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Catalytic Asymmetric Inverse-Electron-Demand Hetero-Diels−Alder Reaction of Dioxopyrrolidines with Hetero-Substituted Alkenes Xinyue Hu,† Yuhang zhou, Yan Lu,† Sijia Zou,† Lili Lin,*,† Xiaohua Liu,† and Xiaoming Feng*,†,‡ †

Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, People’s Republic of China ‡ Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, People’s Republic of China

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ABSTRACT: A highly efficient enantioselective inverse-electrondemand hetero-Diels−Alder reaction of dioxopyrrolidines with heterosubstituted alkenes has been realized by using a N,N′dioxide/Ni(II) complex as the catalyst. A series of chiral bicyclic dihydropyranes were generated in excellent yields, good dr, and excellent ee values. Besides, a catalytic cycle with a possible transition state was proposed.

T

Scheme 1. Catalytic Asymmetric IED Hetero-DA Reaction of Dioxopyrrolidines

he asymmetric inverse-electron-demand hetero-Diels− Alder (IED hetero-DA) reaction is an efficient approach to access optically active hexaheterocyclic compounds.1−3 The IED hetero-DA reactions of linear dienes2 have achieved great progress. Comparably, the reactions of heterodienes, containing a cyclic backbone, which can be conveniently transformed into bicyclic structures, need more development.3 Recently, the catalytic asymmetric IED hetero-DA reactions of dioxopyrrolidines4 have been used for the construction of chiral bicyclic dihydropyranes, which exhibit unique biological activities.5 In 2015, Xu and co-workers6 reported the first catalytic enantioselective IED [4+2] cycloaddition of dioxopyrrolidines with allene ketones catalyzed by a cinchona alkaloid derivative (Scheme 1a). In 2016, Yang, Peng, and Gou7 used the Hayashi−Jørgensen catalyst to promote the enantioselective IED hetero-DA of dioxopyrrolidines with aldehydes as the dienophile precursors. In 2017, Shen and Peng8 demonstrated that the chiral N-heterocyclic carbine (NHC) exhibited a high efficiency over the [4+2] cycloaddition of dioxopyrrolidines with α-haloaldehydes. Although elegant results have been achieved using organocatalysts, developing chiral Lewis acid catalysts, which show different activation modes, could expand the scope of dienophiles for the IED hetero-DA reaction and build new classes of chiral bicyclic dihydropyrane skeletons. Herein, we report a highly diastereo- and enantioselective IED hetero-DA reaction of dioxopyrrolidines with enol ether, ene mercaptan ether, and enecarbamates by using a N,N′-dioxide/ Ni(BF4)2·6H2O complex9 as the catalyst (Scheme 1b). In the initial study, (E)-1-benzyl-4-benzylidenepyrrolidine2,3-dione (1a) and ethoxyethene 2a were chosen as the model substrates to optimize the reaction conditions. By the way, the Z-isomer of heterodienes 1a was not obtained, which might be caused by an unfavorable repulsion force between the phenyl group and carbonyl group. Various metal salts complexing with chiral N,N′-dioxide L-PiPr2 were evaluated (Table 1, entries © 2018 American Chemical Society

1−4). The complex of Zn(OTf)2 showed a great reactivity, but a poor diastereoselectivity and enantioselectivity (40:60 dr, 28% ee; Table 1, entry 1). The complexes of Cu(OTf)2 and Mg(OTf)2 gave a much higher ee, albeit with slightly lower yields and still a low dr value (80 and 88% yield, 48:52 and 52:48 dr, 91 and 98% ee, respectively; Table 1, entries 2 and 3). When Ni(OTf)2 was chosen as a metal salt, higher dr and ee values were given (86% yield, 74:26 dr and 98% ee; Table 1, Received: April 3, 2018 Published: June 5, 2018 8679

DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687

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The Journal of Organic Chemistry

We next turned our attention to the scope of dienophiles. Varying the steric hindrance on R2 illustrated that the substituents with branched groups or linear groups were all suitable (Table 2, entries 16−21). Vinyl sulfide 2h and disubstituted alkenes 2i−2j delivered the products 3ah−3aj in moderate diastereoselectivities and enantioselectivities (Table 2, entries 22−24). Then, enecarbamates bearing various protecting groups were examined. Enecarbamates 2k−2m with aliphatic or aromatic protecting groups all proceeded the reaction well, delivering the desired products in good to excellent yields, dr, and ee values (Table 2, entries 25−27). The absolute configuration of 3aa was determined to be (2S,4S) by X-ray crystallography analysis,10 and the others were also determined to be (2S,4S) by comparison of the CD spectra with that of 3aa.11 To show the synthetic potential of the catalytic system, a gram-scale synthesis of 3aa was carried out. As shown in Scheme 2, 3.0 mmol of 1a reacted smoothly with 31.3 mmol of 2a in the catalytic system, and 1.05 g 3aa (99% yield) was obtained in 90:10 dr and 99% ee. The product 3aa could be further hydrogenated by H2 in methanol with Pd/C, and the double bond was reduced while the benzyl group remained, giving the desired product 4aa in 63% yield with 60:40 dr and 90% ee/99% ee ee values. To gain insight into the reaction mechanism, the operando IR experiments were carried out. It can be clearly seen from Scheme 3a that product 3aa formed with the depletion of 1a and 2a, and no intermediate was detected, which indicated that the reaction might proceed in a concerted pathway. The possibility was further confirmed by the control experiment of the commercially available 7:3 mixture of (E)- and (Z)-1ethoxyprop-1-ene, which gave the product 3aa′ with 67:33 dr (near 7:3 dr). In addition, kinetic profiles of different initial concentrations of substrates and catalysts through operando IR experiments showed that the concentration of 1a was not the factor affecting the reaction rate (Scheme 3c). The rate of this reaction was relevant to the concentrate of 2a and L-PrEt2/ Ni(BF4)2·6H2O complex (Scheme 3b,d). The catalytic composition and coordination between the substrate and catalyst were also investigated by using HRMS analysis.12 The spectrum of a mixture of Ni(BF4)2·6H2O and L-PrEt2 in a 1:1 ratio displayed the [L-PrEt2 + Ni2+ + BF4−]+ ion (m/z 709.3051, calcd 709.3053), suggesting that the ligand coordinated with the metal in a 1:1 ratio. In the spectrum of a mixture of 1a, Ni(BF4)2·6H2O, and L-PrEt2 in a 1:1:1 ratio, a characteristic signal of [L-PrEt2 + Ni2+ + BF4− + 1a]+ at m/z 986.4154 (m/z calcd 986.4156) was also observed, which suggested that the catalyst coordinated with 1a in a 1:1 ratio. Based on the above analysis, the X-ray crystal structure of the product 3aa, and our previous study,13 a catalytic cycle with a possible transition state was proposed. As illustrated in Scheme 4, the tetradentate L-PrEt2 coordinated to Ni(II) to form an octahedral geometry. Then the substrate 1a coordinates to the Lewis acid catalyst through the carbonyl groups to form T1. Since the Re face of the 1a is shielded by the neighboring amide group of the ligand, ethoxyethene 2a attacks T1 from the Si face, which might be the ratedetermining step of the reaction, to form the product 3aa with the (2S,4S) configuration. In summary, we have developed a novel chiral N,N′-dioxide/ Ni(BF4)2·6H2O complex catalytic system to promote the asymmetric IED hetero-DA reaction of dioxopyrrolidines with heterosubstituted alkenes in high reactivities, diastereoselectiv-

Table 1. Optimization of the Reaction Conditions

entrya

ligand

metal salt

yield [%]b

drc

ee [%]d

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

L-PiPr2 L-PiPr2 L-PiPr2 L-PiPr2 L-PiPr2 L-RaPr2 L-PrPr2 L-PrEt2 L-PrEt2 L-PrEt2

Zn(OTf)2 Cu(OTf)2 Mg(OTf)2 Ni(OTf)2 Ni(BF4)2·6H2O Ni(BF4)2·6H2O Ni(BF4)2·6H2O Ni(BF4)2·6H2O Ni(BF4)2·6H2O Ni(BF4)2·6H2O

91 80 88 86 99 87 97 99 94 94

40:60 48:52 52:48 74:26 81:19 82:18 91:9 91:9 81:19 78:22

28 91 98 98 98 99 99 99 98 98

a Unless otherwise noted, the reactions were carried out with 1a (0.1 mmol), 2a (1.04 mmol), and ligand/metal salt (1:1, 10 mol %) in CH2Cl2 (1.0 mL) at 30 °C for 4 h. bYield of the isolated product as a diastereoisomeric mixture. cDetermined by 1H NMR analysis. d Determined by chiral HPLC analysis. e5 mol % catalyst loading. f1 mol % catalyst loading.

entry 4). The investigation of other counterions of nickel showed that the complex of Ni(BF4)2·6H2O could give the product in quantitative yield with good diastereoselectivity and excellent enantioselectivity (99% yield, 81:19 dr and 98% ee; Table 1, entry 5). Exploring different chiral N,N′-dioxides illustrated that L-proline derived L-PrPr2 was superior to Lpipecolic acid derived L-PiPr2 and L-ramipril derived L-RaPr2 (entry 7 vs entries 5 and 6). Additionally, N,N′-dioxide LPrEt2, which has ethyl groups at the ortho-positions of aniline, could give 99% yield, 91:9 dr, and 99% ee (Table 1, entry 8). Unfortunately, the diastereoselectivity decreased obviously when the catalyst loading was decreased to 5 mol % and 1 mol % (Table 1, entries 9 and 10). It is worth mentioning that all of the reactions finished within 4 h. With the optimized conditions in hand, the substrate scope of the reaction was investigated. First, the scope of 1 was taken into account. As shown in Table 2, dioxopyrrolidine 1 with various substituents on the aryl group, regardless of their electronic properties or steric hindrance, transformed to the corresponding products in excellent yields (94−99% yield) with good diastereoselecitivities (87:13 to 92:8 dr) and excellent enantioselectivities (98−99% ee) (Table 2, entries 1−12). Naphthyl or 3-methylbenzo[b]thiophene substituted dioxopyrrolidines were also suitable, delivering the products (3ma−3oa) in quantitative yields with excellent dr and ee values (Table 2, entries 13−15). Unfortunately, all of the attempts for synthesizing 2,4-dioxopyrrolidines bearing an aliphatic substituent (for example, R1 = c-hexyl or benzyl) were not successful. 8680

DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687

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The Journal of Organic Chemistry Table 2. Substrate Scope of the Asymmetric IED Hetero-DA Reaction

Unless otherwise noted, the reactions were carried out with 1 (0.1 mmol), 2 (100 μL), and L-PrEt2/Ni(BF4)2·6H2O (1:1, 10 mol %) in CH2Cl2 (1.0 mL) at 30 °C for 4 h. bYield of the isolated product as a diastereoisomeric mixture. cDetermined by 1H NMR analysis. dDetermined by chiral HPLC analysis. eThe reaction was carried out at 0 °C. f2 (0.11 mmol) was used, and the reaction was carried out at 30 °C for 12 h. a

integration. 13C NMR data were collected at 100 MHz with complete proton decoupling. Chemical shifts were reported in ppm from the tetramethylsilane with the solvent resonance as the internal standard. Metal catalysts obtained from commercial sources were used without further purification. Enantiomeric excesses were determined by chiral HPLC analysis on Daicel Chiralcel IA/IB/IC/ID/IE/OX-H in comparison with the authentic racemates. Optical rotations were reported as follows: [α]Tλ = (c g/100 mL, in CH2Cl2, D 589 nm). HRMS was recorded on a commercial apparatus (ESI Source, TOF). Chiral N,N′-dioxide ligands, (E)-1-benzyl-4-benzylidenepyrrolidine2,3-dione, benzyl vinylcarbamate, ethyl vinylcarbamate, and 9Hfluoren-9-yl vinylcarbamate were prepared according to a previously reported method.14−16

ities, and enantioselectivities. A possible catalytic cycle with a possible transition state was proposed to illustrate the reaction mechanism.

■

EXPERIMENTAL SECTION

General Remarks. Reactions were carried out using commercial available reagents in an oven-dried apparatus. CH2Cl2 was dried over powdered K2CO3 and distilled under nitrogen just before use. 1H NMR spectra were recorded at 400 MHz. The chemical shifts were recorded in ppm relative to tetramethylsilane and with the solvent resonance as the internal standard. Data were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of doublets), coupling constants (Hz), 8681

DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687

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The Journal of Organic Chemistry

(3.4 mg, 0.01 mmol, 10 mol %), and N,N′-dioxide ligand L-PrEt2 (5.6 mg, 0.01 mmol, 10 mol %) was added to a test tube under an inert atmosphere. Anhydrous CH2Cl2 (1.0 mL) was added, and the solution was stirred at 30 °C for 0.5 h. Subsequently, ethoxyethene 2a (100 μL, 1.04 mmol) was added at 30 °C, and the reaction mixture was stirred for an additional 4 h. The product 3aa was purified by flash chromatography (PET/EtOAc = 3.5:2). General Procedure for the Catalytic Asymmtric IED-HeteroDA Reaction of (E)-1-Benzyl-4-benzylidenepyrrolidine-2,3dione with Benzyl Vinylcarbamate (or Ethyl Vinylcarbamate and 9H-Fluoren-9-yl Vinylcarbamate). A mixture of Ni(BF4)2· 6H2O (3.4 mg, 0.01 mmol, 10 mol %) and N,N′-dioxide ligand LPrEt2 (5.6 mg, 0.01 mmol, 10 mol %) was added to a test, and then anhydrous THF and MeOH (10:1) were added; the solution was stirred at 30 °C for 2 h. The solvent was removed under vacuo. Then, (E)-1-benzyl-4-benzylidenepyrrolidine-2,3-dione (1a) (27.7 mg, 0.1 mmol) and anhydrous CH2Cl2 (1.0 mL) were added. The mixture was stirred at 30 °C for 5 min. Subsequently, benzyl vinylcarbamate 2k (19.5 mg, 0.11 mmol) was added under 30 °C, and the reaction mixture was stirred for an additional 12 h. The residue was purified by flash chromatography on silica gel (PET/EtOAc = 1:1) to afford the desired product 3ak. The product 3am was purified by flash chromatography on silica gel (PET/EtOAc/ether = 1:1:1). General Experimental Procedure for the Scale-up Reaction. A mixture of Ni(BF4)2·6H2O (102.1 mg, 0.30 mmol, 10 mol %) and N,N′-dioxide ligand L-PrEt2 (169.4 mg, 0.30 mmol, 10 mol %) was added to a round-bottom flask. Then 10.0 mL of anhydrous THF was added, and the mixture was stirred at 30 °C for 5 h. The solvent was removed under vacuo. Then, (E)-1-benzyl-4-benzylidenepyrrolidine2,3-dione (1a) (0.83 g, 31.2 mmol) and anhydrous CH2Cl2 (30 mL) were added. The mixture was stirred at 30 °C for 5 min. Subsequently, 1,3-ethoxyethene 2a (3.0 mL, 31.2 mmol) was added under 30 °C, and the reaction mixture was stirred for an additional 10 h. The residue was purified by flash chromatography on silica gel (PEt/EtOAc = 3.5:2) to afford the desired product 3aa. Experimental Procedure for the Hydrogenation of Product 3aa. 3aa (34.9 mg, 0.10 mmol) and Pd/C (100 g%, 34.9 mg) were added into a dry reaction tube, and then methanol (2.0 mL) was added; the mixture was stirred under H2 at 30 °C for 48 h, which could be monitored by TLC. Upon completion of the reaction, Pd/C was removed by suction filtration, and the solvent was evaporated off under reduced pressure; the crude material was purified by silica gel chromatography to give the compound 4aa (63% yield, 60:40 dr, 90% ee/99% ee) as a yellow oil. (2S,4R)-6-Benzyl-2-ethoxy-4-phenylhexahydropyrano[2,3-c]pyrrol-7(2H)-one (4aa). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow oil (dr values cannot be separated by flash chromatography): 22.2 mg, 63% yield, 60:40 dr, 90% ee, 99% ee; the ee was determined by HPLC analysis using a chiral IB column (2-propanol/n-hexane = 20:80, 1.0 mL/min, λ = 254 nm), retention time tminor1 = 6.44 min, tminor2 = 6.94 min, tminor1−1 = 7.54 min, tminor−minor = 8.42 min, tminor−minor = 9.12 min, tminor−major = 9.67 min, tmajor−major = 10.66 min, tminor2−2 = 13.19 min; 1H NMR (400 MHz, CDCl3) δ 7.41−7.30 (m, 5H), 7.22−7.16 (m, 3H), 6.86 (d, J = 7.2 Hz, 2H), 5.00 (s, 1H), 4.91 (d, J = 14.4 Hz, 1H), 4.49 (d, J = 7.6 Hz, 1H), 4.35−4.29 (m, 1H), 3.94 (d, J = 14.4 Hz, 1H), 3.58−3.51 (m, 1H), 3.03−2.99 (m, 1H), 2.95−2.88 (m, 1H), 2.80 (d, J = 10.0 Hz, 1H), 2.52−2.46 (m, 1H), 1.96−1.89 (m, 1H), 1.84−1.80 (m, 1H), 1.28−1.25 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 143.2, 136.4, 128.8, 128.6, 128.5, 127.9, 127.8, 126.9, 96.7, 72.5, 64.2, 46.4, 45.8, 37.2, 35.8, 35.2, 15.1; HRMS (ESI-TOF) calcd for C22H25NO3Na+ [M + Na+] 374.1727, found 374.1728. (2S,4S)-6-Benzyl-2-ethoxy-4-phenyl-3,4,5,6-tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3aa). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white solid (dr values cannot be separated by flash chromatography): mp 138.0−140.0 °C; 34.6 mg, 99% yield, 90:10 dr, 99% ee; [α]20.7 D 39.4 (c 0.746, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 6.47 min, tmajor−major = 6.87 min,

Scheme 2. Gram-Scale Synthesis of 3aa and Transformation of Product 3aa

Scheme 3. Operando IR Experiments, Kinetic Analysis, and Control Experiment

Scheme 4. Catalytic Cycle with a Possible Transition State

General Procedure for the Catalytic Asymmtric IED HeteroDA Reaction of (E)-1-Benzyl-4-benzylidenepyrrolidine-2,3dione with Ethoxyethene. A mixture of (E)-1-benzyl-4-benzylidenepyrrolidine-2,3-dione (1a) (27.7 mg, 0.1 mmol), Ni(BF4)2·6H2O 8682

DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687

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The Journal of Organic Chemistry

column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 7.26 min, tmajor−major = 7.93 min, tmajor−minor = 9.27 min, tminor−minor = 12.84 min; 1H NMR (400 MHz, CDCl3) δ 7.33−7.19 (m, 7H), 7.10−7.08 (m, 2H), 5.38−5.25 (m, 1H), 4.87− 4.73 (m, 1H), 4.51−4.34 (m, 1H), 4.09−3.94 (m, 1H), 3.82 (dd, J = 6.0 Hz, 6.0 Hz, 1H), 3.73−3.60 (m, 1H), 3.51−3.35 (m, 2H), 2.37− 2.21 (m, 1H), 2.14−1.89 (m, 1H), 1.26−1.17, (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 142.9, 139.7, 137.0, 133.0, 129.2, 129.1, 128.7, 128.1, 127.6, 123.0, 98.3, 64.7, 47.4, 46.5, 35.9, 34.2, 15.1; HRMS (ESI-TOF) calcd for C22H2234.9689ClNO3Na+ [M + Na+] 406.1180, found 406.1188, calcd for C22H2236.9659ClNO3Na+ [M + Na+] 408.1151, found 408.1167. (2S,4S)-6-Benzyl-4-(3-bromophenyl)-2-ethoxy-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3fa). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white amorphous solid (dr values can be separated by flash chromatography): 41.8 mg, 98% yield, 87:13 dr, 99% ee; the ee was determined by HPLC analysis using a chiral IE column (2-propanol/ n-hexane = 30:70, 1.0 mL/min, λ = 254 nm); retention time tmajor−major = 23.24 min, tmajor−minor = 25.83 min, tminor−major = 29.92 min, tminor−minor = 33.08 min; 1H NMR (400 MHz, CDCl3) δ 7.39− 7.36 (m, 1H), 7.34−7.18 (m, 7H), 7.09−7.06 (m, 1H), 5.38−5.27 (m, 1H), 4.91−4.75 (m, 1H), 4.45−4.34 (m, 1H), 4.06−3.94 (m, 1H), 3.80 (dd, J = 6.0 Hz, 6.0 Hz, 1H), 3.73−3.58 (m, 1H), 3.53− 3.38 (m, 2H), 2.34−1.19 (m, 2H), 1.26−1.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.5, 143.6, 143.0, 137.0, 130.9, 130.5, 130.4, 128.7, 128.1, 127.6, 126.4, 123.0, 122.7, 98.2, 64.7, 47.4, 46.5, 35.8, 34.5, 15.1; HRMS (ESI-TOF) calcd for C22H2278.9183BrNO3H+ [M + H+] 428.0856, found 428.0864, calcd for C22H2280.9163BrNO3H+ [M + H+] 430.0835, found 430.0847. (2S,4S)-6-Benzyl-4-(4-bromophenyl)-2-ethoxy-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ga). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white solid (dr values can be separated by flash chromatography): mp 90.0−92.0 °C; 42.7 mg, 99% yield 88:12 dr, 98% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 7.32 min, tmajor−major = 8.06 min, tmajor−minor = 9.24 min, tminor−minor = 12.97 min; 1H NMR (400 MHz, CDCl3) δ 7.44−7.39 (m, 2H), 7.33−7.19 (m, 5H), 7.05−7.02 (m, 2H), 5.38− 5.25 (m, 1H), 4.87−4.73 (m, 1H), 4.45−4.34 (m, 1H), 4.09−3.94 (m, 1H), 3.80 (dd, J = 5.6 Hz, 5.6 Hz, 1H), 3.73−3.60 (m, 1H), 3.51−3.35 (m, 2H), 2.36−2.20 (m, 1H), 2.14−1.89 (m, 1H), 1.26− 1.90 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 143.0, 140.2, 137.0, 132.1, 129.5, 128.7, 128.1, 127.6, 122.9, 121.1, 98.2, 64.7, 47.4, 46.5, 35.9, 34.2, 15.0; HRMS (ESI-TOF) calcd for C22H2278.9183BrNO3Na+ [M + Na+] 450.0675, found 450.0674, calcd for C22H2280.9163Br NO3Na+ [M + Na+] 452.0655, found 452.0666. (2S,4S)-6-Benzyl-4-(3,4-dichlorophenyl)-2-ethoxy-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ha). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white amorphous solid (dr values can be separated by flash chromatography): 40.9 mg, 98% yield, 88:12 dr, 99% ee; the ee was determined by HPLC analysis using a chiral IE column (2propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 21.71 min, tmajor−minor = 23.54 min, tminor−major = 29.94 min, tminor−minor = 31.14 min; 1H NMR (400 MHz, CDCl3) δ 7.39− 7.37 (m, Hz, 1H), 7.35−7.27 (m, 3H), 7.26−7.20 (m, 3H), 7.02− 6.98 (m, 1H), 5.39−5.28 (m, 1H), 4.91−4.74 (m, 1H), 4.46−4.36 (m, 1H), 4.06−3.94 (m, 1H), 3.81 (dd, J = 5.2, 6.0 Hz, 1H), 3.73− 3.65 (m, 1H), 3.52−3.56 (m, 2H), 2.27−2.22 (m, 1H), 1.95−1.88 (m, 1H), 1.26−1.21 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.3, 143.2, 141.5, 136.9, 133.0, 131.4, 130.9, 129.8, 128.8, 128.1, 127.7, 127.1, 122.2, 98.2, 64.7, 47.3, 46.5, 35.7, 34.1, 15.0; HRMS (ESITOF) calcd for C22H2134.9689Cl2NO3H+ [M + H+] 418.0971, found 418.0972, C22H2136.9659Cl2NO3H+ [M + H+] 420.0942, found 420.0941. (2S,4S)-6-Benzyl-2-ethoxy-4-(o-tolyl)-3,4,5,6-tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ia). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white

tmajor−minor = 8.46 min, tminor−minor = 11.69 min; 1H NMR (400 MHz, CDCl3) δ 7.32−7.27 (m, 4H), 7.27−7.18 (m, 4H), 7.16−7.13 (m, 2H), 5.39−5.24 (m, 1H), 4.88−4.75 (m, 1H), 4.44−4.32 (m, 1H), 4.15−4.00 (m, 1H), 3.83 (dd, J = 5.6 Hz, 6.0 Hz, 1H), 3.78−3.60 (m, 1H), 3.53−3.39 (m, 2H), 2.37−2.23 (m, 1H), 2.17−1.94 (m, 1H), 1.26−1.20 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 142.8, 141.2, 137.1, 128.9, 128.7, 128.1, 127.8, 127.5, 127.2, 123.7, 98.4, 64.6, 47.6, 46.5, 36.0, 34.7, 15.1; HRMS (ESI-TOF) calcd for C22H23NO3Na+ [M + Na+] 372.1570, found 372.1583. (2S,4S)-6-Benzyl-2-ethoxy-4-(3-fluorophenyl)-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ba). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow solid (dr values can be separated by flash chromatography): mp 96.0−98.0 °C; 36.4 mg, 99% yield, 87:13 dr, 99% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 6.78 min, tmajor−major = 7.11 min, tmajor−minor = 8.41 min, tminor−minor = 14.15 min; 1H NMR (400 MHz, CDCl3) δ 7.33−7.19 (m, 6H), 6.96−6.84 (m, 3H), 5.39−5.26 (m, 1H), 4.90− 4.76 (m, 1H), 4.44−4.33 (m, 1H), 4.09−3.95 (m, 1H), 3.84 (dd, J = 5.6 Hz, 6.0 Hz, 1H), 3.76−3.59 (m, 1H), 3.54−3.38 (m, 2H), 2.38− 2.23 (m, 1H), 2.18−1.92 (m, 1H), 1.27−1.17 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 163.0 (d, J = 246), 143.8 (d, J = 7), 142.9, 137.0, 130.5 (d, J = 8), 128.7, 128.1, 127.6, 123.5 (d, J = 3), 122.9, 114.8 (d, J = 22), 114.3 (d, J = 22), 98.3, 64.7, 47.5, 46.5, 35.8, 34.5, 15.1; HRMS (ESI-TOF) calcd for C22H22FNO3Na+ [M + Na+] 390.1476, found 390.1483. (2S,4S)-6-Benzyl-2-ethoxy-4-(4-fluorophenyl)-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ca). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white solid (dr values can be separated by flash chromatography): mp 66.0−68.0 °C; 35.3 mg, 96% yield, 88:12 dr, 99% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 6.73 min, tmajor−major = 7.51 min, tmajor−minor = 10.08 min, tminor−minor = 12.47 min; 1H NMR (400 MHz, CDCl3) δ 7.33−7.19 (m, 5H), 7.13−7.10 (m, 2H), 7.01−6.96 (m, 2H), 5.38− 5.25 (m, 1H), 4.88−4.74 (m, 1H), 4.51−4.34 (m, 1H), 4.10−3.95 (m, 1H), 3.83 (dd, J = 5.6 Hz, 6.0 Hz, 1H), 3.75−3.60 (m, 1H), 3.52−3.35 (m, 2H), 2.37−2.22 (m, 1H), 2.15−1.90 (m, 1H), 1.26− 1.18 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 161.9 (d, J = 225), 142.8, 137.0, 136.9 (d, J = 3), 129.3 (d, J = 8), 128.7, 128.1, 127.6, 123.4, 115.8 (d, J = 21), 98.3, 64.6, 47.5, 46.5, 36.1, 34.0, 15.1; HRMS (ESI-TOF) calcd for C22H22FNO3Na+ [M + Na+] 390.1476, found 390.1478. (2S,4S)-6-Benzyl-4-(3-chlorophenyl)-2-ethoxy-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3da). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow amorphous solid (dr values can be separated by flash chromatography): 36.7 mg, 96% yield, 87:13 dr, 99% ee; the ee was determined by HPLC analysis using a chiral IA column (2propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 22.77 min, tmajor−minor = 25.89 min, tminor−major = 29.84 min, tminor−minor = 33.79 min; 1H NMR of major product (400 MHz, CDCl3) δ 7.32−7.19 (m, 7H), 7.15 (s, 1H), 7.04−7.10 (m, 1H), 5.39−5.37 (m, 1H), 4.78 (d, J = 14.8 Hz, 1H), 4.42 (d, J = 15.2 Hz, 1H), 4.02−3.95 (m, 1H), 3.81 (dd, J = 5.6 Hz, 11.2 Hz, 1H), 3.73− 3.66 (m, 1H), 3.53−3.38 (m, 2H), 2.28−2.22 (m, 1H), 2.00−1.91 (m, 1H), 1.3 (t, J = 7.2 Hz, 3H); 13C NMR of major product (100 MHz, CDCl3) δ 165.4, 143.3, 143.0, 136.9, 134.7, 130.2, 128.6, 128.0, 127.9, 127.5, 127.4, 125.9, 122.7, 98.2, 64.6, 47.4, 46.4, 35.7, 34.5, 15.0; HRMS (ESI-TOF) calcd for C22H2234.9689ClNO3H+ [M + H+] 384.1361, found 384.1364, calcd for C22H2236.9659ClNO3H+[M + H+] 386.1331, found 386.1335. (2S,4S)-6-Benzyl-4-(4-chlorophenyl)-2-ethoxy-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ea). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white solid (dr values can be separated by flash chromatography): mp 108.0−110.0 °C; 37.9 mg, 99% yield, 89:11 dr, 98% ee; the ee was determined by HPLC analysis using a chiral IA 8683

DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687

Note

The Journal of Organic Chemistry amorphous solid (dr values cannot be separated by flash chromatography): 34.1 mg, 94% yield, 91:9 dr, 99% ee; [α]18.8 D 40.50 (c 0.73, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 8.25 min, tmajor−major = 8.58 min, tminor−minor = 11.72 min, tmajor−minor = 12.26 min; 1H NMR (400 MHz, CDCl3) δ 7.32−7.10 (m, 8H), 7.04−7.00 (m, 1H), 5.36−5.30 (m, 1H), 4.88−4.75 (m, 1H), 4.47−4.35 (m, 1H), 4.07 (dd, J = 6.4 Hz, 6.0 Hz, 3H), 3.73−3.62 (m, 1H), 3.60−3.42 (m, 2H), 2.38−2.30 (m, 3H), 2.25−2.19 (m, 1H), 1.93−1.86 (m, 1H), 1.25−1.18 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 143.4, 139.5, 137.1, 136.0, 130.8, 128.7, 128.1, 127.6, 126.9, 126.6, 123.8, 98.4, 64.6, 47.7, 46.5, 35.2, 19.3, 15.1; HRMS (ESI-TOF) calcd for C23H25NO3Na+ [M + Na+] 386.1727, found 386.1729. (2S,4S)-6-Benzyl-2-ethoxy-4-(p-tolyl)-3,4,5,6-tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ja). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow amorphous solid (dr values cannot be separated by flash chromatography): 36.1 mg, 99% yield, 91:9 dr, 99% ee; [α]19.1 D 79.2 (c 0.73, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 7.85 min, tmajor−major = 8.28 min, tmajor−minor = 9.69 min, tminor−minor = 15.77 min; 1H NMR (400 MHz, CDCl3) δ 7.32−7.18 (m, 5H), 7.12−7.10 (m, 2H), 7.04−7.02 (m, 2H), 5.37−5.23 (m, 1H), 4.86−4.74 (m, 1H), 4.49−4.31 (m, 1H), 4.13−3.95 (m, 1H), 3.79 (dd, J = 6.0 Hz, 6.0 Hz, 1H), 3.73−3.65 (m, 1H), 3.73−3.65 (m, 1H), 3.52−3.39 (m, 2H), 2.33−2.30 (m, 3H), 2.26−2.10 (m, 1H), 2.08−1.92 (m, 1H), 1.25−1.22 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 142.6, 138.2, 137.1, 136.9, 129.6, 128.7, 128.8, 128.5, 128.1, 127.7, 127.5, 124.0, 98.4, 64.6, 47.6, 46.5, 36.1, 34.3, 21.0, 15.1; HRMS (ESI-TOF) calcd for C23H25NO3Na+ [M + Na+] 386.1727, found 386.1731. (2S,4S)-6-Benzyl-2-ethoxy-4-(4-methoxyphenyl)-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ka). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow amorphous solid (dr values cannot be separated by flash chromatography): 37.6 mg, 99% yield, 92:8 dr, 99% ee; [α]19.2 D 75.6 (c 0.76, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 7.26 min, tmajor−major = 7.59 min, tmajor−minor = 8.47 min, tminor−minor = 12.69 min; 1 H NMR (400 MHz, CDCl3) δ 7.32−7.18 (m, 5H), 7.08−7.04 (m, 2H), 6.85−6.80 (m, 2H), 5.37−5.23 (m, 1H), 4.87−4.74 (m, 1H), 4.44−4.31 (m, 1H), 4.13−3.95 (m, 1H), 3.80−3.73 (m, 4H), 3.71− 3.65 (m, 1H), 3.52−3.38 (m, 2H), 2.35−2.20 (m, 1H), 2.14−1.91 (m, 1H), 1.26−1.22 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 158.7, 142.6, 137.1, 133.1, 128.8, 128.7, 128.1, 127.5, 124.2, 114.3, 98.5, 64.6, 55.3, 47.6, 46.5, 36.1, 33.8, 15.1; HRMS (ESI-TOF) calcd for C23H25NO4Na+ [M + Na+] 402.1676, found 402.1684. (2S,4S)-6-Benzyl-2-ethoxy-4-(4-(trifluoromethyl)phenyl)-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3la). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white amorphous solid (dr values cannot be separated by flash chromatography): 39.2 mg, 94% yield, 90:10 dr, 98% ee; [α]19.4 D 61.7 (c 0.80, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 20:80, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 9.98 min, tmajor−minor = 10.85 min, tmajor−major = 11.76 min, tminor−minor = 20.72 min; 1H NMR (400 MHz, CDCl3) δ 7.58−7.53 (m, 2H), 7.33−7.26 (m, 5H), 7.25−7.20 (m, 2H), 5.40−5.30 (m, 1H), 4.89−4.75 (m, 1H), 4.45−4.35 (m, 1H), 4.03−3.96 (m, 1H), 3.91 (dd, J = 5.6, 5.6 Hz, 1H), 3.80−3.61 (m, 1H), 3.53−3.36 (m, 2H), 2.30−2.24 (m, 1H), 2.00−1.93 (m, 1H), 1.26−1.15 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 145.4, 143.2, 136.9, 129.7 (J = 33), 128.7, 128.2, 128.1, 127.7, 127.7, 126.0 (J = 4), 122.4, 98.2, 64.7, 47.4, 46.5, 35.9, 34.7, 15.1; HRMS (ESI-TOF) calcd for C23H22F3NO3Na+ [M + Na+] 440.1444, found 440.1452. (2S,4S)-6-Benzyl-2-ethoxy-4-(naphthalen-1-yl)-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ma). This compound was purified by flash chromatography (petroleum ether/EtOAc =

3.5:2) to afford a white solid (dr values cannot be separated by flash chromatography): mp 144.0−146.0 °C; 39.7 mg, 99% yield, 97:3 dr, 90% ee; [α]20.6 D = 39.6 (c 0.67, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IE column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 26.59 min, tmajor−minor = 34.73 min, tminor−mixture = 42.61 min; 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.88−7.86 (m, 1H), 7.76−7.02 (d, J = 8.4 Hz, 1H), 7.50−7.38 (m, 3H), 7.30−7.19 (m, 6H), 5.38−5.35 (m, 1H), 4.76−4.44 (m, 1H), 4.09−3.70 (m, 2H), 3.54−3.50 (m, 2H), 2.39−2.32 (m, 1H), 2.09−1.83 (m, 1H), 1.29−1.25 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 137.1, 129.2, 128.6, 128.0, 127.5, 126.4, 125.9, 125.5, 98.7, 98.7, 64.7, 47.8, 46.4, 35.9, 29.7, 15.1; HRMS (ESI-TOF) calcd for C26H25NO3Na+ [M + Na+] 422.1727, found 422.1738. (2S,4S)-6-Benzyl-2-ethoxy-4-(naphthalen-2-yl)-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3na). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white amorphous solid (dr values cannot be separated by flash chromatography): 39.6 mg, 99% yield, 90:10 dr, 96% ee; [α]20.6 D 62.6 (c 0.78, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IB column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 7.99 min, tmajor−minor = 9.24 min, tminor−major = 10.46 min, tminor−minor = 12.36 min; 1H NMR (400 MHz, CDCl3) δ 7.81−7.73 (m, 3H), 7.63−7.60 (m, 1H), 7.49−7.44 (m, 2H), 7.30−7.17 (m, 6H), 5.42−5.28 (m, 1H), 4.88−4.74 (m, 1H), 4.42−4.29 (m, 1H), 3.75−3.65 (m, 1H), 3.54−3.38 (m, 2H), 2.41−2.29 (m, 1H), 2.27−1.71 (m, 2H), 1.27− 1.18 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 142.9, 138.6, 137.0, 133.5, 132.6, 128.8, 128.7, 128.1, 128.1, 127.7, 127.6, 126.8, 126.4, 126.0, 125.5, 123.7, 98.5, 64.7, 47.7, 46.5, 35.8, 34.9, 15.1; HRMS (ESI-TOF) calcd for C26H25NO3Na+ [M + Na+] 422.1727, found 422.1725. (2S,4R)-4-(Benzo[b]thiophen-3-yl)-6-benzyl-2-ethoxy-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3oa). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow solid (dr values cannot be separated by flash chromatography): mp 74.0−76.0 °C; 40.2 mg 99% yield, 98:2 dr, 93% = 70.6 (c 0.24, in CH2Cl2); the ee was determined by ee; [α]20.5 D HPLC analysis using a chiral IE column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 26.81 min, tmajor−minor = 31.30 min, tminor−mixture = 37.77 min; 1H NMR (400 MHz, CDCl3) δ 7.86−7.84 (m, 1H), 7.70−7.68 (m, 1H), 7.37−7.25 (m, 4H), 7.24−7.14 (m, 4H), 5.42−5.32 (m, 1H), 4.84−4.43 (m, 2H), 4.33−4.28 (m, 1H), 4.08−3.99 (m, 1H), 2.40−2.21 (m, 2H), 1.28−1.19 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 142.7, 140.9, 137.4, 137.0, 135.2, 128.7, 127.9, 127.5, 124.6, 124.3, 123.5, 123.2, 122.9, 121.6, 98.5, 64.7, 47.8, 46.4, 33.6, 29.2, 15.1; HRMS (ESI-TOF) calcd for C24H23N O3SNa+ [M + Na+] 428.1291, found 428.1296. (2S,4S)-6-Benzyl-2-butoxy-4-phenyl-3,4,5,6-tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ab). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white amorphous solid (dr values can be separated by flash chromatography): 35.1 mg, 93% yield, 86:14 dr, 97% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 6.27 min, tmajor−major = 6.93 min, tmajor−minor = 8.38 min, tminor−minor = 15.06 min; 1H NMR (400 MHz, CDCl3) δ 7.34−7.21 (m, 7H), 7.20−7.13 (m, 3H), 7.42−5.22 (m, 1H), 4.86−4.33 (m, 2H), 3.82 (dd, J = 6.0, 6.0 Hz, 1H), 3.66−3.60 (m, 1H), 3.53−3.38 (m, 2H), 2.30−2.23 (m, 1H), 2.17−1.94 (m, 1H), 1.62−1.51 (m, 2H), 1.40−1.29 (m, 2H), 0.93−0.86 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 142.7, 141.2, 137.1, 128.9, 128.7, 128.0, 127.8, 127.5, 127.2, 123.9, 98.6, 68.8, 47.6, 46.4, 36.0, 34.8, 31.6, 19.2, 13.7; HRMS (ESI-TOF) calcd for C24H27NO3Na+ [M + Na+] 400.1883, found 400.1884. (2S,4S)-6-Benzyl-2-(tert-butoxy)-4-phenyl-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ac). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow amorphous solid (dr values can be separated by flash chromatography): 37.5 mg, 99% yield, 89:11 dr, 91% ee; the 8684

DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687

Note

The Journal of Organic Chemistry

(m, 4H), 5.98−5.85 (m, 1H), 5.43−5.14 (m, 3H), 4.87−4.76 (m, 1H), 4.53−4.33 (m, 2H), 4.26−4.11 (m, 1H), 3.85 (dd, J = 6.0, 6.0 Hz, 1H), 3.52−3.38 (m, 2H), 2.41−2.23 (m, 1H), 2.22−1.96 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 165.6, 142.7, 141.1, 137.0, 133.8, 129.0, 128.7, 128.1, 127.8, 127.6, 127.3, 124.0, 117.9, 97.7, 69.5, 47.6, 46.5, 35.8, 34.7; HRMS (ESI-TOF) calcd for C23H23NO3Na+ [M + Na+] 384.1570, found 384.1576. (2R,4S)-6-Benzyl-2-(ethylthio)-4-phenyl-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ah). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow solid (dr values can be separated by flash chromatography): mp 60.0−62.0 °C; 24.8 mg, 68% yield, 75:25 dr, 70% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 6.82 min, tminor−major = 7.89 min, tminor−minor = 9.31 min, tmajor−minor = 11.50 min; 1H NMR (400 MHz, CDCl3) δ 7.32−7.24 (m, 6H), 7.21−7.18 (m, 2H), 7.14−7.11 (m, 2H), 5.73− 5.33 (m, 1H), 4.86−4.71 (m, 1H), 4.48−4.32 (m, 1H), 3.81−3.77 (m, 1H), 3.57−3.40 (m, 2H), 2.95−2.77 (m, 2H), 2.53−2.36 (m, 1H), 2.34−2.14 (m, 1H), 1.36−1.30 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 164.9, 146.0, 143.2, 141.1, 140.9, 137.1, 137.0, 129.0, 129.0, 128.7, 128.1, 128.1, 127.9, 127.8, 127.7, 127.6, 127.4, 123.4, 123.0, 82.3, 81.4, 47.6, 47.3, 46.5, 39.5, 38.0, 37.0, 36.2, 25.0, 24.8, 15.0, 14.9; HRMS (ESI-TOF) calcd for C22H23NO2SNa+ [M + Na+] 388.1342, found 388.1347. (2S,4S)-6-Benzyl-2-ethoxy-2-methyl-4-phenyl-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ai). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow amorphous solid (dr values can be separated by flash chromatography): 34.8 mg, 96% yield, 61:39 dr, 71% ee; the ee was determined by HPLC analysis using a chiral IA column (2propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 6.05 min, tminor−minor = 7.24 min, tminor−major = 7.77 min, tmajor−minor = 8.30 min; 1H NMR (400 MHz, CDCl3) δ 7.31−7.23 (m, 6H), 7.23−7.12 (m, 4H), 4.86−4.39 (m, 2H), 3.83−3.58 (m, 2H), 3.52−3.35 (m, 3H), 3.34−3.15 (m, 2H), 2.30−2.13 (m, 2H), 1.92− 1.85 (m, 1H), 1.61 (s, 1H), 1.53 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 165.8, 165.6, 144.6, 143.2, 141.7, 141.3, 137.2, 137.1, 128.9, 128.7, 128.5, 128.2, 128.1, 127.9, 127.9, 127.6, 127.5, 127.1, 126.9, 124.4, 121.7, 102.8, 101.5, 57.6, 57.5, 47.7, 47.4, 46.6, 46.4, 42.4, 40.5, 37.4, 36.1, 23.2, 22.8, 15.6, 15.3; HRMS (ESI-TOF) calcd for C23H25NO3Na+ [M + Na+] 386.1727, found 386.1725. (2S,4S)-6-Benzyl-2-methoxy-2-methyl-4-phenyl-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3aj). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white amorphous solid (dr values can be separated by flash chromatography): 33.5 mg, 96% yield, 65:35 dr, 78% ee; the ee was determined by HPLC analysis using a chiral IC column (2-propanol/ n-hexane = 20:80, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 19.74 min, tminor−minor = 22.06 min, tmajor−major = 30.02 min, tmajor−minor = 33.58 min; 1H NMR of major product (400 MHz, CDCl3) δ 7.32−7.19 (m, 8H), 7.16−7.14 (m, 2H), 4.83 (d, J = 14.8 Hz, 1H), 4.40 (d, J = 14.8 Hz, 1H), 3.66 (t, J = 6.8 Hz, 1H), 3.55 (q, J = 18 Hz, 2H), 3.34 (s, 3H), 2.26−2.21 (m, 1H), 2.18−2.13 (m, 1H), 1.53 (s, 3H); 13C NMR of major product (100 MHz, CDCl3) δ 165.5, 144.4, 141.7, 137.0, 128.7, 128.5, 128.1, 128.0, 127.5, 126.9, 121.9, 102.8, 49.3, 47.7, 46.5, 40.1, 37.3, 22.2; HRMS (ESI-TOF) calcd for C22H23NO3Na+ [M + Na+] 372.1570, found 372.1579. Benzyl ((2S,4S)-6-Benzyl-7-oxo-4-phenyl-2,3,4,5,6,7hexahydropyrano[2,3-c]pyrrol-2yl) carbamate (3ak). This compound was purified by flash chromatography (petroleum ether/EtOAc = 1:1) to afford a yellow solid (dr values can be separated by flash chromatography): mp 72.0−74.0 °C; 44.9 mg, 99% yield, 86:14 dr, 94% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 11.93 min, tmajor−major = 12.94 min, tmajor−minor = 16.05 min, tminor−minor = 21.25 min; 1H NMR (400 MHz, CDCl3) δ 7.38−7.24 (m, 11H), 7.23−7.16 (m, 2H), 7.15−7.08 (m, 2H), 5.81−5.59 (m, 2H), 5.17−5.09 (m, 2H), 4.85−4.75 (m, 1H), 4.46−4.30 (m, 1H), 3.89−3.69 (m, 1H), 3.62−3.27 (m, 2H), 2.40−

ee was determined by HPLC analysis using a chiral OXH column (methanol/CO2 (supercriticality) = 20:80, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 20.26 min, tmajor−minor = 22.38 min, tminor−mixture= 24.24 min; 1H NMR (400 MHz, CDCl3) δ 7.32−7.23 (m, 6H), 7.22−7.15 (m, 4H), 5.64−5.46 (m, 1H), 4.85−4.75 (m, 1H), 4.42−4.32 (m, 1H), 3.84 (dd, J = 6.0, 5.6 Hz, 1H), 3.52−3.38 (m, 2H), 2.17−2.09 (m, 1H), 1.98−1.91 (m, 1H), 1.32−1.30 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 165.9, 142.8, 141.6, 137.3, 128.8, 128.6, 128.0, 127.9, 127.5, 127.1, 123.4, 93.4, 75.8, 47.6, 46.4, 37.2, 34.7, 28.8; HRMS (ESI-TOF) calcd for C24H27NO3Na+ [M + Na+] 400.1883, found 400.1888. (2S,4S)-6-Benzyl-2-isobutoxy-4-phenyl-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ad). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white amorphous solid (dr values cannot be separated by flash chromatography): 37.3 mg, 99% yield, 95:5 dr, 99% ee; [α]26.0 D 88.5 (c 0.72, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 5.76 min, tmajor−major = 6.34 min, tmajor−minor = 7.72, tminor−minor = 14.67 min; 1H NMR (400 MHz, CDCl3) δ 7.33−7.23 (m, 6H), 7.22−7.13 (m, 4H), 5.36−5.35 (m, 1H), 4.87−4.34 (m, 2H), 3.83 (dd, J = 6.0, 6.0 Hz, 1H), 3.75−3.69 (m, 1H), 3.52−3.27 (m, 3H), 2.38−2.14 (m, 1H), 2.02−1.84 (m, 2H), 1.07−0.72 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 165.7, 142.7, 141.3, 137.1, 128.9, 128.7, 128.0, 127.8, 127.5, 127.2, 123.9, 98.6 (d, J = 2), 75.5, 47.5, 46.4, 36.0, 34.8, 28.4, 19.2, 19.2; HRMS (ESI-TOF) calcd for C24H27NO3Na+ [M + Na+] 400.1883, found 400.1890. (2S,4S)-6-Benzyl-2-isopropoxy-4-phenyl-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ae). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a yellow amorphous solid (dr values cannot be separated by flash chromatography): 31.2 mg, 86% yield, 92:8 dr, 97% ee; [α]20.1 D 69.5 (c 0.67, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 5.75 min, tmajor−major = 6.49 min, tmajor−minor= 7.79 min, tminor−minor= 10.89 min; 1 H NMR (400 MHz, CDCl3) δ 7.31−7.21 (m, 6H), 7.19−7.11 (m, 4H), 5.48−5.33 (m, 1H), 4.86−4.75 (m, 1H), 4.44−4.32 (m, 1H), 4.26−4.14 (m, 1H), 3.85−3.74 (m, 1H), 3.52−3.38 (m, 2H), 2.23− 2.15 (m, 1H), 2.00−1.93 (m, 1H), 1.22−1.14 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 165.8, 142.7, 141.4, 137.2, 128.9, 128.7, 128.0, 127.8, 127.5, 127.2, 123.8, 96.6, 70.4, 47.6, 46.4, 36.4, 34.8, 23.5, 21.7; HRMS (ESI-TOF) calcd for C23H25NO3Na+ [M + Na+] 386.1727, found 386.1732. ( 2 S, 4S ) -6 -Be nz yl- 2- ( cy cloh ex ylo x y) -4 -ph en yl- 3 ,4, 5,6 tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3af). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white amorphous solid (dr values can be separated by flash chromatography): 35.1 mg, 87% yield, 88:12 dr, 95% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/ n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−minor = 6.22 min, tmajor−major = 6.72 min, tmajor−minor= 7.39 min, tminor−major= 18.76 min; 1H NMR (400 MHz, CDCl3) δ 7.34−7.23 (m, 6H), 7.23−7.13 (m, 4H), 5.53−5.52 (m, 1H), 4.88−4.31 (m, 2H), 3.92−3.81 (m, 2H), 3.52−3.38 (m, 2H), 2.24−1.95 (m, 2H), 1.75− 1.70 (m, 2H), 1.56−1.53(m, 1H), 1.36−1.20 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 165.9, 142.8, 141.4, 137.1, 128.9, 128.7, 128.0, 127.8, 127.5, 127.2, 123.8, 96.5, 76.1, 46.4, 36.4, 34.8, 33.5, 31.8, 25.6, 24.2; HRMS (ESI-TOF) calcd for C26H29NO3Na+ [M + Na+] 426.2040, found 426.2039. (2S,4S)-2-(Allyloxy)-6-benzyl-4-phenyl-3,4,5,6-tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3ag). This compound was purified by flash chromatography (petroleum ether/EtOAc = 3.5:2) to afford a white solid (dr values can be separated by flash chromatography): mp 74.0− 76.0 °C; 31.8 mg, 88% yield, 88:12 dr, 99% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 6.68 min, tmajor−major = 7.10 min, tmajor−minor = 8.43 min, tminor−minor = 13.65 min; 1H NMR (400 MHz, CDCl3) δ 7.35−7.24 (m, 6H), 7.23−7.13 8685

DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687

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2.22 (m, 1H), 2.12−1.98 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 164.8, 155.0, 145.5, 140.4, 136.9, 135.8, 129.1, 128.8, 128.7, 128.6, 128.4, 128.1, 128.0, 127.6, 127.4, 122.8, 80.8, 67.4, 47.1, 46.5, 39.4, 37.8; HRMS (ESI-TOF) calcd for C28H26N2O4Na+ [M + Na+] 477.1785, found 477.1794. E t h y l ( ( 2 S , 4 S ) - 6 - B e n z y l - 7 - ox o - 4 - p h e n y l - 2 , 3 , 4 , 5 , 6 , 7 hexahydropyrano[2,3-c]pyrrol-2-yl)carbamate (3al). This compound was purified by flash chromatography (petroleum ether/ EtOAc = 1:1) to afford a white solid (dr values can be separated by flash chromatography): mp 84.0−86.0 °C; 38.9 mg, 99% yield, 82:18 dr, 94% ee; the ee was determined by HPLC analysis using a chiral IA column (2-propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tminor−major = 9.24 min, tmajor−major = 9.73 min, tmajor−minor = 11.56 min, tminor−minor = 15.48 min; 1H NMR (400 MHz, CDCl3) δ 7.34−7.22 (m, 6H), 7.20−7.10 (m, 4H), 5.79−5.63 (m, 2H), 4.84− 4.75 (m, 1H), 4.47−4.31 (m, 1H), 4.19−4.10 (m, 2H), 3.90−3.71 (m, 1H), 3.62−3.34 (m, 2H), 2.40−2.23 (m, 1H), 2.09−2.00 (m, 1H), 1.27−1.23 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 164.9, 155.2, 145.5, 140.5, 136.9, 129.1, 128.7, 128.1, 128.0, 127.6, 127.4, 122.8, 80.8, 61.6, 47.1, 46.5, 39.4, 37.7, 14.5; HRMS (ESI-TOF) calcd for C23H24N2O4Na+ [M + Na+] 415.1628, found 415.1632. 9H-Fluoren-9-yl ((2S,4S)-6-Benzyl-7-oxo-4-phenyl-2,3,4,5,6,7hexahydropyrano[2,3-c]pyrrol-2-yl)carbamate (3am). This compound was purified by flash chromatography (petroleum ether/ EtOAc/Et2O = 1:1:1) to afford a white solid (dr values cannot be separated by flash chromatography): mp 124.0−126.0 °C; 43.8 mg, 83% yield, 90:10 dr, 95% ee, [α]20.5 D −23.0 (c 0.97, in CH2Cl2); the ee was determined by HPLC analysis using a chiral IC column (2propanol/n-hexane = 30:70, 1.0 mL/min, λ = 254 nm), retention time tmajor−major = 58.30 min, tminor−major = 65.67 min, tminor−minor = 112.05 min, tminor−minor = 126.37 min; 1H NMR (400 MHz, CDCl3) δ 7.68− 7.60 (m, 4H), 7.44−7.10 (m, 14H), 6.71−6.69 (m, 1H), 5.90 (t, J = 10.4 Hz, 1H), 5.60 (d, J = 10.4 Hz, 1H), 4.87−4.74 (m, 1H), 4.48− 4.32 (m, 1H), 3.94−3.90 (m, 1H), 3.52−3.35 (m, 2H), 2.46−2.41 (m, 1H), 2.09−2.00 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 164.9, 155.7, 145.5, 141.6, 140.7, 140.4, 136.9, 129.6, 129.1, 128.7, 128.0, 127.8, 127.6, 127.5, 126.2, 126.1, 123.0, 119.9, 81.0, 76.3, 47.1, 46.5, 39.5, 37.7; HRMS (ESI-TOF) calcd for C34H28N2O4Na+ [M + Na+] 551.1941, found 551.1942. (2S,4S)-6-Benzyl-2-ethoxy-3-methyl-4-(naphthalen-1-yl)-3,4,5,6tetrahydropyrano[2,3-c]pyrrol-7(2H)-one (3aa′). This compound was purified by flash chromatography (petroleum ether/EtOAc = 1:1) to afford a white oil (dr values can be separated by flash chromatography): 41.3 mg, 99% yield, 67:33 dr, 99% ee; the ee was determined by HPLC analysis using a chiral IA column (2propanol/n-hexane = 20:80, 1.0 mL/min, λ = 254 nm), retention time tminor1−major = 7.54 min, tminor2−major = 8.23 min, tmajor−major = 8.71 min, tmajor−minor = 9.34 min, tminor1−minor = 10.06 min, tminor3−major = 12.63 min, tminor2−major = 13.09 min, tminor3−minor = 16.34 min; 1H NMR (400 MHz, CDCl3) δ 8.13−7.75 (m, 3H), 7.56−7.08 (m, 9H), 5.20−4.96 (m, 1H), 4.83−4.65 (m, 1H), 4.53−3.82 (m, 3H), 3.81−3.18 (m, 3H), 2.72−2.26 (m, 1H), 1.32−1.25 (m, 3H), 0.92−0.65 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 165.9, 165.8, 165.7, 143.4, 143.1, 141.5, 137.2, 137.1, 137.1, 134.6, 134.2, 134.1, 134.0, 133.9, 132.7, 131.8, 131.0, 130.0, 129.4, 129.1, 129.0, 128.7, 128.6, 128.6, 128.2, 128.1, 127.7, 127.7, 127.6, 127.6, 127.5, 127.4, 126.5, 126.6, 126.5, 126.3, 126.1, 125.8, 125.6, 125.2, 124.8, 124.3, 123.9, 122.8, 122.5, 103.2, 102.4, 102.2, 65.0, 64.6, 47.9, 47.8, 47.6, 46.6, 46.5, 46.3, 43.7, 40.3, 36.2, 35.7, 35.2, 34.4, 15.2, 15.0, 14.6, 13.9, 12.7; HRMS (ESITOF) calcd for C27H27NO3Na+ [M + Na+] 436.1883, found 436.1884.

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Note

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Fax: (+86) 28-8541-8249. ORCID

Xiaohua Liu: 0000-0001-9555-0555 Xiaoming Feng: 0000-0003-4507-0478 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We appreciate the National Natural Science Foundation of China (21572136 and 21432006) for financial support. REFERENCES

(1) For selected reviews on the inverse-electron-demand heteroDiels−Alder (IED hetero-DA) reaction, see: (a) Tietze, L. F.; Saling, P. Enantioselective Intramolecular Hetero Diels-Alder Reactions of 1Oxa-1,3-butadienes with a New Chiral Lewis Acid. Synlett 1992, 1992, 281−282. (b) Tietze, L. F.; Saling, P. Enantioselective Sequential Transformations by Use of Metal Complexes: Tandem-KnoevenagelHetero-Diels−Alder Reactions with New Chiral Lewis Acids. Chirality 1993, 5, 329−333. (c) Evans, D. A.; Johnson, J. S. Catalytic Enantioselective Hetero Diels−Alder Reactions of α,β-Unsaturated Acyl Phosphonates with Enol Ethers. J. Am. Chem. Soc. 1998, 120, 4895−4896. (d) Evans, D. A.; Olhava, E. J.; Johnson, J. S.; Janey, J. M. Chiral C2-Symmetric CuII Complexes as Catalysts for Enantioselective Hetero-Diels−Alder Reactions. Angew. Chem., Int. Ed. 1998, 37, 3372−3375. (e) Thorhauge, J.; Johannsen, M.; Jørgensen, K. A. Highly Enantioselective Catalytic Hetero-Diels−Alder Reaction with Inverse Electron Demand. Angew. Chem., Int. Ed. 1998, 37, 2404− 2406. (f) Evans, D. A.; Johnson, J. S.; Olhava, E. J. Enantioselective Synthesis of Dihydropyrans. Catalysis of Hetero Diels−Alder Reactions by Bis(oxazoline) Copper(II) Complexes. J. Am. Chem. Soc. 2000, 122, 1635−1649. (g) Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. A Novel Catalytic and Highly Enantioselective Approach for the Synthesis of Optically Active Carbohydrate Derivatives. J. Org. Chem. 2000, 65, 4487−4497. (h) Zhuang, W.; Thorhauge, J.; Jørgensen, K. A. Synthesis of Optically Active Amino Sugar Derivatives Using Catalytic Enantioselective Hetero-Diels− Alder Reactions. Chem. Commun. 2000, 459−460. (i) Audrain, H.; Jørgensen, K. A. A New Catalytic Enantioselective Approach to Optically Active Lactones by Addition Reactions to α-Dicarbonyl Compounds. J. Am. Chem. Soc. 2000, 122, 11543−11544. (2) For selected reactions of linear dienes, see: (a) Zhou, Y. H.; Lin, L. L.; Zhang, Y. L.; Zheng, J. F.; Liu, X. H.; Feng, X. M. N,N′Dioxide/Nickel(II)-Catalyzed Asymmetric Inverse-Electron-Demand Hetero-Diels−Alder Reaction of β,γ-Unsaturated α-Ketoesters with Enecarbamates. Chem. - Eur. J. 2014, 20, 16753−16758. (b) Matsumura, Y.; Suzuki, T.; Sakakura, A.; Ishihara, K. Catalytic Enantioselective Inverse Electron Demand Hetero-Diels−Alder Reaction with Allylsilanes. Angew. Chem., Int. Ed. 2014, 53, 6131− 6134. (c) Liu, Q.-J.; Wang, L. J.; Kang, Q.-K.; Zhang, X. P.; Tang, Y. Cy-SaBOX/Copper(II)-Catalyzed Highly Diastereo- and Enantioselective Synthesis of Bicyclic N,O Acetals. Angew. Chem., Int. Ed. 2016, 55, 9220−9223. (d) Lv, J.; Zhang, L.; Luo, S. Z.; Cheng, J.-P. Switchable Diastereoselectivity in Enantioselective [4 + 2] Cycloadditions with Simple Olefins by Asymmetric Binary Acid Catalysis. Angew. Chem., Int. Ed. 2013, 52, 9786−9790. (3) For selected reactions of cyclic dienes, see: (a) Lv, H.; Chen, X.Y.; Sun, L.-H.; Ye, S. Enantioselective Synthesis of Indole-Fused Dihydropyranones via Catalytic Cycloaddition of Ketenes and 3Alkylenyloxindoles. J. Org. Chem. 2010, 75, 6973−6976. (b) Yang, L. M.; Wang, F.; Chua, P. J.; Lv, Y. B.; Zhong, L.-J.; Zhong, G. NHeterocyclic Carbene (NHC)-Catalyzed Highly Diastereo- and Enantioselective Oxo-Diels−Alder Reactions for Synthesis of Fused

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00839. Full optimization details, 1H and 13C NMR spectra, and HPLC data (PDF) Crystal data for 3aa (CIF) 8686

DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687

Note

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DOI: 10.1021/acs.joc.8b00839 J. Org. Chem. 2018, 83, 8679−8687