Enantioselective Michael Addition of Pyrroles with Nitroalkenes in

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Enantioselective Michael Addition of Pyrroles with Nitroalkenes in Aqueous Media Catalyzed by a Water-soluble Catalyst Yang Gui, Yanan Li, Jianan Sun, Zhenggen Zha, and Zhiyong Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01141 • Publication Date (Web): 11 Jun 2018 Downloaded from http://pubs.acs.org on June 12, 2018

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The Journal of Organic Chemistry

Enantioselective Michael Addition of Pyrroles with Nitroalkenes in Aqueous Media Catalyzed by a Watersoluble Catalyst Yang Gui, Yanan Li, Jianan Sun, Zhenggen Zha, Zhiyong Wang*

Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Center for Excellence in Molecular Synthesis of Chinese Academy of Sciences, Collaborative Innovation Center of Suzhou Nano Science and Technology & School of Chemistry and Materials Science, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China E-mail: [email protected]

ABSTRACT: A new water-soluble catalytic system were developed and therefor used in an enantioselective Michael addition of pyrroles with nitroalkenes in water to afford the nitroethylpyrrole derivatives with both excellent yields and ee values. INTRODUCTION Water, as a safe, inexpensive, and environmentally benign reaction medium, has received considerable attention in organic synthesis.1 Since the first example of organic reactions in aqueous media was reported by Breslow in 1980,2 there has been increasing investigation of organic reactions in aqueous media, especially in the reactions under the catalysis of Lewis acids. With the development of the reaction in water, it is found that the hydrogen bond of the reaction transition state, the hydrophobic effect of the molecular structure and the solubility of the reactants in water have different influences on the reactions. Particularly, in many reactions, the use of water as solvent can enhance the reaction activity and the selectivity,3 improve the workup process4 and the catalyst recycle.5 With the in-depth research of the reaction in aqueous media, more attention is focused in the enantioselective synthesis under the catalysis of Lewis acids in water. As far as we known, the

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first enantioselective metal-catalyzed reaction in water was reported as late as in 1998.1b In the past few years, the stereoselective aldol reactions, as well as the asymmetric ring-opening of epoxides with various nucleophiles in water were reported.6 At the same time, quite a few carbon nucleophiles were used as Michael donors to construct the chiral molecules in aqueous media, most of these asymmetric reactions involved the use of organocatalysts.7 However, the Lewis acid catalyzed asymmetric Michael addition in water are rare and these reactions afford the chiral molecules with poor to moderate enantioselectivity,8 perhaps due to the effect of water on the coordination of the metal with the chiral ligand. As for the asymmetric metal-catalyzed Michael addition reaction in aqueous media, we only found one publication for the addition of thiols to α, β-unsaturated ketones in water to afford the β-keto sulphides.9 The weak interactions between chiral ligands, metal ions and substrates are sensitive to the aqueous environment. Thus, it can be seen that employment of the aqueous media as the solvent is a formidable challenge in the asymmetric Michael reaction catalyzed by Lewis acid. A significant development in this aqueous asymmetric Michael addition needs a new catalytic system, which can maintain high activity, stability, and selectivity in the aqueous environment. On the other hand, the nitroethylpyrroles can be the precursors of many functional molecules, which can be used in molecular electronics, photovoltaic devices and chemical/biological sensing.10 More importantly, these nitroethylpyrroles are the synthetic moieties for many pharmaceutical molecules, which have antiarrhythmic, antiamnesic, antihypoxic, psychotropic, and antihypersensitive.11 For example, the nitroethylpyrrole derivatives can be easily transformed to nicotine analogues, which has the bioactivity as rennin inhibitors.12 Recently, enantioselective Michael addition of pyrroles with nitroalkenes was realized in organic solvent (Scheme 1).12a, 13 Our group has been focusing attention on the research of new methodologies to realize organic reactions in water for a long time,14 especially the aqueous asymmetric reactions.15 To expand the scope and facilitate the process for metal-catalyzed enantioselective Michael addition in aqueous media, we prepared a novel water-soluble chiral Schiff based-copper catalyst and therefor used in the addition of pyrrole to nitroalkenes in water. Herein we report an asymmetric Michael addition, which was carried out in water and catalyzed by Lewis acid to give the desired nitroethylpyrroles with high yields and excellent ee values.


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Scheme 1. Previous study and this work on enantioselective Michael addition of pyrroles with nitroalkenes

RESULTS AND DISCUSSION The protocol to generate this water-soluble catalytic system was designed based on our previous studies 12a, 16 The introduction of tertiary amines to the Schiff base ligand can favor the formation of ammonium salts and enhance the water solubility as well as promote the coordination with the copper salt (CuBr2). To test our hypothesis, ligand L1 was treated with CuBr2 in methanol for 0.5 h to give a blue solution. When diethyl ether was added to the blue solution, a large amount of blue precipitated in the solution (Scheme 2, b1), which can be dissolved in water. We think that this structure of the Cu-complex in (Scheme 2a) is similar to the previous structure,12a that is, a dinuclear copper complex with a central Cu2O2 four-membered ring. To our delight, using this water-soluble blue complex as the catalyst, the addition of pyrrole with nitroalkene 3a in water gave an acceptable result of 64% ee of the desired product. In order to make it easier for the manipulation, we mixed up the water-insoluble ligand L1 with CuBr2 in water directly, a homogeneous blue solution (pH = 7) formed in 30 minutes and this catalytic system gave the same result of 64% ee, as shown in Scheme 2b(2).



Scheme 2. The design of water-soluble chiral Schiff base-copper catalyst By virtue of this catalytic system, the reaction of pyrrole with nitroalkene 3a was carried out in the presence of copper salts and Schiff base ligands in water to optimize the reaction conditions. The experimental results were summarized in Table 1. Initially, various copper salts were examined in the presence of Ligand L1. It was found that the counter ions of the copper salts had an influence on the catalytic activity. Cu(OAc)2 gave the worst yield and the ee value while CuCl2, Cu(NO3)2 and Cu(OTf)2 provided good yields and poor ee values (entries 1-4). Gratifyingly, the use of CuBr2 gave the best result with a yield of 88% and the ee value of 64% (entry 5). When L1 was replaced with ligand L2 under the same conditions, the reaction can afford the desired product with a higher enantioselectivity of 71% ee, perhaps due to the increase of electronegativity of nitrogen of amino group in L2 in comparison with that of L1 (entry 6). Next, in order to make the water-insoluble nitroalkene 3a fully expose in the catalytic system, different phase transfer catalyst (PTC) was added into the reaction mixture. It was found that the addition of PTC enhanced the reaction rate largely and the reaction yield a little while had little


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influence on the enantiomeric excess (entry 7). Then, about 9% organic solvent (0.1 mL in 1 mL water) was added in the reaction, attempting to convert the reaction mixture to the liquid-liquid phase from the liquid-solid phase. After screening of the organic solvent (entries 8-12), we found that a small amount of CHCl3 favored the enantioselectivity of Michael adduct with an ee value of 83% (entry 10). When the reaction temperature was reduced to 0 °C and the reaction time was prolonged to 72 h, moreover, the adduct 4a can be obtained with an excellent enantioselectivity of 91% ee although the reaction yield was sacrificed to a lower yield of 71% (entry 13). Afterwards, various PTCs were examined in this reaction to harmony the yield and the ee value. It was found that sodium laurylsulfonate was the best in this reaction, which can enhance the reaction yield to 93% while the excellent enantioselectivity (91% ee) can be maintained (entry 18). As a result, the optimal reaction conditions were as follows: CuBr2 as the Lewis acid, L2 as the chiral ligand, sodium laurylsulfonate as the PTC, 1.0 mL H2O containing 0.1 mL CHCl3 as the solvent, and the reaction being carried out at 0 °C for 72 h. Table 1. Optimization of reaction conditionsa

entry

CuX2

ligand

solvent

PTC

yieldb (%)

ee c (%)

1

CuCl2

L1

H2O

-

84

43

2

Cu(OTf)2

L1

H2O

-

87

52

3

Cu(OAc)2

L1

H2O

-

56

31

4

Cu(NO3)2

L1

H2O

-

77

48

5

CuBr2

L1

H2O

-

88

64

6

CuBr2

L2

H2O

-

90

71



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7

CuBr2

L2

H2O

PTC 5

93

70

8

CuBr2

L2

H2O/toluene = 10:1

-

83

68

9

CuBr2

L2

H2O/dichloromethane = 10:1

-

89

74

10

CuBr2

L2

H2O/chloroform = 10:1

-

92

83

11

CuBr2

L2

H2O/carbon tetrachloride = 10:1

-

75

79

12

CuBr2

L2

H2O/1,2-dichloroethane = 10:1

-

84

80

13d

CuBr2

L2


-

73

91

14d

CuBr2

L2


PTC 1

83

89

15d

CuBr2

L2


PTC 2

82

88

16d

CuBr2

L2


PTC 3

87

90

17d

CuBr2

L2


PTC 4

91

88

18d

CuBr2

L2


PTC 5

93

91

19d

CuBr2

L2


PTC 6

83

89

a

Unless otherwise noted, all reactions were performed with 2a (0.6 mmol), 3a (0.2 mmol), L (10

mol %), CuBr2 (10 mol %) and PTC (10 mol %) in solvent (1.1 mL), 24 h. bIsolated yield. c

Determined by chiral HPLC analysis. dThe reaction was performed at 0 °C for 72 h. PTC 1 =

Tetrabuylammonium bromide. PTC 2 = Tetrabutylammonium iodide. PTC 3 = Sodium dodecyl sulfate. PTC 4 = Sodium octanesulfonate. PTC 5 = Sodium laurylsulfonate. PTC 6 = Sodium hexadecane-1-sulphonate. With the optimal reaction conditions in hand, we examined the scope of the Michael reaction with a variety of pyrroles and nitroolefins in water. As shown in table 2, various aromatic nitroolefins can be employed as Michael acceptors for pyrrole to afford the desired adducts with high enantioselectivities (90 – 96%) regardless of either electron-deficient or electron-rich substituents on the phenyl ring of nitroolefins. Nevertheless, the electron-withdrawing group, such as fluoro, chloro, bromo, trifluoromethyl groups on the para-position of R1 favored the reaction a little in comparison with the electron-donating groups such as methoxy, methyl groups (entries 1-7). On the other hand, the steric effect had a negative influence on the reaction. For instance, the nitroalkenes 3h and 3i bearing a substituent at ortho-position of the phenyl ring were less reactive under the


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standard conditions to deliver the desired products with poor yields and ee values. The modified conditions with higher reaction temperature (5 °C) and longer reaction time (96 h) were indispensable to carry out these two reactions to give the desired products with both good yields and enantioselectivities (entries 8-9). Substitution at meta-position of the phenyl group can tolerate this reaction, affording the desired products with excellent yield and enantioselectivity (entry 10). The scope of the reaction substrates can be extended to the hetero-aromatic nitroolefins. For example, the nitroolefins bearing thienyl and furan ring can be employed as the reaction substrates in this reaction to give the desired products with excellent yields and ee values (entries 11-12). Moreover, ring-fused, aliphatic nitroolefins were successfully used in the reaction to give the desired products with both good yields and ee values under the standard conditions or the modified conditions (entries 13-16). When 3,4-disubstituted pyrrole (ethyl 4-methyl-1H-pyrrole-3carboxylate) was used in the reaction, 5-alkylation product can be obtained with excellent regioselectivity and enantioselectivity (entry 17). Table 2. The enantioselective Michael addition of pyrrole with nitroalkenes in watera

entry

3

R1

4

yieldb (%)

ee c (%)

1

3a

Ph

4a

93

91

2

3b

4-FPh

4b

93

91

3

3c

4-ClPh

4c

95

94

4

3d

4-BrPh

4d

97

94

5

3e

4-CF3Ph

4e

95

96

6

3f

4-MePh

4f

88

91

7

3g

4-MeOPh

4g

76

90

8d

3h

2-Cl

4h

84

89

9d

3i

2-Br

4i

83

90



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10

3j

3-Cl

4j

90

92

11

3k

2-furyl

4k

91

89

12

3l

2-thienyl

4l

96

92

13d

3m

1-napthyl

4m

85

89

14

3n

2-napthyl

4n

94

93

15

3o

n-Pr

4o

92

94

16d

3p

cyclohexyl

4p

87

88

17e

3q

Ph

4q

94

91

a

Unless otherwise noted, all reactions were performed with 2a (0.6 mmol), 3a (0.2 mmol), CuBr2

(10 mol %), L2 (10 mol %), sodium laurylsulfonate (10 mol %), 0 °C for 72 h. bIsolated yield. c

Determined by chiral HPLC analysis. d5 °C for 96 h. eEthyl 4-methyl-1H-pyrrole-3-carboxylate

was used instead of 2a. To demonstrate the practicality and effectiveness of this catalytic system for asymmetric Michael addition in water, a gram-scale reaction was performed using 3d and pyrrole as the substrates under the standard conditions for 96 h. To our delight, the desired product 4d can be obtained in 84% yield with an enantioselectivity of 92%. Scheme 3. Asymmetric Michael Reaction on a Gram Scalea, b, c

a

The reaction was performed with 2a (15 mmol), 3d (5.0 mmol), L2 (5 mol %), CuBr2 (5 mol %),

sodium laurylsulfonate (10 mol %), in water (25 mL) and CHCl3 (2.5 mL) at 0 °C, 96 h. bIsolated yield. cDetermined by chiral HPLC analysis. Based on these results and our previous mechanism study,12a the dinuclear dimeric structure is dissociated into the monomers in situ, which then coordinates the substrates, that is, a hypothetical bifunctional mode of action in the transition state is proposed (Figure 1). The nitroalkene is activated


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by chelating with a metal center in the catalyst complex, while the NH in pyrrole is served as a hydrogen bond donating group to direct the pyrrole to attack the nitroalkene on the Re face. In this way, the enantioselectivity was obtained.

Figure 1. Proposed bifunctional mode of action in the transition state In summary, we designed and prepared a series of Schiff based ligands, which were tertiary amines derived from amino acids. Moreover, these ligands mixed with CuBr2 can afford the water-soluble ammonium salts in situ, giving new catalytic systems for the Michael addition of pyrroles to nitroalkenes in water. By virtue of this water-soluble catalytic system, we developed a Lewis acid catalyzed Michael addition with carbon nucleophiles in water, delivering a series of nitroethylpyrrole derivatives with excellent yields and enantioselectivities. Besides, a gram scale of the asymmetric Michael reaction in water could be achieved by using this water-soluble catalyst. Further studies on this new catalytic system for other reactions are ongoing in our group.

EXPERIMENT SECTION General Information: 1H NMR and

13C

NMR were recorded on a 400MHz Nuclear Magnetic

Resonance Spectrometer (1H NMR: 400MHz, 13C NMR: 100MHz) using TMS as internal reference. The chemical shifts (δ) and coupling constants (J) were expressed in ppm and Hz, respectively. UVVis Spectrophotometry was carried out on infrared spectrometer. HPLC analysis was carried out on HPLC with a multiple wavelength detector by commercial chiral columns. Optical rotations were measured on a Polarimeter. HRMS (ESI) were recorded on a Q-TOF Premier. Commercially



available compounds were used without further purification. Solvents were purified according to the standard procedures unless otherwise noted. Nitroalkenes were prepared according to literature procedures.13 Preparation for ligand L1 To a round bottom flask was added magnesium strips (0.36 g, 15 mmol), one small crystal of iodine, and 4-bromo-N, N-dimethylbenzylamine in dry THF (25 mL). The reaction mixture was stirred at reflux to start the reaction. A solution of 4-bromo-N, N-dimethylbenzylamine (3.20 g, 15 mmol) in dry THF (5 ml) was added dropwise over 30 min. After addition, the reaction mixture was continued to stirring at reflux for 2 hours and cooled to room temperature. Then a solution of methyl (tertbutoxycarbonyl)-L-phenylalaninate (1.40 g, 5 mmol) in dry THF (5 ml) was added dropwise to the Grignard reagent at room temperature over 30 min. The resulting mixture was further stirred overnight and was then quenched with saturated aqueous solution of NH4Cl. The product was extracted with ethyl acetate and the combined organic phase was dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was used for next step without purification. The crude product in CH2Cl2 (15 mL) was added 2,2,2-Trifluoroacetic acid (10 mL), then the reaction mixture was stirred at room temperature for 5h and concentrated under reduced pressure. To the residue was added aqueous HCl (2 M, 5.0 mL) and the mixture was extracted with ethyl acetate (3 x 5 mL). The aqueous layer was basified with aqueous buffer solution of NH3 (1 M)/NH4Cl (1 M) and extracted with dichloromethane (3 x 10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was purified by column chromatography (CH2Cl2/MeOH/NEt3 = 100:10:1) to give product (S)-2-amino-1,1-bis(4-((dimethylamino)methyl)phenyl)-3-phenylpropan-1-ol as a colorless oil (1.73 g, 83% yield). [α]D20 = -45.5 (c =1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.60-7.53 (m, 4 H), 7.31-7.13 (m, 9 H), 4.52 (br, 1H), 4.16-4.12 (m, 1 H), 3.45-3.32 (m, 4 H), 2.65-2.60 (m, 1 H), 2.46-2.30 (m, 1 H), 2.20 (s, 12 H),1.42 (br, 2 H); 13C NMR (100 MHz, CDCl3) δ 145.7, 143.3, 139.7, 137.3, 136.9, 129.2, 129.1, 129.0, 128.7, 126.5, 125.8, 125.4, 78.5, 64.0, 63.9, 58.3, 45.43, 45.40, 36.8; HRMS (ESI) calcd for C27H36N3O+ [M+H]+ 418.2858, found 418.2857.


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To a solution of chiral amino alcohol (2 mmol) in methanol (10 mL) was added salicylaldehyde derivative (2 mmol). The solution was stirred for 2 h at room temperature then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH = 5/1 as eluent) to give the corresponding Schiff base ligand L1 quantitatively as yellow foam. [α]D 20 = -54.2 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 13.91 (br, 1 H), 7.647.30 (m, 8 H), 7.20-7.11 (m, 5 H), 7.00-6.94 (m, 3 H), 6.80-6.70 (m, 1 H), 4.35-4.31 (m, 1 H), 3.513.22 (m, 4 H), 3.10-3.01 (m, 2 H), 2.91-2.79 (m, 1 H), 2.24 (s, 6 H), 2.11 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 165.8, 160.0, 144.0, 142.7, 138.7, 137.7, 137.4, 135.1, 129.9, 129.7, 129.3, 129.2, 128.5, 126.5, 126.0, 125.9, 124.9-122.2 (q, J = 270.0 Hz), 118.8, 118.4-117.5 (q, J = 30.0 Hz), 117.3, 79.6, 78.7, 63.9, 63.7, 45.4, 45.2, 37.2; 19F NMR (376 MHz, CDCl3) δ -62.6; HRMS (M+H)+ calcd for C35H39F3N3O2 590.2994, found 590.2995. Preparation for ligand L2 To a round bottom flask was added magnesium strips (0.36 g, 15 mmol), one small crystal of iodine, and 2-(4-bromophenyl)-N, N-dimethylethan-1-amine in dry THF (25 mL). The reaction mixture was stirred at reflux to start the reaction. A solution of 2-(4-bromophenyl)-N, N-dimethylethan-1-amine (3.41 g, 15 mmol) in dry THF (5 ml) was added dropwise over 30 min. After addition, the reaction mixture was continued to stirring at reflux for 2 hours and cooled to room temperature. Then a solution of methyl (tert-butoxycarbonyl)-L-phenylalaninate (1.40 g, 5 mmol) in dry THF (5 ml) was added dropwise to the Grignard reagent at room temperature over 30 min. The resulting mixture was further stirred overnight and was then quenched with saturated aqueous solution of NH4Cl. The product was extracted with ethyl acetate and the combined organic phase was dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography (CH2Cl2/MeOH/NEt3 = 100:10:1) to give tert-butyl (1,1-bis(4-(2(dimethylamino)ethyl)phenyl)-1-hydroxy-3-phenylpropan-2-yl)carbamate as a colorless oil (2.37g, 87% yield). [α]D20 = -11.5 (c =1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.48-7.40 (m, 4 H), 7.28-7.04 (m, 9 H), 4.93 (d, J = 9.4 Hz, 1 H),4.72-4.60 (m, 1 H), 4.13 (br, 1 H), 2.90-2.53 (m, 6 H), 2.54-2.40 (m, 4 H), 2.28 (s, 6 H), 2.25 (s, 6 H), 1.20 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 155.9, 143.7, 143.1, 139.2, 138.7, 138.5, 129.3, 128.7, 128.3, 128.2, 126.1, 126.0, 125.6, 115.7, 80.8, 79.3,



61.4, 61.2, 46.0, 45.4, 45.3, 36.1, 33.7, 33.5, 28.1; HRMS (ESI) calcd for C34H48N3O3 [M+H]+ 546.3696, found 546.3694. The product in CH2Cl2 (15 mL) was added 2,2,2-Trifluoroacetic acid (10 mL), then the reaction mixture was stirred at room temperature for 5h and concentrated under reduced pressure. To the residue was added aqueous HCl (2 M, 5.0 mL) and the mixture was extracted with ethyl acetate (3 x 5 mL). The aqueous layer was basified with aqueous buffer solution of NH3 (1 M)/NH4Cl (1 M) and extracted with dichloromethane (3 x 10 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure, the crude product was used for next step without purification. To a solution of chiral amino alcohol (2 mmol) in methanol (10 mL) was added salicylaldehyde derivative (2 mmol). The solution was stirred for 2 h at room temperature then the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH = 5/1 as eluent) to give the corresponding Schiff base ligand L2 quantitatively as yellow foam. [α]D 20 = -76.6 (c = 1.0, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.54-7.50 (m, 4 H), 7.40-7.31 (m, 2 H), 7.25-7.00 (m, 8 H), 7.05-6.91 (m, 3 H), 6.81-6.70 (m, 1 H), 4.31 (d, J = 8.9 Hz, 1 H), 3.38 (br, 1 H), 3.08-3.01 (d, J = 13.0 Hz, 1 H), 2.88-2.72 (m, 4 H), 2.71-2.64 (m, 2 H), 2.622.51 (m, 2 H), 2.50-2.41 (m, 2 H), 2.30 (s, 6 H), 2.23 (s, 6 H); 13C NMR (100 MHz, CDCl3): δ 165.6, 160.5, 142.9, 141.8, 139.0, 138.9, 138.7, 135.2, 130.0, 129.7, 128.8, 128.6, 128.4, 126.5, 126.3, 126.1, 125.0-122.3 (q, J = 270.9 Hz), 118.8, 118.2-117.9 (q, J = 30.4 Hz), 117.1, 79.4, 78.5, 61.2, 61.1, 45.3, 45.2, 37.3, 33.7, 33.5; 19F NMR (376 MHz, CDCl3) δ -62.6; HRMS (M+H )+ calcd for C37H43F3N3O2 618.3307, found 618.3307. General procedures for Michael addition of Pyrroles with Nitroalkenes in Aqueous Media: A mixture of Ligand L2 (0.02 mmol, 12.4 mg), CuBr2 (0.02 mmol, 4.5 mg) in water (1.0 mL) was stirred for 1h at ambient atmosphere, nitroalkenes (0.2 mmol), CHCl3 (0.1mL) and sodium laurylsulfonate (0.02 mmol, 5.4 mg) were then added. The resulting mixture was cooled to 0 °C. After 30 min, corresponding pyrrole (0.6 mmol) was added slowly by syringe. After reactions were


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finished (monitored by TLC), the organic phase was separated, evaporated in vacuo. Purification by column chromatograph afforded Michael adducts. Experimental data of Michael adducts (S)-2-(2-nitro-1-phenylethyl)-1H-pyrrole (4a) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 93% yield. [α]D20 -88.4 (c = 1.0, CH2Cl2, 91%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 9.1 min (major), tR = 10.0 min (minor).1H NMR (400 MHz, CDCl3): δ 7.84 (br, 1 H), 7.40-7.27 (m, 3 H), 7.25-7.20 (m, 2 H), 6.68 (m, 1 H), 6.16 (dd, J = 6.0 Hz, 3.2 Hz, 1 H), 6.08 (m, 1 H), 4.97 (dd, J = 12.0 Hz, 7.2 Hz, 1 H), 4.89 (t, J = 7.5 Hz, 1 H), 4.80 (dd, J = 12.0 Hz, 7.6Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 138.0, 129.2, 128.9, 128.2, 127.9, 118.2, 108.7, 105.8, 79.2, 42.9; (S)-2-(1-(4-fluorophenyl)-2-nitroethyl)-1H-pyrrole (4b) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a white solid in 93% yield. m.p. 91-92°C; [α]D20 89.3 (c =1.0, CH2Cl2, 91%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 95: 5, flow rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 24.0 min (major), tR = 25.6 min (minor). 1H NMR (400 MHz, CDCl3): δ 7.86 (br, 1 H), 7.26-7.15 (m, 2 H), 7.07-6.90 (m, 2 H), 6.70 (m, 1 H), 6.17 (dd, J = 6.1 Hz, 2.8 Hz, 1 H), 6.07 (m, 1 H), 4.97 (dd, J = 12.2 Hz, 7.1 Hz, 1 H), 4.88 (t, J = 7.7 Hz, 1 H), 4.76 (dd, J = 12.2 Hz, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 163.6, 161.2, 133.8, 129.64, 129.56, 128.7, 118.4, 116.3, 116.1, 108.7, 105.9, 79.2, 42.2; 19F NMR (376 MHz, CDCl3)

δ -113.7; (S)-2-(1-(4-chlorophenyl)-2-nitroethyl)-1H-pyrrole (4c) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a white solid in 95% yield. m.p. 103-104°C; [α]D20 -75.9 (c = 1.2, CH2Cl2, 94%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90:10, flow



rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 11.5 min (minor), tR = 12.3 min (major). 1H NMR (400 MHz, CDCl3): δ 7.86 (br, 1 H), 7.34-7.29 (m, 2 H), 7.18-7.14 (m, 2 H), 6.70 (m, 1 H), 6.16 (dd, J = 6.1 Hz, 2.8 Hz, 1 H), 6.06 (s, 1 H), 4.96 (dd, J = 12.2 Hz, 7.1 Hz, 1 H), 4.86 (t, J = 7.8 Hz, 1 H), 4.77 (dd, J = 12.2 Hz, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 136.5, 134.1, 129.4, 129.3, 128.3, 118.5, 108.8, 106.0, 79.0, 42.3; (S)-2-(1-(4-bromophenyl)-2-nitroethyl)-1H-pyrrole (4d) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a white solid in 97% yield. m.p. 94-95°C; [α]D20 60.4 (c = 1.2, CH2Cl2, 94%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 12.3 min (minor), tR = 13.8 min (major). 1H NMR (400 MHz, CDCl3): δ 7.86 (br, 1 H), 7.49-7.45 (m, 2H), 7.12-7.07 (m, 2 H), 6.70 (m, 1 H), 6.16 (dd, J = 6.1 Hz, 2.8 Hz, 1 H), 6.06 (m, 1 H), 4.96 (dd, J = 12.2 Hz, 7.0 Hz, 1 H), 4.85 (t, J = 7.8 Hz, 1 H), 4.77 (dd, J = 12.2 Hz, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 137.1, 132.4, 129.6, 128.2, 122.2, 118.5, 108.8, 106.0, 78.9, 42.4; (S)-2-(2-nitro-1-(4-(trifluoromethyl)phenyl)ethyl)-1H-pyrrole (4e) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a white solid in 95% yield. m.p. 89-90°C; [α]D20 58.6 (c = 0.81, CH2Cl2, 96%ee); HPLC: Daicel Chiralpak OJ-H, hexane: 2-propanol = 70: 30, flow rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 15.9 min (major), tR = 22.1 min (minor). 1H NMR (400 MHz, CDCl3): δ 7.91 (br, 1 H), 7.62 (d, J = 8.1 Hz, 2 H), 7.37 (d, J = 8.1 H, 2 H), 6.72 (m, 1 H), 6.19 (dd, J = 6.0 Hz, 2.9 Hz, 1 H), 6.10 (m, 1 H), 5.10-4.90 (m, 2 H), 4.88-4.80 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 142.1, 130.9-129.9 (q, J = 32.6 Hz ), 128.4, 127.9, 126.2, 125.2-119.8 (q, J = 270.6 Hz ), 118.7, 108.9, 106.3, 78.8, 42.7; 19F NMR (376 MHz, CDCl3) δ -62.7;

(S)-2-(2-nitro-1-(p-tolyl)ethyl)-1H-pyrrole (4f) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a white solid in 88% yield. m.p. 101-102°C; [α]D20


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-72.2 (c = 1.4, CH2Cl2, 91%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 95: 5, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 16.7 min (major), tR = 18.1 min (minor). 1H NMR (400 MHz, CDCl3): δ 7.81 (br, 1 H), 7.16-7.08 (m, 4 H), 6.66 (m, 1 H), 6.15 (m, 1 H), 6.06 (s, 1 H), 4.95 (dd, J = 11.9 Hz, 7.0 Hz, 1 H), 4.84 (m, 1 H), 4.77 (dd, J = 11.9 Hz, 7.9 Hz, 1 H), 2.32 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 136.9, 133.8, 128.9, 128.1, 126.8, 117.0, 107.6, 104.6, 78.3, 41.5, 20.0; (S)-2-(1-(4-methoxyphenyl)-2-nitroethyl)-1H-pyrrole (4g) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 76% yield. [α]D20 -70.3 (c = 1.0, CH2Cl2, 90%ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-propanol = 80: 20, flow rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 26.4 min (minor), tR = 34.6 min (major). 1H NMR (400 MHz, CDCl3): δ 7.84 (br, 1 H), 7.16-7.11 (m, 2 H), 6.89-6.83 (m, 2 H), 6.68 (m, 1 H), 6.15 (m, 1 H), 6.06 (m, 1 H), 4.95 (dd, J = 12.0 Hz, 7.0 Hz, 1 H), 4.84 (m, 1 H), 4.75 (dd, J = 12.0 Hz, 8.1 Hz, 1 H), 3.78 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 159.3, 129.8, 129.3, 129.1, 118.1, 114.6, 108.6, 105.6, 79.4, 55.3, 42.2; (S)-2-(1-(2-chlorophenyl)-2-nitroethyl)-1H-pyrrole (4h) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 84% yield. [α]D20 -79.7 (c = 0.8, CH2Cl2, 89%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 9.5 min (major), tR = 10.8 min (minor). 1H NMR (400 MHz, CDCl3): δ 8.01 (br, 1 H), 7.45-7.38 (m, 1 H), 7.27-7.18 (m, 2 H), 7.15-7.09 (m, 1 H), 6.70 (m, 1 H), 6.18-6.12 (m, 2 H), 5.45 (m, 1 H), 4.96-4.83 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ 135.7, 133.6, 130.2, 129.3, 129.0, 127.9, 127.7, 118.4, 108.7, 106.3, 77.2, 39.3; (S)-2-(1-(2-bromophenyl)-2-nitroethyl)-1H-pyrrole (4i) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 83% yield. [α]D20 -83.5 (c = 1.0,



CH2Cl2, 90%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 95: 5, flow rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 21.2 min (major), tR = 26.0 min (minor). 1H NMR (400 MHz, CDCl3): δ 8.01 (br, 1 H), 7.61 (dd, J = 7.9 Hz, 1.2 Hz, 1 H), 7.29-7.24 (m, 1 H), 7.18-7.05 (m, 2 H), 6.71 (m, 1 H), 6.18-6.09 (m, 2 H), 5.45 (m, 1 H), 4.94-4.80 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ 137.4, 133.6, 129.5, 129.1, 128.3, 127.9, 124.2, 118.4, 108.7, 106.3, 77.3, 41.8; (S)-2-(1-(3-chlorophenyl)-2-nitroethyl)-1H-pyrrole (4j) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 90% yield. [α]D20 -88.6 (c = 1.0, CH2Cl2, 92%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 9.0 min (major), tR = 9.9 min (minor). 1H NMR (400 MHz, CDCl3): δ 7.90 (br, 1 H), 7.30-7.25 (m, 2 H), 7.21 (s, 1 H), 7.15-7.09 (m, 1 H), 6.70 (m, 1 H), 6.17 (dd, J = 6.2 Hz, 2.8 Hz, 1 H), 6.07 (m, 1 H), 4.96 (dd, J = 12.1 Hz, 7.1 Hz, 1 H), 4.86 (m, 1 H), 4.78 (dd, J = 12.1 Hz, 7.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 140.1, 135.1, 130.5, 128.4, 128.12, 128.08, 126.1, 118.6, 108.8, 106.1, 78.9, 42.6; (S)-2-(1-(furan-2-yl)-2-nitroethyl)-1H-pyrrole (4k) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 91% yield. [α]D20 +16.1 (c = 1.0, CH2Cl2, 89%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 9.5 min (minor), tR = 10.8 min (major). 1H NMR (400 MHz, CDCl3): δ 8.24 (br, 1 H), 7.40 (m, 1 H), 6.71 (m, 1 H), 6.33 (dd, J = 3.2 Hz, 1.9 Hz, 1 H), 6.20-6.07 (m, 3 H), 5.01 (t, J = 7.7 Hz, 1 H), 4.92-4.78 (m, 2 H); 13C NMR (100 MHz, CDCl3): δ 150.7, 142.8, 126.3, 118.4, 110.7, 108.9, 107.9, 106.7, 77.8, 37.7; (S)-2-(2-nitro-1-(thiophen-2-yl)ethyl)-1H-pyrrole (4l) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 96% yield. [α]D20 -44.2 (c = 1.0, CH2Cl2, 92%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0


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mL/min, T = 23°C, UV = 254 nm, tR = 11.0 min (minor), tR = 11.8 min (major). 1H NMR (400 MHz, CDCl3): δ 8.02 (br, 1 H), 7.25 (dd, J = 4.9 Hz, 1.3 Hz, 1 H), 6.98-6.92 (m, 2 H), 6.70 (m, 1 H), 6.17 (m, 1 H), 6.10 (m, 1 H), 5.20 (m, 1 H), 4.94 (dd, J = 12.9 Hz, 7.5 Hz, 1 H), 4.81 (dd, J = 12.9 Hz, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 141.0, 128.3, 127.2, 125.9, 125.6, 118.3, 108.9, 106.0, 79.7, 38.2; (S)-2-(1-(naphthalen-1-yl)-2-nitroethyl)-1H-pyrrole (4m) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 85% yield. [α]D20 -50.5 (c = 1.1, CH2Cl2, 89%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 95: 5, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 19.7 min (minor), tR = 20.8 min (major). 1H NMR (400 MHz, CDCl3): δ 8.11 (m, 1 H), 7.90-7.69 (m, 3 H), 7.60-7.47 (m, 2 H), 7.41 (m, 1 H), 7.24 (m, 1 H), 6.62 (m, 1 H), 6.21-6.14 (m, 2 H), 5.75 (m, 1 H), 5.04 (dd, J = 13.1 Hz, 9.0 Hz, 1 H), 4.93 (dd, J = 13.2 Hz, 6.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 134.2, 133.6, 131.0, 129.3, 129.0, 128.9, 127.2, 126.2, 125.5, 122.4, 118.3, 108.7, 106.5, 78.5, 38.8; (S)-2-(1-(naphthalen-2-yl)-2-nitroethyl)-1H-pyrrole (4n) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 94% yield. [α]D20 -62.6 (c = 1.2, CH2Cl2, 93%ee); HPLC: Daicel Chiralpak AD-H, hexane: 2-propanol = 90: 10, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 14.1 min (minor), tR = 17.0 min (major). 1H NMR (400 MHz, CDCl3): δ 7.84-7.70 (m, 4 H), 7.68 (m, 1 H), 7.53-7.45 (m, 2 H), 7.31-7.27 (m, 1 H), 6.66 (m, 1 H), 6.18 (m, 1 H), 6.12 (m, 1 H), 5.08-5.00 (m, 2 H), 4.94-4.85 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 135.3, 133.4, 132.9, 129.2, 128.9, 127.9, 127.8, 127.0, 126.7, 126.5, 125.4, 118.4, 108.7, 105.9, 79.1, 43.1; (S)-2-(1-nitropentan-2-yl)-1H-pyrrole (4o) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 92% yield. [α]D20 +30.3 (c = 1.0,



CH2Cl2, 94%ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-propanol = 98: 2, flow rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 50.7 min (major), tR = 56.9 min (minor). 1H NMR (400 MHz, CDCl3): δ 8.10 (br, 1 H), 6.69 (m, 1 H), 6.16 (m, 1 H), 6.00 (m, 1 H), 4.51 (m, 2 H), 3.52 (m, 1 H), 1.66 (m, 2 H), 1.32 (m, 2 H), 0.91 (t, J = 7.4 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 130.0, 117.3, 108.8, 105.4, 80.4, 37.3, 34.5, 20.2, 13.8; (S)-2-(1-cyclohexyl-2-nitroethyl)-1H-pyrrole (4p) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a light yellow oil in 87% yield. [α]D20 +10.3 (c = 0.81, CH2Cl2, 88%ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-propanol = 95: 5, flow rate = 1.0 mL/min, T = 23°C, UV = 254 nm, tR = 23.7 min (major), tR = 26.3 min (minor). 1H NMR (400 MHz, CDCl3): δ 8.04 (br, 1 H), 6.67 (m, 1 H), 6.15 (m, 1 H), 5.96 (m, 1 H), 4.72-4.52 (m, 2 H), 3.34 (m, 1 H), 1.78-1.53 (m, 6 H), 1.30-0.93 (m, 5 H); 13C NMR (100 MHz, CDCl3): δ 128.9, 117.0, 108.6, 106.0, 78.1, 43.5, 40.6, 31.1, 30.1, 26.2, 26.09,26.08; ethyl (S)-4-methyl-5-(2-nitro-1-phenylethyl)-1H-pyrrole-3-carboxylate (4q) The title compound was prepared according to the general working procedure and purified by column chromatography to give the product as a colorless oil in 94% yield. The regioselectivity was determined to be >20:1 by 1H NMR analysis. [α]D20 +88.7 (c = 1.2, CH2Cl2, 91%ee); HPLC: Daicel Chiralpak OD-H, hexane: 2-propanol = 80: 20, flow rate = 0.8 mL/min, T = 23°C, UV = 254 nm, tR = 22.5 min (major), tR = 30.4 min (minor). 1H NMR (400 MHz, CDCl3): δ 8.68 (br, 1 H), 7.367.20 (m, 6 H), 5.06-4.84 (m, 3 H), 4.24 (dd, J = 7.1 Hz, 14.2 Hz, 1H), 2.29 (s, 3 H), 1.30 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 164.7, 136.1, 128.3, 126.9, 126.2, 124.9, 123.1, 117.0, 114.6, 58.6, 39.4, 13.4, 9.3; ASSOCIATED CONTENT Supporting Information 1H

NMR and 13C NMR spectra for all the products; HPLC profiles. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author


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Fax: 86-551-3631760. E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (21432009, 21672200 and 21772185). This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDB20000000. REFERENCES (1) (a) Li, C.-J. Organic Reaction in Aqueous Media—With a Focus on Carbon-Carbon Bond Formation. Chem. Rev. 1993, 93, 2023. (b) Otto, S.; Boccaletti, G.; Engberts, J. B. F. N. A Chiral Lewis-Acid-Catalyzed Diels-Alder Reaction. Water-Enhanced Enantioselectivity. J. Am. Chem. Soc. 1998, 120, 4238. (c) Li, C.-J. Organic Reactions in Aqueous Media with a Focus on CarbonCarbon Bond Formations: A Decade Update. Chem. Rev. 2005, 105, 3095. (d) Organic Reactions in Water: Principles, Strategies and Applications; Lindström, U. M., Eds.; Blackwell Publishing: Oxford, 2007. (e) Marcus, Y. Effect of Ions on the Structure of Water: Structure Making and Breaking. Chem. Rev. 2009, 109, 1346. (f) Simon, M.-O.; Li, C.-J. Green chemistry oriented organic synthesis in water. Chem. Soc. Rev. 2012, 41, 1415. (2) Rideout, D. C.; Breslow R. Hydrophobic Acceleration of Diels-Alder Reactions. J. Am. Chem. Soc. 1980, 102, 7816. (3) (a) Breslow, R. Hydrophobic Effects on Simple Organic Reactions in Water. Acc. Chem. Res. 1991, 24, 159. (b) Azoulay, S.; Manabe, K.; Kobayashi, S. Catalytic Asymmetric Ring Opening of meso-Epoxides with Aromatic Amines in Water. Org. Lett. 2005, 7, 4593. (c) Aplander, K.; Ding, R.; Krasavin, M.; Marcus Lindström, U.; Wennerberg, J. Asymmetric Lewis Acid Catalysis in Water: α-Amino Acids as Effective Ligands in Aqueous Biphasic Catalytic Michael Additions. Eur. J. Org. Chem. 2009, 810. (4) (a) Baron, A.; Blériot, Y.; Sollogoub, M.; Vauzeilles, B. Phenylenediamine catalysis of “click glycosylations” in water: practical and direct access to unprotected neoglycoconjugates. Org. Biomol. Chem. 2008, 6, 1898. (b) Butler, R. N.; Coyne, A. G.; Moloney, E. M. Organic synthesis in water: 1,3-dipolar cycloaddition reactions at ambient temperature with aqueous suspensions of solid reactants. Tetrahedron Lett. 2007, 48, 3501.



(5) (a) Matsushita, M.; Kamata, K.; Yamaguchi, K.; Mizuno, N. Heterogeneously Catalyzed Aerobic Oxidative Biaryl Coupling of 2-Naphthols and Substituted Phenols in Water. J. Am. Chem. Soc. 2005, 127, 6632. (b) Firouzabadi, H.; Iranpoor, N.; Gholinejad, M. 2-Aminophenyl diphenylphosphinite as a new ligand for heterogeneous palladium-catalyzed Heck–Mizoroki reactions in water in the absence of any organic co-solvent. Tetrahedron 2009, 65, 7079. (c) Uozumi, Y.; Nakao, R. Catalytic Oxidation of Alcohols in Water under Atmospheric Oxygen by Use of an Amphiphilic Resin-Dispersion of a Nanopalladium Catalyst. Angew. Chem., Int. Ed. 2003, 42, 194. (d) Shaughnessy, K. H. Hydrophilic Ligands and Their Application in Aqueous-Phase MetalCatalyzed Reactions. Chem. Rev. 2009, 109, 643. (6) (a) Kobayashi, S.; Manabe, K. Development of Novel Lewis Acid Catalysts for Selective Organic Reactions in AqueousMedia. Acc. Chem. Res. 2002, 35, 209. (b) Ooi, T.; Maruoka, K. Recent Advanced in Asymmetric Phase-Transfer Catalysis. Angew. Chem., Int. Ed. 2007, 46, 4222. (c) Kitanosono, T.; Kobayashi, S. Mukaiyama Aldol Reactions in Aqueous Media. Adv. Synth. Catal. 2013, 355, 3095. (7) For some recent examples of organocatalyzed Michael reactions in aqueous media, see: (a) Zheng, Z.-L.; Perkins, B.-L.; Ni, B. Diarylprolinol Silyl Ether Salts as New, Efficient, WaterSoluble, and Recyclable Organocatalysts for the Asymmetric Michael Addition on Water. J. Am. Chem. Soc. 2010, 132, 50. (b) Dey, S.; Jäschke, A. Tuning the Stereoselectivity of a DNA-Catalyzed Michael Addition through Covalent Modification. Angew. Chem., Int. Ed. 2015, 54, 11279. (c) Akagawa, K.; Iwasaki, Y.; Kudo, K. Library Screening in Aqueous Media to Develop a Highly Active Peptide Catalyst for Enantioselective Michael Addition of a Malonate. Eur. J. Org. Chem. 2016, 4460. (d) Zhang, K.; An, J.-Z.; Su, Y.-C.; Zhang, J.-Y.; Wang, Z.-Y.; Cheng, T.-Y.; Liu, G.H. Amphiphilic Hyperbranched Polyethoxysiloxane: A Self-Templating Assembled Platform to Fabricate Functionalized Mesostructured Silicas for Aqueous Enantioselective Reactions. ACS Catal. 2016, 6, 6229. (e) Sim, J.-H.; Song, C.-E. Water-Enabled Catalytic Asymmetric Michael Reactions of Unreactive Nitroalkenes: One-Pot Synthesis of Chiral GABA-Analogs with AllCarbon Quaternary Stereogenic Centers. Angew. Chem., Int. Ed. 2017, 56, 1835. (8) (a) Kobayashi, S.; Kakumoto, K.; Mori, Y.; Manabe, K. Chiral Lewis Acid-Catalyzed Enantioselective Michael Reactions in Water. Isr. J. Chem. 2001, 41, 247. (b) Shirakawa, S.;


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Enantioselective Michael Addition of Pyrroles with Nitroalkenes in

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