Article Cite This: Macromolecules XXXX, XXX, XXX−XXX
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Polymerization Amplified Stereoselectivity (PASS) of Asymmetric Michael Addition Reaction and Aldol Reaction Catalyzed by Helical Poly(phenyl isocyanide) Bearing Secondary Amine Pendants Ling Shen,† Lei Xu,† Xiao-Hua Hou, Na Liu,* and Zong-Quan Wu*
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Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, and Anhui Key Laboratory of Advanced Catalytic Materials and Reaction Engineering, Hefei University of Technology, 193 Tunxi Road, Hefei 230009 Anhui Province China S Supporting Information *
ABSTRACT: A novel enantiopure phenyl isocyanide (1) carrying tert-butyloxycarboryl (Boc) protected L-prolinol ester was designed and synthesized. Living polymerization of 1 using a alkyne−Pd(II) catalyst afforded helical poly-1ms in high yields with controlled molecular weights (Mns) and narrow molecular weight distributions (Mw/Mns). Removing the protecting Boc groups on the L-prolinol ester pendants lead to the formation of helical poly-2m, which showed high optical activity owing to the preferred left-handed helix of polyisocyanide main chain. The poly-2ms showed excellent catalytic ability on asymmetric Michael addition reaction. Both the enantiomeric excess (ee) and diastereomeric ratio (dr) values of the product were linearly correlated to the Mn and optical activity of poly-2m. Increasing the Mn of poly-2ms will amplify the stereoselectivity of the asymmetric Michael addition reaction until the Mn reached to 44.9 kDa, revealing the polymerization amplified stereoselectivity (PASS) behavior of the asymmetric reaction. Under optimized the reaction condition, the ee and dr values of the Michael addition reaction product can be up to 99% and >99/1, respectively. Poly-2200 can be easily recovered and reused in the Michael addition reaction for at least 5 cycles without loss of its activity and stereoselectivity significantly. The poly-2200 can also be used to catalyze the asymmetric aldol reaction. The ee and dr values of the model aldol reaction were respectively up to 99% and >99/1. Moreover, the poly-2200 can be facilely recovered and alternatively catalyzed Michael addition reaction and aldol reactions for at least six cycles with maintained selectivity and activity.
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INTRODUCTION Asymmetric organocatalysis has gain great attentions in the past 2 decades, owing to their inherent nonmetal feature, mild reaction conditions, and broad functional groups tolerance.1−6 However, a large amount of organocatalyst is usually required in the organocatalyzed reactions, which is not economic and may cause difficulty in the product purification. An effect solution to this challenge is polymer-based chiral organocatalyst which can be easily recovered from the reaction mixture and possibility of reuse.7−9 Generally, polymer catalysts were fabricated just by incorporate well-established small chiral catalytic units onto polymer pendants, far from the polymer scaffold to avoid the any unfavorable perturbation to the chiral catalysis sites. However, for the next-generation of polymer-based catalyst, the polymer should not only just serve as a scaffold but also can significantly enhance or amplify the activity and stereoselectivity. Helix is one of the most important secondary structure in biomacromolecules, and plays vital roles in living system including catalysis, recognition, replication and so forth.10,11 Helix is inherently chiral, synthetic helical polymers can be optically active just by taking a preferred one-handed helix.12−14 Many researches have been paid on synthetic © XXXX American Chemical Society
helical polymers due to their great potentials in enantiomer separation, chiral recognition, asymmetric catalysis, liquid crystals, etc.15−20 Immobilize organocatalyst onto helical polymers may exhibit unique advantages on asymmetric reactions.21−24 Besides the high molecular weight facilitate the polymer catalyst recovery and recycle use, more importantly, the helical sense of polymer backbone can provide additional asymmetric environment, which may exhibit synergistic effect to amplify the stereoselectivity of asymmetric reactions. It is well-known that, introducing bulky substituents adjacent to the catalytic point could improve the stereoselectivity.5,6 However, polymerization amplified the stereoselectivity of an asymmetric reaction has never been reported to date. Helical polymers may have a chiral amplification effect, supporting them with considerable optical activity.10−12 Fabrication of helical polymers with catalytic functional pendants would endows them with good performance in asymmetric catalysis owing to their intriguing optically active Received: September 28, 2018 Revised: November 11, 2018
A
DOI: 10.1021/acs.macromol.8b02088 Macromolecules XXXX, XXX, XXX−XXX
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Macromolecules helices. Among the reported helical polymers, polyisocyanide is a kind of static helical polymer. It has good environmental stability, and can maintain helicity in various solvents even at higher temperatures.12 Thus, organocatalyst based on helical polyisocyanide may have broad solvents and temperature tolerance. In this contribution, we report on design and synthesis of a new phenyl isocyanide (1) carrying a chiral secondary amine derived from Boc-L-prolinol ester (Scheme 1). Living polymerization of monomer 1 using a alkyne−
can be facilely recovered, and it alternatively catalyzed the asymmetric Michael addition and aldol reaction for at least 6 cycles with maintained selectivity and activity.
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RESULTS AND DISCUSSION As shown in Scheme 1, monomer 1 was facilely synthesized through the transesterification of Boc-L-prolinol with phenyl isocyanide (3) bearing pentafluorophenyl ester in THF at 55 °C with the presence of 4-dimethylaminopyridinne (DMAP) as catalyst.25 After the isolated monomer 1 was fully characterized by 1H and 13C NMR, FT-IR, mass spectrum and elemental analyses (Figure S1−S3, Supporting Information), it was polymerized in THF at 55 °C using the alkyne− Pd(II) as catalyst. Because of the living nature of the Pd(II)mediated isocyanide polymerization, a series of poly-1ms with different Mn and narrow Mw/Mn were facilely obtained in high yields just through the variation on the initial feed ratio of monomer to catalyst.26 The Mn and Mw/Mn values of poly-1ms were characterized by size exclusion chromatography (SEC) analyses and were summarized in Table 1. All the isolated poly-
Scheme 1. Synthesis of Helical Poly-2m and the Analogue Compound 2
Table 1. Characterization Data for Poly-1ms and Poly-2ms run
polymer
Mnb (kDa)
Mw/Mnb
yieldc (%)
θ364d (×103)
[α]D25f
1 2 3 4 5 6 7 8 9 10 11 12
poly-150 poly-250 poly-1100 poly-2100 poly-1150 poly-2150 poly-1200 poly-2200 poly-1250 poly-2250 poly-1300 poly-2300
17.2 11.5 31.4 21.8 47.5 33.1 62.5 44.9 79.8 55.8 95.2 66.7
1.12 1.09 1.14 1.04 1.10 1.19 1.08 1.13 1.14 1.12 1.08 1.09
82 78 85 79 83 76 80 74 82 76 81 74
−7.41 −2.74 −8.61 −3.51 −9.38 −4.59 −10.01 −5.38 −10.02 −5.45 −10.02 −5.48
−134 −68 −162 −89 −174 −122 −187 −151 −187 −153 −188 −153
a
The polymers were synthesized according to Scheme 1. bThe Mn and Mw/Mn were determined by SEC with equivalent to polystyrene standards. cIsolated yields. dThe CD intensity at 364 nm of poly-1ms measured in THF, and poly-2ms measured in CH3OH at 25 °C. fThe optical rotations of poly-1ms measured in THF, and poly-2ms measured in CH3OH, respectively (c = 0.20 mg/mL, 25 °C).
Pd(II) catalyst afforded helical poly-1ms in high yields with controlled molecular weight (Mn) and narrow molecular weight distribution (Mw/Mn). After removing the protecting Boc group, the resulting poly-2m bearing amine pendants also exhibited high optical activity due to the preferred left-handed helix of polyisocyanide backbone. Poly-2ms showed excellent organocatalytic activity for asymmetric Michael addition reaction. Very interestingly, the stereoselectivity of the reaction were linearly correlated to the Mn and helicity of the polymer backbone. Increasing the Mn of poly-2ms can linearly increase the stereoselectivity of the asymmetric reaction, until the Mn reached to 44.9 kDa. This is the first report that disclose the polymerization amplified stereoselectivity (PASS) of an asymmetric reaction catalyzed by a polymer-based organocatalyst. Under the optimized reaction conditions, the asymmetric Michael addition reaction catalyzed by poly-2200 gave the desired product in high yield (>91%) with 99/1 diastereomeric ratio (dr) and up to 99% enantiomeric excess (ee) of the main product. Moreover, poly-2200 can also catalyze the aldol reaction. Comparing to the polyisocyanide bearing proline pendants we reported previously,24 this new polymer catalyst showed improved activity and stereoselectivity. The ee and dr of the aldol reaction product can also be up to 99% and 99/1, respectively. Taking advantage of its high Mn, poly-2200
1ms showed symmetrical and unimodal elution peaks on SEC curves and shifted to higher-Mn region with the increased ratio of monomer to catalyst (Figure 1a). As expected, the isolated poly-1ms showed desired Mn and narrow Mw/Mn values (Table 1). The 1H NMR and FT-IR analyses also confirmed the formation of expected polyisocyanides bearing prolinol ester pendants (Figures S4 and S5, Supporting Information). 1H NMR spectrum of poly-1200 showed the expected resonances come from the phenyl rings and the prolinol ester pendants. While the FT-IR spectrum of poly-1200 showed the characteristic vibration of the C = N bonds around 1600 cm−1. The optical activity of poly-1ms were investigated by circular dichroism (CD) and UV−vis spectra. As shown in Figure 1b, the isolated poly-1ms showed intense negative CD at the absorption region of the polyisocyanide backbone around 364 nm, suggesting the formation of a preferred left-handed helix.27 The ellipticity of the polyisocyanide backbone at 364 nm (θ364) increased with the increase of Mn and reached to a constant value when the Mn higher than 62.5 kDa, indicated B
DOI: 10.1021/acs.macromol.8b02088 Macromolecules XXXX, XXX, XXX−XXX
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Figure 1. (a) Size exclusion chromatograms of poly-1ms prepared from the polymerization of 1 with alkyne−Pd(II) in CHCl3 at 55 °C in different initial feed ratios of 1 to alkyne−Pd(II). (b) CD and UV−vis spectra of poly-1ms with different Mn measured in THF at 20 °C (c = 0.2 mg/mL).
Figure 2. (a) SEC curves for poly-2ms with different degree of polymerization. (b) CD and UV−vis spectra of poly-2ms with different Mn measured in CH3OH at 25 °C (c = 0.20 mg/mL). (c) Plots of ellipticity at 364 nm of poly-2ms as a function of the Mn. (d) CD and UV−vis spectra of poly2200 measured in CH3OH at different temperature (c = 0.20 mg/mL).
of poly-2200 (Figure S9, Supporting Information). Because of the formation of new N−H bonds on the pendant, a new broad vibration band located at 3216 cm−1 was clearly observed on the FT-IR spectra of poly-2200 (Figure S5, Supporting Information). The isolated poly-2200 also showed intense negative CD at the absorption region of the polyisocyanide backbone due to the preferred left-handed helix of the main chain. The CD and UV−vis spectra of the isolated poly-2200 were almost the same patterns to those of poly-1200 (Figure 2). However, comparing to poly-1m, CD intensity of poly-2m was decreased because of remove of the bulky Boc group. The ellipticity of poly-2ms was also dependent on the Mn, it increased with the increasing Mn until the degree of the polymerization reached to ca. 200 (Figure S10, Supporting Information). The CD intensity of poly-2m was maintained at the temperature range of −15 to 50 °C in THF (Figure 2d), suggesting the preferred left-handed helical structure was quite stable (Figure 2d). Moreover, the helicity of poly-2200 can be maintained in most of the tested
poly-1m can form a stable helix when the degree of the polymerization reached to 200 (Figure S6, Supporting Information). Further studies revealing that the helicity of poly-1200 was quite stable, no substantial changes could be observed on its CD and UV−vis spectra at various organic solvents at the temperature range from −15 to +50 °C (Figures S7 and S8, Supporting Information). The protecting Boc groups on the poly-1m pendants can be readily removed by treated it with trifluoroacetic acid (TFA) in dichloromethane at room temperature, and then neutralized by ammonia (Scheme 1). The afforded poly-2m showed improved solubility in polar solvents such as CH3OH and DMF, because of the yielded polar amine pendants. All the isolated poly-2ms showed symmetric and single model elution peaks on SEC curves, and shifted to low Mn-region as comparing to the poly1ms precursors (Figure 2a). The Mn was reasonably decreased due to the remove of the Boc groups on the pendants (Table 1). The deprotection was also confirmed by the disappearance of the t-butyl resonance at 1.46 ppm on the 1H NMR spectrum C
DOI: 10.1021/acs.macromol.8b02088 Macromolecules XXXX, XXX, XXX−XXX
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the Michael addition reaction under the same experimental conditions (run 1, Table 2). The dr and ee of the isolated product was only 68/23 and 18%, respectively, which were very low although the yield was acceptable (74%). Then the catalytic ability of helical polymers was investigated by using poly-2200 as the model catalyst in the reaction because of its high optical activity. The Michael addition reaction of cyclohexanone and trans-nitrostyrene catalyzed by poly-2200 was performed in dichloromethane with 30% loading at room temperature, the identical experimental conditions to those of 2 and L-prolinol (Table 2). To our delight, the polymer did catalyze the Michael addition reaction, and produce expected product in high yields (81%) with 91/9 dr. The ee of the main product was determined to be 91%, much higher than those of the products catalyzed by 2 and L-prolinol, indicating the poly2200 is a good organocatalyst for asymmetric Michael addition reaction. Thus, a series of poly-2ms with different Mns and narrow Mw/Mns was applied in the asymmetric Michael addition reaction of cyclohexanone and trans-nitrostyrene under the same experimental conditions. The results of the organocatalyzed asymmetric reactions were summarized in Table 2. After carefully pore on the ee values on Table 2, it was found that the ee of the isolated product was quite different and seems correlated to the Mn of poly-2ms. For example, the ee of the major Michael addition product was 62% catalyzed by poly-250, 71% by poly-2100, and 78% by poly-2150, respectively (Table 2). The ee values of the isolated products were then plotted against the Mns of poly-2m catalysts. As displayed in Figure 3a, the ee of the main product increased linearly to the Mn of poly-2m and became constant when the Mn reached to 44.9 kDa, corresponding to the degree of the polymerization of 200. This behavior was very similar to that of the relationship between the Mn with the optical activity of the polymer backbone, strongly suggested the enantioselectivity of the asymmetric Michael addition reaction was rely on Mn and the helicity of poly-2m backbone. Actually, the ee of the product was also linearly correlated to the ellipticity of poly-2m backbone (Figure 3b). Further studies revealed that the diastereomeric excess (de) values of the Michael addition products were also linearly correlated to the Mn and the helicity of poly-2m, until the Mn reached to ca. 50 kDa, similar to those of the ee behavior (Figure 3a and 3b). Collectively, these studies confirm the polymerization amplified stereoselectivity of organocatalyzed asymmetric Michael addition reaction by using helical polyisocyanide-based organocatalyst. Probably, the mechanism of the polymerization amplified stereoselectivity is that the stereoselectivity of asymmetric Michael addition reaction is rely on the chirality of polymer catalyst. While the helical chirality is dependent on the molecular weight, thus polymerization can give a higher-Mn helical polymer with stable helical conformation and high optical activity. Thus, the polymerization can amplify stereoselectivity of the asymmetric reaction. For comparison, an oligomer of 2 (poly-210) was then prepared and applied in the asymmetric Michael addition reaction. Because of the short chain length, this oligomer showed almost no CD at the absorption region of polyisocyanide backbone. Although it can catalyze the Michael addition reaction under the same condition to that of poly-2200, the ee and dr values of the product are quite low, similar to those using compound 2 (run 3, Table 2).
common organic solvents (Figure S11, Supporting Information). The high optical activity of helical structure of poly-2ms was further supported by polarimetry analyses (Table 1). With optically active helical poly-2ms in hands, our effort was directed to exploring their application in organocatalyzed asymmetric reactions. It is well-known that amine can catalyze Michael addition reaction, which can construct two chiral carbon centers at the same time from achiral materials, and was widely used in synthesis of natural products and medicines.28,29 Thus, the poly-2ms were then utilized as organocatalyst in asymmetric Michael addition reaction by using cyclohexanone and trans-nitrostyrene as model substrates. For comparison, an analogue compound 2 with similar structure to the repeating unit of poly-2m was then prepared (Scheme 1, and Figures S12−S14 in Supporting Information) and was employed in the same reaction of cyclohexanone and trans-nitrostyrene in dichloromethane at 25 °C with 30% loading (Scheme 1). As anticipated, the reaction yielded the expected product in 71% yield. The dr of the product was determined to be 79/21 by high performance liquid chromatography (HPLC), and the ee of the main product was 41% (run 2, Table 2). It was found that both the dr and ee values were quite low, probably because there was no bulky group close to the catalytic point. Noted that the L-prolinol also showed poor performance on Table 2. Optimization the Reaction Condition for Michael addition Reactiona
run
catalyst
solvent
temp (°C)
X
syn/antib
ee (%)b
yield (%)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
L-prolinol
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 THF MeOH toluene DMSO water DMF brine THF CH2Cl2 brine brine brine
r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. r.t. 0 0 0 0 −10
30 30 30 30 30 30 30 30 30 10 30 30 30 30 30 30 30 30 30 30 30 10 30
68/32 79/21 80/20 72/28 74/26 78/22 81/19 83/17 83/17 83/17 93/7 95/5 86/14 --93/7 78/22 87/13 89/11 91/9 91/9 91/9 89/11
18 41 43 62 71 78 86 86 86 86 72 78 55 --81 6 88 79 88 91 91 90
74 71 68 81 84 86 87 87 88 86 85 84 68 n.d.d n.d.d 84 64 86 86 89 91 90 89
2 poly-210 poly-250 poly-2100 poly-2150 poly-2200 poly-2250 poly-2300 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200 poly-2200
a
Unless otherwise denoted, all reactions were carried out with transnitrostyrene (0.20 mmol), cyclohexanone (0.80 mmol) in a specific solvent (1.0 mL). bThe dr and ee values were determined by HPLC analysis using a chiral stationary phase. cYield of isolated products. d Not detected. D
DOI: 10.1021/acs.macromol.8b02088 Macromolecules XXXX, XXX, XXX−XXX
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Figure 3. (a) Plots of ee and de of the asymmetric Michael addition reaction product of cyclohexanone and trans-nitrostyrene with the Mn of poly2m catalysts. (b) Plots of ee and de of the asymmetric Michael addition reaction product as a function to the CD intensity of poly-2ms.
Since poly-2200 showed good performance in the asymmetric Michael addition reaction, its catalytic activity was studied in more details. Optimization on the reaction conditions revealed brine and dichloromethane are good solvents for the asymmetric Michael addition reaction (Table 2). Decreased the poly-2200 loading from 30 to 10%, no significantly decreases on the enantioselectivity and the yield of the product were discerned (run 21 and 22 in Table 2). Moreover, lower the reaction temperature from room temperature to 0 °C can further increase the enantioselectivity, while maintained the high yield (run 18 and 21 in Table 2). Further lower the reaction temperature could not enhance the stereoselectivity and yield of the product (run 21 and 23, in Table 2). Thus, the optimized condition for the Michael addition reaction is using 10% loading of poly-2200 and carried out in brine at 0 °C. Under this condition, the reaction of cyclohexanone with transnitrostyrene catalyzed by poly-2200 can produce expected product in 91% yield, with 91/9 dr and 91% ee of the main product (run 21, Table 2). It should be noted that the reagents of Michael addition reaction have poor solubility in brine. However, the slightly dissolved materials can participate in reactions, which make the reagents further dissolved in solution until they were consumed.30 After the asymmetric Michael addition reaction catalyzed by the poly-2200 was established, the scope of the substrates was then explored. As summarized in Table 3, the optimized reaction condition was applied to different substituted transnitrostyrene and cycloketone. To our delighted, most of the tested substrates showed high yields (86−91%) with good diastereoselectivity and excellent enantioselectivity (91−99% ee). For the reaction of trans-4-fluoro-nitrostyrene, trans-4trifluorome-nitrostyrene with cyclohexanone, and trans-nitrostyrene with tetrahydro-4H-thiopyran-4-one, the ee of the main product were higher than 99%. It seems that introducing electron-withdraw group onto the phenyl ring could improve the selectivity of the reactions. One of the advantages of polymer-based organocatalyst is the possibility of recovery and recycle use in the reactions owing to its high Mn. Therefore, poly-2200 was attempted to be recovered from the reaction mixture after the reaction. Because of its high Mn and hydrophobic backbone, poly-2200 showed poor solubility in brine. Thus, it was facilely isolated from the reaction mixture in almost quantitative yield just by centrifugation and filtration. The recovered poly-2200 showed almost the same CD and UV−vis spectra to that of the fresh one, suggesting the helix-sense of the main chain was maintained during the asymmetric Michael addition reaction. Thus, the recovered poly-2200 was reused in the asymmetric
Table 3. Substrate Scope for Poly-2200-Catalyzed Michael Addition Reactionsa
a
Reaction conditions: 4 (0.20 mmol), 5 (0.80 mmol), and poly-2200 (10% loading). The reaction was carried in brine (1.0 mL) at 0 °C. The dr and ee were determined by HPLC analysis using a chiral stationary phase.
Michael addition reaction by using cyclohexanone and trans-4fluoro-nitrostyrene as substrates and was performed in brine at 0 °C with 30% catalyst loading. The higher catalyst loading used here was to just facilitate the catalyst recovery. As anticipated, the recovered poly-2200 can also catalyze the reaction with high activity and selectivity. The reaction gives the expected product in 91% yield with 88/12 dr, and 99% ee of the major product. These results were almost the same to those reactions using the fresh poly-2200 as catalyst under the same experimental conditions. The recovered poly-2200 was further recycle used in the reaction. The yield and ee values of the isolated product were plotted against with the recycle times and were displayed in Figure 4a. It was found that the poly-2200 can be recycle used for at least 5 times without significantly loss its activity and stereoselectivity. E
DOI: 10.1021/acs.macromol.8b02088 Macromolecules XXXX, XXX, XXX−XXX
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Figure 4. (a) Recycle using of poly-2200 (with 30% loading) in the Michael addition reaction of trans-4-fluoro-nitrostyrene (0.20 mmol) and cyclohexanone (0.80 mmol) in brine at 0 °C. (b) The recycle using of poly-2200 (with 30% loading) in alternatively catalyzed Michael addition of trans-4-fluoro-nitrostyrene (0.20 mmol) and cyclohexanone (0.80 mmol) in brine at 0 °C, and aldol reaction of 4-formylbenzonitrile (0.20 mmol) and cyclohexanone (0.80 mmol) in dichloromethane at 0 °C.
product were 88/12 and 99%, respectively, while the dr and ee values of the aldol reaction product were respectively determined to be 99/1 and 99%. These results indicated the helical polyisocyanide catalyst is a good catalyst for alternatively catalyzed the two asymmetric reactions. The polymer catalyst has been recycle used alternatively in the two reactions for at least 6 times with maintained activity and stereoselectivity (Figure 4b). In contrast to the excellent performance of poly-2200, prolinol and monomer 2 showed very poor performance on the asymmetric aldol reaction under the identical experimental conditions. The ee of the asymmetric aldol reaction product is just 22% by prolinol and is 34% by monomer 2, respectively (runs 1 and 2 in Table S3 in the Supporting Information). Moreover, the oligomer poly-210 also showed low stereoselectivity on the same aldol reaction. The ee of the isolated product is 33%, similar to that using monomer 2 (run 3 in Table S3, Supporting Information). The Michael addition reaction was performed using trans-4fluoro-nitrostyrene (0.20 mmol) and cyclohexanone (0.80 mmol) by poly-2200 with 30% loading in brine at 0 °C. The aldol reaction was performed using 4-formylbenzonitrile (0.20 mmol) and cyclohexanone (0.80 mmol) in dichloromethane at 0 °C by poly-2200 with 30% loading. The dr and ee values were determined by HPLC analyses using a chiral stationary phase.
More interestingly, poly-2200 can not only catalyze the asymmetric Michael addition reaction but also other reactions such as asymmetric aldol reaction. For example, it can catalyze the aldol reaction of cyclohexanone with 4-formylbenzonitrile. It has been reported that introducing electron-withdraw group on the substrates can improve activity of the asymmetric aldol reactions.24 The cyano substituent on 4-formylbenzonitrile may promote the asymmetric reaction. The optimized aldol reaction condition is carry out the reaction in dichloromethane at 0 °C with 30% polymer catalyst loading (Table S3, Supporting Information), which yield the expected product in 83% yield with 99% of ee and 99/1 dr (Scheme 2). This result Scheme 2. Alternatively Catalyzed Michael Addition Reaction and Aldol Reaction by Using Poly-2200
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CONCLUSIONS In summary, we have developed a series of novel helical polyisocyanide-based catalysts bearing L-prolinol ester pendants. These polymers showed high optical activity due to the preferred left-handed helix of the main chain. Comparing to the analogue small molecules, the polymers exhibited amplified stereoselectivity in organocatalyzed asymmetric Michael addition reaction. The stereoselectivity of the reaction was depending on the degree of the polymerization, revealing the polymerization amplified the stereoselectivity (PASS) of the reactions. Under the optimized reaction condition, the Michael addition reaction yielded the desired product in high yield with good stereoselectivity. The ee and dr values of the product can be up to 99% and 99/1, respectively. The polymer catalyst can be facilely recovered and reused for at least 5 times without significant loss in its activity and stereoselectivity. Moreover, the polymer catalyst can also catalyze the asymmetric aldol reaction, and gave the desired product in 83% yield with 99% ee and 99/1 dr. Interestingly, the polymer catalyst can alternatively catalyze both the asymmetric Michael addition
is acceptable, suggesting the poly-2200 is also an excellent catalyst for aldol reaction. It is worthy to note that the stereoselectivity of poly-2200 is much higher than that using the polyisocyanide catalyst bearing L-proline pendants as we reported previously.24 In that case, the ee and dr of the aldol reaction product are 77% and 77/23, respectively, under the same experimental conditions and using the same substrates. Moreover, the recovered poly-2200 can be used to alternatively catalyze the Michael addition reaction and aldol reaction (Figure 4b). That is the poly-2200 was recovered from the Michael addition reaction and can be further used in aldol reaction, and then the Michael addition reaction again. As shown in Scheme 2, the poly-2200 can catalyze the Michael addition reaction of trans-4-fluoro-nitrostyreneand cyclohexanone, and then recovered and catalyzed the aldol reaction of 4-formylbenzonitrile and cyclohexanone. Both the reactions gave the expected products in high yields with excellent stereoselectivity. The dr and ee of the Michael addition F
DOI: 10.1021/acs.macromol.8b02088 Macromolecules XXXX, XXX, XXX−XXX
Article
Macromolecules
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reaction and aldol reaction, and can be recycled and used in the two asymmetric reactions at least 6 times with maintained activity and stereoselectivity. We believe the present study will provide not only a family of novel excellent polymer-supported organocatalyst for various asymmetric reactions but also a rule of polymerization amplified stereoselectivity for polymersupported catalysts which is a useful clue for designing novel polymer-supported chiral organocatalysts in the future.
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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/acs.macromol.8b02088. Synthetic procedures and additional spectroscopic data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (Z.-Q.W.). *E-mail:
[email protected] (N.L.). ORCID
Zong-Quan Wu: 0000-0001-6657-9316 Author Contributions †
These authors contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is supported by the National Science Foundation of China (NSFC, 21622402, 51673057, and 21574036) and the Fundamental Research Funds for the Central Universities of China. Z.-Q.W. thanks the 1000plan Program for Young Talents of China. N.L. thanks Anhui Provincial Natural Science Foundation (1608085MB41).
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DOI: 10.1021/acs.macromol.8b02088 Macromolecules XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.macromol.8b02088 Macromolecules XXXX, XXX, XXX−XXX
