc/hexane) to give the product as a white solid (0.110 g, 85% yield). 1H NMR (400 MHz, CDCl3): δ 8.15 (d, J = 6.9 Hz, 1H), 7.33 (t, J = 5.1 Hz, 1H), 6.47 (t, J = 5.6 Hz, 1H), 4.36−4.27 (m, 3H), 3.68 (dd, J = 10.8 Hz, 1H), 3.40 (dd, J = 10.7 Hz, 1H), 3.19−3.13 (m, 4H), 2.27 (t, 2H), 2.18−1.97 (m, 4H), 1.43 (br s, 15H), 1.23 (br s, 34H), 0.84 (br s, 15H), 0.04 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 172.5, 155.8, 147.7, 118.9, 80.3, 70.3, 60, 55.4, 53, 39.8, 39.1, 31.9, 29.6, 29.5, 29.3, 27, 26.9, 25.6, 22.6, 14.9, −4.7, −4.9. IR: 3296, 2925, 1643, 1464, 1254, 962, 776 cm−1. MALDI-TOF-MS: (M + Na)+ calcd for C45H88N4O6Si, 831.63; found, 831.63. Then N-Boc-protected compound 4 (966 mg, 1.194 mmol) was dissolved in 8.23 mL of mixture solvent trifluoroacetic acid/ DCM = (1:4) and stirred for 6 h under an argon atmosphere at room temperature. After completion of the reaction, the solvent was removed by a rotary evaporator, and the residue was redissolved with CHCl3 and washed with NaHCO3 solution (3 × 30 mL), water (2 × 30 mL), and brine (2 × 30 mL). The resulting organic portion was dried over anhydrous Na2SO4 and concentrated under reduced pressure. Then, it was subjected to flash column chromatography (MeOH/EtOAc = 10/90) on silica gel to give the desired product 5 as a white solid (0.609 g, 72% yield). 1H NMR (400 MHz, CDCl3): δ 8.50 (d, J = 7 Hz, 1H), 6.40 (t, J = 5.3 Hz, 1H), 5.34 (t, J = 5.1 Hz, 1H), 4.51−4.38 (m, 2H), 3.22−3.15 (m, 4H), 2.35−2.30 (m, 3H), 2.21−2.10 (m, 2H), 2.09−2.02 (m, 2H), 1.65−1.48 (m, 5H) 1.25 (br s, 39H), 0.88 (br s, 14H), 0.08 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 175.4, 172.4, 171, 73.5, 59.7, 55.9, 52, 40, 39.7, 33.6,

raphy (TLC). After completion of the reaction, the aldehyde and ketone were again added to the reaction mixture without adding the other things. The same procedure was repeated six times (Figure 5 cycle 1−6), and it produced a high yield and

Figure 5. Reusability of the supramolecular catalyst.

overall 92% enantioselectivities. On the other hand, we also examined the reaction with low catalyst loading (0.3 mol %) under the same reaction conditions and obtained the product with good yield and 86% enantioselectivities (Figure 5 cycle 7). So, from the result, definitely we can say that the continuous cycle process is appropriate for this reaction.

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CONCLUSIONS In conclusion, we have synthesized dipeptides composed of Lproline and glutamic acid with homochiral and heterochiral centers to investigate their self-assembly as well as asymmetric catalysis. Both of the compounds could self-assemble into nanofibers and immobilized the solvent to form organogels. However, the dipeptide with homochiral centres was more efficient in forming the nanofibers, showing an obvious supramolecular chirality. When these fibers were used as catalysts for the asymmetric aldol reaction, high isolated yields (up to 97%), anti-diastereoselectivity (up to 99%), and enantioselectivity (up to >99%) were obtained in the presence of water. For this catalytic process, only 2 mol % of the catalyst was used to complete the reaction within a very short span of time (1.5−8 h). The catalyst could also be reused by the continuous cycle process for up to six cycles without a significant loss of catalytic activity. It was found that the molecular state catalyst could only provide lower enantioselectivity (36%). Thus, it is concluded that both the collective or supramolecular chirality and molecular chirality played an important role in the asymmetric catalysis, whereas the synergistic play of two chiral centers contributed to the supramolecular chirality of the nanofibers. The present result opens new possibility in the design of a supramolecular catalyst for asymmetric reactions.

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EXPERIMENTAL DETAILS General. All aldehydes, ketones, and other reagents were used as received. The 1H and 13C NMR spectra were recorded on Bruker AV400 MHz spectrophotometers using trimethylsilane as an internal standard and CDCl3 as a dissolving solvent. Chemical shifts were given in parts per million (δ-scale). Matrixassisted laser desorption ionization time-of-flight (MALDITOF) mass spectrometry (MS) spectra were recorded on a BIFLEIII instrument. SEM was carried out on a Hitachi S4300 8334

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33.1, 31.9, 29.9, 29.6, 29.6, 29.6, 29.5, 29.5, 29.3, 29.3, 27, 26.9, 25.7, 22.7, 18, 14.1, −4.7, −4.8. IR: 3292, 3096, 2922, 1558, 1468, 1253, 1077, 901, 776 cm−1. MALDI-TOF-MS: (M + H)+ calcd for C40H80N4O4Si, 709.59; found, 709.60. Same procedure was followed for the preparation of compound 6. D-Glutamic acid was taken instead of L-glutamic acid. General Procedure for the Enantioselective Direct Aldol Reaction. First, xerogel of nanocatalyst 5 (0.02 mmol) was taken, and then, acid additive (benzoic acid, 0.02 mmol), ketone (4.00 mmol), and water (0.1 mL) were mixed with it. After 15 min of stirring, aromatic aldehyde (1.00 mmol) was added and stirred at room temperature for the mentioned time. The reaction was monitored by TLC, and after completion of the reaction, it was quenched with 10 mL of saturated NaHCO3 solution and extracted with EtOAc (3 × 10 mL) and brine (10 mL). Then, the organic solvent was dried over Na2SO4 and evaporated by a rotary evaporator. Thereafter, the crude mixture was purified by column chromatography to afford the pure chiral product. Finally, enantioselectivity was determined by chiral HPLC analysis, and the ratio of syn and anti was examined with the crude mixture by NMR spectroscopy.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b00852.

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Characterization spectra of compounds 4, 5, and L−L 1 and HPLC data and all spectra of racemic/chiral aldol products (PDF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (M.L.). ORCID

Minghua Liu: 0000-0002-6603-1251 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (nos. 21473219 and 91427302), and the Fund of the Chinese Academy of Sciences (no. XDB12020200). S.B. acknowledges the Chinese Academy of Science for the fellowship (grant no. 2016PM055).

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REFERENCES

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DOI: 10.1021/acsomega.8b00852 ACS Omega 2018, 3, 8329−8336

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DOI: 10.1021/acsomega.8b00852 ACS Omega 2018, 3, 8329−8336