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Organocatalytic asymmetric Michael addition of pyrazoleamides to β-phthalimidonitroethene
Tetrahedron 73 (2017) 6217e6222
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Organocatalytic asymmetric Michael addition of pyrazoleamides to b-phthalimidonitroethene Yuan Luo a, c, Ke-Xin Xie b, Deng-Feng Yue a, c, Xiao-Mei Zhang a, Xiao-Ying Xu a, **, Wei-Cheng Yuan a, * a b c
National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 August 2017 Received in revised form 6 September 2017 Accepted 12 September 2017 Available online 14 September 2017
A highly organocatalyzed asymmetric Michael addition reaction of pyrazoleamides to b-phthalimidonitroethene has been developed with a chiral bifunctional thiourea-tertiary amine as the catalyst. A wide range of g-nitro b-amino amides were readily obtained in good to excellent yields with high diastereoand enantioselectivities (up to 99% yield, 99% ee and >20:1 dr). The large scale experiment and transformation of the product have also been demonstrated. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Michael addition Pyrazoleamides b-Phthalimidonitroethene b-Amino acid derivatives
1. Introduction
b-Amino acids and related derivatives are privileged structural motifs presented in numerous natural products, drugs and pharmaceutically active compounds.1 Notably, they are also fundamental building blocks for the preparation of peptides, peptidomimetics and b-lactams.2 Accordingly, development of efficient asymmetric strategies for the construction of chiral bamino acids and related derivatives has drawn a great deal of attention and a variety of efficient strategies for the synthesis of these interesting molecules have been reported.3 In light of our literature search, we noticed that the reported protocols mainly focused on the synthesis of simple chiral b-amino acids and their derivatives bearing one nitrogen-atom with various substitution patterns.4 However, to the best of our knowledge, the generation of chiral b,g-amino acid derivatives containing 1,2-diamine scaffolds which are useful complements to b-amino acids is limited.5 In this context, it is still desirable to develop new and efficient asymmetric approaches to access such types of new b-amino acids.
* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (X.-Y. Xu), [email protected] (W.-C. Yuan). http://dx.doi.org/10.1016/j.tet.2017.09.019 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
In the past decade, the use of ester equivalents as pronucleophiles in asymmetric Michael reactions was considered an alternative way to access chiral carboxylic acid derivatives and a series of ester equivalents were developed as donors in Michael reactions.6 In 2012, Barbas and co-workers reported an asymmetric Michael reaction of pyrazoleamides as a donor.7 In this study, pyrazoleamides are featured with stability and easy preparation. Furthermore, the pyrazole moiety of the donor not only served as a directing group to enhance reactivity and stereoselectivity but also as a good leaving group for further transformations. To date, there are only few examples concerning the use of pyrazoleamides as donors.8 On the other hand, b-phthalimidonitroethene could serve as a useful electrophile to access diverse nitrogen-containing compounds containing two vicinal amino functionalities.9 Recently, our group reported an organocatalytic asymmetric Michael addition reaction of 3-pyrrolyloxindoles to b-phthalimidonitroethene to construct 3,30 -disubstituted oxindoles bearing a contiguous 3,a,b-triamino functionality in good results.10 Meanwhile, based on our continuing interest in the construction of diverse nitrogen-containing compounds with organocatalysis,11 we have an interest in developing new strategies for the construction of b-amino acid derivatives containing 1,2-diamine scaffolds. Herein, we wish to report our original research results with respect to the asymmetric Michael addition reaction of pyrazoleamides to
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b-phthalimidonitroethene to access g-nitro b-amino amides bearing two consecutive trisubstituted stereogenic centers with organocatalysis (Scheme 1). 2. Results and discussion We commenced our investigation with the reaction of pyrazoleamide 1a with b-phthalimidonitroethene 2 in toluene at 30 C. Initially, using quinine-thiourea A as the catalyst, the reaction proceeded smoothly and afforded the desired product 3a in 72% yield with 92% ee and >20:1 dr after 36 h (Table 1, entry 1). Then, other chiral bifunctional thiourea-tertiary amine catalysts B-D derived from cinchona alkaloids were evaluated with the model reaction. It was found that the yields were improved applying catalyst C and catalyst D while the enantioselectivities decreased slightly (Table 1, entry 1 vs. entries 2e4). In terms of stereoselectivity, catalyst A was selected as the most suitable catalyst for further screening. Afterwards, a series of solvents, including CH2Cl2, CH3CN, EtOAc, THF, mesitylene and n-hexane were investigated. A
Scheme 1. Strategy for the synthesis of g-nitro b-amino amides containing 1,2diamine scaffolds.
survey of various solvents revealed that mesitylene was the most suitable reaction media, furnishing the desired product 3a in 90% yield with 92% ee and >20:1 dr (Table 1, entry 9). To further improve the reaction outcomes, the reaction temperature was evaluated. Increasing the reaction temperature to 50 C, the yield obviously decreased to 61%. To our delight, lowering the reaction temperature led to an increase in enantioselectivity and yield. When the reaction was performed at 10 C, the corresponding product 3a could be obtained in 90% yield with 95% ee and >20:1 dr (Table 1, entry 13). However, further lowering the reaction temperature to 20 C, a decrease in the yield was observed with almost unchangeable enantioselectivity. As conditions of choice, we utilized mesitylene as the solvent at 10 C and 20 mol % catalyst A with 2:1 molar ratio of pyrazoleamides to bphthalimidonitroethene. Under the optimal reaction conditions, the generality and substrate scope of this asymmetric Michael addition of various pyrazoleamides to b-phthalimidonitroethene were investigated and the results were summarized in Scheme 2. A series of pyrazoleamides bearing either an electron-withdrawing group or an electron-donating group at the different positions of the aromatic rings proceeded smoothly in this transformation, furnishing the corresponding products 3b-3k in good to excellent yields (81e99%) with good to excellent ee values (86e99% ee) and extraordinary diastereoselectivities (>20:1 dr). It is noteworthy that 3,4dimethoxyl substituted pyrazoleamide was tolerated in this conversion, affording the g-nitro b-amino amide 3j in 96% yield with 99% ee and >20:1 dr. Additionally, 4-phenyl substituted pyrazoleamide also worked well under the optimized conditions and gave the product 3l in 85% yield with 95% ee and >20:1 dr. These
Table 1 Optimization of the reaction conditions.a
Entry
Cat.
Solvent
T (oC)
Yield (%)b
drc
ee (%)d
1 2 3 4 5 6 7 8 9 10 11 12 13 14
A B C D A A A A A A A A A A
toluene toluene toluene toluene CH2Cl2 CH3CN EtOAc THF mesitylene n-hexane mesitylene mesitylene mesitylene mesitylene
30 30 30 30 30 30 30 30 30 30 50 0 10 20
72 70 77 81 79 55 79 55 90 63 61 88 90 72
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
92 89 88 90 87 82 86 89 92 90 93 93 95 94
a The reactions were carried out with amide 1a (0.2 mmol), nitroolefin 2 (0.1 mmol), and catalyst (0.02 mmol) in 0.5 mL of solvent. b Isolated yields. c Determined by NMR. d Determined by chiral HPLC analysis.
Scheme 2. Substrate scope of the reaction. a The reactions were carried out with amides 1 (0.2 mmol), nitroolefin 2 (0.1 mmol), and catalyst A (0.02 mmol) in 0.5 mL of mesitylene. b Isolated yields. c Determined by NMR. d Determined by chiral HPLC analysis.
Y. Luo et al. / Tetrahedron 73 (2017) 6217e6222
results suggested that the electronic property of the group at the aromatic ring had no obvious effects on the reactivity and stereoselectivity. Moreover, this optimal protocol was also expanded to the sterically hindered 1-naphthyl pyrazoleamide and the desired product 3m was obtained in good results (92% yield, 91% ee and >20:1 dr). Nevertheless, heteroaromatic ring substituted pyrazoleamide also proved to be amenable to this developed protocol, and the corresponding product 3n was obtained with the acceptable results (88% yield, 85% ee and >20:1 dr). The effect of dimethyl substituents on the pyrazole ring was also evaluated and moderate results were obtained for the desired product 3o. However, we also investigated benzyl substituted pyrazoleamide and a-methyl and phenyl substituted pyrazoleamide and no desired products were observed, probably due to the low reactivity for the substrates. The absolute configuration of the major isomer 3b was determined to be (C7S, C8R) by single-crystal X-ray analysis (Fig. 1). The configurations of the other products in Scheme 2 were assumed by analogy.12 To demonstrate the synthetic utility of this developed protocol, the reaction was scaled up to 4 mmol for 2, which is 40 times larger than the scale of the model reaction. The gram-scale reaction proceeded well and afforded 3a in 99% yield with 94% ee and >20:1 dr (Scheme 3). As shown in Scheme 3, product 3a could be easily transformed to the corresponding b-amino acid ester 4 in 97% yield with a slight increase in entantioselectivity. To further understand the superiority of pyrazoleamides, a control reaction of ethyl 2-phenylacetate with 2 was investigated. As shown in Scheme 4, the reaction could not be achieved under the standard conditions. This result suggest that the pyrazol moiety of the pyrazoleamides plays a very important role in substrate activation. Based on our experimental results and the absolute configuration of the major isomer, a plausible transition state model is proposed to account for the observed stereoselectivity. As shown in
Fig. 1. X-ray crystallographic structure of 3b.
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Scheme 4. Control reaction of ethyl 2-phenylacetate with 2.
Fig. 2. A proposed transition state for the Michael addition reaction.
Fig. 2, the tertiary amine moiety of chiral-thiourea catalyst A deprotonates from pyrazoleamide to generate an ammonium ion and an enolate, and hydrogen bonding might be formed between pyrazol moiety and the protonated amine. Simultaneously, dual hydrogen bonding from the thiourea unit of catalyst A to the nitro group of b-phthalimidonitroethene. Preferentially, the Michael attack of enolates from the Re face to the Re face of b-phthalimidonitroethene thus leads to the formation of the major stereoisomer. 3. Conclusion In conclusion, we have developed a highly efficient methodology for the diastereo- and enantioselective Michael reaction of pyrazoleamides to b-phthalimidonitroethene with a chiral bifunctional amine-thiourea as the catalyst. With this developed protocol, a wide range of g-nitro b-amino acid derivatives bearing two consecutive trisubstituted stereogenic centers were readily obtained in good to excellent yields with high diastereo- and enantioselectivities (up to 99% yield, 99% ee and >20:1 dr). The promising applicability of this protocol was also demonstrated by a large scale experiment. A plausible working model was proposed to elucidate the observed high stereoselectivity. Preliminary experiments revealed that the pyrazol group of the Michael donors is crucial to promoting this reaction with high reaction activity and stereoselectivity. 4. Experimental section 4.1. General
Scheme 3. Preparative-scale experiment and the transformation of 3a.
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by TLC. 1H NMR and 13C NMR spectra were recorded in CDCl3 and DMSO-d6. 1H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s ¼ singlet, br s ¼ broad singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), coupling constants (Hz) and integration. 13C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl3 at 77.20 ppm, DMSO-d6 at 39.51 ppm). Melting
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points were recorded on a melting point apparatus. 4.2. General experimental procedures for asymmetric synthesis of compounds 3 In an ordinary vial equipped with a magnetic stirring bar, the bphthalimidonitroethene 2 (0.1 mmol, 1.0 equiv.), pyrazoleamides 1 (0.2 mmol, 2.0 equiv.) and catalyst A (11.8 mg, 20 mol %, 0.02 mmol) were placed in 0.5 mL of mesitylene at - 10 C, and the resulting mixture was stirred at this temperature until the reaction completed (monitored by TLC). The residue was purified by column chromatography (petroleum ether/ethyl acetate ¼ 5/1) to give the desired product 3. 4.2.1. 2-(1-Nitro-4-oxo-3-phenyl-4-(1H-pyrazol-1-yl)butan-2-yl) isoindoline-1,3-dione (3a) White solid; 36.4 mg, 90% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 91.5 (c 1.0, CH2Cl2); m.p. 129.1e130.5 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 6.9 min (minor), 7.5 min (major); 1H NMR (300 MHz, CDCl3) d 8.03 (d, J ¼ 2.9 Hz, 1H), 7.91e7.76 (m, 2H), 7.75e7.66 (m, 2H), 7.66e7.60 (m, 3H), 7.46e7.29 (m, 3H), 6.35e6.24 (m, 1H), 6.17 (d, J ¼ 11.8 Hz, 1H), 5.95e5.82 (m, 1H), 5.19 (dd, J ¼ 13.1, 11.4 Hz, 1H), 4.30 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.1, 144.6, 134.3, 133.0, 131.1, 129.7, 129.1, 128.9, 128.7, 123.7, 110.3, 73.4, 50.5, 48.8; HRMS (ESI) calcd. for C21H16N4NaO5 [M þ Na]þ 427.1013, found: 427.0999. 4.2.2. 2-(3-(3-chlorophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3b) White solid; 38.2 mg, 87% yield; >20:1 dr, 96% ee; [a]20 D ¼ - 100.8 (c 1.9, CH2Cl2); m.p. 160.1e162.9 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 6.9 min (minor), 7.2 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.8 Hz, 1H), 7.90e7.76 (m, 2H), 7.76e7.61 (m, 4H), 7.61e7.48 (m, 1H), 7.44e7.24 (m, 2H), 6.37e6.28 (m, 1H), 6.16 (d, J ¼ 11.7 Hz, 1H), 5.93e5.75 (m, 1H), 5.17 (dd, J ¼ 13.0, 10.9 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 167.9, 167.1, 144.9, 135.6, 135.0, 134.5, 131.2, 131.0, 129.5, 129.1, 128.8, 127.1, 123.9, 110.6, 73.3, 50.3, 48.4; HRMS (ESI) calcd. for C21H15ClN4NaO5 [M þ Na]þ 461.0623, found: 461.0625. 4.2.3. 2-(3-(3-chlorophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3c) White solid; 40.3 mg, 92% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 181.8 (c 2.0, CH2Cl2); m.p. 165.3e166.8 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 13.2 min (minor), 19.2 min (major); 1H NMR (300 MHz, CDCl3) d 8.07 (d, J ¼ 2.9 Hz, 1H), 7.89e7.78 (m, 2H), 7.78e7.69 (m, 2H), 7.69e7.63 (m, 1H), 7.59 (d, J ¼ 0.8 Hz, 1H), 7.54e7.44 (m, 1H), 7.44e7.27 (m, 2H), 6.71 (d, J ¼ 11.3 Hz, 1H), 6.34e6.26 (m, 1H), 5.88e5.67 (m, 1H), 5.40 (dd, J ¼ 13.1, 11.4 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.1, 144.9, 135.0, 134.4, 131.4, 131.2, 130.7, 130.3, 128.7, 128.1, 123.8, 110.5, 72.7, 51.1, 45.0; HRMS (ESI) calcd. for C21H15ClN4NaO5 [M þ Na]þ 461.0623, found: 461.0629. 4.2.4. 2-(3-(4-chlorophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3d) White solid; 43.4 mg, 99% yield; >20:1 dr, 86% ee; [a]20 D ¼ - 54.7 (c 2.2, CH2Cl2); m.p. 176.8e179.6 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 30.9 min (minor), 36.3 min (major); 1H NMR (300 MHz, CDCl3) d 8.03 (d, J ¼ 2.7 Hz, 1H), 7.88e7.78 (m, 2H), 7.75e7.67 (m, 2H), 7.65e7.55 (m, 3H), 7.39 (d, J ¼ 8.5 Hz, 2H), 6.35e6.27 (m, 1H), 6.17
(d, J ¼ 11.8 Hz, 1H), 5.92e5.77 (m, 1H), 5.16 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.31 (dd, J ¼ 13.0, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.0, 167.1, 144.8, 135.3, 134.4, 131.5, 131.1, 130.3, 129.9, 128.8, 123.8, 110.5, 73.4, 50.3, 48.2; HRMS (ESI) calcd. for C21H15ClN4NaO5 [M þ Na]þ 461.0623, found: 461.0624. 4.2.5. 2-(3-(4-bromophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3e) White solid; 45.6 mg, 94% yield; >20:1 dr, 94% ee; [a]20 D ¼ - 51.2 (c 2.3, CH2Cl2); m.p. 169.4e170.7 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 20/80, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 8.5 min (minor), 9.2 min (major); 1H NMR (300 MHz, CDCl3) d 8.03 (d, J ¼ 2.9 Hz, 1H), 7.90e7.76 (m, 2H), 7.76e7.66 (m, 2H), 7.65e7.59 (m, 1H), 7.59e7.48 (m, 4H), 6.36e6.26 (m, 1H), 6.16 (d, J ¼ 11.7 Hz, 1H), 5.91e5.76 (m, 1H), 5.16 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.31 (dd, J ¼ 13.0, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.0, 167.1, 144.8, 134.5, 132.9, 132.1, 131.2, 130.7, 128.8, 123.9, 123.5, 110.6, 73.4, 50.3, 48.3; HRMS (ESI) calcd. for C21H15BrN4NaO5 [M þ Na]þ 505.0118, found: 505.0114. 4.2.6. 2-(3-(4-fluorophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3f) White solid; 37.7 mg, 89% yield; >20:1 dr, 97% ee; [a]20 D ¼ - 80.2 (c 1.9, CH2Cl2); m.p. 172.0e174.5 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 5.7 min (minor), 6.0 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.9 Hz, 1H), 7.88e7.79 (m, 2H), 7.78e7.68 (m, 2H), 7.67e7.56 (m, 3H), 7.17e7.03 (m, 2H), 6.36e6.27 (m, 1H), 6.18 (d, J ¼ 11.8 Hz, 1H), 5.92e5.76 (m, 1H), 5.16 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.2, 163.0 (d, J ¼ 247.5 Hz, 1C), 144.7, 134.4, 131.2, 130.8 (d, J ¼ 8.3 Hz, 1C), 128.9 (d, J ¼ 3.8 Hz, 1C), 128.8, 123.8, 116.8 (d, J ¼ 21.8 Hz, 1C), 110.5, 73.4, 50.5, 48.0; HRMS (ESI) calcd. for C21H15FN4NaO5 [M þ Na]þ 445.0919, found: 445.0928. 4.2.7. 2-(1-Nitro-4-oxo-4-(1H-pyrazol-1-yl)-3-(4-(trifluoromethyl) phenyl)butan-2-yl)isoindoline-1,3-dione (3g) White solid; 44.8 mg, 95% yield; >20:1 dr, 94% ee; [a]20 D ¼ - 81.7 (c 2.2, CH2Cl2); m.p. 189.6e191.0 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 50/50, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 15.5 min (minor), 18.2 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.9 Hz, 1H), 7.89e7.77 (m, 4H), 7.77e7.66 (m, 4H), 7.66e7.61 (m, 1H), 6.37e6.22 (m, 2H), 5.97e5.80 (m, 1H), 5.17 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.27 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 167.8, 167.1, 144.9, 137.1, 134.5, 131.4 (q, J ¼ 32.8 Hz, 1C), 131.2, 129.6, 128.8, 126.7 (q, J ¼ 3.8 Hz, 1C), 123.6 (q, J ¼ 270.8 Hz, 1C), 123.9, 110.7, 73.3, 50.3, 48.6; HRMS (ESI) calcd. for C22H15F3N4NaO5 [M þ Na]þ 495.0887, found: 495.0867. 4.2.8. 2-(3-(3-methoxyphenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3h) White solid; 38.8 mg, 89% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 89.2 (c 1.9, CH2Cl2); m.p. 154.3e157.6 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 15/85, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 10.1 min (minor), 10.6 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (dd, J ¼ 2.9, 0.5 Hz, 1H), 7.90e7.77 (m, 2H), 7.76e7.66 (m, 2H), 7.65e7.61 (m, 1H), 7.38e7.28 (m, 1H), 7.24e7.13 (m, 2H), 6.93e6.83 (m, 1H), 6.34e6.26 (m, 1H), 6.13 (d, J ¼ 11.7 Hz, 1H), 5.95e5.78 (m, 1H), 5.18 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.32 (dd, J ¼ 13.1, 3.3 Hz, 1H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.2, 160.5, 144.6, 134.4, 131.2, 130.7, 128.7, 123.8, 121.0, 114.7, 114.4, 110.3, 73.5, 55.4, 50.5, 48.8; HRMS (ESI) calcd. for C22H18N4NaO6 [M þ Na]þ 457.1119, found: 457.1125.
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4.2.9. 2-(1-Nitro-4-oxo-4-(1H-pyrazol-1-yl)-3-(p-tolyl)butan-2-yl) isoindoline-1,3-dione (3i) White solid; 34.0 mg, 81% yield; >20:1 dr, 94% ee; [a]20 D ¼ - 96.8 (c 1.7, CH2Cl2); m.p. 131.6e134.8 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 50/50, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 18.1 min (minor), 21.6 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.9 Hz, 1H), 7.88e7.75 (m, 2H), 7.75e7.65 (m, 2H), 7.65e7.58 (m, 1H), 7.51 (d, J ¼ 8.1 Hz, 2H), 7.21 (d, J ¼ 8.0 Hz, 2H), 6.33e6.24 (m, 1H), 6.12 (d, J ¼ 11.8 Hz, 1H), 5.93e5.77 (m, 1H), 5.17 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.2 Hz, 1H), 2.33 (s, 3H); 13 C NMR (75 MHz, CDCl3) d 168.5, 167.2, 144.6, 139.2, 134.4, 131.2, 130.4, 130.0, 128.8, 128.7, 123.8, 110.3, 73.5, 50.5, 48.4, 21.1; HRMS (ESI) calcd. for C22H18N4NaO5 [M þ Na]þ 441.1169, found: 441.1165. 4.2.10. 2-(3-(3,4-dimethoxyphenyl)-1-nitro-4-oxo-4-(1H-pyrazol1-yl)butan-2-yl)isoindoline-1,3-dione (3j) White solid; 44.4 mg, 96% yield; >20:1 dr, 99% ee; [a]20 D ¼ - 67.4 (c 2.2, CH2Cl2); m.p. 142.8e144.7 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 18.8 min (minor), 20.3 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.9 Hz, 1H), 7.87e7.74 (m, 2H), 7.74e7.66 (m, 2H), 7.65e7.58 (m, 1H), 7.22e7.06 (m, 2H), 6.87 (d, J ¼ 8.3 Hz, 1H), 6.34e6.25 (m, 1H), 6.10 (d, J ¼ 11.8 Hz, 1H), 5.92e5.75 (m, 1H), 5.16 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.35 (dd, J ¼ 13.0, 3.3 Hz, 1H), 3.93 (s, 3H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) d 168.5, 167.2, 149.7, 149.6, 144.5, 134.4, 131.2, 128.7, 125.1, 123.8, 121.4, 111.8, 111.4, 110.3, 73.5, 56.1, 55.8, 50.5, 48.3; HRMS (ESI) calcd. for C23H20N4NaO7 [M þ Na]þ 487.1224, found: 487.1223. 4.2.11. 2-(3-(benzo[d][1,3]dioxol-5-ylmethyl)-1-nitro-4-oxo-4-(1Hpyrazol-1-yl)butan-2-yl)isoindoline-1,3-dione (3k) White solid; 38.1 mg, 85% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 40.8 (c 1.9, CH2Cl2); m.p. 200.2e201.8 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 50/50, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 19.3 min (major), 30.5 min (minor); 1H NMR (300 MHz, DMSOd6) d 8.28 (d, J ¼ 2.8 Hz, 1H), 7.97e7.79 (m, 5H), 7.13e7.04 (m, 1H), 7.04e6.91 (m, 2H), 6.55e6.46 (m, 1H), 6.09e5.90 (m, 3H), 5.69e5.51 (m, 1H), 5.17 (dd, J ¼ 13.7, 9.4 Hz, 1H), 4.63 (dd, J ¼ 13.7, 4.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d 168.4, 166.9, 148.0, 147.8, 145.2, 135.1, 130.7, 129.4, 126.5, 123.7, 122.5, 111.0, 109.2, 109.1, 101.6, 74.5, 50.0, 48.2; HRMS (ESI) calcd. for C22H16N4NaO7 [M þ Na]þ: 471.0911, found: 471.0912. 4.2.12. 2-(3-([1,10 -biphenyl]-4-yl)-1-nitro-4-oxo-4-(1H-pyrazol-1yl)butan-2-yl)isoindoline-1,3-dione (3l) White solid; 41.0 mg, 85% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 35.4 (c 2.1, CH2Cl2); m.p. 134.6e136.8 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 8.3 min (minor), 8.9 min (major); 1H NMR (300 MHz, CDCl3) d 8.11e8.03 (m, 1H), 7.90e7.80 (m, 2H), 7.77e7.68 (m, 4H), 7.67e7.61 (m, 3H), 7.59e7.53 (m, 2H), 7.50e7.40 (m, 2H), 7.40e7.32 (m, 1H), 6.36e6.28 (m, 1H), 6.23 (d, J ¼ 11.8 Hz, 1H), 6.01e5.85 (m, 1H), 5.23 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.39 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.2, 144.7, 142.1, 139.9, 134.4, 131.9, 131.2, 129.4, 128.9, 128.8, 128.4, 127.8, 127.0, 123.8, 110.4, 73.5, 50.5, 48.5; HRMS (ESI) calcd. for C27H20N4NaO5 [M þ Na]þ 503.1326, found: 503.1330. 4.2.13. 2-(3-(naphthalen-2-yl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3m) White solid; 41.6 mg, 92% yield; >20:1 dr, 91% ee; [a]20 D ¼ - 74.1 (c 2.1, CH2Cl2); m.p. 144.3e146.6 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 22.5 min (minor), 24.6 min (major); 1H NMR (300 MHz, CDCl3) d 8.12 (s, 1H), 8.06 (d, J ¼ 2.9 Hz, 1H), 7.96e7.79 (m, 5H), 7.79e7.66
6221
(m, 3H), 7.65e7.59 (m, 1H), 7.58e7.45 (m, 2H), 6.43e6.23 (m, 2H), 6.11e5.92 (m, 1H), 5.23 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.2, 144.7, 134.4, 133.4, 133.3, 131.2, 130.4, 129.7, 128.7, 128.6, 128.1, 127.7, 127.0, 126.9, 125.8, 123.8, 110.3, 73.5, 50.6, 48.9; HRMS (ESI) calcd. for C25H19N4O5 [M þ H]þ 455.1350, found: 455.1366. 4.2.14. 2-(1-Nitro-4-oxo-4-(1H-pyrazol-1-yl)-3-(thiophen-2-yl) butan-2-yl)isoindoline-1,3-dione (3n) White solid; 36.2 mg, 88% yield; >20:1 dr, 85% ee; [a]20 D ¼ - 24.3 (c 1.8, CH2Cl2); m.p. 153.1e155.4 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 6.0 min (minor), 7.0 min (major); 1H NMR (300 MHz, CDCl3) d 8.10e8.02 (m, 1H), 7.89e7.77 (m, 2H), 7.75e7.67 (m, 2H), 7.67e7.62 (m, 1H), 7.38e7.30 (m, 2H), 7.08e6.99 (m, 1H), 6.47 (d, J ¼ 11.5 Hz, 1H), 6.36e6.29 (m, 1H), 5.90e5.77 (m, 1H), 5.33e5.16 (m, 1H), 4.48 (dd, J ¼ 13.2, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 167.7, 167.0, 144.8, 134.4, 131.2, 128.9, 128.5, 127.7, 127.5, 123.8, 110.7, 73.4, 51.1, 43.9; HRMS (ESI) calcd. for C19H15N4O5S [M þ H]þ 411.0758, found: 411.0756. 4.2.15. 2-(4-(3,5-dimethyl-1H-pyrazol-1-yl)-1-nitro-4-oxo-3phenylbutan-2-yl)isoindoline-1,3-dione (3o) White solid; 23.8 mg, 55% yield; 1.2:1 dr, 80% ee; [a]20 D ¼ - 23.5 (c 1.2, CH2Cl2); m.p. 173.4e174.8 C; HPLC (Chiral OD-H, i-propanol/nhexane ¼ 10/90, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 9.4 min (minor), 9.9 min (major); 1H NMR (300 MHz, CDCl3) d 7.90e7.80 (m, 3H), 7.78e7.66 (m, 3H), 7.65e7.60 (m, 2H), 7.45e7.37 (m, 2H), 7.34e7.26 (m, 2H), 6.14 (d, J ¼ 11.7 Hz, 1H), 5.89e5.73 (m, 2H), 5.19 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.26 (dd, J ¼ 13.1, 3.3 Hz, 1H), 2.34 (s, 3H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) d 169.8, 167.3, 152.5, 144.3, 134.2, 134.0, 131.4, 129.5, 129.1, 128.8, 123.7, 111.7, 73.6, 50.8, 49.4, 14.2, 13.8; HRMS (ESI) calcd. for C23H20N4NaO5 [M þ Na]þ 455.1326, found: 455.1329. 4.3. Synthesis of compound 4 Compound 3a (161.6 mg, 0.4 mmol) and DBU (30.6 mg, 0.12 mmol) in 4 mL methanol was stirred for 1 h at 30 C. The resulting mixture was concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate ¼ 5:1) to give the product 4. 4.3.1. Methyl-3-(1,3-dioxoisoindolin-2-yl)-4-nitro-2phenylbutanoate (4) White solid; 142.4 mg, 97% yield; >20:1 dr, 97% ee; [a]20 D ¼ - 48.3 (c 1.0, CH2Cl2); m.p. 130.2e133.4 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 10.7 min (minor), 12.7 min (major); 1H NMR (300 MHz, CDCl3) d 7.94e7.81 (m, 2H), 7.81e7.70 (m, 2H), 7.57e7.30 (m, 5H), 5.75e5.58 (m, 1H), 5.08 (dd, J ¼ 13.0, 11.1 Hz, 1H), 4.61 (d, J ¼ 11.7 Hz, 1H), 4.21 (dd, J ¼ 13.1, 3.3 Hz, 1H), 3.52 (s, 3H); 13C NMR (75 MHz, CDCl3) d 170.4, 167.2, 134.5, 133.6, 131.3, 129.7, 129.1, 128.4, 123.8, 73.4, 52.6, 51.1, 50.8; HRMS (ESI) calcd. for C19H16N2NaO6 [M þ Na]þ 391.0901, found: 391.0906. Acknowledgements We are grateful for financial support from the National Natural Science Foundation of China (No. 21372217, 21572223, 21572224 and 21602217), and Sichuan Youth Science and Technology Foundation (2015JQ0041 and 2016JQ0024).
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Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.09.019.
6.
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Tetrahedron journal homepage: www.elsevier.com/locate/tet
Organocatalytic asymmetric Michael addition of pyrazoleamides to b-phthalimidonitroethene Yuan Luo a, c, Ke-Xin Xie b, Deng-Feng Yue a, c, Xiao-Mei Zhang a, Xiao-Ying Xu a, **, Wei-Cheng Yuan a, * a b c
National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China University of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 2 August 2017 Received in revised form 6 September 2017 Accepted 12 September 2017 Available online 14 September 2017
A highly organocatalyzed asymmetric Michael addition reaction of pyrazoleamides to b-phthalimidonitroethene has been developed with a chiral bifunctional thiourea-tertiary amine as the catalyst. A wide range of g-nitro b-amino amides were readily obtained in good to excellent yields with high diastereoand enantioselectivities (up to 99% yield, 99% ee and >20:1 dr). The large scale experiment and transformation of the product have also been demonstrated. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Michael addition Pyrazoleamides b-Phthalimidonitroethene b-Amino acid derivatives
1. Introduction
b-Amino acids and related derivatives are privileged structural motifs presented in numerous natural products, drugs and pharmaceutically active compounds.1 Notably, they are also fundamental building blocks for the preparation of peptides, peptidomimetics and b-lactams.2 Accordingly, development of efficient asymmetric strategies for the construction of chiral bamino acids and related derivatives has drawn a great deal of attention and a variety of efficient strategies for the synthesis of these interesting molecules have been reported.3 In light of our literature search, we noticed that the reported protocols mainly focused on the synthesis of simple chiral b-amino acids and their derivatives bearing one nitrogen-atom with various substitution patterns.4 However, to the best of our knowledge, the generation of chiral b,g-amino acid derivatives containing 1,2-diamine scaffolds which are useful complements to b-amino acids is limited.5 In this context, it is still desirable to develop new and efficient asymmetric approaches to access such types of new b-amino acids.
* Corresponding author. ** Corresponding author. E-mail addresses: [email protected] (X.-Y. Xu), [email protected] (W.-C. Yuan). http://dx.doi.org/10.1016/j.tet.2017.09.019 0040-4020/© 2017 Elsevier Ltd. All rights reserved.
In the past decade, the use of ester equivalents as pronucleophiles in asymmetric Michael reactions was considered an alternative way to access chiral carboxylic acid derivatives and a series of ester equivalents were developed as donors in Michael reactions.6 In 2012, Barbas and co-workers reported an asymmetric Michael reaction of pyrazoleamides as a donor.7 In this study, pyrazoleamides are featured with stability and easy preparation. Furthermore, the pyrazole moiety of the donor not only served as a directing group to enhance reactivity and stereoselectivity but also as a good leaving group for further transformations. To date, there are only few examples concerning the use of pyrazoleamides as donors.8 On the other hand, b-phthalimidonitroethene could serve as a useful electrophile to access diverse nitrogen-containing compounds containing two vicinal amino functionalities.9 Recently, our group reported an organocatalytic asymmetric Michael addition reaction of 3-pyrrolyloxindoles to b-phthalimidonitroethene to construct 3,30 -disubstituted oxindoles bearing a contiguous 3,a,b-triamino functionality in good results.10 Meanwhile, based on our continuing interest in the construction of diverse nitrogen-containing compounds with organocatalysis,11 we have an interest in developing new strategies for the construction of b-amino acid derivatives containing 1,2-diamine scaffolds. Herein, we wish to report our original research results with respect to the asymmetric Michael addition reaction of pyrazoleamides to
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b-phthalimidonitroethene to access g-nitro b-amino amides bearing two consecutive trisubstituted stereogenic centers with organocatalysis (Scheme 1). 2. Results and discussion We commenced our investigation with the reaction of pyrazoleamide 1a with b-phthalimidonitroethene 2 in toluene at 30 C. Initially, using quinine-thiourea A as the catalyst, the reaction proceeded smoothly and afforded the desired product 3a in 72% yield with 92% ee and >20:1 dr after 36 h (Table 1, entry 1). Then, other chiral bifunctional thiourea-tertiary amine catalysts B-D derived from cinchona alkaloids were evaluated with the model reaction. It was found that the yields were improved applying catalyst C and catalyst D while the enantioselectivities decreased slightly (Table 1, entry 1 vs. entries 2e4). In terms of stereoselectivity, catalyst A was selected as the most suitable catalyst for further screening. Afterwards, a series of solvents, including CH2Cl2, CH3CN, EtOAc, THF, mesitylene and n-hexane were investigated. A
Scheme 1. Strategy for the synthesis of g-nitro b-amino amides containing 1,2diamine scaffolds.
survey of various solvents revealed that mesitylene was the most suitable reaction media, furnishing the desired product 3a in 90% yield with 92% ee and >20:1 dr (Table 1, entry 9). To further improve the reaction outcomes, the reaction temperature was evaluated. Increasing the reaction temperature to 50 C, the yield obviously decreased to 61%. To our delight, lowering the reaction temperature led to an increase in enantioselectivity and yield. When the reaction was performed at 10 C, the corresponding product 3a could be obtained in 90% yield with 95% ee and >20:1 dr (Table 1, entry 13). However, further lowering the reaction temperature to 20 C, a decrease in the yield was observed with almost unchangeable enantioselectivity. As conditions of choice, we utilized mesitylene as the solvent at 10 C and 20 mol % catalyst A with 2:1 molar ratio of pyrazoleamides to bphthalimidonitroethene. Under the optimal reaction conditions, the generality and substrate scope of this asymmetric Michael addition of various pyrazoleamides to b-phthalimidonitroethene were investigated and the results were summarized in Scheme 2. A series of pyrazoleamides bearing either an electron-withdrawing group or an electron-donating group at the different positions of the aromatic rings proceeded smoothly in this transformation, furnishing the corresponding products 3b-3k in good to excellent yields (81e99%) with good to excellent ee values (86e99% ee) and extraordinary diastereoselectivities (>20:1 dr). It is noteworthy that 3,4dimethoxyl substituted pyrazoleamide was tolerated in this conversion, affording the g-nitro b-amino amide 3j in 96% yield with 99% ee and >20:1 dr. Additionally, 4-phenyl substituted pyrazoleamide also worked well under the optimized conditions and gave the product 3l in 85% yield with 95% ee and >20:1 dr. These
Table 1 Optimization of the reaction conditions.a
Entry
Cat.
Solvent
T (oC)
Yield (%)b
drc
ee (%)d
1 2 3 4 5 6 7 8 9 10 11 12 13 14
A B C D A A A A A A A A A A
toluene toluene toluene toluene CH2Cl2 CH3CN EtOAc THF mesitylene n-hexane mesitylene mesitylene mesitylene mesitylene
30 30 30 30 30 30 30 30 30 30 50 0 10 20
72 70 77 81 79 55 79 55 90 63 61 88 90 72
>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1
92 89 88 90 87 82 86 89 92 90 93 93 95 94
a The reactions were carried out with amide 1a (0.2 mmol), nitroolefin 2 (0.1 mmol), and catalyst (0.02 mmol) in 0.5 mL of solvent. b Isolated yields. c Determined by NMR. d Determined by chiral HPLC analysis.
Scheme 2. Substrate scope of the reaction. a The reactions were carried out with amides 1 (0.2 mmol), nitroolefin 2 (0.1 mmol), and catalyst A (0.02 mmol) in 0.5 mL of mesitylene. b Isolated yields. c Determined by NMR. d Determined by chiral HPLC analysis.
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results suggested that the electronic property of the group at the aromatic ring had no obvious effects on the reactivity and stereoselectivity. Moreover, this optimal protocol was also expanded to the sterically hindered 1-naphthyl pyrazoleamide and the desired product 3m was obtained in good results (92% yield, 91% ee and >20:1 dr). Nevertheless, heteroaromatic ring substituted pyrazoleamide also proved to be amenable to this developed protocol, and the corresponding product 3n was obtained with the acceptable results (88% yield, 85% ee and >20:1 dr). The effect of dimethyl substituents on the pyrazole ring was also evaluated and moderate results were obtained for the desired product 3o. However, we also investigated benzyl substituted pyrazoleamide and a-methyl and phenyl substituted pyrazoleamide and no desired products were observed, probably due to the low reactivity for the substrates. The absolute configuration of the major isomer 3b was determined to be (C7S, C8R) by single-crystal X-ray analysis (Fig. 1). The configurations of the other products in Scheme 2 were assumed by analogy.12 To demonstrate the synthetic utility of this developed protocol, the reaction was scaled up to 4 mmol for 2, which is 40 times larger than the scale of the model reaction. The gram-scale reaction proceeded well and afforded 3a in 99% yield with 94% ee and >20:1 dr (Scheme 3). As shown in Scheme 3, product 3a could be easily transformed to the corresponding b-amino acid ester 4 in 97% yield with a slight increase in entantioselectivity. To further understand the superiority of pyrazoleamides, a control reaction of ethyl 2-phenylacetate with 2 was investigated. As shown in Scheme 4, the reaction could not be achieved under the standard conditions. This result suggest that the pyrazol moiety of the pyrazoleamides plays a very important role in substrate activation. Based on our experimental results and the absolute configuration of the major isomer, a plausible transition state model is proposed to account for the observed stereoselectivity. As shown in
Fig. 1. X-ray crystallographic structure of 3b.
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Scheme 4. Control reaction of ethyl 2-phenylacetate with 2.
Fig. 2. A proposed transition state for the Michael addition reaction.
Fig. 2, the tertiary amine moiety of chiral-thiourea catalyst A deprotonates from pyrazoleamide to generate an ammonium ion and an enolate, and hydrogen bonding might be formed between pyrazol moiety and the protonated amine. Simultaneously, dual hydrogen bonding from the thiourea unit of catalyst A to the nitro group of b-phthalimidonitroethene. Preferentially, the Michael attack of enolates from the Re face to the Re face of b-phthalimidonitroethene thus leads to the formation of the major stereoisomer. 3. Conclusion In conclusion, we have developed a highly efficient methodology for the diastereo- and enantioselective Michael reaction of pyrazoleamides to b-phthalimidonitroethene with a chiral bifunctional amine-thiourea as the catalyst. With this developed protocol, a wide range of g-nitro b-amino acid derivatives bearing two consecutive trisubstituted stereogenic centers were readily obtained in good to excellent yields with high diastereo- and enantioselectivities (up to 99% yield, 99% ee and >20:1 dr). The promising applicability of this protocol was also demonstrated by a large scale experiment. A plausible working model was proposed to elucidate the observed high stereoselectivity. Preliminary experiments revealed that the pyrazol group of the Michael donors is crucial to promoting this reaction with high reaction activity and stereoselectivity. 4. Experimental section 4.1. General
Scheme 3. Preparative-scale experiment and the transformation of 3a.
Reagents were purchased from commercial sources and were used as received unless mentioned otherwise. Reactions were monitored by TLC. 1H NMR and 13C NMR spectra were recorded in CDCl3 and DMSO-d6. 1H NMR chemical shifts are reported in ppm relative to tetramethylsilane (TMS) with the solvent resonance employed as the internal standard (CDCl3 at 7.26 ppm, DMSO-d6 at 2.50 ppm). Data are reported as follows: chemical shift, multiplicity (s ¼ singlet, br s ¼ broad singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), coupling constants (Hz) and integration. 13C NMR chemical shifts are reported in ppm from tetramethylsilane (TMS) with the solvent resonance as the internal standard (CDCl3 at 77.20 ppm, DMSO-d6 at 39.51 ppm). Melting
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points were recorded on a melting point apparatus. 4.2. General experimental procedures for asymmetric synthesis of compounds 3 In an ordinary vial equipped with a magnetic stirring bar, the bphthalimidonitroethene 2 (0.1 mmol, 1.0 equiv.), pyrazoleamides 1 (0.2 mmol, 2.0 equiv.) and catalyst A (11.8 mg, 20 mol %, 0.02 mmol) were placed in 0.5 mL of mesitylene at - 10 C, and the resulting mixture was stirred at this temperature until the reaction completed (monitored by TLC). The residue was purified by column chromatography (petroleum ether/ethyl acetate ¼ 5/1) to give the desired product 3. 4.2.1. 2-(1-Nitro-4-oxo-3-phenyl-4-(1H-pyrazol-1-yl)butan-2-yl) isoindoline-1,3-dione (3a) White solid; 36.4 mg, 90% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 91.5 (c 1.0, CH2Cl2); m.p. 129.1e130.5 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 6.9 min (minor), 7.5 min (major); 1H NMR (300 MHz, CDCl3) d 8.03 (d, J ¼ 2.9 Hz, 1H), 7.91e7.76 (m, 2H), 7.75e7.66 (m, 2H), 7.66e7.60 (m, 3H), 7.46e7.29 (m, 3H), 6.35e6.24 (m, 1H), 6.17 (d, J ¼ 11.8 Hz, 1H), 5.95e5.82 (m, 1H), 5.19 (dd, J ¼ 13.1, 11.4 Hz, 1H), 4.30 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.1, 144.6, 134.3, 133.0, 131.1, 129.7, 129.1, 128.9, 128.7, 123.7, 110.3, 73.4, 50.5, 48.8; HRMS (ESI) calcd. for C21H16N4NaO5 [M þ Na]þ 427.1013, found: 427.0999. 4.2.2. 2-(3-(3-chlorophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3b) White solid; 38.2 mg, 87% yield; >20:1 dr, 96% ee; [a]20 D ¼ - 100.8 (c 1.9, CH2Cl2); m.p. 160.1e162.9 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 6.9 min (minor), 7.2 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.8 Hz, 1H), 7.90e7.76 (m, 2H), 7.76e7.61 (m, 4H), 7.61e7.48 (m, 1H), 7.44e7.24 (m, 2H), 6.37e6.28 (m, 1H), 6.16 (d, J ¼ 11.7 Hz, 1H), 5.93e5.75 (m, 1H), 5.17 (dd, J ¼ 13.0, 10.9 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 167.9, 167.1, 144.9, 135.6, 135.0, 134.5, 131.2, 131.0, 129.5, 129.1, 128.8, 127.1, 123.9, 110.6, 73.3, 50.3, 48.4; HRMS (ESI) calcd. for C21H15ClN4NaO5 [M þ Na]þ 461.0623, found: 461.0625. 4.2.3. 2-(3-(3-chlorophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3c) White solid; 40.3 mg, 92% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 181.8 (c 2.0, CH2Cl2); m.p. 165.3e166.8 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 13.2 min (minor), 19.2 min (major); 1H NMR (300 MHz, CDCl3) d 8.07 (d, J ¼ 2.9 Hz, 1H), 7.89e7.78 (m, 2H), 7.78e7.69 (m, 2H), 7.69e7.63 (m, 1H), 7.59 (d, J ¼ 0.8 Hz, 1H), 7.54e7.44 (m, 1H), 7.44e7.27 (m, 2H), 6.71 (d, J ¼ 11.3 Hz, 1H), 6.34e6.26 (m, 1H), 5.88e5.67 (m, 1H), 5.40 (dd, J ¼ 13.1, 11.4 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.1, 144.9, 135.0, 134.4, 131.4, 131.2, 130.7, 130.3, 128.7, 128.1, 123.8, 110.5, 72.7, 51.1, 45.0; HRMS (ESI) calcd. for C21H15ClN4NaO5 [M þ Na]þ 461.0623, found: 461.0629. 4.2.4. 2-(3-(4-chlorophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3d) White solid; 43.4 mg, 99% yield; >20:1 dr, 86% ee; [a]20 D ¼ - 54.7 (c 2.2, CH2Cl2); m.p. 176.8e179.6 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 30.9 min (minor), 36.3 min (major); 1H NMR (300 MHz, CDCl3) d 8.03 (d, J ¼ 2.7 Hz, 1H), 7.88e7.78 (m, 2H), 7.75e7.67 (m, 2H), 7.65e7.55 (m, 3H), 7.39 (d, J ¼ 8.5 Hz, 2H), 6.35e6.27 (m, 1H), 6.17
(d, J ¼ 11.8 Hz, 1H), 5.92e5.77 (m, 1H), 5.16 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.31 (dd, J ¼ 13.0, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.0, 167.1, 144.8, 135.3, 134.4, 131.5, 131.1, 130.3, 129.9, 128.8, 123.8, 110.5, 73.4, 50.3, 48.2; HRMS (ESI) calcd. for C21H15ClN4NaO5 [M þ Na]þ 461.0623, found: 461.0624. 4.2.5. 2-(3-(4-bromophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3e) White solid; 45.6 mg, 94% yield; >20:1 dr, 94% ee; [a]20 D ¼ - 51.2 (c 2.3, CH2Cl2); m.p. 169.4e170.7 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 20/80, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 8.5 min (minor), 9.2 min (major); 1H NMR (300 MHz, CDCl3) d 8.03 (d, J ¼ 2.9 Hz, 1H), 7.90e7.76 (m, 2H), 7.76e7.66 (m, 2H), 7.65e7.59 (m, 1H), 7.59e7.48 (m, 4H), 6.36e6.26 (m, 1H), 6.16 (d, J ¼ 11.7 Hz, 1H), 5.91e5.76 (m, 1H), 5.16 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.31 (dd, J ¼ 13.0, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.0, 167.1, 144.8, 134.5, 132.9, 132.1, 131.2, 130.7, 128.8, 123.9, 123.5, 110.6, 73.4, 50.3, 48.3; HRMS (ESI) calcd. for C21H15BrN4NaO5 [M þ Na]þ 505.0118, found: 505.0114. 4.2.6. 2-(3-(4-fluorophenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3f) White solid; 37.7 mg, 89% yield; >20:1 dr, 97% ee; [a]20 D ¼ - 80.2 (c 1.9, CH2Cl2); m.p. 172.0e174.5 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 5.7 min (minor), 6.0 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.9 Hz, 1H), 7.88e7.79 (m, 2H), 7.78e7.68 (m, 2H), 7.67e7.56 (m, 3H), 7.17e7.03 (m, 2H), 6.36e6.27 (m, 1H), 6.18 (d, J ¼ 11.8 Hz, 1H), 5.92e5.76 (m, 1H), 5.16 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.2, 163.0 (d, J ¼ 247.5 Hz, 1C), 144.7, 134.4, 131.2, 130.8 (d, J ¼ 8.3 Hz, 1C), 128.9 (d, J ¼ 3.8 Hz, 1C), 128.8, 123.8, 116.8 (d, J ¼ 21.8 Hz, 1C), 110.5, 73.4, 50.5, 48.0; HRMS (ESI) calcd. for C21H15FN4NaO5 [M þ Na]þ 445.0919, found: 445.0928. 4.2.7. 2-(1-Nitro-4-oxo-4-(1H-pyrazol-1-yl)-3-(4-(trifluoromethyl) phenyl)butan-2-yl)isoindoline-1,3-dione (3g) White solid; 44.8 mg, 95% yield; >20:1 dr, 94% ee; [a]20 D ¼ - 81.7 (c 2.2, CH2Cl2); m.p. 189.6e191.0 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 50/50, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 15.5 min (minor), 18.2 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.9 Hz, 1H), 7.89e7.77 (m, 4H), 7.77e7.66 (m, 4H), 7.66e7.61 (m, 1H), 6.37e6.22 (m, 2H), 5.97e5.80 (m, 1H), 5.17 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.27 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 167.8, 167.1, 144.9, 137.1, 134.5, 131.4 (q, J ¼ 32.8 Hz, 1C), 131.2, 129.6, 128.8, 126.7 (q, J ¼ 3.8 Hz, 1C), 123.6 (q, J ¼ 270.8 Hz, 1C), 123.9, 110.7, 73.3, 50.3, 48.6; HRMS (ESI) calcd. for C22H15F3N4NaO5 [M þ Na]þ 495.0887, found: 495.0867. 4.2.8. 2-(3-(3-methoxyphenyl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3h) White solid; 38.8 mg, 89% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 89.2 (c 1.9, CH2Cl2); m.p. 154.3e157.6 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 15/85, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 10.1 min (minor), 10.6 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (dd, J ¼ 2.9, 0.5 Hz, 1H), 7.90e7.77 (m, 2H), 7.76e7.66 (m, 2H), 7.65e7.61 (m, 1H), 7.38e7.28 (m, 1H), 7.24e7.13 (m, 2H), 6.93e6.83 (m, 1H), 6.34e6.26 (m, 1H), 6.13 (d, J ¼ 11.7 Hz, 1H), 5.95e5.78 (m, 1H), 5.18 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.32 (dd, J ¼ 13.1, 3.3 Hz, 1H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.2, 160.5, 144.6, 134.4, 131.2, 130.7, 128.7, 123.8, 121.0, 114.7, 114.4, 110.3, 73.5, 55.4, 50.5, 48.8; HRMS (ESI) calcd. for C22H18N4NaO6 [M þ Na]þ 457.1119, found: 457.1125.
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4.2.9. 2-(1-Nitro-4-oxo-4-(1H-pyrazol-1-yl)-3-(p-tolyl)butan-2-yl) isoindoline-1,3-dione (3i) White solid; 34.0 mg, 81% yield; >20:1 dr, 94% ee; [a]20 D ¼ - 96.8 (c 1.7, CH2Cl2); m.p. 131.6e134.8 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 50/50, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 18.1 min (minor), 21.6 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.9 Hz, 1H), 7.88e7.75 (m, 2H), 7.75e7.65 (m, 2H), 7.65e7.58 (m, 1H), 7.51 (d, J ¼ 8.1 Hz, 2H), 7.21 (d, J ¼ 8.0 Hz, 2H), 6.33e6.24 (m, 1H), 6.12 (d, J ¼ 11.8 Hz, 1H), 5.93e5.77 (m, 1H), 5.17 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.2 Hz, 1H), 2.33 (s, 3H); 13 C NMR (75 MHz, CDCl3) d 168.5, 167.2, 144.6, 139.2, 134.4, 131.2, 130.4, 130.0, 128.8, 128.7, 123.8, 110.3, 73.5, 50.5, 48.4, 21.1; HRMS (ESI) calcd. for C22H18N4NaO5 [M þ Na]þ 441.1169, found: 441.1165. 4.2.10. 2-(3-(3,4-dimethoxyphenyl)-1-nitro-4-oxo-4-(1H-pyrazol1-yl)butan-2-yl)isoindoline-1,3-dione (3j) White solid; 44.4 mg, 96% yield; >20:1 dr, 99% ee; [a]20 D ¼ - 67.4 (c 2.2, CH2Cl2); m.p. 142.8e144.7 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 18.8 min (minor), 20.3 min (major); 1H NMR (300 MHz, CDCl3) d 8.04 (d, J ¼ 2.9 Hz, 1H), 7.87e7.74 (m, 2H), 7.74e7.66 (m, 2H), 7.65e7.58 (m, 1H), 7.22e7.06 (m, 2H), 6.87 (d, J ¼ 8.3 Hz, 1H), 6.34e6.25 (m, 1H), 6.10 (d, J ¼ 11.8 Hz, 1H), 5.92e5.75 (m, 1H), 5.16 (dd, J ¼ 13.0, 10.8 Hz, 1H), 4.35 (dd, J ¼ 13.0, 3.3 Hz, 1H), 3.93 (s, 3H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) d 168.5, 167.2, 149.7, 149.6, 144.5, 134.4, 131.2, 128.7, 125.1, 123.8, 121.4, 111.8, 111.4, 110.3, 73.5, 56.1, 55.8, 50.5, 48.3; HRMS (ESI) calcd. for C23H20N4NaO7 [M þ Na]þ 487.1224, found: 487.1223. 4.2.11. 2-(3-(benzo[d][1,3]dioxol-5-ylmethyl)-1-nitro-4-oxo-4-(1Hpyrazol-1-yl)butan-2-yl)isoindoline-1,3-dione (3k) White solid; 38.1 mg, 85% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 40.8 (c 1.9, CH2Cl2); m.p. 200.2e201.8 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 50/50, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 19.3 min (major), 30.5 min (minor); 1H NMR (300 MHz, DMSOd6) d 8.28 (d, J ¼ 2.8 Hz, 1H), 7.97e7.79 (m, 5H), 7.13e7.04 (m, 1H), 7.04e6.91 (m, 2H), 6.55e6.46 (m, 1H), 6.09e5.90 (m, 3H), 5.69e5.51 (m, 1H), 5.17 (dd, J ¼ 13.7, 9.4 Hz, 1H), 4.63 (dd, J ¼ 13.7, 4.1 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d 168.4, 166.9, 148.0, 147.8, 145.2, 135.1, 130.7, 129.4, 126.5, 123.7, 122.5, 111.0, 109.2, 109.1, 101.6, 74.5, 50.0, 48.2; HRMS (ESI) calcd. for C22H16N4NaO7 [M þ Na]þ: 471.0911, found: 471.0912. 4.2.12. 2-(3-([1,10 -biphenyl]-4-yl)-1-nitro-4-oxo-4-(1H-pyrazol-1yl)butan-2-yl)isoindoline-1,3-dione (3l) White solid; 41.0 mg, 85% yield; >20:1 dr, 95% ee; [a]20 D ¼ - 35.4 (c 2.1, CH2Cl2); m.p. 134.6e136.8 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 8.3 min (minor), 8.9 min (major); 1H NMR (300 MHz, CDCl3) d 8.11e8.03 (m, 1H), 7.90e7.80 (m, 2H), 7.77e7.68 (m, 4H), 7.67e7.61 (m, 3H), 7.59e7.53 (m, 2H), 7.50e7.40 (m, 2H), 7.40e7.32 (m, 1H), 6.36e6.28 (m, 1H), 6.23 (d, J ¼ 11.8 Hz, 1H), 6.01e5.85 (m, 1H), 5.23 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.39 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.2, 144.7, 142.1, 139.9, 134.4, 131.9, 131.2, 129.4, 128.9, 128.8, 128.4, 127.8, 127.0, 123.8, 110.4, 73.5, 50.5, 48.5; HRMS (ESI) calcd. for C27H20N4NaO5 [M þ Na]þ 503.1326, found: 503.1330. 4.2.13. 2-(3-(naphthalen-2-yl)-1-nitro-4-oxo-4-(1H-pyrazol-1-yl) butan-2-yl)isoindoline-1,3-dione (3m) White solid; 41.6 mg, 92% yield; >20:1 dr, 91% ee; [a]20 D ¼ - 74.1 (c 2.1, CH2Cl2); m.p. 144.3e146.6 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 22.5 min (minor), 24.6 min (major); 1H NMR (300 MHz, CDCl3) d 8.12 (s, 1H), 8.06 (d, J ¼ 2.9 Hz, 1H), 7.96e7.79 (m, 5H), 7.79e7.66
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(m, 3H), 7.65e7.59 (m, 1H), 7.58e7.45 (m, 2H), 6.43e6.23 (m, 2H), 6.11e5.92 (m, 1H), 5.23 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.31 (dd, J ¼ 13.1, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 168.3, 167.2, 144.7, 134.4, 133.4, 133.3, 131.2, 130.4, 129.7, 128.7, 128.6, 128.1, 127.7, 127.0, 126.9, 125.8, 123.8, 110.3, 73.5, 50.6, 48.9; HRMS (ESI) calcd. for C25H19N4O5 [M þ H]þ 455.1350, found: 455.1366. 4.2.14. 2-(1-Nitro-4-oxo-4-(1H-pyrazol-1-yl)-3-(thiophen-2-yl) butan-2-yl)isoindoline-1,3-dione (3n) White solid; 36.2 mg, 88% yield; >20:1 dr, 85% ee; [a]20 D ¼ - 24.3 (c 1.8, CH2Cl2); m.p. 153.1e155.4 C; HPLC (Chiral OD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 6.0 min (minor), 7.0 min (major); 1H NMR (300 MHz, CDCl3) d 8.10e8.02 (m, 1H), 7.89e7.77 (m, 2H), 7.75e7.67 (m, 2H), 7.67e7.62 (m, 1H), 7.38e7.30 (m, 2H), 7.08e6.99 (m, 1H), 6.47 (d, J ¼ 11.5 Hz, 1H), 6.36e6.29 (m, 1H), 5.90e5.77 (m, 1H), 5.33e5.16 (m, 1H), 4.48 (dd, J ¼ 13.2, 3.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 167.7, 167.0, 144.8, 134.4, 131.2, 128.9, 128.5, 127.7, 127.5, 123.8, 110.7, 73.4, 51.1, 43.9; HRMS (ESI) calcd. for C19H15N4O5S [M þ H]þ 411.0758, found: 411.0756. 4.2.15. 2-(4-(3,5-dimethyl-1H-pyrazol-1-yl)-1-nitro-4-oxo-3phenylbutan-2-yl)isoindoline-1,3-dione (3o) White solid; 23.8 mg, 55% yield; 1.2:1 dr, 80% ee; [a]20 D ¼ - 23.5 (c 1.2, CH2Cl2); m.p. 173.4e174.8 C; HPLC (Chiral OD-H, i-propanol/nhexane ¼ 10/90, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 9.4 min (minor), 9.9 min (major); 1H NMR (300 MHz, CDCl3) d 7.90e7.80 (m, 3H), 7.78e7.66 (m, 3H), 7.65e7.60 (m, 2H), 7.45e7.37 (m, 2H), 7.34e7.26 (m, 2H), 6.14 (d, J ¼ 11.7 Hz, 1H), 5.89e5.73 (m, 2H), 5.19 (dd, J ¼ 13.1, 11.0 Hz, 1H), 4.26 (dd, J ¼ 13.1, 3.3 Hz, 1H), 2.34 (s, 3H), 2.09 (s, 3H); 13C NMR (75 MHz, CDCl3) d 169.8, 167.3, 152.5, 144.3, 134.2, 134.0, 131.4, 129.5, 129.1, 128.8, 123.7, 111.7, 73.6, 50.8, 49.4, 14.2, 13.8; HRMS (ESI) calcd. for C23H20N4NaO5 [M þ Na]þ 455.1326, found: 455.1329. 4.3. Synthesis of compound 4 Compound 3a (161.6 mg, 0.4 mmol) and DBU (30.6 mg, 0.12 mmol) in 4 mL methanol was stirred for 1 h at 30 C. The resulting mixture was concentrated and the residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate ¼ 5:1) to give the product 4. 4.3.1. Methyl-3-(1,3-dioxoisoindolin-2-yl)-4-nitro-2phenylbutanoate (4) White solid; 142.4 mg, 97% yield; >20:1 dr, 97% ee; [a]20 D ¼ - 48.3 (c 1.0, CH2Cl2); m.p. 130.2e133.4 C; HPLC (Chiral AD-H, i-propanol/ n-hexane ¼ 30/70, flow rate ¼ 1.0 mL/min, l ¼ 254 nm) tR ¼ 10.7 min (minor), 12.7 min (major); 1H NMR (300 MHz, CDCl3) d 7.94e7.81 (m, 2H), 7.81e7.70 (m, 2H), 7.57e7.30 (m, 5H), 5.75e5.58 (m, 1H), 5.08 (dd, J ¼ 13.0, 11.1 Hz, 1H), 4.61 (d, J ¼ 11.7 Hz, 1H), 4.21 (dd, J ¼ 13.1, 3.3 Hz, 1H), 3.52 (s, 3H); 13C NMR (75 MHz, CDCl3) d 170.4, 167.2, 134.5, 133.6, 131.3, 129.7, 129.1, 128.4, 123.8, 73.4, 52.6, 51.1, 50.8; HRMS (ESI) calcd. for C19H16N2NaO6 [M þ Na]þ 391.0901, found: 391.0906. Acknowledgements We are grateful for financial support from the National Natural Science Foundation of China (No. 21372217, 21572223, 21572224 and 21602217), and Sichuan Youth Science and Technology Foundation (2015JQ0041 and 2016JQ0024).
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Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2017.09.019.
6.
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