An Enantioselective Hetero-Diels-Alder Reaction and the Synthesis of

Figure 1. Chiral spiropyrrolidone scaffold in bioactive compounds. Page 1 of 22 ... 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48...
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Cite This: J. Org. Chem. 2018, 83, 8464−8472

Enantioselective Hetero-Diels−Alder Reaction and the Synthesis of Spiropyrrolidone Derivatives Yekai Huang, Yanan Li, Jianan Sun, Jindong Li, Zhenggen Zha,* and Zhiyong Wang* Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Center for Excellence in Molecular Synthesis of Chinese Academy of Sciences, Collaborative Innovation Center of Suzhou Nano Science and Technology & School of Chemistry and Materials Science in University of Science and Technology of China, Hefei, Anhui 230026, P. R. China Downloaded via UNIV OF WOLLONGONG on August 3, 2018 at 09:48:13 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: An efficient enantioselective hetero-Diels− Alder reaction was developed under catalysis of a chiral copper complex. A variety of spiropyrrolidones, which bear a tetra-substituted carbon stereocenter, can be obtained in good yields with excellent enantioselectivities by virtue of this method. Furthermore, a substrate-dependent reaction pathway was proposed on the basis of the isolated intermediates.

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In these HDA reactions, 2,3-dioxopyrrolidines8a were widely used in the construction of the chiral annulations. We envisioned that our previous catalyst system, which demonstrated excellent results in the traditional HDA reaction between Danishefsky’s diene8b and β,γ-unsaturated α-ketoesters or glyoxals, may be capable of facilitating the construction of the chiral spiropyrrolidone skeleton by employment of 2,3dioxopyrrolidines. Herein, we report an enantioselective hetero-Diels−Alder reaction catalyzed by a copper complex,9 affording a variety of chiral spiropyrrolidones bearing tetrasubstituted carbon stereocenters with great yields and high enantioselectivities.

INTRODUCTION

The spiropyrrolidone skeleton as a privileged structure has been widely found in natural products and medicinal compounds (Figure 1).1 For instance, this exists in the potent histone deacetylase (HDAC) inhibitor, which has the activity of inhibiting the proliferation of glioma U87MG, U251, SHG44, and C6 cells, therefore becoming one of the classical anticancer agents. Recently, a structure−function relationship study indicated that a modification on the spirochromane core moiety had a crucial effect on the HDAC and antiproliferative activity. Therefore, development of an efficient method for constructing chiral spiropyrrolidones is in great demand. However, the traditional method to synthesize chiral spiropyrrolidones is to construct the racemic isomers following the chiral separation. The other is to extract the compound from the corresponding natural products by some biochemical techniques, which is normally limited by the raw material sources. Therefore, it is still a challenge to construct chiral spiropyrrolidones with a simple and efficient method. As far as we know, the hetero-Diels−Alder (HDA) reaction plays an important role in constructing optically active six-membered oxygen-containing carbocycles or heterocycles.2,3,5−7 Various catalytic systems in the HDA reaction, including Lewis acid catalysts, Brønsted acid catalysts, and organocatalysts, have been extensively employed to build a variety of chiral pyrrolidone derivatives.4 For instance, a cinchona alkaloidderived amine and chiral phosphines were shown to be efficient for the HDA reaction of 2,3-dioxopyrrolidines with allenoates.4a,b In addition, aminocatalyst systems4c,g and carbine organocatalysts4d were also applied to [4+2] cycloaddition reactions. Furthermore, the N,N′-dioxide/metal complex4e,f was successfully applied to construct the chiral spiral rings in good yields with excellent enantioselectivities (Scheme 1). © 2018 American Chemical Society

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RESULTS AND DISCUSSION We began our study by choosing 1-benzyl-4-benzylidenepyrrolidine-2,3-dione and Danishefsky’s diene as model substrates and using L1-Cu(OTf)2-Cs2CO3 as a catalyst (Table 1). The reaction was carried out in different solvents, including CHCl3, CH3CN, and EtOAc. To our delight, the best result can be obtained in THF among these solvents (entries 1−5). This implied that ethers should favor this reaction since THF is a kind of ether. Therefore, we further investigated other different ethers (entries 6−8). In terms of Table 1, diethyl ether presented the best result, which should be the optimal solvent for this reaction. Then, further exploration of different bases for this reaction was conducted (entry 10−17). The experimental result showed that Cs2CO3 was the optimal base in terms of the yield and the enantioselectivity. In view of the effect of the temperature on the enantioselectivity of the reaction, the reaction temperature was screened subsequently. When we lowered the temperature to 0 °C (entry 18), the enantioselectivity was slightly increased to 98%, and the yield Received: April 28, 2018 Published: July 5, 2018 8464

DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472

Article

The Journal of Organic Chemistry

Figure 1. Chiral spiropyrrolidone scaffold in bioactive compounds.

(entries 3b−3h). Moreover, the substrate bearing multisubstituents could also be carried out smoothly to afford the desired product with excellent yield and enantioselectivity (3i). However, the substitution position had an influence on the yields, while the ee value could be maintained. For instance, fluoro-substituted groups at the para position of the phenyl ring of R1 decreased the yield while the meta and ortho substitution gave the higher yields. In these cases, however, the reaction ee values can be almost the same (3e, 3f, 3j−3m). As for the bromo and methyl substitution, the hindrance effect had little influence on the reaction (3o, 3p). On the other hand, we found that the substrate bearing 1-naphthyl group could give the desired product with excellent yield and enantioselectivity (3n). To further investigate the scope of the substrates, different R2 substituents were tested and the corresponding products could be obtained in good yields with excellent enantioselectivitis (3q, 3r). Moreover, the absolute configuration of product 3c was confirmed by X-ray crystallographic analysis.10 To further evaluate the robust nature and practicability of this new method, a preparative scale synthesis of product 3a was carried out. As shown in Scheme 2, the product 3a was obtained in 83% yield with 98% ee. In order to gain more insight into what pathway the reaction was going through, some control experiments were conducted. Normally, the reaction involved the traditional Diels−Alder cycloaddition or a Mukaiyama-aldol reaction, a Lewis acid complex was chosen to catalyze the oxo-Diels−Alder reaction.11−13 Here, the substrates 1h, 2a, and 2b were employed to study the reaction process. For the HDA reaction of Danishefsky’s diene 2a with 1h, as shown in Scheme 3, the intermediates 4 and 5 were detected by HRMS (see SI page S4) before the treatment of TFA. Moreover, intermediate 5 can be isolated by silica gel chromatography and identified by 1 H NMR, 13C NMR, IR, and HRMS (see SI pages S57 and S4). As expected, the ee vaule of the final product was consistent with the Mukaiyama-aldol pathway. In contrast, when 2a was replaced by 2b as the diene, the cycloaddition intermediate 6 was obtained with 97% ee, which was also confirmed by 1H NMR, 13C NMR, IR, and HRMS (see SI pages S58 and S5). This indicated that the HDA reaction of Danishefsky’s diene 2b with 1h proceeded a cycloaddition

Scheme 1. Previous Work and This Work on a HeteroDiels−Alder Reaction of Danishefsky’s Diene with 2,3Dioxopyrrolidines

was kept at 85%. However, when the temperature was below 0 °C, the reaction yield decreased significantly in spite of a slight increase in enantioselectivity (entry 19). As a result, the optimized reaction conditions were identified as follows: L1Cu(OTf)2 complex as the catalyst, Et2O as the reaction solvent, Cs2CO3 as the base, and the HDA reaction being carried out at 0 °C. With the optimal reaction conditions in hand, we next examined the substrate scope of 2,3-dioxopyrrolidines for the reaction. All of the investigated reactions could be completed within 24 h to afford the desired products in good yields with excellent enantioselectivities, most above 95% ee, as shown in Table 2. First of all, the effect of the substitution was investigated. 2,3-Dioxopyrrolidines with a meta-substituent at the phenyl rings of R1 were tested to investigate the electronic effect. Remarkably, it was found that the electronic effect had little influence on the enantioselectivity and a little influence on the yield. Both electron-donating and electron-withdrawing groups can survive the reaction to give the desired products in moderate to good yields with excellent enantioselectivities 8465

DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472

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The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa−c

entry

solvent

base

T (°C)

yield (%)b

ee (%)c

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

toluene CHCl3 CH3CN EtOAc THF 1,4-dioxane CPME MTBE Et2O Et2O Et2O Et2O Et2O Et2O Et2O Et2O Et2O Et2O Et2O

Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 K2CO3 t-BuOK DIPEA piperidine Et3N N-ethyl morpholine DBU DABCO Cs2CO3 Cs2CO3

rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt 0 −10

85 83 80 84 87 85 88 85 87 80 83 87 86 86 85 84 90 85 75

85 89 59 94 95 95 96 96 97 91 93 93 93 92 92 94 95 98 99

a Unless otherwise noted, all reactions were performed with 1a (0.1 mmol), 2a (0.2 mmol), L1 (2 mol %), Cs2CO3 (2 mol %), and Cu(OTf)2 (2 mol %). bIsolated yield. cDetermined by chiral HPLC analysis. MTBE = Methyl tert-butyl ether. CPME = Cyclopentyl methyl ether. DIPEA = 1,8Diisopropylethylamine. DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene. DABCO = 1,4-Diazabicyclooctane.

various pyrrolidones, and Danishefsky’s diene were prepared according to literature procedures. General Procedures of a Hetero-Diels−Alder Reaction. A mixture of ligand (L, 2 mol %, 2.2 mg), Cu(OTf)2 (2 mol %, 1.8 mg), and Cs2CO3 (2 mol %, 1.7 mg) in corresponding solvent (1.5 mL) was stirred for 2 h at ambient atmosphere, and the resulting mixture was cooled to 0 °C. After 30 min, the corresponding pyrrolidone (0.25 mmol) and Danishefsky’s diene (0.5 mmol) were then added. After the reaction was finished (monitored by TLC), 5.0 equiv of TFA was added to quench the reaction. The system was quenched by saturated sodium bicarbonate after 2 h and then extracted by ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and evaporated in vacuo. Purification of the residue by column chromatography (PE/EA = 10/1−3/1) afforded the desired HDA adducts. Experimental Data of Substrates. (E)-1-Benzyl-4-benzylidenepyrrolidine-2,3-dione (1a). Yellow solid. mp 214−216 °C. 1H NMR (400 MHz, CDCl3, δ): 7.69 (s, 1H), 7.45−7.34 (m, 10H), 4.81 (s, 2H), 4.42 (s, 2H). 13C NMR (100 MHz, CDCl3, δ): 186.4, 160.5, 138.2, 134.6, 133.3, 131.5, 131.2, 129.4, 129.1, 128.5, 128.4, 124.7, 48.1, 46.4. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H16NO2, 278.1181; found, 278.1176. (E)-1-Benzyl-4-(3-methylbenzylidene)pyrrolidine-2,3-dione (1b). Yellow solid. mp 173−174 °C. 1H NMR (400 MHz, CDCl3, δ): 7.67 (s, 1H), 7.40−731 (m, 6H), 7.28−7.26 (m, 1H), 7.22−7.20 (m, 2H), 4.81 (s, 2H), 4.41 (s, 2H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 186.4, 160.2, 139.2, 138.5, 134.7, 133.3, 132.4, 132.3, 129.2, 129.1, 128.42, 128.35, 128.0, 124.5, 48.0, 46.4, 21.4. HRMS (ESI-TOF) (m/ z): [M + Na]+ calcd for C19H17NO2Na, 314.1157; found, 314.1149. (E)-1-Benzyl-4-(3-methoxybenzylidene)pyrrolidine-2,3-dione (1c). Yellow solid. mp 169−170 °C. 1H NMR (400 MHz, CDCl3, δ): 7.65 (s, 1H), 7.39−7.34 (m, 6H), 7.01−6.99 (m, 2H), 6.93 (s, 1H), 4.81 (s, 2H), 4.40 (s, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 186.4, 160.5, 160.0, 138.1, 134.59, 134.57, 130.3, 129.1, 128.5,

process. Thus, on the basis of the results above, the pathways of this HDA reaction were greatly dependent on the diene substrate.

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CONCLUSIONS In conclusion, a copper-complex-catalyzed asymmetric HDA reaction of Danishefsky’s diene with 2,3-dioxopyrrolidines was developed under mild conditions to give the spiropyrrolidones in good yields with excellent enantioselectivities. This efficient method provides a facial access to construct a tetra-substituted carbon stereocenter of spiropyrrolidone derivatives. The study of the reaction mechanism indicated that the two reaction pathways were involved, which were depending equally on the diene substrate. Furthermore, the gram scale synthesis can be carried out to afford the desired product in 83% yield with 98% ee by using 2 mol % of the L1−Cu complex. Further studies to expand the scope of this process and to develop more challenging asymmetric reactions are ongoing in our laboratory.

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EXPERIMENTAL SECTION

General Information. 1H NMR and 13C NMR were recorded on a 400 MHz nuclear magnetic resonance spectrometer (1H NMR, 400 MHz; 13C NMR, 100 MHz) using TMS as an internal reference. The chemical shifts (δ) and coupling constants (J) are expressed in ppm and Hz, respectively. UV−vis spectrophotometry was carried out on an infrared spectrometer. HPLC analysis was carried out on an HPLC with a multiple wavelength detector by commercial chiral columns. Optical rotations were measured on a polarimeter. HRMS (ESI) were recorded on a Q-TOF Premier. Commercially available compounds were used without further purification. Solvents were purified according to the standard procedures, unless otherwise noted. Ligand, 8466

DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472

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The Journal of Organic Chemistry Table 2. Scope of 2,3-Dioxopyrrolidinesa−d

Scheme 3. Mechanism Pathway of the Hetero-Diels−Alder Reaction

entry

R1

R2

t (h)

3

yieldb (%)

eec (%)

1 2 3 4d 5 6 7d 8 9 10d 11 12 13 14 15 16 17 18d

C6H5 m-MeC6H4 m-OMeC6H4 m-NO2C6H4 m-CF3C6H4 m-FC6H4 m-ClC6H4 m-BrC6H4 3,5-FC6H4 p-CF3C6H4 o-CF3C6H4 p-FC6H4 o-FC6H4 1-naphthyl o-MeC6H4 o-BrC6H4 C6H5 C6H5

Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn Bn propyl phenyl

18 18 18 16 18 18 24 18 18 17 18 18 18 18 18 18 18 18

3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p 3q 3r

85 86 78 99 85 86 94 90 92 65 97 76 94 90 86 93 70 86

98 98 98 97 99 99 97 97 98 96 97 97 98 97 96 99 95 95

a Unless otherwise noted, the reaction of 1 (0.25 mmol) and 2a (0.5 mmol) was performed in the presence of L1 (2 mol %), Cs2CO3 (2 mol %), and Cu(OTf)2 (2 mol %) in Et2O (1.5 mL) at 0 °C. b Isolated yield. cDetermined by chiral HPLC analysis. dWith 10 mol % catalyst.

(E)-1-Benzyl-4-(3-fluorobenzylidene)pyrrolidine-2,3-dione (1f). Yellow solid. mp 195−196 °C. 1H NMR (400 MHz, CDCl3, δ): 7.64 (s, 1H), 7.46−7.34 (m, 6H), 7.23−7.21 (m, 1H), 7.18−7.14 (m, 1H), 7.10−7.07 (m, 1H), 4.81 (s, 2H), 4.41 (s, 2H). 19F (376 MHz, CDCl3, δ): −110.96. 13C NMR (100 MHz, CDCl3, δ): 186.4, 162.8 (d, 1JCF = 247.0 Hz, 1C), 160.2, 136.6 (d, 4JCF = 2.6 Hz, 1C), 135.3 (d, 3JCF = 7.5 Hz, 1C), 134.4, 131.0 (d, 3JCF = 8.2 Hz, 1C), 129.1, 128.49, 128.45, 127.2 (d, 4JCF = 2.9 Hz, 1C), 125.6, 118.4 (d, 2JCF = 21.3 Hz, 1C), 117.2 (d, 2JCF = 21.9 Hz, 1C), 48.1, 46.2. HRMS (ESITOF) (m/z): [M + H]+ calcd for C18H15FNO2, 296.1087; found, 296.1083. (E)-1-Benzyl-4-(3-chlorobenzylidene)pyrrolidine-2,3-dione (1g). Yellow solid. mp 198−201 °C. 1H NMR (400 MHz, CDCl3, δ): 7.61 (s, 1H), 7.44−7.27 (m, 9H), 4.82 (s, 2H), 4.42 (s, 2H). 13C NMR (100 MHz, CDCl3, δ): 186.3, 160.2, 136.4, 135.3, 135.0, 134.5, 131.3, 130.65, 130.56, 129.1, 128.5, 125.7, 48.1, 46.2. HRMS (ESITOF) (m/z): [M + H]+ calcd for C18H15ClNO2, 312.0791; found, 312.0791. (E)-1-Benzyl-4-(3-bromobenzylidene)pyrrolidine-2,3-dione (1h). Yellow solid. mp 203−205 °C. 1H NMR (400 MHz, CDCl3, δ): 7.56−7.52 (m, 3H), 7.40−7.29 (m, 7H), 4.80 (s, 2H), 4.41 (s, 2H). 13 C NMR (100 MHz, CDCl3, δ): 186.3, 160.1, 136.2, 135.2, 134.4, 134.1, 133.6, 130.7, 129.4, 129.1, 128.41, 128.38, 125.7, 123.3, 48.0, 46.1. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H15BrNO2, 356.0286; found, 356.0291. (E)-1-Benzyl-4-(3,5-difluorobenzylidene)pyrrolidine-2,3-dione (1i). Yellow solid. mp 185−187 °C. 1H NMR (400 MHz, CDCl3, δ): 7.56 (s, 1H), 7.42−7.34 (m, 5H), 6.94−6.90 (m, 3H), 4.81 (s, 2H), 4.39 (s, 2H). 19F (376 MHz, CDCl3, δ): −107.38. 13C NMR (100 MHz, CDCl3, δ): 186.3, 163.2 (dd, 1JCF = 249.5 Hz, 3JCF = 12.4 Hz, 2C), 159.9, 136.1 (t, 3JCF = 9.5 Hz, 2C), 135.2 (t, 4JCF = 2.7 Hz, 1C), 134.3, 129.2, 128.55, 128.53, 126.6, 113.6 (dd, 2JCF = 18.9 Hz, 4JCF = 7.3 Hz, 2C), 106.7 (t, 2JCF = 25.1 Hz, 1C), 48.2, 46.0. HRMS (ESITOF) (m/z): [M + H]+ calcd for C18H14F2NO2, 314.0993; found, 314.0994. (E)-1-Benzyl-4-(4-(trifluoromethyl)benzylidene)pyrrolidine-2,3dione (1j). Yellow solid. mp 205−208 °C. 1H NMR (400 MHz, CDCl3, δ): 7.71−7.69 (m, 3H), 7.54−7.52 (m, 2H), 7.41−7.34 (m, 5H), 4.82 (s, 2H), 4.43 (s, 2H). 19F (376 MHz, CDCl3, δ): −63.12. 13 C NMR (100 MHz, CDCl3, δ): 186.4, 160.0, 136.6, 135.9, 134.3,

Scheme 2. Asymmetric Hetero-Diels−Alder Reaction on a Gram Scalea−c

a

The reaction of 1a (5 mmol) and 2a (10 mmol) was performed in the presence of L1 (2 mol %), Cs2CO3 (2 mol %), and Cu(OTf)2 (2 mol %) in Et2O (10 mL) at 0 °C. bIsolated yield. cDetermined by chiral HPLC analysis.

128.4, 124.9, 123.4, 116.9, 116.8, 55.4, 48.1, 46.3. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C19H18NO3, 308.1287; found, 308.1288. (E)-1-Benzyl-4-(3-nitrobenzylidene)pyrrolidine-2,3-dione (1d). Yellow solid. mp 185−187 °C. 1H NMR (400 MHz, CDCl3, δ): 8.31−8.29 (m, 1H), 8.25 (s, 1H), 7.78−7.76 (m, 1H), 7.70−7.66 (m, 2H), 7.42−7.35 (m, 5H), 4.84 (s, 2H), 4.51 (s, 2H). 13C NMR (100 MHz, CDCl3, δ): 186.3, 159.8, 148.6, 136.5, 134.8, 134.2, 130.5, 129.1, 128.50, 128.48, 127.0, 125.4, 124.8, 48.1, 46.1. HRMS (ESITOF) (m/z): [M + H]+ calcd for C18H15N2O4, 323.1032; found, 323.1030. (E)-1-Benzyl-4-(3-(trifluoromethyl)benzylidene)pyrrolidine-2,3dione (1e). Yellow solid. mp 186−188 °C. 1H NMR (400 MHz, CDCl3, δ): 7.71−7.59 (m, 5H), 7.41−7.34 (m, 5H), 4.82 (s, 2H), 4.43 (s, 2H). 19F (376 MHz, CDCl3, δ): −63.03. 13C NMR (100 MHz, CDCl3, δ): 186.3, 160.0, 136.1, 134.4, 134.0, 133.7, 131.9 (q, 2 JCF = 32.6 Hz, 1C), 130.0, 129.2, 128.5, 127.7 (q, 3JCF = 3.5 Hz, 1C), 127.5 (q, 3JCF = 3.8 Hz, 1C), 126.1, 123.4 (q, 1JCF = 270.9 Hz, 1C), 48.1, 46.1. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C19H15F3NO2, 346.1055; found, 346.1054. 8467

DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472

Article

The Journal of Organic Chemistry 132.6 (q, 2JCF = 32.8 Hz, 1C), 131.1, 129.2, 128.5, 126.6, 126.2 (q, 3 JCF = 3.8 Hz, 2C), 123.4 (q, 1JCF = 271.1 Hz, 1C), 48.1, 46.2. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C19H15F3NO2, 346.1055; found, 346.1056. (E)-1-Benzyl-4-(2-(trifluoromethyl)benzylidene)pyrrolidine-2,3dione (1k). Yellow solid. mp 180−183 °C. 1H NMR (400 MHz, CDCl3, δ): 7.99 (m, 1H), 7.77−7.75 (m, 1H), 7.62−7.52 (m, 2H), 7.40−7.30 (m, 6H), 4.77 (s, 2H), 4.29 (m, 2H). 19F (376 MHz, CDCl3, δ): −59.14. 13C NMR (100 MHz, CDCl3, δ): 186.0, 160.1, 134.4, 133.7 (q, 3JCF = 1.8 Hz, 1C), 132.1, 131.6, 130.34, 130.3 (q, 2 JCF = 30.5 Hz, 1C), 129.4, 129.1, 128.5, 128.4, 127.8, 126.8 (q, 3JCF = 5.5 Hz, 1C), 123.5 (q, 1JCF = 272.4 Hz, 1C), 48.1, 45.6. HRMS (ESITOF) (m/z): [M + H]+ calcd for C19H15F3NO2, 346.1055; found, 346.1053. (E)-1-Benzyl-4-(4-fluorobenzylidene)pyrrolidine-2,3-dione (1l). Yellow solid. mp 200−201 °C. 1H NMR (400 MHz, CDCl3, δ): 7.66 (s, 1H), 7.45−7.34 (m, 7H), 7.16−7.12 (m, 2H), 4.81 (s, 2H), 4.39 (s, 2H). 19F (376 MHz, CDCl3, δ): −105.86. 13C NMR (100 MHz, CDCl3, δ): 186.3, 164.3 (d, 1JCF = 254.3 Hz, 1C), 160.5, 136.9, 134.5, 133.4 (d, 3JCF = 8.8 Hz, 2C), 129.7 (d, 4JCF = 3.2 Hz, 1C), 129.1, 128.5, 128.4, 124.2 (d, 5JCF = 2.5 Hz, 1C), 116.8 (d, 2JCF = 21.9 Hz, 2C), 48.1, 46.2. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H15FNO2 [M + H]+, 296.1087; found, 296.1086. (E)-1-Benzyl-4-(2-fluorobenzylidene)pyrrolidine-2,3-dione (1m). Yellow solid. mp 200−202 °C. 1H NMR (400 MHz, CDCl3, δ): 7.90 (s, 1H), 7.47−7.42 (m, 1H), 7.40−7.29 (m, 6H), 7.22−7.18 (m, 1H), 7.17−7.12 (m, 1H), 4.79 (s, 2H), 4.37 (s, 2H). 19F (376 MHz, CDCl3, δ): −111.02. 13C NMR (100 MHz, CDCl3, δ): 186.3, 161.9 (d, 1JCF = 254.7 Hz, 1C), 160.3, 134.5, 133.4 (d, 3JCF = 8.8 Hz, 1C), 130.5 (d, 4JCF = 1.5 Hz, 1C), 130.3 (d, 3JCF = 5.3 Hz, 1C), 129.1, 128.5, 128.4, 126.1 (d, 4JCF = 1.3 Hz, 1C), 124.8 (d, 3JCF = 3.7 Hz, 1C), 121.4 (d, 2JCF = 12.2 Hz, 1C), 116.5 (d, 2JCF = 21.9 Hz, 1C), 48.0, 46.3 (d, JCF = 5.8 Hz, 1C). HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H15FNO2, 296.1087; found, 296.1086. (E)-1-Benzyl-4-(naphthalen-1-ylmethylene)pyrrolidine-2,3-dione (1n). Yellow solid. mp 189−191 °C. 1H NMR (400 MHz, CDCl3, δ): 8.52 (s, 1H), 8.15−8.13 (m, 1H), 7.95−7.88 (m, 2H), 7.63−7.55 (m, 2H), 7.51−7.45 (m, 2H), 7.38−7.31 (m, 5H), 4.79 (s, 2H), 4.38 (s, 2H). 13C NMR (100 MHz, CDCl3, δ): 186.2, 160.7, 135.0, 134.7, 133.7, 132.3, 132.0, 129.9, 129.1, 129.0, 128.5, 128.4, 127.6, 127.4, 126.8, 126.7, 125.1, 123.4, 48.1, 46.3. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C22H18NO2, 328.1338; found, 328.1334. (E)-1-Benzyl-4-(2-methylbenzylidene)pyrrolidine-2,3-dione (1o). Yellow solid. mp 162−164 °C. 1H NMR (400 MHz, CDCl3, δ): 7.98 (s, 1H), 7.40−7.31 (m, 6H), 7.27 (s, 1H), 7.23−7.22 (m, 2H), 4.79 (s, 2H), 4.36 (s, 2H), 2.46 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 186.4, 160.7, 140.6, 135.8, 134.6, 132.0, 131.4, 131.3, 129.1, 128.50, 128.46, 128.37, 126.5, 125.2, 48.1, 46.3, 20.0. HRMS (ESI-TOF) (m/ z): [M + H]+ calcd for C19H18NO2, 292.1338; found, 292.1332. (E)-1-Benzyl-4-(2-bromobenzylidene)pyrrolidine-2,3-dione (1p). Yellow solid. mp 190−192 °C. 1H NMR (400 MHz, CDCl3, δ): 8.01−8.00 (m, 1H), 7,67−7.65 (m, 1H), 7.39−7.25 (m, 8H), 4.78 (s, 2H), 4.33 (m, 2H). 13C NMR (100 MHz, CDCl3, δ): 186.2, 160.2, 136.6, 134.4, 134.0, 133.0, 132.1, 129.6, 129.1, 128.5, 128.4, 127.8, 127.3, 126.5, 48.0, 45.8. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C18H15BrNO2, 356.0286; found, 356.0284. (E)-4-Benzylidene-1-propylpyrrolidine-2,3-dione (1q). Yellow solid. mp 158−159 °C. 1H NMR (400 MHz, CDCl3, δ): 7.71−7.70 (m, 1H), 7.51 (m, 5H), 4.56 (d, 2H), 3.61 (t, 2H), 1.76 (m, 2H), 1.00 (t, 3H). 13C NMR (100 MHz, CDCl3, δ): 186.7, 160.7, 137.8, 133.5, 131.5, 131.2, 129.4, 124.8, 47.0, 45.8, 20.4, 11.2. HRMS (ESITOF) (m/z): [M + H]+ calcd for C14H16NO2, 230.1181; found, 230.1182. (E)-4-Benzylidene-1-phenylpyrrolidine-2,3-dione (1r). Yellow solid. mp 176−178 °C. 1H NMR (400 MHz, CDCl3, δ): 7.94−7.92 (m, 2H), 7.80 (s, 1H), 7.58−7.47 (m, 7H), 7.33−7.27 (m, 1H), 4.98 (s, 2H). 13C NMR (100 MHz, CDCl3, δ): 185.8, 159.3, 138.6, 138.1, 133.4, 131.8, 131.4, 129.5, 129.4, 126.8, 124.1, 119.5, 47.8. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C17H14NO2, 264.1025; found, 264.1024.

Experimental DatA of HDA Adducts. (S,E)-2-Benzyl-4benzylidene-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3a). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow solid. 73.4 mg, 85% yield. mp 45−47 °C. [α]D20 +265.1 (c = 1.30, CHCl3, 98% ee). HPLC: Daicel Chiralpak AD-H, hexane:2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23 °C, UV = 240 nm, tR = 13.74 min (major), tR = 15.25 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.38−7.26 (m, 9H), 7.17−7.15 (m, 2H), 6.84 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.67 (d, J = 14.8, 1H), 4.51 (d, J = 14.8 Hz, 1H), 4.28 (d, J = 14.2 Hz, 1H), 4.04 (d, J = 14.2 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.79 (d, J = 16.9 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 189.7, 168.7, 160.5, 134.9, 134.4, 131.6, 129.2, 129.0, 128.75, 128.73, 128.6, 128.1, 128.0, 106.4, 83.7, 48.4, 46.8, 41.3. IR (film, ν/cm−1): 2922, 2852, 1702, 1676, 1596, 1399, 1268, 1224, 1028, 749, 696. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H19NO3Na, 368.1263; found, 368.1257. (S,E)-2-Benzyl-4-(3-methylbenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3b). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 77.3 mg, 86% yield. [α]D20 +75.6 (c = 1.09, CHCl3, 98% ee). HPLC: Daicel Chiralpak IC, hexane:2-propanol = 40:60, flow rate = 0.6 mL/min, T = 23 °C, UV = 215 nm, tR = 56.19 min (major), tR = 74.76 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.38−7.22 (m, 7H), 7.12−7.10 (m, 1H), 6.99−6.94 (m, 2H), 6.81 (s, 1H), 5.54 (d, J = 6.2 Hz, 1H), 4.67 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.29 (d, J = 14.1 Hz, 1H), 4.04 (d, J = 14.1 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.78 (d, J = 16.9 Hz, 1H), 2.33 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 189.8, 168.7, 160.5, 138.4, 134.9, 134.3, 131.3, 129.7, 129.42, 129.39, 128.9, 128.6, 128.0, 127.9, 125.5, 106.3, 83.7, 48.4, 46.8, 41.2, 21.3. IR (film, ν/cm−1): 2923, 2854, 1692, 1597, 1440, 1400, 1270, 1223, 1029, 750, 698. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C23H21NO3Na, 382.1419; found, 382.1428. (S,E)-2-Benzyl-4-(3-methoxybenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3c). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow solid. 73.2 mg, 78% yield. mp 113−116 °C. [α]D20 +249.0 (c = 0.51, CHCl3, 98% ee). HPLC: Daicel Chiralpak AD-H, hexane:2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23 °C, UV = 254 nm, tR = 16.56 min (major), tR = 19.77 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.38−7.24 (m, 7H), 6.86−6.83 (m, 1H), 6.80 (s, 1H), 6.75−6.73 (m, 1H), 6.68 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.51 (d, J = 14.8 Hz, 1H), 4.28 (dd, J1 = 14.1 Hz, J2 = 2.3 Hz, 1H), 4.04 (dd, J1 = 14.1 Hz, J2 = 2.0 Hz, 1H), 3.78 (s, 3H), 3.29 (d, J = 16.9 Hz, 1H), 2.78 (d, J = 16.9 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 189.7, 168.6, 160.5, 159.6, 135.6, 134.9, 132.0, 129.7, 129.2, 129.0, 128.0, 127.96, 121.0, 114.5, 114.0, 106.4, 83.7, 55.3, 48.4, 46.8, 41.2. IR (film, ν/cm−1): 2921, 2851, 1698, 1671, 1597, 1576, 1270, 1232, 1037, 786, 693. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C23H21NO4Na, 398.1368; found, 398.1367. (S,E)-2-Benzyl-4-(3-nitrobenzylidene)-6-oxa-2-azaspiro[4.5]dec7-ene-1,9-dione (3d). The title compound was prepared according to the general working procedure (16 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow solid. 96.6 mg, 99% yield. mp 51−53 °C. [α]D20 +186.7 (c = 1.44, CHCl3, 97% ee). HPLC: Daicel Chiralpak IC, hexane:2propanol = 0:100, flow rate = 0.25 mL/min, T = 23 °C, UV = 254 nm, tR = 269.60 min (minor), tR = 297.44 min (major). 1H NMR (400 MHz, CDCl3, δ): 8.17−8.15 (m, 1H), 8.02 (s, 1H), 7.58−754 (m, 1H), 7.51−7.49 (m, 1H), 7.39−7.26 (m, 6H), 6.91−6.90 (m, 1H), 5.58 (d, J = 6.4 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.55 (d, J = 14.8 Hz, 1H), 4.29 (dd, J1 = 14.3 Hz, J2 = 2.3 Hz, 1H), 4.08 (dd, J1 = 14.3 Hz, J2 = 2.1 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.79 (d, J = 16.9 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 189.2, 168.3, 160.4, 148.4, 135.9, 135.1, 134.6, 134.4, 129.8, 129.0, 128.2, 128.0, 126.7, 123.2, 123.1, 106.5, 83.3, 47.9, 46.9, 41.3. IR (film, ν/cm−1): 2922, 2852, 8468

DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472

Article

The Journal of Organic Chemistry

1H), 2.76 (d, J = 16.9 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 189.4, 168.5, 160.4, 136.3, 134.8, 133.3, 131.6, 131.5, 130.2, 129.0, 128.1, 127.9, 127.7, 127.1, 122.8, 106.4, 83.5, 48.1, 46.8, 41.2. IR (film, ν/cm−1): 2922, 2852, 1703, 1672, 1595, 1399, 1266, 1223, 1029, 995, 781, 737, 699, 683. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H18BrNO3Na, 446.0368; found, 446.0368. (S,E)-2-Benzyl-4-(3,5-difluorobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3i). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 87.7 mg, 92% yield. [α]D20 +148.9 (c = 1.36, CHCl3, 98% ee). HPLC: Daicel Chiralpak IC, hexane:2-propanol = 60:40, flow rate = 0.8 mL/min, T = 23 °C, UV = 240 nm, tR = 68.37 min (minor), tR = 93.28 min (major). 1H NMR (400 MHz, CDCl3, δ): 7.40−7.31 (m, 4H), 7.28−7.26 (m, 2H), 6.79−6.73 (m, 2H), 6.71− 6.66 (m, 2H), 5.56 (d, J = 6.2 Hz, 1H), 4.65 (d, J = 14.8 Hz, 1H), 4.54 (d, J = 14.8 Hz, 1H), 4.23 (dd, J1 = 14.3 Hz, J2 = 2.4 Hz, 1H), 4.03 (dd, J1 = 14.3 Hz, J2 = 2.2 Hz, 1H), 3.25 (d, J = 16.9 Hz, 1H), 2.76 (dd, J1 = 16.9 Hz, J2 = 0.3 Hz, 1H). 19F (376 MHz, CDCl3, δ): −108.59. 13C NMR (100 MHz, CDCl3, δ): 189.2, 168.3, 162.9 (dd, 1 JCF = 248.1 Hz, 3JCF = 13.0 Hz, 2C), 160.4, 137.2 (t, 3JCF = 9.5 Hz, 1C), 134.7, 134.6, 129.0, 128.2, 128.0, 126.9 (t, 4JCF = 2.3 Hz, 1C), 111.5 (dd, 2JCF = 18.7 Hz, 4JCF = 7.2 Hz, 2C), 106.5, 104.0 (t, 2JCF = 25.2 Hz, 1C), 83.3, 48.0, 46.8, 41.3. IR (film, ν/cm−1): 2293, 2853, 1705, 1677, 1619, 1589, 1433, 1399, 1269, 1225, 1118, 989, 847, 699. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H17F2NO3Na, 404.1074; found, 404.1070. (S,E)-2-Benzyl-4-(4-(trifluoromethyl)benzylidene)-6-oxa-2azaspiro[4.5]dec-7-ene-1,9-dione (3j). The title compound was prepared according to the general working procedure (17 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 67.2 mg, 65% yield. [α]D20 +196.6 (c = 1.22, CHCl3, 96% ee). HPLC: Daicel Chiralpak AD-H, hexane:2propanol = 80:20, flow rate = 1.0 mL/min, T = 23 °C, UV = 230 nm, tR = 14.76 min (major), tR = 16.52 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.62−7.60 (m, 2H), 7.39−7.26 (m, 8H), 6.87 (s, 1H), 5.56 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.25 (d, J = 14.2 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.78 (d, J = 16.9 Hz, 1H). 19F (376 MHz, CDCl3, δ): −62.76. 13C NMR (100 MHz, CDCl3, δ): 189.3, 168.4, 160.4, 137.8, 134.7, 134.4, 130.4(q, 2JCF = 32.6 Hz, 1C), 129.1, 128.9, 128.2, 128.0, 127.7, 125.7 (q, 3JCF = 3.7 Hz, 2C), 123.7 (q, 1JCF = 270.7 Hz, 1C), 106.5, 83.5, 48.1, 46.9, 41.3. IR (film, ν/cm−1): 2923, 2853, 1705, 1673, 1597, 1322, 1269, 1164, 1113, 1067, 699. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C23H18F3NO3Na, 436.1136; found, 436.1130. (S,E)-2-Benzyl-4-(2-(trifluoromethyl)benzylidene)-6-oxa-2azaspiro[4.5]dec-7-ene-1,9-dione (3k). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 100.2 mg, 97% yield. [α]D20 +102.6 (c = 1.43, CHCl3, 97% ee). HPLC: Daicel Chiralpak AD-H, hexane:2propanol = 80:20, flow rate = 1.0 mL/min, T = 23 °C, UV = 240 nm, tR = 9.34 min (minor), tR = 11.74 min (major). 1H NMR (400 MHz, CDCl3, δ): 7.69−7.67 (m, 1H), 7.52−7.49 (m, 1H), 7.44−7.29 (m, 5H), 7.22−7.16 (m, 4H), 5.56 (d, J = 6.2 Hz, 1H), 4.61 (d, J = 14.8 Hz, 1H), 4.49 (d, J = 14.8 Hz, 1H), 4.02 (dd, J1 = 14.2 Hz, J2 = 2.4 Hz, 1H), 3.80 (dd, J1 = 14.2 Hz, J2 = 2.2 Hz, 1H), 3.26 (d, J = 16.8 Hz, 1H), 2.80 (d, J = 16.8 Hz, 1H). 19F (376 MHz, CDCl3, δ): −60.41. 13C NMR (100 MHz, CDCl3, δ): 189.1, 168.7, 160.5, 134.9, 134.7, 132.8, 131.9, 129.3, 129.0, 128.95−128.06 (q, 2JCF = 30.0 Hz, 1C), 128.4, 128.1, 127.9, 126.3 (q, 3JCF = 5.3 Hz, 1C), 125.8, 123.7 (q, 1JCF = 272.3 Hz, 1C), 106.6, 82.9, 47.3, 46.8, 41.1. IR (film, ν/ cm−1): 2922, 2853, 1706, 1678, 1598, 1314, 1269, 1160, 1108, 1034, 769, 700. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C23H18F3NO3Na, 436.1136; found, 436.1136. (S,E)-2-Benzyl-4-(4-fluorobenzylidene)-6-oxa-2-azaspiro[4.5]dec7-ene-1,9-dione (3l). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint

1703, 1645, 1597, 1526, 1349, 1268, 1223, 727, 670, 676. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H18N2O5Na, 413.1113; found, 413.1112. (S,E)-2-Benzyl-4-(3-(trifluoromethyl)benzylidene)-6-oxa-2azaspiro[4.5]dec-7-ene-1,9-dione (3e). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 87.8 mg, 85% yield. [α]D20 +168.4 (c = 1.23, CHCl3, 99% ee). HPLC: Daicel Chiralpak OD-H, hexane:2propanol = 70:30, flow rate = 1.0 mL/min, T = 23 °C, UV = 230 nm, tR = 16.16 min (major), tR = 20.99 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.57−7.55 (m, 1H), 7.51−7.47 (m, 1H), 7.42−7.26 (m, 8H), 6.88 (s, 1H), 5.56 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.26 (d, J = 14.2 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.28 (d, J = 16.9 Hz, 1H), 2.78 (d, J = 16.9 Hz, 1H). 19F (376 MHz, CDCl3, δ): −62.85. 13C NMR (100 MHz, CDCl3, δ): 189.4, 168.4, 160.4, 135.0, 134.7, 133.8, 131.6, 131.2 (q, 2JCF = 32.3 Hz, 1C), 129.3, 129.0, 128.1, 128.0, 127.7, 125.5 (q, 3JCF = 3.9 Hz, 1C), 125.2 (q, 3JCF = 3.6 Hz, 1C), 123.6 (q, 1JCF = 270.9 Hz, 1C), 106.5, 83.4, 48.0, 46.8, 41.3. IR (film, ν/cm−1): 2923, 2854, 1706, 1677, 1598, 1329, 1269, 1165, 1121, 1073, 995, 910, 751, 697. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C23H18F3NO3Na, 436.1136; found, 436.1135. (S,E)-2-Benzyl-4-(3-fluorobenzylidene)-6-oxa-2-azaspiro[4.5]dec7-ene-1,9-dione (3f). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 78.1 mg, 86% yield. [α]D20 +193.5 (c = 1.35, CHCl3, 99% ee). HPLC: Daicel Chiralpak OD-H, hexane:2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23 °C, UV = 240 nm, tR = 32.29 min (minor), tR = 33.76 min (major). 1H NMR (400 MHz, CDCl3, δ): 7.39−7.26 (m, 7H), 7.02−6.94 (m, 2H), 6.87−6.81 (m, 2H), 5.55 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.26 (d, J = 14.2 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.27 (d, J = 16.9 Hz, 1H), 2.77 (d, J = 16.9 Hz, 1H). 19F (376 MHz, CDCl3, δ): −112.06. 13C NMR (100 MHz, CDCl3, δ): 189.4, 168.5, 162.7 (d, 1JCF = 245.6 Hz, 1C), 160.4, 136.4 (d, 3JCF = 7.6 Hz, 1C), 134.8, 133.1, 130.3 (d, 3JCF = 8.5 Hz, 1C), 129.0, 128.1, 128.0, 127.97, 124.6 (d, 4JCF = 2.9 Hz, 1C), 115.45, 115.44 (d, 2JCF = 43.3 Hz, 1C), 106.4, 83.5, 48.2, 46.8, 41.3. IR (film, ν/cm−1): 2921, 2852, 1703, 1676, 1600, 1583, 1484, 1433, 1400, 1269, 1223, 751, 699. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H18FNO3Na, 386.1168; found, 386.1167. (S,E)-2-Benzyl-4-(3-chlorobenzylidene)-6-ozxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3g). The title compound was prepared according to the general working procedure (24 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 89.3 mg, 94% yield. [α]D20 +203.7 (c = 1.24, CHCl3, 97% ee). HPLC: Daicel Chiralpak IC, hexane:2-propanol = 0:100, flow rate = 0.25 mL/min, T = 23 °C, UV = 230 nm, tR = 97.18 min (minor), tR = 103.89 min (major). 1H NMR (400 MHz, CDCl3, δ): 7.39−7.26 (m, 8H), 7.15 (s, 1H), 7.04−7.02 (m, 1H), 6.78 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.26 (dd, J1 = 14.2 Hz, J2 = 2.2 Hz, 1H), 4.03 (dd, J1 = 14.2 Hz, J2 = 1.8 Hz, 1H), 3.27 (d, J = 16.9 Hz, 1H), 2.77 (d, J = 16.9 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 189.4, 168.5, 160.4, 136.0, 134.8, 134.7, 133.3, 130.0, 129.0, 128.6, 128.1, 128.0, 127.8, 126.8, 106.5, 83.5, 48.1, 46.8, 41.3. IR (film, ν/cm−1): 2923, 2854, 1705, 1677, 1596, 1268, 1225, 753. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H18ClNO3Na, 402.0873; found, 402.0874. (S,E)-2-Benzyl-4-(3-bromobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3h). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 95.5 mg, 90% yield. [α]D20 +132.6 (c = 1.59, CHCl3, 97% ee). HPLC: Daicel Chiralpak AD-H, hexane:2-propanol = 90:10, flow rate = 0.5 mL/min, T = 23 °C, UV = 240 nm, tR = 67.16 min (major), tR = 73.02 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.44−7.20 (m, 9H), 7.09−7.07 (m, 1H), 6.77 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.66 (d, J = 14.8 Hz, 1H), 4.53 (d, J = 14.8 Hz, 1H), 4.25 (d, J = 14.2 Hz, 1H), 4.02 (d, J = 14.2 Hz, 1H), 3.27 (d, J = 16.9 Hz, 8469

DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472

Article

The Journal of Organic Chemistry yellow oil. 69.0 mg, 76% yield. [α]D20 +206.9 (c = 1.11, CHCl3, 97% ee). HPLC: Daicel Chiralpak IC, hexane:2-propanol = 60:40, flow rate = 1.0 mL/min, T = 23 °C, UV = 254 nm, tR = 73.61 min (major), tR = 91.23 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.39−7.26 (m, 6H), 7.16−7.12 (m, 2H), 7.06−7.02 (m, 2H), 6.80 (s, 1H), 5.55 (d, J = 6.2 Hz, 1H), 4.67 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.25 (d, J = 14.0 Hz, 1H), 4.00 (d, J = 14.0 Hz, 1H), 3.28 (d, J = 17.0 Hz, 1H), 2.77 (d, J = 17.0 Hz, 1H). 19F (376 MHz, CDCl3, δ): −111.53. 13C NMR (100 MHz, CDCl3, δ): 189.6, 168.6, 162.5 (d, 1 JCF = 248.7 Hz, 1C), 160.4, 134.8, 131.4 (d, 4JCF = 1.5 Hz, 1C), 130.6, 130.56, 130.5, 129.0, 128.1, 128.0, 115.8 (d, 2JCF = 21.7 Hz, 1C), 106.4, 83.6, 48.2, 46.8, 41.2. IR (film, ν/cm−1): 2922, 2852, 1703, 1678, 1597, 1509, 1400, 1270, 1224, 1029, 992, 700. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H18FNO3Na, 386.1168; found, 386.1167. (S,E)-2-Benzyl-4-(2-fluorobenzylidene)-6-oxa-2-azaspiro[4.5]dec7-ene-1,9-dione (3m). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 85.4 mg, 94% yield. [α]D20 +138.0 (c = 1.21, CHCl3, 98% ee). HPLC: Daicel Chiralpak IC, hexane:2-propanol = 40:60, flow rate = 0.6 mL/min, T = 23 °C, UV = 215 nm, tR = 46.53 min (major), tR = 55.94 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.38−7.24 (m, 7H), 7.14−7.05 (m, 3H), 6.95 (s, 1H), 5.55 (d, J = 6.3 Hz, 1H), 4.62 (d, J = 14.8 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.2 Hz, 1H), 3.95 (d, J = 14.2 Hz, 1H), 3.24 (d, J = 16.9 Hz, 1H), 2.81 (d, J = 16.9 Hz, 1H). 19F (376 MHz, CDCl3, δ): −114.16. 13C NMR (100 MHz, CDCl3, δ): 189.3, 168.7, 160.5, 160.0 (d, 1JCF = 249.3 Hz, 1C), 134.9, 134.0, 130.5 (d, 3JCF = 8.5 Hz, 1C), 129.4 (d, 4JCF = 2.7 Hz, 1C), 129.0, 128.1, 128.0, 124.2 (d, 3JCF = 3.6 Hz, 1C), 122.2 (d, 2 JCF = 13.5 Hz, 1C), 121.6 (d, 3JCF = 4.3 Hz, 1C), 116.0 (d, 2JCF = 21.9 Hz, 1C), 106.5, 83.5, 48.1 (d, JCF = 4.5 Hz, 1C), 46.8, 41.3. IR (film, ν/cm−1): 2922, 2852, 1703, 1676, 1597, 1484, 1268, 1223, 1030, 990, 752, 700. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H18FNO3Na, 386.1168; found, 386.1169. (S,E)-2-Benzyl-4-(naphthalen-1-ylmethylene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3n). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 89.0 mg, 90% yield. [α]D20 +204.7 (c = 1.50, CHCl3, 97% ee). HPLC: Daicel Chiralpak AD-H, hexane:2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23 °C, UV = 240 nm, tR = 11.81 min (minor), tR = 14.46 min (major). 1H NMR (400 MHz, CDCl3, δ): 7.86−7.80 (m, 3H), 7.55−7.48 (m, 3H), 7.42−7.38 (m, 2H), 7.34− 7.25 (m, 3H), 7.22−7.20 (m, 3H), 5.59 (d, J = 6.2 Hz, 1H), 4.62 (d, J = 14.8 Hz, 1H), 4.44 (d, J = 14.8 Hz, 1H), 4.15 (dd, J1 = 14.2 Hz, J2 = 2.3 Hz, 1H), 3.86 (dd, J1 = 14.2 Hz, J2 = 2.1 Hz, 1H), 3.41 (d, J = 16.8 Hz, 1H), 2.90 (d, J = 16.8 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 189.7, 168.8, 160.5, 134.9, 134.1, 133.4, 131.08, 131.07, 129.1, 128.9, 128.6, 127.98, 127.94, 127.1, 126.8, 126.3, 125.8, 125.0, 123.8, 106.5, 83.4, 48.0, 46.8, 41.3. IR (film, ν/cm−1): 2921, 2851, 1703, 1672, 1596, 1398, 1267, 1029, 988, 778, 699. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C26H21NO3Na, 418.1419; found, 418.1418. (S,E)-2-Benzyl-4-(2-methylbenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3o). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow solid. 77.3 mg, 86% yield. [α]D20 +25.9 (c = 1.48, CHCl3, 96% ee). HPLC: Daicel Chiralpak OD-H, hexane:2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23 °C, UV = 254 nm, tR = 28.91 min (minor), tR = 37.97 min (major). 1H NMR (400 MHz, CDCl3, δ): 7.37−7.12 (m, 9H), 7.00−6.99 (m, 2H), 5.55 (d, J = 6.2 Hz, 1H), 4.65 (d, J = 14.8 Hz, 1H), 4.47 (d, J = 14.8 Hz, 1H), 4.16 (d, J = 14.1 Hz, 1H), 3.88 (d, J = 14.1 Hz, 1H), 3.33 (d, J = 16.8 Hz, 1H), 2.77 (d, J = 16.8 Hz, 1H), 2.26 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 189.8, 168.8, 160.5, 136.9, 134.9, 133.1, 132.2, 130.5, 128.9, 128.7, 128.01, 127.99, 127.8, 127.6, 125.9, 106.4, 83.5, 47.9, 46.8, 41.2, 19.6. IR (film, ν/cm−1): 2922, 2853, 1692, 1598, 1453, 1267, 1029, 748, 699. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C23H21NO3Na, 382.1419; found, 382.1421.

(S,E)-2-Benzyl-4-(2-bromobenzylidene)-6-oxa-2-azaspiro[4.5]dec-7-ene-1,9-dione (3p). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 98.6 mg, 93% yield. mp 46−48 °C. [α]D20 +167.3 (c = 1.38, CHCl3, 99% ee). HPLC: Daicel Chiralpak IC, hexane:2propanol = 50:50, flow rate = 0.75 mL/min, T = 23 °C, UV = 240 nm, tR = 54.89 min (major), tR = 81.83 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.60−7.58 (m, 1H), 7.38−7.23 (m, 7H), 7.19−7.14 (m, 1H), 7.09−7.06 (m, 2H), 5.57 (dd, J1 = 6.2 Hz, J2 = 0.4 Hz, 1H), 4.64 (d, J = 14.8 Hz, 1H), 4.48 (d, J = 14.8 Hz, 1H), 4.13 (dd, J1 = 14.2 Hz, J2 = 2.4 Hz, 1H), 3.88 (dd, J1 = 14.2 Hz, J2 = 2.2 Hz, 1H), 3.30 (d, J = 16.9 Hz, 1H), 2.83 (dd, J1 = 16.9 Hz, J2 = 0.4 Hz, 1H). 13 C NMR (100 MHz, CDCl3, δ): 189.4, 168.7, 160.5, 134.8, 134.2, 133.6, 133.2, 130.0, 129.0, 128.98, 128.5, 128.1, 128.0, 127.4, 124.3, 106.5, 83.3, 47.6, 46.8, 41.2. IR (film, ν/cm−1): 2921, 2851, 1705, 1674, 1596, 1432, 1398, 1266, 1223, 1025, 996, 750, 736, 699. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C22H18BrNO3Na, 446.0368; found, 446.0363. (S,E)-4-Benzylidene-2-propyl-6-oxa-2-azaspiro[4.5]dec-7-ene1,9-dione (3q). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 52.0 mg, 70% yield. [α]D20 +331.7 (c = 1.10, CHCl3, 95% ee). HPLC: Daicel Chiralpak AD-H, hexane:2-propanol = 80:20, flow rate = 1.0 mL/min, T = 23 °C, UV = 230 nm, tR = 9.44 min (major), tR = 10.62 min (minor). 1H NMR (400 MHz, CDCl3, δ): 7.43−7.23 (m, 7H), 6.85−6.84 (m, 1H), 5.23 (dd, J1 = 6.2 Hz, J2 = 0.6 Hz, 1H), 4.41 (dd, J1 = 14.0 Hz, J2 = 2.4 Hz, 1H), 4.14 (dd, J1 = 14.0 Hz, J2 = 2.1 Hz, 1H), 3.45−3.33 (m, 2H), 3.27 (d, J = 17.0 Hz, 1H), 2.74 (dd, J1 = 17.0 Hz, J2 = 0.6 Hz, 1H), 1.67−1.61 (m, 2H), 0.94 (t, J = 7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3, δ): 189.9, 168.5, 160.5, 134.5, 132.1, 129.0, 128.80, 128.76, 128.6, 106.3, 83.9, 48.8, 44.5, 41.2, 20.2, 11.1. IR (film, ν/cm−1): 2963, 2929, 2873, 1701, 1676, 1596, 1400, 1270, 1224, 1036, 994, 755, 727. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C18H19NO3Na, 320.1263; found, 320.1262. (S,E)-4-Benzylidene-2-phenyl-6-oxa-2-azaspiro[4.5]dec-7-ene1,9-dione (3r). The title compound was prepared according to the general working procedure (18 h) and purified by column chromatography (PE/EA = 10/1−3/1) to give the product as a faint yellow oil. 71.2 mg, 86% yield. mp 54−57 °C. [α]D20 +167.8 (c = 1.06, CHCl3, 95% ee). HPLC: Daicel Chiralpak OD-H, hexane:2propanol = 70:30, flow rate = 1.0 mL/min, T = 23 °C, UV = 254 nm, tR = 35.43 min (minor), tR = 43.24 min (major). 1H NMR (400 MHz, CDCl3, δ): 7.73−7.71 (m, 2H), 7.45−7.28 (m, 8H), 7.24−7.20 (m, 1H), 6.91 (s, 1H), 5.57 (d, J = 6.2 Hz, 1H), 4.85 (d, J = 13.6 Hz, 1H), 4.62 (d, J = 13.6 Hz, 1H), 3.35 (d, J = 17.0 Hz, 1H), 2.86 (d, J = 17.0 Hz, 1H). 13C NMR (100 MHz, CDCl3, δ): 189.6, 167.5, 160.3, 137.9, 134.3, 130.6, 129.5, 129.1, 128.83, 128.80, 125.8, 120.2, 106.5, 84.6, 49.9, 41.0. IR (film, ν/cm−1): 2922, 2853, 1706, 1665, 1595, 1493, 1396, 1272, 1221, 1203, 1037, 990, 755, 688. HRMS (ESI-TOF) (m/ z): [M + Na]+ calcd for C21H17NO3Na, 354.1106; found, 354.1105. (S,E)-1-Benzyl-4-(3-bromobenzylidene)-3-hydroxy-3-((E)-4-methoxy-2-oxobut-3-en-1-yl)pyrrolidin-2-one (5). The title compound was prepared according to the general working procedure and purified by column chromatography (PE/EA = 2:1) to give the product as a colorless oil. [α]D20 −99.3 (c = 1.37, CHCl3, 97% ee). HPLC: Daicel Chiralpak IC, hexane:2-propanol = 50:50, flow rate = 0.75 mL/min, T = 23 °C, UV = 240 nm, tR = 26.94 min (minor), tR = 46.16 min (major). 1H NMR (400 MHz, CD3COCD3, δ): 7.53 (s, 1H), 7.48− 7.45 (m, 1H), 7.37−7.26 (m, 7H), 6.86 (t, J = 2.4 Hz, 1H), 5.40− 5.38 (m, 1H), 4.66 (d, J = 14.9 Hz, 1H), 4.50 (d, J = 14.9 Hz, 1H), 4.41 (dd, J1 = 14.9 Hz, J2 = 2.4 Hz, 1H), 4.34 (dd, J1 = 14.9 Hz, J2 = 2.4 Hz, 1H), 3.54 (s, 3H), 3.15 (dd, J1 = 16.4 Hz, J2 = 3.5 Hz, 1H), 3.06 (d, J = 16.3 Hz, 1H), 2.55−2.50 (m, 2H). 13C NMR (100 MHz, CD3COCD3, δ): 202.9, 172.3, 138.7, 137.6, 137.0, 132.3, 131.5, 131.4, 129.6, 128.6, 128.4, 128.1, 127.0, 123.1, 100.7, 79.4, 56.4, 49.2, 46.6, 46.3, 46.2. IR (film, ν/cm−1): 2900, 1727, 1696, 1306, 1197, 8470

DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472

Article

The Journal of Organic Chemistry 1110, 1062, 1007. HRMS (ESI-TOF) (m/z): [M + Na]+ calcd for C23H22BrNO4Na, 478.0630; found, 478.0630. (5S,E)-2-Benzyl-4-(3-bromobenzylidene)-9-((tertbutyldimethylsilyl)oxy)-7-methoxy-6-oxa-2-azaspiro[4.5]dec-8-en1-one (6). The title compound was prepared according to the general working procedure and purified by column chromatography (PE/EA = 5:1) to give the product as a colorless oil. [α]D20 −24.8 (c = 1.20, CHCl3, 97% ee). HPLC: Daicel Chiralpak AD-H, hexane:2-propanol = 90:10, flow rate = 1.0 mL/min, T = 23 °C, UV = 240 nm, tR = 6.58 min (major), tR = 8.11 min (minor). 1H NMR (400 MHz, CD3COCD3, δ): 7.45−7.43 (m, 2H), 7.36−7.25 (m, 7H), 6.93− 6.92 (m, 1H), 5.53 (m, 1H), 4.99−4.98 (m, 1H), 4.64 (d, J = 15.0 Hz, 1H), 4.55 (d, J = 15.0 Hz, 1H), 4.33 (dd, J1 = 14.3 Hz, J2 = 2.3 Hz, 1H), 4.21 (dd, J1 = 14.3 Hz, J2 = 2.3 Hz, 1H), 3.37 (m, 3H), 2.63− 2.59 (m, 1H), 2.46−2.41 (m, 1H), 0.98−0.96 (m, 9H), 0.27−0.25 (m, 6H). 13C NMR (100 MHz, CD3COCD3, δ): 171.6, 150.7, 139.1, 138.7, 137.4, 132.1, 131.3, 131.25, 129.5, 128.6, 128.3, 128.1, 126.1, 123.0, 103.8, 99.0, 77.9, 54.4, 48.8, 46.6, 35.8, 26.0, 18.6, −4.2. IR (film, ν/cm−1): 2928, 2857, 1707, 1682, 1253, 1178, 1132, 1064, 913, 838, 783, 757. HRMS (ESI-TOF) (m/z): [M + H]+ calcd for C29H37BrNO4Si, 570.1675; found, 570.1675.

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(2) For selected reviews on the hetero-Diels−Alder reaction, see: (a) Jørgensen, K. A. Catalytic Asymmetric Hetero-Diels-Alder Reactions of Carbonyl Compounds and Imines. Angew. Chem., Int. Ed. 2000, 39, 3558−3588. (b) Reymond, S.; Cossy, J. CopperCatalyzed Diels-Alder Reactions. Chem. Rev. 2008, 108, 5359−5406. (c) Heravi, M. M.; Ahmadi, T.; Ghavidel, M.; Heidari, B.; Hamidi, H. Recent applications of the hetero Diels-Alder reaction in the total synthesis of natural products. RSC Adv. 2015, 5, 101999−102075. (d) Pellissier, H. Asymmetric hetero-Diels-Alder reactions of carbonyl compounds. Tetrahedron 2009, 65, 2839−2877. (e) Moyano, A.; Rios, R. Asymmetric Organocatalytic Cyclization and Cycloaddition Reactions. Chem. Rev. 2011, 111, 4703−4832. (3) For examples of asymmetric HDA reactions of aldehydes with Danishefsky’s dienes, see: (a) Wang, B.; Feng, X. M.; Cui, X.; Liu, H.; Jiang, Y. Z. Highly efficient enantioselective synthesis of optically active dihydropyrones by chiral titanium(IV) (5,5′,6,6’,7,7’,8,8’octahydro-1,1’-bi-2-naphthol) complexes. Chem. Commun. 2000, 0, 1605−1606. (b) Bednarski, M.; Danishefsky, S. Interactivity of Chiral Catalysts and Chiral Auxiliaries in the Cycloaddition of Activated Dienes with Aldehydes: A Synthesis of L-Glucose. J. Am. Chem. Soc. 1986, 108, 7060−7067. (c) Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H. Asymmetric hetero-Diels-Alder reaction catalyzed by a chiral organoaluminum reagent. J. Am. Chem. Soc. 1988, 110, 310− 312. (d) Long, J.; Hu, J. Y.; Shen, X. Q.; Ji, B. M.; Ding, K. L. Discovery of Exceptionally Efficient Catalysts for Solvent-Free Enantioselective Hetero-Diels-Alder Reaction. J. Am. Chem. Soc. 2002, 124, 10−11. (e) Anada, M.; Washio, T.; Shimada, N.; Kitagaki, S.; Nakajima, M.; Shiro, S.; Hashimoto, M. A New Dirhodium(II) Carboxamidate Complex as a Chiral Lewis Acid Catalyst for Enantioselective Hetero-Diels-Alder Reactions*. Angew. Chem., Int. Ed. 2004, 43, 2665−2668. (f) Schaus, S. E.; Brånalt, J.; Jacobsen, E. N. Asymmetric Hetero-Diels-Alder Reactions Catalyzed by Chiral (Salen)Chromium(III) Complexes. J. Org. Chem. 1998, 63, 403−405. (g) Gong, L. Z.; Pu, L. The asymmetric hetero-Diels-Alder reaction of enamide aldehydes with Danishefsky’s diene and an efficient synthesis of chiral binaphthyl ligands. Tetrahedron Lett. 2000, 41, 2327−2331. (h) Yu, Z. P.; Liu, X. H.; Dong, Z. H.; Xie, M. S.; Feng, X. M. An N,N’-Dioxide/In(OTf)3 Catalyst for the Asymmetric Hetero-DielsAlder Reaction Between Danishefsky’s Dienes and Aldehydes: Application in the Total Synthesis of Triketide*. Angew. Chem., Int. Ed. 2008, 47, 1308−1311. (4) For recent of reports of the HDA reaction of 2,3dioxopyrrolidines, see: (a) Zhang, S.; Luo, Y. C.; Hu, X. Q.; Wang, Z. Y.; Liang, Y. M.; Xu, P. F. Enantioselective Amine-Catalyzed [4 + 2] Annulations of Allene Ketones and 2,3-Dioxopyrrolidine Derivatives: Synthesis of 4H-Pyran Derivatives. J. Org. Chem. 2015, 80, 7288−7294. (b) Wang, C.; Jia, H.; Zhang, C.; Gao, Z. Z.; Zhou, L. J.; Yuan, C. H.; Xiao, Y. M.; Guo, H. C. Phosphine-Catalyzed Enantioselective [2 + 4] Cycloaddition to Synthesize Pyrrolidin-2-one Fused Dihydropyrans Using α-Substituted Allenoates as C2 Synthons. J. Org. Chem. 2017, 82, 633−641. (c) Li, J. L.; Yang, K. C.; Li, Y.; Li, Q.; Zhu, H. P.; Han, B.; Peng, C.; Zhi, Y. G.; Gou, X. J. Asymmetric synthesis of bicyclic dihydropyrans via organocatalytic inverseelectron-demand oxo-Diels−Alder reactions of enolizable aliphatic aldehydes. Chem. Commun. 2016, 52, 10617−10620. (d) Li, J. L.; Fu, L.; Wu, J.; Yang, K. C.; Li, Q. Z.; Gou, X. J.; Peng, C.; Han, B.; Shen, X. D. Highly enantioselective synthesis of fused bicyclic dihydropyranones via low-loading N-heterocyclic carbene organocatalysis. Chem. Commun. 2017, 53, 6875−6878. (e) Lu, Y.; Zhou, Y. H.; Lin, L. L.; Zheng, H. F.; Fu, K.; Liu, X. H.; Feng, X. M. N,N’-Dioxide/nickel(II)catalyzed asymmetric Diels-Alder reaction of cyclopentadiene with 2,3-dioxopyrrolidines and 2-alkenoyl pyridines. Chem. Commun. 2016, 52, 8255−8258. (f) Zheng, J. F.; Lin, L. L.; Fu, K.; Zhang, Y. L.; Liu, X. H.; Feng, X. M. Asymmetric Hetero-Diels-Alder Reaction of Danishefsky’s Diene with α-Ketoesters and Isatins Catalyzed by a Chiral N,N’-Dioxide/Magnesium(II) Complex. Chem. - Eur. J. 2014, 20, 14493−14498. (g) Li, Q.; Zhou, L.; Shen, X. D.; Yang, K. C.; Zhang, X.; Dai, Q. S.; Leng, H. J.; Li, Q. Z.; Li, J. L. Stereoselective Construction of Halogenated Quaternary Carbon Centers by

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01057. Preparation of substrates, 1H NMR and 13C NMR spectra for all of the products, and HPLC profiles and crystallographic data of compound 3c (PDF) X-ray crystallographic data for compound 3c (CCDC 1590154) (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]; Fax: 86-551-3631760; E-mail: [email protected]. *E-mail: [email protected]. ORCID

Zhiyong Wang: 0000-0002-3400-2851 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for the financial support from the National Natural Science Foundation of China (21432009, 21672200, 21472177, and 21772185) and for the assistance of the product characterization from the Chemistry Experiment Teaching Center of University of Science and Technology of China. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant XDB20000000.

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REFERENCES

(1) For selected reports of the pyrrospirone scaffold in medical chemistry, see: (a) Zhang, X. J.; Li, X.; Sun, H. P.; Jiang, Z. Y.; Tao, L.; Gao, Y.; Guo, Q. L.; You, Q. D. Synthesis and evaluation of novel aza-caged Garcinia xanthones. Org. Biomol. Chem. 2012, 10, 3288− 3299. (b) Song, T. F.; Chen, M. X.; Chai, W. Y.; Zhang, Z. Z.; Lian, X. Y. New bioactive pyrrospirones C-I from a marine-derived fungus Penicillium sp. ZZ380. Tetrahedron 2018, 74, 884−891. (c) Thaler, F.; Moretti, L.; Amici, R.; Abate, A.; Colombo, A.; Carenzi, G.; Fulco, M. C.; Boggio, R.; Dondio, G.; Gagliardi, S.; Minucci, S.; Sartori, L.; Varasi, M.; Mercurio, C. Synthesis, biological characterization and molecular modeling insights of spirochromanes as potent HDAC inhibitors. Eur. J. Med. Chem. 2016, 108, 53−67. 8471

DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472

Article

The Journal of Organic Chemistry Brønsted Base Catalyzed [4 + 2] Cycloaddition of α-Haloaldehydes. Angew. Chem., Int. Ed. 2018, 57, 1913−1917. (5) For examples of asymmetric HDA reactions of aldehydes, see: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J.; Krishnan, K. Asymmetric hetero Diels-Alder reactions of Danishefsky’s diene and glyoxylate esters catalyzed by chiral bisoxazoline derived catalysts. Tetrahedron: Asymmetry 1996, 7, 2165−2168. (b) Du, H. F.; Long, J.; Hu, J. Y.; Li, X.; Ding, K. L. 3,3′-Br2-BINOL-Zn Complex: A Highly Efficient Catalyst for the Enantioselective Hetero-Diels-Alder Reaction. Org. Lett. 2002, 4, 4349−4352. (c) Guin, J.; Rabalakos, C.; List, B. Highly Enantioselective Hetero-Diels-Alder Reaction of 1,3-Bis(silyloxy)-1,3-dienes with Aldehydes Catalyzed by Chiral Disulfonimide*. Angew. Chem., Int. Ed. 2012, 51, 8859−8863. (d) Du, H. F.; Ding, K. L. Enantioselective Catalysis of Hetero Diels-Alder Reaction and Diethylzinc Addition Using a Single Catalyst. Org. Lett. 2003, 5, 1091−1093. (e) Fan, Q.; Lin, L. L.; Liu, J.; Huang, Y. Z.; Feng, X. M.; Zhang, G. L. Highly Enantioselective Hetero-Diels-Alder Reaction of Brassard Diene with Aromatic Aldehydes. Org. Lett. 2004, 6, 2185−2188. (f) Tonoi, T.; Mikami, K. Chiral bis-trifluoromethanesulfonylamide as a chiral Brønsted acid catalyst for the asymmetric hetero DielsAlder reaction with Danishefsky’s diene. Tetrahedron Lett. 2005, 46, 6355−6358. (g) Shen, J. F.; Liu, D. L.; An, Q. J.; Liu, Y. G.; Zhang, W. B. The Synthesis of trans-Perhydroindolic Acids and their Application in Asymmetric Domino Reactions of Aldehyde Esters with β,γ-Unsaturated α-Keto Esters. Adv. Synth. Catal. 2012, 354, 3311−3325. (h) An, Q. J.; Shen, J. F.; Butt, N.; Liu, D. L.; Liu, Y. G.; Zhang, W.-B. The Construction of 3-Methyl-4-arylpiperidines via a trans-Perhydroindolic Acid-Catalyzed Asymmetric Aza-Diels-Alder Reaction. Adv. Synth. Catal. 2015, 357, 3627−3638. (6) For recent examples of chiral Lewis acid catalysts, see: (a) Desimoni, G.; Faita, G.; Toscanini, M.; Boiocchi, M. Peri- and Enantioselectivity of Thermal, Scandium-, and [Pybox/Scandium]Catalyzed Diels-Alder and Hetero-Diels-Alder Reactions of Methyl (E)-2-Oxo-4-aryl-butenoates with Cyclopentadiene. Chem. - Eur. J. 2007, 13, 9478−9485. (b) Zhu, Y.; Chen, X. H.; Xie, M. S.; Dong, S. X.; Qiao, Z.; Lin, L. L.; Liu, X. H.; Feng, X. M. Asymmetric DielsAlder and Inverse-Electron-Demand Hetero-Diels-Alder Reactions of β,γ-Unsaturated α-Ketoesters with Cyclopentadiene Catalyzed by N,N’-Dioxide Copper(II) Complex. Chem. - Eur. J. 2010, 16, 11963− 11968. (c) Lin, L. L.; Kuang, Y. L.; Liu, X. H.; Feng, X. M. Indium(III)-Catalyzed Asymmetric Hetero-Diels-Alder Reaction of Brassard-Type Diene with Aliphatic Aldehydes. Org. Lett. 2011, 13, 3868−3871. (d) Zhao, B.; Loh, T. P. Asymmetric Hetero-Diels-Alder Reaction of Danishefsky’s Dienes with α-Carbonyl Esters Catalyzed by an Indium(III)-PyBox Complex. Org. Lett. 2013, 15, 2914−2917. (e) Zheng, J. F.; Lin, L. L.; Fu, K.; Zhang, Y. L.; Liu, X. H.; Feng, X. M. Asymmetric Hetero-Diels-Alder Reaction of Danishefsky’s Diene with α-Ketoesters and Isatins Catalyzed by a Chiral N,N’-Dioxide/ Magnesium(II) Complex. Chem. - Eur. J. 2014, 20, 14493−14498. (f) Hu, Y. B.; Xu, K.; Zhang, S.; Guo, F. F.; Zha, Z. G.; Wang, Z. Y. Copper-Catalyzed Enantioselective Hetero-Diels-Alder Reaction of Danishefsky’s Diene with β,γ-Unsaturated α-Ketoesters. Org. Lett. 2014, 16, 3564−3567. (g) Li, Y. N.; Hu, Y. B.; Zhang, S.; Sun, J. N.; Li, L. J.; Zha, Z. G.; Wang, Z. Y. Copper-Catalyzed Enantioselective Hetero-Diels-Alder Reaction of Danishefsky’s Diene with Glyoxals. J. Org. Chem. 2016, 81, 2993−2999. (7) For recent examples of other catalysts, see: (a) Gao, T. P.; Lin, J. B.; Hu, X. Q.; Xu, P. F. A catalytic asymmetric hetero-Diels-Alder reaction of olefinic azlactones and isatins: facile access to chiral spirooxindole dihydropyranones. Chem. Commun. 2014, 50, 8934− 8936. (b) Cui, H. L.; Chouthaiwale, P. V.; Yin, F.; Tanaka, F. Reaction-Based Mechanistic Investigations of Asymmetric HeteroDiels-Alder Reactions of Enones with Isatins Catalyzed by AmineBased Three-Component Catalyst Systems. Asian J. Org. Chem. 2016, 5, 153−161. (c) Yang, X. B.; Feng, J.; Zhang, J.; Wang, N.; Wang, L.; Liu, J. L.; Yu, X. Q. Highly Enantioselective Hetero-Diels-Alder Reaction of trans-1-Methoxy-2-methyl-3-trimethylsiloxybuta-1,3diene with Aromatic and Aliphatic Aldehydes Catalyzed by 3-

Substituted BINOL-Titanium Complex. Org. Lett. 2008, 10, 1299− 1302. (8) For the synthesis of 2,3-dioxopyrrolidines and Danishefsky’s diene, see: (a) Southwick, P. L.; Crouch, R. T. The Condensation of Oxalic Esters with Esters of β-Alanine and N-Substituted βAminopropionic Acids. Synthesis of Some Derivatives of 2,3Dioxopyrrolidine and 2-Oxo-3-methoxy-3-pyrroline. J. Am. Chem. Soc. 1953, 75, 3413−3417. (b) Danishefsky, S.; Kitahara, T. Useful diene for the Diels-Alder reaction. J. Am. Chem. Soc. 1974, 96, 7807− 7808. (9) For the application of the ligands, see: (a) Lai, G. Y.; Guo, F. F.; Zheng, Y. Q.; Fang, Y.; Song, H. G.; Xu, K.; Wang, S. J.; Zha, Z. G.; Wang, Z. Y. Highly Enantioselective Henry Reactions in Water Catalyzed by a Copper Tertiary Amine Complex and Applied in the Synthesis of (S)-N-trans-Feruloyl Octopamine. Chem. - Eur. J. 2011, 17, 1114−1117. (b) Xu, K.; Lai, G. Y.; Zha, Z. G.; Pan, S. S.; Chen, H. W.; Wang, Z. Y. A Highly anti-Selective Asymmetric Henry Reaction Catalyzed by a Chiral Copper Complex: Applications to the Syntheses of (+)-Spisulosine and a Pyrroloisoquinoline Derivative. Chem. - Eur. J. 2012, 18, 12357−12362. (c) Zhang, S.; Xu, K.; Guo, F. F.; Hu, Y. B.; Zha, Z. G.; Wang, Z. Y. Enantioselective Copper(I/II)-Catalyzed Conjugate Addition of Nitro Esters to β,γ-Unsaturated α-Ketoesters. Chem. - Eur. J. 2014, 20, 979−982. (d) Li, L. J.; Zhang, S.; Hu, Y. B.; Li, Y. N.; Li, C.; Zha, Z. G.; Wang, Z. Y. Highly Diastereo- and Enantioselective Michael Addition of Nitroalkanes to 2-EnoylPyridine N-Oxides Catalyzed by Scandium(III)/Copper(II) Complexes. Chem. - Eur. J. 2015, 21, 12885−12888. (e) Hu, Y. B.; Li, Y. N.; Zhang, S.; Li, C.; Li, L. J.; Zha, Z. G.; Wang, Z. Y. Org. Lett. 2015, 17, 4018−4021. (f) Li, Y. N.; Huang, Y. K.; Gui, Y.; Sun, J. N.; Li, J. D.; Zha, Z. G.; Wang, Z. Y. Copper-Catalyzed Enantioselective Henry Reaction of β,γ-Unsaturated α-Ketoesters with Nitromethane in Water. Org. Lett. 2017, 19, 6416−6419. (10) Details of the crystal structure analysis are provided free of charge from the CCDC 1590154 of the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif or from the Supporting Information of this article. (11) For both types of mechanisms of the HDA reactions of aldehydes and Danishefsky’s diene, see: Roberson, M.; Jepsen, A. S.; Jørgensen, K. A. On the mechanism of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral aluminum complexes-a concerted, step-wise or Mukaiyamaaldol pathway. Tetrahedron 2001, 57, 907−913. (12) For the [4+2] cycloaddition pathway, see: (a) Bednarski, M.; Danishefsky, S. Mild Lewis Acid Catalysis: Eu(fod)3-Mediated Hetero-Diels-Alder Reaction. J. Am. Chem. Soc. 1983, 105, 3716− 3717. (b) Zhang, X.; Du, H. F.; Wang, Z.; Wu, Y. D.; Ding, K. L. Experimental and Theoretical Studies on the Hydrogen-BondPromoted Enantioselective Hetero-Diels-Alder Reaction of Danishefsky’s Diene with Benzaldehyde. J. Org. Chem. 2006, 71, 2862−2869. (13) For the Mukaiyama-aldol pathway, see: (a) Qian, C. T.; Wang, L. C. Asymmetric hetero-Diels-Alder reaction of glyoxylate esters and Danishefsky’s diene catalyzed by chiral bis(oxazoline)-lanthanide complexes. Tetrahedron Lett. 2000, 41, 2203−2206. (b) Yamashita, Y.; Saito, S.; Ishitani, H.; Kobayashi, S. Chiral Hetero Diels-Alder Products by Enantioselective and Diastereoselective Zirconium Catalysis. Scope, Limitation, Mechanism, and Application to the Concise Synthesis of (+)-Prelactone C and (+)-9-Deoxygoniopypyrone. J. Am. Chem. Soc. 2003, 125, 3793−3798.

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DOI: 10.1021/acs.joc.8b01057 J. Org. Chem. 2018, 83, 8464−8472