Novel bifunctional l -prolinamide derivatives as highly efficient organocatalysts for asymmetric nitro-Michael reactions

Tetrahedron: Asymmetry 27 (2016) 1121–1132

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Novel bifunctional L-prolinamide derivatives as highly efficient organocatalysts for asymmetric nitro-Michael reactions Dan Xu a,c,y, Junliang Wang b,y, Lijun Yan a, Mingquan Yuan b, Xiaotian Xie a,c,⇑, Yongchao Wang a,⇑ a

School of Vocational and Technical Education, Yunnan Normal University, Kunming 650092, PR China School of Chemical Science and Technology (Yunnan University), Advanced Analysis and Measurement Center, Yunnan University, Kunming 650091, PR China c School of Chemistry and Chemical Engineering, Yunnan Normal University, Kunming 650092, PR China b

a r t i c l e

i n f o

Article history: Received 1 July 2016 Accepted 29 August 2016 Available online 4 October 2016

a b s t r a c t A series of novel bifunctional L-prolinamide derivatives was synthesised, of which (S)-N-((S)-2-oxo-1phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6 was found to be the most effective catalyst in terms of both the yield and stereoselectivity for the nitro-Michael reaction of aldehydes to nitroalkenes. Under these optimized reaction conditions, 17 corresponding novel nitro-Michael addition adducts had high yields (up to 94%) and showed excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity (up to 98 ee) under mild reaction conditions. Ó 2016 Elsevier Ltd. All rights reserved.

1. Introduction As a powerful, atom-economic and environmentally friendly carbon–carbon bond-forming methodology, asymmetric nitroMichael reactions have promoted the progress of organic synthesis and green chemistry.1 Specifically, asymmetric nitro-Michael reactions have been used to synthesise c-nitroaldehydes, which are important starting materials and key intermediates in the enantioselective syntheses of many pharmaceutical molecules and natural products2 such as, (R)-Baclofen 1,3 (R)-Roliprom 24 and (+)-Femoxetine 3 (Fig. 1).5 Recently, the development of highly efficient and stereoselective chiral catalysts for the asymmetric nitro-Michael additions under mild conditions has attracted widespread attention.1b,6 Studies on the reactivity, selectivity, and the mechanism of asymmetric organic synthesis have led to the discovery of many valuable catalysts for nitro-Michael addition reactions.7 In particular, organocatalytic enamine-active nitro-Michael additions have been the subject of extensive development.8 For example, the most widely used modern organocatalysis based on enamine activation, chiral pyrrolidine derivatives, such as diarylprolinol silyl ethers and prolinamides, have been designed and applied in asymmetric Michael additions.9 In addition, proline-based dipeptides and tripeptides, some of the most important of which are L-proli⇑ Corresponding authors. E-mail addresses: [email protected] (X. Xie), [email protected] (Y. Wang). y These authors contributed equally to the work. http://dx.doi.org/10.1016/j.tetasy.2016.08.019 0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

namides, have been developed as highly efficient catalysts in asymmetric Aldol reactions10 and applied in the synthesis of c-nitroketones.11 To the best of our knowledge, proline-based short peptides have rarely been used as organocatalysts to synthesise c-nitroaldehydes. Herein, based on the environmentally friendly asymmetric organic synthesis principle, we have designed several types of organocatalysts and applied them to asymmetric Michael additions.12 We describe a highly efficient and stereoselective method for nitro-Michael addition reactions of aldehydes to nitroalkenes catalyzed by bifunctional proline-based dipeptides 410b and 5–9 (Fig. 2). Our findings provide an effective method to synthesise valuable c-nitroaldehydes. 2. Results and discussion Four novel bifunctional L-proline-based dipeptides 5–8 were designed and prepared in four easy steps from commercially available materials (Scheme 1). These include, Step 1: homochiral N-Boc-a-amino acids 10 were treated with tritylamine 11a or benzhydrylamine 11b in the presence of dicyclohexylcarbodiimide (DCC) in dichloromethane to obtain the corresponding intermediate amides 12a–12d; Step 2: chiral primary amines 13a–13d were synthesized by deprotecting the Boc group of 12a–12d in the presence of TFA; Step 3: the acquired chiral primary amines were further treated with N-Boc-L-proline 14a to prepare the intermediates 15a–15d in the presence of 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (EDCI) and 4-dimethylaminopyridine (DMAP); Step 4: the N-Boc group of 15a–15d was deprotected to synthesize the target compounds 5–8.

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D. Xu et al. / Tetrahedron: Asymmetry 27 (2016) 1121–1132

O OMe

NH OH

O

O

NH3 Cl

O MeO

N

Cl

Me (R )-Baclofen .HCl 1

( R )-Roliprom 2

(+)-Femoxetine 3

Figure 1. Representative bioactive molecules from c-nitroaldehyde intermediates.

O

O

O O

O HN

NH

N H

NH

HN

NH NH

NH

4

5

6

O

O

O

O

O

O NH

HN

NH

HN

NH

HN

NH NH

NH

8

7

9

Figure 2. Bifunctional L-prolinamide derivatives 4–9.

NH 2 R2

O

R2 = Ph 1 1a

R1 HN

O

R2 = H 1 1b

OH

DCC, CH2 Cl2

Boc

R2

R1 N H

HN

0 oC

O

TFA, CH2 Cl2 0

oC

R1

to r. t. NH2

Boc

R2 N H

10 12a-12d

13a-13d

O N

R1

OH

Boc 14a EDCI, DMAP CH2 Cl2 , r. t.

O

O NH N

R1

O

NH

HN

O R2

HN

TFA, CH2 Cl2 0

oC

to r. t.

Boc 15a-15d R1

= i-butyl,

R2

NH 5-8

R2

= Ph 1 2a, 13a, 15a, 5

R 1 = Ph, R 2 = Ph 1 2b, 13b, 15b, 6 R 1 = Bn, R 2 = Ph 1 2c, 13c, 15c, 7 R 1 = Ph, R 2 = H 1 2d, 13d, 15d, 8

Scheme 1. The synthetic route of L-prolinamide derivatives 5–8.

Furthermore, a D-prolinamide derivative 9, as the epimer of 6, was also prepared by using a similar synthetic method (Scheme 2). The directed nitro-Michael addition of isovaleraldehyde 16a to nitrostyrene 17a was selected as the model reaction to evaluate the feasibility of our self-assembled organocatalysts 4–9 in the presence of benzoic acid (10 mol %) in toluene at room temperature (Table 1). The results showed the model reaction failed when it lacked a catalyst (Table 1, entry 1). The prolinamide organocatalysts 4–9 exhibited different catalytic activities and stereoselectivities for the model nitro-Michael addition. Among the organocatalysts surveyed, L-prolinamide 4 showed high catalytic

activity (91% yield) and moderate enantioselectivity (84% ee, Table 1, entry 2). L-prolinamide 5 was able to catalyze the nitroMichael addition. Although the yield (89%) was high, the enantioselectivity (63% ee) was low (Table 1, entry 3). When the bifunctional L-prolinamide derivative 6 was used, relatively high yield (92%), diastereoselectivity (95:5 dr) and enantioselectivity (90% ee) were observed (Table 1, entry 4). To further understand the chiral mechanism of organocatalysts in nitro-Michael addition, the stereoisomer 9 (of 6) was analysed and an enantiomer was obtained with relatively high yield (89%), diastereoselectivity (94:6 dr) and enantioselectivity (88% ee) in the model reaction

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D. Xu et al. / Tetrahedron: Asymmetry 27 (2016) 1121–1132 O N

O H 2N

OH

Boc 14b

HN

O

O O

TFA, CH2 Cl2 NH

EDCI, DMAP CH2Cl2 , r. t.

HN

O NH

0 o C to r. t.

N Boc

13b

HN

NH 15e

9

Scheme 2. The synthetic route of D-prolinamide derivative 9.

Table 1 Screening of catalysts, catalyst loading and reaction temperaturea

catalyst toluene

NO2

O +

16a

17a

O NO2

benzoic acid (10 mol%) temperature 18a

Entry

Catalyst

1 2 3 4 5 6 7e 8 9 10 11

None 4 (10 mol %) 5 (10 mol %) 6 (10 mol %) 7 (10 mol %) 8 (10 mol %) 9 (10 mol %) 6 (5 mol %) 6 (1 mol %) 6 (5 mol %) 6 (5 mol %)

Temperature

Time [h]

rt rt rt rt rt rt rt rt rt 0 °C 20 °C

24 24 24 24 24 24 24 24 36 24 24

Yield [%]b <5 91 89 92 61 85 89 91 55 80 68

syn/antic

ee [%]d

Nd 81:19 90:10 95:5 92:8 93:7 94:6 96:4 91:9 96:4 95:5

Nd 84 63 90 86 78 88 91 81 90 90

a All reactions were carried out with 16a (1.5 mmol) and 17a (1.0 mmol) in the presence of catalyst and benzoic acid (10 mol %) in toluene (1.0 mL) at the corresponding temperature (the numbers of catalyst were all marked in bold, the entry 8 represents the optimum reaction condition). b Yield of the isolated products. c Determined by 1H NMR analysis of the isolated products. d Determined by chiral HPLC, and the absolute configuration was established by comparing with the data from the literatures.10,13 e The absolute configuration was (2S,3R), and established by comparison with the data from the literature.2b,14

(Table 1, entry 7). To explore the role of the catalysts, L-prolinamides 7 and 8 were synthesized and screened (Table 1, entries 5 and 6) in model nitro-Michael additions, although the results revealed moderate yield (61%, entry 5) and stereoselectivity (78% ee, entry 6). Based on these results, bifunctional L-prolinamide (S)-N-((S)-2-oxo-1-phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6 was confirmed to be the most effective catalyst in terms of yield, diastereoselectivity and enantioselectivity for the nitro-Michael reaction of aldehydes to nitroalkenes. We examined the effects of catalyst loading on the model reaction (Table 1, entries 8 and 9). When the loading of catalyst 6 was reduced to 5 mol %, better enantioselectivity (91% vs 90% ee) was achieved despite a slight reduction in the yield (92% vs 91%). However, when the catalyst loading was reduced to 1 mol %, relatively poor yield (55%) and moderate enantioselectivity (81% ee) were observed even when the reaction time was prolonged to 36 h (Table 1, entry 9). When the effect of temperature on the nitroMichael additions was explored (Table 1, entries 8, 10 and 11), the results indicated that the diastereoselectivity (both are 96:4 dr) and enantioselectivity (91% vs 90% ee) were very similar at both room temperature and 0 °C (Table 1, entries 8 and 10). However, when reducing the reaction temperature to 20 °C, the yield decreased from 91% (found at room temperature) to 68% (20 °C) (Table 1, entries 8 and 11). In summary, the best loading

of catalyst 6 to the model nitro-Michael reaction was established as 5 mol % at room temperature. To further optimize the reaction conditions, additional solvents and additives were screened for the model reaction. Catalyst 6 (5 mol %) and benzoic acid (10 mol %) were analysed and the model reaction was performed at the room temperature (Table 2). In addition, a series of typical and practical solvents, including toluene, MeOH, EtOH, CH2Cl2, CHCl3, THF, acetonitrile and 1,4dioxane were investigated in the model nitro-Michael reaction (Table 2, entries 1–8). Our results indicated that toluene gave the best results both in terms of the yield and stereoselectivity (Tables 2, entry 1). The other protic and aprotic solvents presented moderate yields (59–87%) and enantioselectivities (70–85% ee) (Table 2, entries 2–8). Therefore, toluene was established as the most effective solvent for the nitro-Michael reaction. As a proton donor, the additives play an important role with regards to the yield and stereoselectivity of the model reaction (Tables 2, entries 9–14). Among all of the screened additives, benzoic acid exhibited the best yield and stereoselectivity in the reaction (Tables 2, entry 1). The effect of benzoic acid loading on the model reaction was further investigated, and the results indicated that 10 mol % of benzoic acid was the optimal reaction additive. Based on the overall investigation and evaluation, the catalytic system consisting of 5 mol % bifunctional chiral catalyst L-proli-

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Table 2 Screening of solvents and additives for the model reactiona

catalyst 6 (5 mol%) Solvent

NO2

O

O NO2

+

16a

additive r. t., 24h

17a

18a

Yield [%]b

Entry

Solvent

Additive

1 2 3 4 5 6 7 8 9 10 11 12 13 14

Toluene MeOH EtOH CH2Cl2 CHCl3 THF 1,4-Dioxane Acetonitrile Toluene Toluene Toluene Toluene Toluene Toluene

Benzoic acid (10 mol %) Benzoic acid (10 mol %) Benzoic acid (10 mol %) Benzoic acid (10 mol %) Benzoic acid (10 mol %) Benzoic acid (10 mol %) Benzoic acid (10 mol %) Benzoic acid (10 mol %) HCOOH (10 mol %) CH3COOH (10 mol %) CF3COOH (10 mol %) p-TSA (10 mol %) Benzoic acid (5 mol %) Benzoic acid (1 mol %)

91 78 65 87 86 73 62 59 91 69 63 54 81 43

syn/antic

ee [%]d

96:4 88:12 84:16 90:10 91:9 85:15 81:19 83:17 86:14 87:13 80:20 76:24 90:10 75:25

91 79 73 85 84 76 70 72 79 74 64 69 86 74

a All reactions were carried out with 16a (1.5 mmol) and 17a (1.0 mmol) in the presence of catalyst 6 (5 mol %) and the corresponding additive in solvents (1.0 mL) (entry 1 marked in bold represents the optimum reaction condition). b Yield of the isolated products. c Determined by 1H NMR analysis of the isolated products. d Determined by chiral HPLC.

Table 3 Asymmetric nitro-Michael reactions of aldehydes to aromatic nitroalkenes catalysed by 6a O

R1 +

O

R2

NO2

R3

17a-17g

16a-16b

R3

catalyst 6 (5 mol%) Toluene benzoic acid (10 mol%) r. t., 24h

NO2 R1

R2 18a-18k

Entry

Compounds 16

Compounds 17

O

Yield [%]b

Product 18

syn/antic

ee [%]d

91

96:4

91

89

96:4

85

86

96:4

97

NO2 O

1

16a

17a

NO2

H

18a O

NO2

16a

O

17b

2

NO2

H

18b O

16a

3

NO2

CF3

F 3C O

17c

NO2

H

18c

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D. Xu et al. / Tetrahedron: Asymmetry 27 (2016) 1121–1132 Table 3 (continued) Entry

Compounds 16

Compounds 17 NO2

O

Yield [%]b

Product 18

syn/antic

ee [%]d

88

97:3

94

92

96:4

99

82

99:1

94

84

97:3

99

83

—

86

87

—

87

89

—

90

82

—

86

Cl

Cl

16a

O

17d

4

NO2

H

18d O

5

NO2 O

Cl

16a

17e

Cl NO2

H

18e O

NO2 Cl

16a

Cl

Cl O

17f

6

Cl NO2

H

18f O

NO2

Br

Br

16a

O

17g

7

NO2

H

18g O

NO2 O

8

16a

17a

NO2

H 18h NO2

O Me

16b

9

O

17b

NO2

H 18i NO2

O

Cl

Cl

16b

O

17d

10

NO2

H 18j NO2

O 16b

11

Br

Br O

17g

NO2

H 18k a

All reactions were carried out with 16 (1.5 mmol) and 17 (1.0 mmol) in the presence of catalyst 6 (5 mol %) and benzoic acid (10 mol %) in toluene (1.0 mL) at room temperature. b Yield of the isolated products. c Determined by 1H NMR analysis of the isolated products. d Determined by chiral HPLC.

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namide (S)-N-((S)-2-oxo-1-phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6 and 10 mol % benzoic acid in toluene at room temperature was proposed to be the most efficient condition for the asymmetric nitro-Michael addition model reaction of aldehydes to nitrostyrenes. Under the optimal reaction conditions mentioned above, we further explored the scope of the asymmetric nitro-Michael addition of aldehydes to nitrostyrenes. Initially, isovaleraldehyde 16a was selected as a representative Michael donor to evaluate the

generality of this asymmetric catalytic system (Table 3, entries 1–7). As shown in Table 3, when isovaleraldehyde 16a was treated with a series of nitrostyrenes 17a–17g bearing b-aryl substituents with electron-withdrawing or electron-donating groups, high yields (82–92%), excellent diastereoselectivities (96:4–99:1) and enantioselectivities (85–99% ee) were achieved. The enamine activation of a,a-disubstituted aldehydes suffers from several drawbacks, such as the steric hindrance and irreversible nature of a,a-disubstituted intermediates. These draw-

Table 4 Asymmetric nitro-Michael reactions of aldehydes to aliphatic nitroalkenes catalysed by 6a

R1

NO2

O +

catalyst 6 (5 mol%) toluene O benzoic acid (10 mol%) r. t., 24h

R2 16a-16g

NO 2

19 R1

R2 20a-20f

Entry

Compounds 16

Yield [%]b

Product 20

syn/antic

ee [%]d

91

88:12

86

90

65:35

99

94

64:36

99

93

90:10

99

93

99:1

99

O

1 16c O NO2

H 20a O

2 16d O NO2

H

20b O

3

16e O NO2

H O 20c 16a

4 O NO2

H

20d O

5

16f O NO2

H

20e

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D. Xu et al. / Tetrahedron: Asymmetry 27 (2016) 1121–1132 Table 4 (continued) Entry

Compounds 16

Yield [%]b

Product 20

94

NO2

H

16g

ee [%]d

60:40

97

O

O

6

syn/antic

20f a

All reactions were carried out with 16 (1.5 mmol) and 18 (1.0 mmol) in the presence of catalyst 6 (5 mol %) and benzoic acid (10 mol %) in toluene (1.0 mL) at room temperature. b Yield of the isolated products. c Determined by 1H NMR analysis of the isolated products. d Determined by chiral HPLC.

backs would limit the success in developing stereoselective carbon–carbon bond-forming reactions of a-branched aldehydes.15 Catalyst 6 could be used for the organocatalytic nitro-Michael reactions of a,a-disubstituted aldehydes to nitrostyrenes with superior yields (82–89%) and enantioselectivities (86–90% ee), to provide access to valuable a,a-disubstituted blocks-c-nitroaldehyde (Table 3, entries 8–11). Based on the conditions described above, the catalytic nitroMichael reactions of aldehydes to aliphatic nitroalkenes catalysed by catalyst 6 were also investigated to further explore the scope of the asymmetric Michael addition reaction (see Table 4). The results indicated that the steric hindrance of aliphatic chain aldehydes had a strong influence on the diastereoselectivity and enantioselectivity. The nitro-Michael addition of propionaldehyde 16c and aliphatic nitroalkenes 19 displayed moderate enantioselectivity (86% ee, Table 4, entry 1), while that of n-butanal 16d exhibited excellent stereoselectivity (99% ee, Table 4, entry 2). In addition, a series of aliphatic chain aldehydes, including n-pentanal, i-pentanal, n-hexaldehyde and phenylpropionaldehyde were also employed as Michael reaction donors, and the corresponding novel nitro-Michael adducts were obtained in high yield (90–94%), with excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity (up to 99% ee). Based on these results, the steric hindrance of aliphatic chain aldehydes is suspected to be beneficial for increasing the diastereoselectivity of nitro-Michael reactions. We propose a possible transition-state model (Scheme 3) that accounts for the high stereoselectivity of organocatalytic nitroMichael reactions found herein. In our experiments, the addition and function of chiral pyrrolidine is to activate the aldehyde through the formation of an enamine intermediate. As a consequence, the increase in energy to the HOMO frontier orbital of the enamine intermediate can lead to the formation of an active nucleophile.16 Based on our findings, this bulky aromatic amide

O O N H

N

N H

R1

O N O R2

Scheme 3. Possible transition-state model for the nitro-Michael reactions.

group plays an important role with regards to the high stereoselectivity. In addition, it is noteworthy that we found that the addition of benzoic acid to promote the formation of the hydrogen bonds between the NH groups of the peptide and the nitro group can have a positive effect on the enantioselectivity and diastereoselectivity. Some typical empirical research discoveries and theoretical computation insights were used to support this possible transitionstate model.17 3. Conclusions In conclusion, we have synthesised a series of novel bifunctional prolinamide derivatives 5–9 and developed a highly efficient catalytic system using bifunctional L-prolinamide (S)-N-((S)-2-oxo-1phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6 (5 mol %) in the presence of benzoic acid (10 mol %) in toluene at room temperature. This catalytic system exhibited universal application, high catalytic efficiency (up to 94% yield), excellent diastereoselectivity (up to 99:1 dr) and enantioselectivity (up to 99% ee). Its application to additional catalysts and catalytic systems is currently under investigation. 4. Experimental 4.1. General All commercially available reagents and materials were used without further purification, and solvents were purified by standard procedures and distilled prior to column chromatography. The reactions were monitored by thin layer chromatography (TLC) using silica gel GF254, all compounds were visualized by UV and spraying with H2SO4 (10%) in ethanol and followed by heating. Column chromatography was performed on silica gel (200–300 mesh). Mass spectroscopic data were obtained from an Agilent 1100 LC/MSD Trap LC-mass spectrometer. The NMR spectra were recorded on a Bruker DRX400 (1H: 400 MHz, 13C: 100 MHz) and DRX500 (1H: 500 MHz, 13C: 125 MHz) with TMS as the internal standard. Chemical shifts (d) are expressed in ppm and J values are given in Hz. Deuterated CDCl3 was used as the solvent. HPLC analysis was performed with a Shimadzu LC-10A equipped with Daicel HPLC columns. IR spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using KBr pellet. Optical rotations were recorded on a Perkin-Elmer 341 polarimeter in a 10 mm cell and the melting points were determined with an XT-4A melting-point apparatus.

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4.2. Procedures for the synthesis of catalysts 4.2.1. Procedures for the synthesis of intermediates 12a–12d 4.2.1.1. Procedures for the synthesis of tert-butyl (S)-(4-methyl1-oxo-1-(tritylamino)pentan-2-yl)carbamate 12a. At first, EDCI (1.22 g, 5.5 mmol) was added into a stirring solution of (tert-butoxycarbonyl)leucine 10 (1.16 g, 5.0 mmol) and DMAP (210 mg, 1.5 mmol) in dry dichloromethane (15 mL). The mixture was stirred for 15 min and then cooled to 0 °C. Triphenylmethanamine 11a (1.04 g, 4 mmol) was added to the mixture and stirred at the same temperature for 30 min. The resulting solution was stirred at room temperature until complete consumption of triphenylmethanamine (monitored by TLC). The reaction was quenched with water (50 mL) and extracted with dichloromethane (3  50 mL). The combined organic layers were washed with saturated brine solution (30 mL), followed by drying over Na2SO4 and evaporation in vacuo. The crude product was purified by column chromatography to give pure tert-butyl (S)-(4-methyl-1-oxo-1(tritylamino)pentan-2-yl)carbamate 12a. 94% yield; White solid, mp 68–69 °C; [a]20 D = 38.3 (c 1.0, CHCl3); IR (KBr) 628, 699, 1168, 1367, 1449, 1492, 1690, 2958, 3303 cm1; HRMS (EI) calcd for C30H36N2O3 [M+Na]+ 495.2618, found 495.2616; 1H NMR (400 MHz, CDCl3): d 7.48 (s, 1H), 7.29–7.19 (m, 15H), 4.88 (t, J = 8.0 Hz, 1H), 4.22 (s, 1H), 1.63 (d, J = 2.0 Hz, 2H), 1.42 (s, 9H), 0.92–0.88 (m, 6H); 13C NMR (100 MHz, CDCl3): d 171.0, 156.1, 144.6, 128.6, 127.9, 127.0, 80.3, 70.3, 53.9, 40.0, 28.3, 24.7, 22.9, 22.0. 4.2.1.2. Procedures for the synthesis of tert-Butyl (S)-(2-oxo-1phenyl-2-(tritylamino)ethyl)carbamate 12b. The synthetic method of 12b was similar to that of 12a. 93% yield; White solid, mp 84–87 °C; [a]20 D = 32.6 (c 1.0, CHCl3); IR (KBr) 697, 1165, 1246, 1366, 1490, 1683, 1717, 2978, 3307 cm1; HRMS (EI) calcd for C32H32N2O3 [M+Na]+ 515.2305, found 515.2307; 1H NMR (400 MHz, CDCl3): d 7.39–7.30 (m, 5H), 7.28–7.23 (m, 9H), 7.10 (t, J = 7.6 Hz, 6H), 6.87 (s, 1H), 5.88 (s, 1H), 5.26 (s, 1H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3): d 176.2, 168.8, 155.4, 144.1, 138.0, 129.1, 128.5, 128.0, 127.3, 127.1, 80.1, 70.6, 59.4, 28.3, 20.7. 4.2.1.3. Procedures for the synthesis of tert-Butyl (S)-(1-oxo-3phenyl-1-(tritylamino)propan-2-yl)carbamate 12c. The synthetic method of 12c was similar to that of 12a. 88% yield; Amorphous solid; [a]20 D = +13.0 (c 1.0, CHCl3); IR (KBr) 695, 892, 1087, 1167, 1244, 1311, 1576, 1627, 2850, 2916, 3328 cm1; HRMS (EI) calcd C33H34N2O3, [M+H]+ 507.2642, found for 507.2645; 1H NMR (400 MHz, CDCl3): d 7.32–7.24 (m, 12H), 7.20 (d, J = 7.2 Hz, 2H), 7.14–7.08 (m, 6H), 5.04 (s, 1H), 4.45 (d, J = 6.4 Hz, 1H), 3.45 (s, 1H), 3.16–2.99 (m, 2H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3): d 169.5, 156.8, 144.3, 136.8, 129.5, 128.8, 128.6, 127.9, 127.0, 70.3, 49.2, 37.5, 34.0, 28.2, 25.6, 25.0. 4.2.1.4. Procedures for the synthesis of tert-Butyl (S)-(2-(benzhydrylamino)-2-oxo-1-phenylethyl)carbamate 12d. The synthetic method of 12d was similar to that of 12a. 89% yield; White solid, mp 136–138 °C; [a]20 D = 0.7 (c 1.0, CHCl3); IR (KBr) 704, 1152, 1370, 1496, 1527, 1647, 2978, 3275, 3347 cm1; HRMS (EI) calcd for C26H28N2O3 [M+Na]+ 439.1992, found 439.1995; 1H NMR (400 MHz, CDCl3): d 7.34–7.24 (m, 9H), 7.23–7.15 (m, 5H), 6.93–6.89 (m, 1H), 6.49 (d, J = 7.6 Hz, 1H), 6.18 (d, J = 8.0 Hz, 1H), 5.80 (s, 1H), 5.22 (s, 1H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3): d 169.3, 155.2, 141.0, 141.0, 138.3, 129.0, 128.7, 128.5, 128.4, 127.7, 127.6, 127.4, 127.3, 127.0, 80.1, 58.8, 57.1, 28.3. 4.2.2. Procedures for the synthesis of intermediates 13a–13d 4.2.2.1. Procedures for the synthesis of (S)-2-amino-4-methylN-tritylpentanamide 13a. At first, TFA (3 mL) was added to a

solution of tert-butyl S-(4-methyl-1-oxo-1-(tritylamino)pentan-2yl)carbamate 12a (1.88 g, 4 mmol) in dry CH2Cl2 (10 mL) at 0 °C, and then stirred for 30 min. The solution was concentrated under vacuum to leave a glutinous phase. The pH of the mixture was raised to 12 by the addition of 2 M NaOH. The aqueous phase was extracted with ethyl acetate (3  50 mL). The ethyl acetate extracts were pooled, washed with brine (30 mL), dried over anhydrous Na2SO4, filtered off and the solvent was evaporated at low pressure to obtain a crude residue, which was further purified by column chromatography to obtain pure (S)-2-amino-4-methyl-Ntritylpentanamide 13a. 96% yield; White solid; mp 89–90 °C; [a]20 D = 29.9 (c 1.0, CHCl3); IR (KBr) 634, 703, 748, 867, 1034, 1387, 1448, 1515, 1680, 2875, 2960, 3287 cm1; HRMS (EI) calcd C25H28N2O, [M+Na]+ 395.2093, found for 305.2093; 1H NMR (400 MHz, CDCl3): d 8.88 (s, 1H), 7.30–7.20 (m, 15H), 3.38–3.35 (m, 1H), 1.73–1.68 (m, 2H), 1.47 (s, 2H), 1.35 (t, J = 18.4 Hz, 1H), 0.94 (d, J = 5.6 Hz, 3H), 0.89 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 174.3, 145.1, 128.7, 128.5, 128.0, 127.7, 127.1, 127.0, 69.6, 54.2, 49.0, 44.0, 29.7, 25.7, 25.0, 23.5, 21.4. 4.2.2.2. Procedures for the synthesis of (S)-2-Amino-2-phenylN-tritylacetamide 13b. The synthetic method of 13b was similar to that of 13a. 96% yield; White solid, mp 162–165 °C; [a]20 D = 0.9 (c 1.0, CHCl3); IR (KBr) 638, 696, 754, 964, 1190, 1444, 1490, 1672, 3273 cm1; HRMS (EI) calcd C27H24N2O, [M+H]+ 393.1961, found for 393.1962; 1H NMR (400 MHz, CDCl3): d 8.50 (s, 1H), 7.46 (d, J = 1.6 Hz, 2H), 7.44–7.34 (m, 3H), 7.30–7.23 (m, 9H), 7.19–7.15 (m, 6H), 4.55 (s, 1H), 1.91 (s, 2H); 13C NMR (100 MHz, CDCl3): d 171.6, 144.8, 140.8, 128.8, 128.6, 128.0, 128.0, 127.0, 126.8, 69.8, 60.6. 4.2.2.3. Procedures for the synthesis of (S)-2-Amino-3-phenylN-tritylpropanamide 13c. The synthetic method of 13c was similar to that of 13a. 90% yield; White solid, mp 64–66 °C; [a]20 D = +77.5 (c 0.5, CHCl3); IR (KBr) 698, 748, 1033, 1447, 1490, 1627, 1676, 2850, 2928 cm1; HRMS (EI) calcd C28H26N2O, [M +Na]+ 3429.1937, found for 429.1936; 1H NMR (400 MHz, CDCl3): d 8.95 (s, 1H), 7.38–7.31 (m, 12H), 7.29–7.24 (m, 8H), 3.67–3.64 (m, 1H), 3.30–3.25 (m, 1H), 2.09 (s, 1H), 1.31 (t, J = 14.4 Hz, 2H),; 13 C NMR (100 MHz, CDCl3): d 172.9, 145.0, 138.0, 129.5, 128.7, 128.0, 127.0, 126.8, 69.8, 57.1, 40.6. 4.2.2.4. Procedures for the synthesis of (S)-2-Amino-N-benzhydryl-2-phenylacetamide 13d. The synthetic method of 13d was similar to that of 13a. 89% yield; White solid, mp 124– 127 °C; [a]20 D = 49.0 (c 1.0, CHCl3); IR (KBr) 639, 700, 754, 1028, 1453, 1511, 1583, 1666, 3023, 3370 cm1; HRMS (EI) calcd C21H20N2O, [M+H]+ 317.1648, found for 317.1646; 1H NMR (400 MHz, CDCl3): d 7.82 (d, J = 8.0 Hz, 1H), 7.38–7.33 (m, 3H), 7.30–7.27 (m, 9H), 7.26–7.14 (m, 3H), 6.22 (d, J = 8.8 Hz, 1H), 4.55 (s, 1H), 1.82 (s, 2H); 13C NMR (100 MHz, CDCl3): d 172.0, 141.6, 141.6, 141.0, 128.9, 128.6, 128.6, 128.0, 127.4, 127.3, 127.3, 127.0, 59.9, 56.5. 4.2.3. Procedures for the synthesis of intermediates 15a–15e 4.2.3.1. Procedures for the synthesis of tert-butyl (S)-2-(((S)-4methyl-1-oxo-1-(tritylamino)pentan-2-yl)carbamoyl)pyrrolidine-1-carboxylate 15a. At first, EDCI (887 mg, 4 mmol) was added to a stirred solution of N-t-butyloxycarbonyl-L-proline 14a (753 mg, 3.5 mmol) and DMAP (140 mg, 1 mmol) in dry dichloromethane (10 mL). The mixture was stirred for 15 min and then cooled to 0 °C, after which (S)-2-amino-4-methyl-N-tritylpentanamide 13a (780 mg, 3 mmol) was added and stirred at the same temperature for 30 min. The resulting solution was finally stirred at room temperature until complete consumption of 13a (monitored by TLC). The reaction was quenched with water (50 mL)

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and extracted with dichloromethane (3  50 mL). The combined organic layers were washed with saturated brine solution (30 mL), followed by drying over Na2SO4 and evaporation in vacuo. The crude product was purified by column chromatography to obtain pure tert-butyl (S)-2-(((S)-4-methyl-1-oxo-1-(tritylamino) pentan-2-yl)carbamoyl)pyrrolidine-1-carboxylate 15a. 90% yield; White solid, mp 73–74 °C; [a]20 D = 56.8 (c 1.0, CHCl3); IR (KBr) 701, 769, 1125, 1164, 1367, 1389, 1449, 1525, 1700, 3307 cm1; HRMS (EI) calcd for C35H43N3O4 [M+Na]+ 592.3145, found 592.3141; 1H NMR (400 MHz, CDCl3): d 7.70 (s, 1H), 7.28–7.18 (m, 15H), 4.66–4.64 (m, 1H), 4.38–4.26 (m, 1H), 4.13–4.10 (m, 1H), 3.44–4.42 (m, 2H), 2.04 (s, 9H), 1.93–1.85 (m, 4H), 1.27– 1.23 (m, 3H), 0.88 (d, J = 15.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): d 176.3, 144.4, 128.6, 127.8, 126.9, 80.6, 60.4, 59.0, 52.7, 46.9, 29.7, 28.3, 24.7, 23.6, 22.9, 21.8, 21.0, 20.7, 14.2. 4.2.3.2. Procedures for the synthesis of tert-Butyl (S)-2-(((S)-2oxo-1-phenyl-2-(tritylamino)ethyl)carbamoyl)pyrrolidine-1carboxylate 15b. The synthetic method of 15b was similar to that of 15a. 92% yield; Amorphous solid; [a]20 D = 57.5 (c 1.0, CHCl3); IR (KBr) 1135, 1167, 1375, 1396, 1515, 1677, 1778, 2312, 3275 cm1; HRMS (EI) calcd for C37H39N3O4 [M+Na]+ 612.2832, found 612.2830; 1H NMR (400 MHz, CDCl3): d 9.89 (s, 2H), 7.25– 7.22 (m, 15H), 7.08 (s, 5H), 5.76–5.64 (m, 1H), 4.33–4.16 (m, 2H), 3.55–3.44 (m, 5H), 2.06 (m, 9H); 13C NMR (100 MHz, CDCl3): d 178.6, 176.7, 176.1, 168.5, 154.0, 144.0, 137.1, 129.0, 128.5, 127.9, 127.0, 81.0, 80.5, 80.3, 70.7, 59.0, 46.9, 46.3, 30.8, 29.0, 28.4, 28.3, 24.3, 23.7, 20.8. 4.2.3.3. Procedures for the synthesis of tert-Butyl (S)-2-(((S)-1oxo-3-phenyl-1-(tritylamino)propan-2-yl)carbamoyl)pyrrolidine-1-carboxylate 15c. The synthetic method of 15c was similar to that of 15a. 88% yield; White solid, mp 76–77 °C; [a]20 D = +10.7 (c 0.5, CHCl3); IR (KBr) 699, 748, 1163, 1248, 1395, 1449, 1492, 1700, 2976 cm1; HRMS (EI) calcd for C38H41N3O4 [M+Na]+ 626.2989, found 626.2987; 1H NMR (400 MHz, CDCl3): 9.88 (s, 2H), 7.29–7.21 (m, 15H), 7.08 (s, 5H), 5.36–5.34 (m, 1H), 4.38– 4.14 (m, 2H), 3.54–3.45 (m, 5H), 2.70–2.67 (m, 2H), 2.06 (m, 9H); 13 C NMR (100 MHz, CDCl3): d 176.6, 169.5, 144.2, 136.6, 129.5, 128.6, 127.8, 126.9, 80.7, 76.7, 70.5, 60.4, 59.0, 55.2, 47.1, 33.6, 28.3, 25.5, 24.8, 23.7, 21.0, 20.7, 14.2. 4.2.3.4. Procedures for the synthesis of tert-Butyl (S)-2-(((S)2-(benzhydrylamino)-2-oxo-1-phenylethyl)carbamoyl)pyrrolidine-1-carboxylate 15d. The synthetic method of 15d was similar to that of 15a. 90% yield; Amorphous solid; [a]20 D = 61.5 (c 1.0, CHCl3); IR (KBr) 699, 1129, 1161, 1367, 1391, 1535, 1644, 1700, 2977, 3294 cm1; HRMS (EI) calcd for C31H35N3O4 [M+Na]+ 536.2519, found 536.2517; 1H NMR (400 MHz, CDCl3): d 9.77 (s, 2H), 7.53–7.46 (m, 3H), 7.35–7.18 (m, 10H), 7.00 (s, 2H), 6.21 (d, J = 8.0 Hz, 1H), 5.91 (s, 1H), 4.34–4.10 (m, 2H), 3.54–3.37 (m, 4H), 2.02 (s, 9H), 1.87–1.78 (m, 1H); 13C NMR (100 MHz, CDCl3): d 176.2, 169.4, 154.0, 141.0, 137.3, 128.8, 128.6, 128.4, 128.2, 127.7, 127.5, 127.3, 127.1, 80.6, 80.3, 59.0, 57.2, 47.0, 46.8, 46.3, 31.2, 30.8, 29.3, 28.4, 28.2, 28.1, 24.3, 23.6, 20.7. 4.2.3.5. Procedures for the synthesis of tert-Butyl (R)-2-(((S)2-oxo-1-phenyl-2-(tritylamino)ethyl)carbamoyl)pyrrolidine-1carboxylate 15e. The synthetic method of 15e was similar to that of 15a. 93% yield; Amorphous solid; [a]20 D = 7.1 (c 1.0, CHCl3); IR (KBr) 1142, 1175, 1374, 1388, 1564, 1687, 1788, 2321, 3287 cm1; HRMS (EI) calcd for C37H39N3O4 [M+Na]+ 612.2832, found 612.2834; 1H NMR (400 MHz, CDCl3): d 9.78–9.37 (m, 2H), 7.62–7.05 (m, 20H), 5.72–5.60 (m, 1H), 4.31–4.14 (m, 1H), 3.43– 3.31 (m, 2H), 2.07 (s, 9H), 1.47–1.41 (m, 2H), 1.28–1.15 (m, 2H); 13 C NMR (100 MHz, CDCl3): d 177.2, 168.6, 144.0, 129.1, 128.5,

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127.9, 127.3, 127.0, 80.6, 70.7, 60.8, 60.2, 59.0, 57.4, 46.9, 31.1, 28.3, 23.7, 20.8. 4.2.4. Procedures for the synthesis of bifunctional L-prolinamide derivatives 5–9 4.2.4.1. Procedures for the synthesis of (S)-N-((S)-4-methyl-1oxo-1-(tritylamino)pentan-2-yl)pyrrolidine-2-carboxamide 5. At first, TFA (3 mL) was added to a solution of tert-butyl (S)-2-(((S)4-methyl-1-oxo-1-(tritylamino)pentan-2-yl)carbamoyl)pyrrolidine-1-carboxylate 15a (1.41 g, 3 mmol) in dry CH2Cl2 (10 mL) at 0 °C and stirred for 30 min. The solution was then concentrated under vacuum to leave a glutinous phase. The pH of the mixture was raised to 12 by the addition of 2 M NaOH. The aqueous phase was extracted with ethyl acetate (3  50 mL). The ethyl acetate extracts were pooled, washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered off. The resulting solvent was evaporated at low pressure to obtain a crude residue, which was further purified by column chromatography to obtain pure (S)-N-((S)4-methyl-1-oxo-1-(tritylamino)pentan-2-yl)pyrrolidine-2-carboxamide 5. 90% yield; Amorphous powder; [a]20 D = 21.9 (c 0.5, CHCl3); IR (KBr) 626, 699, 757, 1449, 1513, 1653, 1700, 2869, 3295 cm1; HRMS (EI) calcd C30H35N3O2, [M+H]+ 470.2802, found for 470.2803; 1H NMR (400 MHz, CDCl3): d 8.03–7.98 (m, 2H), 7.29–7.19 (m, 15H), 4.56–4.51 (m, 1H), 4.35–4.25 (m, 2H), 3.78–3.72 (m, 1H), 3.03–2.98 (m, 1H), 2.92–2.88 (m, 1H), 2.15–2.08 (m, 1H), 2.03–1.98 (m, 1H), 1.86–1.82 (m, 1H), 1.72–1.52 (m, 4H), 0.98–0.87 (m, 5H); 13C NMR (100 MHz, CDCl3): d 175.4, 170.5, 144.5, 128.4, 128.4, 127.6, 127.6, 126.6, 126.6, 69.8, 60.0, 51.7, 47.0, 40.3, 40.1, 40.0, 39.7, 39.4, 30.7, 25.9. 24.6, 22.9, 21.7. 4.2.4.2. Procedures for the synthesis of (S)-N-((S)-2-Oxo-1phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 6. The synthetic method of 6 was similar to that of 5. 95% yield; White solid, mp 235–237 °C; [a]20 D = 39.6 (c 1.0, CHCl3); IR (KBr) 697, 1037, 1447, 1510, 1648, 1695, 3298, 3338 cm1; HRMS (EI) calcd C32H31N3O2, [M+H]+ 490.2489, found for 490.2489; 1H NMR (400 MHz, CDCl3): d 8.49 (d, J = 7.6 Hz, 1H), 7.35–7.26 (m, 5H), 7.24–7.18 (m, 10H), 7.10–7.03 (m, 5H), 5.63 (d, J = 7.6 Hz, 1H), 3.66–3.62 (m, 1H), 2.93–2.79 (m, 2H), 2.43 (s, 1H), 2.05–1.96 (m, 1H), 1.83–1.75 (m, 1H), 1.68–1.54 (m, 3H); 13C NMR (100 MHz, CDCl3): d 175.2, 168.7, 144.2, 137.6, 128.9, 128.6, 128.3, 128.2, 127.9, 127.8, 127.6, 127.3, 127.0, 126.9, 70.5, 60.4, 57.5, 47.2, 30.8, 26.1. 4.2.4.3. Procedures for the synthesis of (S)-N-((S)-1-Oxo-3phenyl-1-(tritylamino)propan-2-yl)pyrrolidine-2-carboxamide 7. The synthetic method of 7 was similar to that of 5. 95% yield; White solid, mp 161–162 °C; [a]20 D = +12.1 (c 1.0, CHCl3); IR (KBr) 697, 1168, 1289, 1515, 1661, 1689, 3305, 3332 cm1; HRMS (EI) calcd C33H33N3O2, [M+H]+ 526.2464, found for 526.2464; 1H NMR (400 MHz, CDCl3): d 8.05 (d, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.29–7.15 (m, 14H), 7.10–7.04 (m, 6H), 4.74–4.68 (m, 1H), 4.12– 4.09 (m, 2H), 3.75–3.71 (m, 1H), 3.75–3.12 (m, 1H), 2.99–2.90 (m, 2H), 2.83–2.78 (m, 1H), 2.06–2.00 (m, 1H), 1.70–1.46 (m, 2H); 13C NMR (100 MHz, CDCl3): d 175.4, 169.3, 144.4, 137.0, 129.5, 128.6, 127.9, 127.6, 126.9, 126.8, 70.3, 59.9, 55.1, 47.0, 36.8, 30.2, 28.0, 25.9. 4.2.4.4. Procedures for the synthesis of (S)-N-((S)-2-(Benzhydrylamino)-2-oxo-1-phenylethyl)pyrrolidine-2-carboxamide 8. The synthetic method of 8 was similar to that of 5. 96% yield; White solid, mp 164–167 °C; [a]20 D = 76.5 (c 1.0, CHCl3); IR (KBr) 700, 1214, 1532, 1638, 3215, 3312, 3330 cm1; HRMS (EI) calcd C26H27N3O2, [M+H]+ 414.2176, found for 414.2175; 1H NMR (400 MHz, CDCl3): d 8.68 (d, J = 8.0 Hz, 1H), 7.40–7.33 (m, 3H),

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7.29–7.16 (m, 11H), 7.00–6.98 (m, 2H), 6.18 (d, J = 8.0 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 3.61–3.57 (m, 1H), 2.96–2.88 (m, 2H), 1.98 (s, 1H), 1.94–1.85 (m, 1H), 1.75–1.54 (m, 3H); 13C NMR (100 MHz, CDCl3): d 175.2, 169.4, 141.2, 137.9, 128.8, 128.6, 128.4, 128.2, 127.7, 127.5 127.4, 127.2, 127.1, 60.5, 57.2, 56.5, 47.2, 30.6, 26.2. 4.2.4.5. Procedures for the synthesis of (R)-N-((S)-2-Oxo-1phenyl-2-(tritylamino)ethyl)pyrrolidine-2-carboxamide 9. The synthetic method of 9 was similar to that of 5. 93% yield; White solid, mp 236–239 °C; [a]20 D = 16.7 (c 1.0, CHCl3); IR (KBr) 712, 1033, 1453, 1517, 1620, 1685, 3278, 3344 cm1; HRMS (EI) calcd C32H31N3O2, [M+H]+ 490.2489, found for 490.2489; 1H NMR (400 MHz, CDCl3): d 8.63 (s, 1H), 7.30–7.07 (m, 20H), 5.64 (s, 1H), 3.65 (s, 1H), 2.91 (d, J = 5.2 Hz, 2H), 2.30 (s, 2H), 2.01 (d, J = 21.6 Hz, 2H), 1.71–1.60 (m, 2H); 13C NMR (100 MHz, CDCl3): d 175.0, 168.6, 144.3, 144.2 138.0 129.0, 128.6128.5, 128.3, 127.9, 127.5, 127.3, 127.0, 70.6, 60.4, 57.4, 47.2, 30.7, 26.1. 4.3. General procedures for the enantioselective Michael reactions Additives and catalysts were added to a stirred mixture of the corresponding freshly distilled aldehyde (1.5 mmol, 1.5 equiv) in the indicated solvent (1 mL). The mixture was stirred at the indicated temperature for 30 min, then the corresponding nitroalkene (1.0 mmol, 1.0 equiv) was added and stirred at the same temperature until complete consumption of the nitroalkene (monitored by TLC). The solvent was quenched with ice water (10 mL), and extracted with ethyl acetate (3  10 mL). Then the combined organic phase was dried over Na2SO4, after removing the solvent, the crude products was purified by flash chromatography to obtain the corresponding Michael adducts. All newly synthesised compounds were characterized by 1H NMR, 13C NMR, HRMS, and IR spectroscopy. Enantioselectivity was determined by chiral HPLC analysis. 4.3.1. Procedures for the synthesis of (2R,3S)-2-Isopropyl-4nitro-3-phenylbutanal 18a 91% yield; yellow liquid; [a]20 D = +30.0 (c 1.0, CHCl3); HRMS (EI) calcd for C13H17NO3 [M+H]+ 236.1281, found 236.1285; 1H NMR (400 MHz, CDCl3): d 9.93 (d, J = 2.4 Hz, 1H), 7.36–7.27 (m, 3H), 7.19 (d, J = 7.2 Hz, 2H), 4.70–4.65 (m, 1H), 4.60–4.55 (m, 1H), 3.93–3.87 (m, 1H), 2.80–2.76 (m, 1H), 1.74–1.70 (m, 1H), 1.09 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.4, 191.0, 141.0, 137.1, 134.7, 131.0, 129.5, 129.2, 128.4, 128.1, 128.0, 127.8, 79.0, 58.7, 41.9, 27.9, 21.7, 17.0; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 96:4, flow rate: 0.5 mL min1, k = 254 nm), Tmajor = 21.5, Tminor = 25.4, 91% ee.

4.3.2. Procedures for the synthesis of (2R,3S)-2-Isopropyl-4nitro-3-(p-tolyl)butanal 18b 89% yield; yellow liquid; [a]20 D = +46.5 (c 1.0, CHCl3); HRMS (EI) calcd for C14H19NO3 [M+Na]+ 272.1257, found 272.1260; 1H NMR (400 MHz, CDCl3): d 9.92 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 4.67–4.63 (m, 1H), 4.57–4.52 (m, 1H), 3.90–3.83 (m, 1H), 2.77–2.72 (m, 1H), 2.30 (s, 3H), 1.75–1.70 (m, 1H), 1.11 (d, J = 5.2 Hz, 3H), 0.95 (d, J = 3.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.6, 137.8, 133.9, 130.2, 129.9, 129.5, 129.5, 128.5, 127.8, 79.1, 58.8, 41.6, 27.9, 21.7, 21.1, 17.0; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 98:2, flow rate: 1.0 mL min1, k = 254 nm), Tmajor = 13.1, Tminor = 18.0, 85% ee.

4.3.3. Procedures for the synthesis of (2R,3S)-2-Isopropyl-4nitro-3-(4-(trifluoromethyl)phenyl)butanal 18c 86% yield; yellow liquid; [a]20 D = +49.2 (c 1.0, CHCl3); HRMS (EI) calcd for C14H16F3NO3 [MH] 302.1009, found 302.1008; 1H NMR (400 MHz, CDCl3): d 9.92 (d, J = 1.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 4.75–4.70 (m, 1H), 4.63– 4.58 (m, 1H), 4.02–3.96 (m, 1H), 2.84–2.80 (m, 1H), 1.70–1.65 (m, 1H), 1.13 (d, J = 7.2 Hz, 3H), 0.94 (d, J = 4.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 203.7, 141.4, 133.8, 130.6, 130.2, 130.2, 128.5, 128.5, 128.3, 126.2, 126.2, 126.1, 125.2, 122.5, 78.5, 58.4, 41.7, 28.0, 21.6, 17.0; HPLC (Chiralcel AD-H, n-hexane: i-PrOH = 96:4, flow rate: 1.0 mL min1, k = 254 nm), Tmajor = 15.4, Tminor = 16.7, 97% ee. 4.3.4. Procedures for the synthesis of (2R,3S)-3-(4-Chlorophenyl)2-isopropyl-4-nitrobutanal 18d 88% yield; yellow liquid; [a]20 D = +50.4 (c 1.0, CHCl3); HRMS (EI) calcd for C13H16ClNO3 [MH] 268.0745, found 268.0744; 1H NMR (400 MHz, CDCl3): d 9.92 (d, J = 2.4 Hz, 1H), 7.36–7.26 (m, 2H), 7.19 (d, J = 7.2 Hz, 2H), 4.70–4.65 (m, 1H), 4.60–4.54 (m, 1H), 3.93–3.87 (m, 1H), 2.80–2.75 (m, 1H), 1.73–1.68 (m, 1H), 1.09 (d, J = 7.2 Hz, 3H), 0.87 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.4, 137.1, 129.2, 128.0, 79.0, 58.7, 42.0, 28.0, 21.7, 17.0; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 97:3, flow rate: 1.0 mL min1, k = 254 nm), Tmajor = 12.1, Tminor = 14.5, 94% ee. 4.3.5. Procedures for the synthesis of (2R,3S)-3-(2-Chlorophenyl)2-isopropyl-4-nitrobutanal 18e 92% yield; yellow liquid; [a]20 D = +103.2 (c 1.0, CHCl3); HRMS (EI) calcd for C13H16ClNO3 [MH] 268.0745, found 268.0745; 1H NMR (400 MHz, CDCl3): d 9.92 (d, J = 1.6 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.27–7.18 (m, 4H), 4.87–4.81 (m, 1H), 4.68–4.64 (m, 1H), 4.46–4.41 (m, 1H), 3.09 (d, J = 6.4 Hz, 1H), 1.79–1.74 (m, 1H), 1.17 (d, J = 7.2 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.0, 134.6, 134.3, 133.8, 130.7, 130.2, 129.2, 128.5, 127.5, 77.0, 57.5, 28.3, 21.7, 17.7; HPLC (Chiralcel AD-H, n-hexane:iPrOH = 96:4, flow rate: 1.0 mL min1, k = 254 nm), Tmajor = 8.8, Tmajor = 9.3, 99% ee. 4.3.6. Procedures for the synthesis of (2R,3S)-3-(2,4-Dichlorophenyl)-2-isopropyl-4-nitrobutanal 18f 82% yield; yellow liquid; [a]20 D = +33.0 (c 1.0, CHCl3); HRMS (EI) calcd for C13H15Cl2NO3 [MH] 302.0356, found 302.0360; 1H NMR (400 MHz, CDCl3): d 9.91 (s, 1H), 7.62–7.43 (m, 1H), 7.27– 7.24 (m, 1H), 7.14 (d, J = 8.4 Hz, 1H), 4.85–4.80 (m, 1H), 4.68– 4.64 (m, 1H),4.41–4.35 (m, 1H), 3.06 (d, J = 5.6 Hz, 1H), 1.77–1.72 (m, 1H), 1.18 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 203.8, 135.0, 133.7, 133.3, 131.0, 130.5, 130.2, 129.5, 128.5, 127.9, 76.8, 57.4, 28.4, 21.7, 17.7; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 96:4, flow rate: 1.0 mL min1, k = 254 nm), Tmajor = 14.3, Tminor = 16.7, 94% ee. 4.3.7. Procedures for the synthesis of (2R,3S)-3-(4-Bromophenyl)2-isopropyl-4-nitrobutanal 18g 84% yield; yellow liquid; [a]20 D = +41.3 (c 1.0, CHCl3); HRMS (EI) calcd for C13H16BrNO3 [MH] 312.0240, found 312.0243; 1H NMR (400 MHz, CDCl3): d 9.91 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.12–7.08 (m, 2H), 4.73–4.65 (m, 1H), 4.57–4.51 (m, 1H), 3.91–3.85 (m, 1H), 2.77–2.73 (m, 1H), 1.72–1.68 (m, 1H), 1.10 (d, J = 0.8 Hz, 3H), 0.91 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.0, 136.2, 132.4, 129.7, 129.5, 122.1, 78.7, 58.5, 41.4, 28.0, 21.6, 17.0; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 99:1, flow rate: 0.6 mL min1, k = 254 nm), Tmajor = 20.4, Tminor = 16.9, 99% ee.

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4.3.8. Procedures for the synthesis of (R)-2,2-Dimethyl-4-nitro3-phenylbutanal 18h 83% yield; yellow liquid; [a]20 D = 9.3 (c 0.5, CHCl3); HRMS (EI) calcd for C12H15NO3 [MH] 220.0979, found 220.0975; 1H NMR (400 MHz, CDCl3): d 9.53 (s, 1H), 7.62 (t, J = 14.8 Hz, 2H), 7.48 (t, J = 15.6 Hz, 3H), 4.86 (d, J = 1.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 3.80–3.77 (m, 1H), 1.14 (s, 3H), 1.01 (s, 3H); 13C NMR (100 MHz, CDCl3): d 204.3, 133.8, 130.2, 129.4, 129.1, 128.7, 128.5, 128.2, 125.4, 76.3, 48.5, 48.2, 21.7, 18.9; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 97:3, flow rate: 0.5 mL min1, k = 254 nm), Tmajor = 25.6, Tminor = 27.0, 86% ee. 4.3.9. Procedures for the synthesis of (R)-2,2-Dimethyl-4-nitro3-(p-tolyl)butanal 18i 87% yield; yellow liquid; [a]20 D = 3.4 (c 1.0, CHCl3); HRMS (EI) calcd for C13H17NO3 [MH] 234.1135, found 234.1136; 1H NMR (400 MHz, CDCl3): d 9.45 (s, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 4.75 (d, J = 1.2 Hz, 1H), 4.60 (d, J = 4.0 Hz, 1H), 3.68–3.64 (m, 1H), 2.24 (s, 3H), 1.04 (s, 3H), 0.92 s, 3H); 13C NMR (100 MHz, CDCl3): d 204.5, 172.1, 133.8, 130.3, 129.4, 129.2, 128.9, 76.4, 48.3, 48.2, 21.6, 18.9; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 97:3, flow rate: 0.5 mL min1, k = 254 nm), Tmajor = 28.4, Tminor = 25.6, 87% ee. 4.3.10. Procedures for the synthesis of (R)-3-(4-Chlorophenyl)2,2-dimethyl-4-nitrobutanal 18j 89% yield; yellow liquid; [a]20 D = 8.8 (c 1.0, CHCl3); HRMS (EI) calcd for C12H14ClNO3 [MH] 254.0589, found 254.0590; 1H NMR (400 MHz, CDCl3): d 9.50 (s, 1H), 7.48 (t, J = 15.2 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 4.82 (d, J = 1.2 Hz, 1H), 4.71 (d, J = 4.4 Hz, 1H), 3.79–3.75 (m, 1H), 1.21 (s, 3H), 1.00 (s, 3H); 13C NMR (100 MHz, CDCl3): d 203.9, 134.2, 134.0, 130.4, 130.2, 129.0, 128.5, 76.2, 48.2, 48.0, 21.7, 18.9; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 96:4, flow rate: 1.0 mL min1, k = 254 nm), Tmajor = 14.2, Tminor = 19.8, 90% ee. 4.3.11. Procedures for the synthesis of (R)-3-(4-Bromophenyl)2,2-dimethyl-4-nitrobutanal 18k 82% yield; yellow liquid; [a]20 D = 4.0 (c 0.5, CHCl3); HRMS (EI) calcd for C12H14BrNO3 [MH] 298.0084, found 298.0088; 1H NMR (400 MHz, CDCl3): d 9.50 (s, 1H), 7.56–7.46 (m, 4H), 4.82 (d, J = 1.2 Hz, 1H), 4.71 (d, J = 4.4 Hz, 1H), 3.78–3.74 (m, 1H), 1.13 (s, 3H), 1.04 (s, 3H); 13C NMR (100 MHz, CDCl3): d 203.8, 133.7, 132.8, 132.0, 130.7, 130.4, 1302, 129.4, 128.5, 76.1, 48.1, 48.0, 21.8, 19.0; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 96:4, flow rate: 1.0 mL min1, k = 254 nm), Tmajor = 15.0, Tminor = 22.8, 86% ee. 4.3.12. Procedures for the synthesis of (2R,3R)-2-Methyl-3(nitromethyl)-5-phenylpentanal 20a 91% yield; yellow liquid; [a]20 D = 0.6 (c 1.0, CHCl3); HRMS (EI) calcd for C13H17NO3 [M+H]+ 236.1281, found 236.1284; 1H NMR (400 MHz, CDCl3): d 9.61 (s, 1H), 7.31–7.27 (m, 2H), 7.25–7.19 (m, 2H), 7.17–7.14 (m, 1H), 4.55–4.51 (m, 1H), 4.46–4.41 (m, 1H), 2.82–2.72 (m, 1H), 2.70–2.63 (m, 1H), 2.61–2.54 (m, 2H), 1.71–1.64 (m, 2H), 1.62 (d, J = 5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 202.6, 140.5, 128.7, 128.3, 126.4, 77.4, 47.0, 36.8, 33.2, 30.2, 9.1; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 90:10, flow rate: 0.5 mL min1, k = 210 nm), Tmajor = 15.5, Tminor = 12.8, 86% ee. 4.3.13. Procedures for the synthesis of (2R,3R)-2-Ethyl-3(nitromethyl)-5-phenylpentanal 20b 90% yield; yellow liquid; [a]20 D = +21.4 (c 1.0, CHCl3); HRMS (EI) calcd for C14H19NO3 [M+H]+ 250.1438, found 250.1435; 1H NMR (400 MHz, CDCl3): d 9.67 (d, J = 3.6 Hz, 1H), 7.46–7.11 (m, 5H), 4.55–4.40 (m, 2H), 2.72–2.57 (m, 4H), 2.47–2.43 (m, 1H), 1.83– 1.67 (m, 4H), 1.57–1.50 (m, 1H), 1.00–0.91 (m, 3H); 13C NMR

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(100 MHz, CDCl3): d 203.2, 203.0, 140.5, 133.8, 130.2, 128.7, 128.7, 128.5, 128.3, 128.3, 126.4, 126.4, 77.4, 53.9, 53.8, 36.6, 36.2, 33.3, 33.0, 31.0, 30.7, 19.0, 18.7, 12.0, 12.0; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 90:10, flow rate: 0.5 mL min1, k = 210 nm), Tmajor = 35.2, Tminor = 37.4, 99% ee. 4.3.14. Procedures for the synthesis of (2R,3R)-3-(Nitromethyl)5-phenyl-2-propylpentanal 20c 94% yield; yellow liquid; [a]20 D = +10.2 (c 1.0, CHCl3); HRMS (EI) calcd for C15H21NO3 [M+H]+ 264.1594, found 264.1599; 1H NMR (400 MHz, CDCl3): d 9.64 (d, J = 6.8 Hz, 1H), 7.29–7.18 (m, 5H), 4.54–4.37 (m, 2H), 2.74–2.60 (m, 2H), 2.59–2.49 (m, 1H), 2.49– 2.04 (m, 1H), 1.80–1.45 (m, 2H), 1.44–1.22 (m, 2H), 0.95–0.89 (m, 5H); 13C NMR (100 MHz, CDCl3): d 203.2, 203.0, 140.5, 140.5, 128.6, 128.3, 128.3, 126.4, 126.4, 77.4, 77.0, 52.2, 52.0, 36.8, 36.6, 33.3, 33.1, 31.0, 30.7, 27.9, 27.6, 20.8, 20.8, 14.1, 14.0; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 90:10, flow rate: 0.5 mL min1, k = 210 nm), Tmajor = 31.5, Tminor = 34.1, 99% ee. 4.3.15. Procedures for the synthesis of (2R,3R)-2-Isopropyl-3(nitromethyl)-5-phenylpentanal 20d 93% yield; yellow liquid; [a]20 D = +38.6 (c 1.0, CHCl3); HRMS (EI) calcd for C15H21NO3 [M+H]+ 264.1594, found 264.1596; 1H NMR (400 MHz, CDCl3): d 9.81 (d, J = 2.4 Hz, 1H), 7.29 (t, J = 14.8 Hz, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.16 (t, J = 15.2 Hz, 2H), 4.57–4.50 (m, 1H), 4.48–4.45 (m, 1H), 2.70–2.62 (m, 4H), 2.49–2.45 (m, 1H), 2.12–2.04 (m, 2H), 1.79–1.73 (m, 2H), 1.08 (d, J = 7.2 Hz, 3H), 0.97 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 204.8, 140.6, 128.7, 128.6, 128.4, 128.3, 126.3, 58.0, 35.6, 32.6, 31.8, 27.1, 21.0, 19.7; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 90:10, flow rate: 0.5 mL min1, k = 210 nm), Tmajor = 21.0, Tminor = 24.6, 99% ee.

4.3.16. Procedures for the synthesis of (R)-2-((R)-1-Nitro-4phenylbutan-2-yl)hexanal 20e 93% yield; yellow liquid; [a]20 D = +21.5 (c 1.0, CHCl3); HRMS (EI) calcd for C16H23NO3 [M+H]+ 278.1751, found 278.1749; 1H NMR (400 MHz, CDCl3): d 9.86 (s, 1H), 7.82–7.80 (m, 2H), 7.30–7.13 (m, 3H), 4.84–4.38 (m, 2H), 2.65–2.33 (m, 4H), 1.76–1.67 (m, 4H), 1.44–1.31 (m, 4H), 0.91 (d, J = 5.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 203.0, 140.5, 128.6, 128.3, 128.3, 126.4, 77.4, 52.3, 36.6, 33.1, 31.0, 29.7, 25.2, 22.7, 13.8; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 96:4, flow rate: 0.5 mL min1, k = 210 nm), Tmajor = 16.0, Tminor = 16.5, 99% ee. 4.3.17. Procedures for the synthesis of (2R,3R)-2-Benzyl-3(nitromethyl)-5-phenylpentanal 20f 94% yield; yellow liquid; [a]20 D = +6.2 (c 1.0, CHCl3); HRMS (EI) calcd for C19H21NO3 [M+H]+ 312.1594, found 312.1591; 1H NMR (400 MHz, CDCl3): d 9.64 (s, 1H), 7.63–7.42 (m, 5H), 7.32–6.96 (m, 5H), 4.57–4.50 (m, 2H), 3.08–3.04 (m, 2H), 2.76–2.65 (m, 3H), 1.90–1.85 (m, 3H); 13C NMR (100 MHz, CDCl3): d 202.6, 202.3, 140.3, 138.0, 137.8, 133.8, 130.2, 129.0, 128.8, 128.7, 128.7, 128.5, 128.4, 128.3, 127.0, 126.9, 126.5, 126.4, 77.4, 54.2, 53.7, 36.8, 36.6, 33.4, 33.2, 32.0, 31.7, 31.2, 30.4; HPLC (Chiralcel AD-H, n-hexane:i-PrOH = 96:4, flow rate: 0.5 mL min1, k = 210 nm), Tmajor = 25.5, Tminor = 24.6, 97% ee. Acknowledgments We are grateful to Dr. Kevin S. Burgess from Columbus State University, USA for his assistance in improving the English. This work was supported by Doctor Research Project of Yunnan Normal University (No. 150025), Yunnan Applied Basic Research Project (Youth Project) and Fellowship for Outstanding PhD Student in Yunnan Province.

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D. Xu et al. / Tetrahedron: Asymmetry 27 (2016) 1121–1132

A. Supplementary data Supplementary data (1H and 13C NMR spectra for all synthesised intermediates and chiral catalysts and the 1H, 13C NMR and HPLC spectrum of compounds 18a–18k, 20a–20f) are associated with this article can be found, in the online version, at http:// dx.doi.org/10.1016/j.tetasy.2016.08.019.

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