Organocatalytic Asymmetric Synthesis of 3,3′-Pyrrolidinyl

(7,8) Very recently, Chen's grpup described an asymmetric [3+2] annulation reaction ... (10,11) Also, many studies have documented the stereoselective...
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Article Cite This: J. Org. Chem. 2018, 83, 7741−7750

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Organocatalytic Asymmetric Synthesis of 3,3′-Pyrrolidinylbispirooxindoles via Michael/N‑Hemiketalization Cascade Reaction between 3‑Aminooxindoles and Isatin-Derived β,γ-Unsaturated α‑Keto Esters Ye Lin, Bo-Liang Zhao, and Da-Ming Du*

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School of Chemistry and Chemical Engineering, Beijing Institute of Technology, 5 South Zhongguancun Street, Beijing 100081, People’s Republic of China S Supporting Information *

ABSTRACT: A novel strategy for the construction of 3,3′pyrrolidinyl-bispirooxindoles through a Michael/N-hemiketalization cascade reaction of 3-aminooxindoles and isatinderived β,γ-unsaturated α-keto esters was developed. Under mild conditions, a series of 3,3′-pyrrolidinyl-bispirooxindoles were obtained in moderate to good yields with high diastereoand enantioselectivities by using a cinchona-derived bifunctional squaramide organocatalyst. This work represents the first example using the 3-aminooxindoles for the construction of 3,3′-pyrrolidinyl-bispirooxindoles.

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INTRODUCTION

which is probably due to the challenge imposed by constructing such structurally rigid bis-spirooxindole frameworks containing multiple vicinal stereogenic centers. As a pioneer work, Shi’s group first reported an elegant approach to the asymmetric synthesis of 3,3′-pyrrolidinyl-bispirooxindoles via a chiral phosphoric acid-catalyzed 1,3-dipolar cycloaddition of isatin-derived azomethine ylides with methyleneindolinones (Scheme 1a).5 Subsequently, Enders’ group developed a highly stereoselective synthesis of this related framework through an organocatalytic Mannich/Boc-deprotecion/aza-Michael sequence (Scheme 1b).6 Next, Lu and Enders’ groups reported the asymmetric synthesis of trifluoromethyl-substituted 3,3′pyrrolidinyl-bispirooxindoles through bifunctional catalyzed 1,3-dipolar cycloaddition reactions (Scheme 1c).7,8 Very recently, Chen’s grpup described an asymmetric [3+2] annulation reaction of Morita−Baylis−Hillman carbonates from isatins and isatin-based N-Boc-ketimines (Scheme 1d).9 In spite of these remarkable advances, it is still highly desirable to develop catalytic asymmetric strategies for the construction of this class of 3,3′-pyrrolidinyl-dispirooxindole framework. Recently, 3-aminooxindoles containing two reactive sites as spirooxindole skeleton synthons have attracted great interest from synthetic chemists.10,11 Also, many studies have documented the stereoselective construction of structurally diverse pyrrolidinyl spirooxindoles using 3-aminooxindoles as powerful and versatile precursors via a cascade reaction.11

A great deal of elegant synthetic methods for the construction of spirocyclic oxindoles have been developed over the past decade1 due to their prevalent presence in various alkaloid natural products and pharmacologically active agents.2−4 Among various spirocyclic oxindole cores, the pyrrolidinylspirooxindole represents a very important class because of its rich bioactivities.3 In particular, as an important subtype of spirooxindoles, the 3,3′-pyrrolidinyl-bispirooxindoles have been demonstrated to possess a wide range of biological activities,4 such as antimicrobial,4a antifungal,4b antibacterial, and anticancer activities4c (Figure 1). As a consequence, it is strongly desired to develop efficient synthetic methods for the construction of diverse 3,3′pyrrolidinyl-bispirooxindoles. However, only limited examples of catalytic asymmetric synthesis have been reported as yet,5−8

Figure 1. Representative biologically active compounds containing the 3,3′-pyrrolidinyl-bispirooxindole skeleton. © 2018 American Chemical Society

Received: March 10, 2018 Published: July 11, 2018 7741

DOI: 10.1021/acs.joc.8b00632 J. Org. Chem. 2018, 83, 7741−7750

Article

The Journal of Organic Chemistry

squaramide catalysts could smoothly catalyze the model reaction, affording the desired products in good yields with respectable diastereo- and enantioselectivities, while hydrocinchonidine-derived squaramide C8 bearing the 4-CF3 group on the aromatic ring gave the best yield of 85% and enantioselectivity in 87% ee, albeit with a moderate erosion in diastereoselectivity (7:1 dr, Table 1, entry 8). A significant decline in yield and enantioselectivity was obtained when (1S,2S)-1,2-diaminocyclohexane-derived squaramide C7 and glucose-derived squaramide C9 were used (Table 1, entries 7 and 9). In addition, a quinine-derived thiourea C10 was also screened in comparison with the used squaramides. Unfortunately, the outcome was unsatisfactory. To further optimize the reaction conditions, other parameters were evaluated. A series of solvents including chloroform, arenes, acetonitrile, tetrahydrofuran, and diethyl ether were evaluated (Table 1, entries 11−16). It was found that dichloromethane remained the suitable solvent. Subsequent investigations on the loading of catalyst showed that a better result was obtained when increasing the loading of catalyst to 10 mol % (Table 1, entry 18). Finally, we investigated the impact of the temperature on the reaction. When the temperature was lowered to 0 °C, the reaction proceeded for 3 h with the best overall results (85% yield, 16:1 dr, 90% ee, Table 1, entry 19). When the temperature was reduced to −20 °C, no improvement was obtained (Table 1, entry 20). With the optimized conditions in hand, we probed the generality of our protocol using isatin-derived β,γ-unsaturated α-keto ester 2a and a series of 3-aminooxindoles 1a−1k. As shown in Scheme 2, most of the reactions proceeded smoothly to afford the corresponding 3,3′-pyrrolidinyl-bispirooxindoles 3 in good yields with high stereoselectivities. The corresponding N1-protected substrates 1a−1d were tolerated and provided the corresponding products 3aa−3da with good results, while the unprotected substrate 1e gave an inferior result in diastereoselectivity (2:1 dr). Various halogens and electron-donating substituents at the 5- or 6-position on the oxindole ring had a very little influence on enantioselectivity (85−90% ee). Subsequently, the substituent on the 3-amino group of the oxindole was examined (3ka), and it was found that the amine with N-acyl worked well for the reaction. To further explore the substrate scope of the asymmetric Michael/N-hemiketalization cascade reaction, the structural variations of isatin-derived β,γ-unsaturated α-keto esters 2 were also investigated. As can be seen from the results shown in Scheme 3, the effects of the N-protecting groups on the oxindole skeleton were first evaluated for this transformation. It was found that the corresponding reactions were performed well, and the desired products 3ab−3ad were obtained in good yields (75−85%) with high diastereoselectivities and enantioselectivities, respectively (up to 10:1 dr and 90−91% ee). Afterward, a variety of substituents on the oxindole ring were evaluated. The substrates 2e and 2f, bearing electron-donating substituents (5-MeO, 5-Me) were well-tolerated in the cascade reactions, while the substrates 2g−2j bearing halogen substituents (5-F, 5-Cl, 5-Br, and 6-Cl) on the oxindole ring gave the desired products 3ag−3ai in moderate yields (60− 67%) with lower diastereoselectivities (99% ee after recrystallization) (Figure 7743

DOI: 10.1021/acs.joc.8b00632 J. Org. Chem. 2018, 83, 7741−7750

Article

The Journal of Organic Chemistry Scheme 2. Substrate Scope of 3-Aminooxindoles 1a−1ka,b,c,d

a

Unless otherwise specified, reactions were carried out with 1 (0.12 mmol), 2a (0.1 mmol), and catalyst C8 (10 mol %) in 0.5 mL of CH2Cl2 and were stirred at 0 °C for 3 h. bYield of the mixtures of 3 and diastereomer 3′ after column chromatography. cThe diastereomeric ratio (dr) value was determined by 1H NMR analysis of the crude products. dThe enantiomeric excess (ee) value was determined by HPLC.

Scheme 3. Substrate Scope of Isatin-derived β,γ-Unsaturated α-Keto Esters 2a−2ka,b,c,d

a Unless otherwise specified, reactions were carried out with 1a (0.12 mmol), 2 (0.1 mmol), and catalyst C8 (10 mol %) in 0.5 mL of CH2Cl2 and were stirred at 0 °C for 3 h. bYield of the mixtures of 3 and diastereomer 3′ after column chromatography. cThe diastereomeric ratio (dr) value was determined by 1H NMR analysis of the crude products. dThe enantiomeric excess (ee) value was determined by HPLC. eThe reaction was performed at −50 °C in the presence of 20 mol % C8.

7744

DOI: 10.1021/acs.joc.8b00632 J. Org. Chem. 2018, 83, 7741−7750

Article

The Journal of Organic Chemistry

Figure 3. X-ray crystal structure of 3ab.

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3),15 and the configurations of other products were assigned by analogy. To probe the efficiency of the asymmetric Michael/Nhemiketalization strategy, a gram-scale reaction of 1a and 2a was investigated under the optimal reaction conditions. As shown in Scheme 4, the reaction could be performed well on the gram scale without an obvious loss of diastereoselectivity and enantioselectivity.

CONCLUSIONS In conclusion, we have developed a novel strategy for the construction of 3,3′-pyrrolidinyl-bispirooxindoles via the Michael/N-hemiketalization cascade reaction of 3-aminooxindoles and isatin-derived β,γ-unsaturated α-keto esters. Under mild conditions, a series of 3,3′-pyrrolidinyl-bispirooxindoles were obtained in moderate to good yields with high diastereo- and enantioselectivities by using a cinchona-derived bifunctional squaramide organocatalyst. Notably, this work represents the first example using the 3-aminooxindoles for the construction of 3,3′-pyrrolidinyl-bispirooxindoles. This straightforward process will serve as a powerful tool for the enantioselective construction of potentially bioactive pyrrolidinyl-bispirooxindole scaffolds.

Scheme 4. Gram-Scale Synthesis

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EXPERIMENTAL SECTION

General Information. Commercially available compounds were used without further purification. Solvents were dried according to standard procedures. Column chromatography was carried out using silica gel (200−300 mesh). Melting points were measured with a melting point apparatus without correction. The 1H NMR spectra were recorded with a 400 MHz spectrometer. Chemical shifts were reported in δ (ppm) units relative to tetramethylsilane (TMS) as the internal standard. 13C NMR spectra were recorded at 100 or 176 MHz. Chemical shifts were reported in ppm relative to TMS with the solvent resonance as an internal standard. High-resolution mass spectra were measured with an Accurate-Mass-Q-TOF MS system equipped with an electrospray ionization (ESI) source. Optical rotations were measured with a polarimeter at the indicated concentration with the units of g per 100 mL. The enantiomeric excesses of the products were determined by chiral HPLC analysis on Daicel Chiralpak IA or IB columns. Materials. The 3-aminooxindoles 1a−1k were prepared according to the reported literature procedures.12a,16 The isatin-derived β,γunsaturated α-keto esters 2a−2k were prepared according to the reported literature procedures.14a−c General Procedure for the Asymmetric Michael/N-Hemiketalization Cascade Reaction. 3-Aminoxindoles 1 (0.12 mmol), isatin-derived β,γ-unsaturated α-keto esters 2 (0.1 mmol), and catalyst C8 (5.2 mg, 0.01 mmol) were dissolved in CH2Cl2 (0.5 mL), and the mixture was stirred at 0 °C for 3 h. After completion of the reaction, the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1 to 2:1) to afford the pure major isomers 3 as a solid. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-1′-formyl-5′-hydroxy-2,2′′dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3aa): white solid (51.1 mg, 85% yield); mp 118−119 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/ min, detection at 254 nm) major diastereomer tR = 47.5 min (minor), tR = 23.5 min (major), minor diastereomer tR = 14.6 min; 90% ee;

Finally, based on our experiment results and the absolute configuration of the major isomer 3ab, a plausible transitionstate model is proposed. As shown in Scheme 5, the 3Scheme 5. Proposed Transition State for This Reaction

aminooxindole 1a was enolized by the tertiary amine moiety, while the isatin-derived β,γ-unsaturated α-keto ester 2b was activated by double hydrogen bonding to the squaramide moiety of the catalyst. Then, the electron-rich α-carbon atom of 3-aminooxindole 1a predominantly from the si face attacks the si face of the electron-deficient isatin-derived β,γunsaturated α-keto ester 2b to generate the Michael adduct intermediate, and subsequent intramolecular N-hemiketalization afforded the desired product 3ab. 7745

DOI: 10.1021/acs.joc.8b00632 J. Org. Chem. 2018, 83, 7741−7750

Article

The Journal of Organic Chemistry 1 [α]20 D +311.1 (c 2.10, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.34 (s, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.28 (s, 2H), 7.15− 7.04 (m, 7H), 6.97 (t, J = 7.4 Hz, 2H), 6.61 (t, J = 8.0 Hz, 2H), 6.51 (d, J = 7.6 Hz, 2H), 6.35 (t, J = 7.4 Hz, 2H), 5.11 (d, J = 16.0 Hz, 2H), 4.57 (d, J = 15.6 Hz, 1H), 4.49−4.42 (m, 3H), 3.60 (d, J = 14.4 Hz, 1H), 2.75 (d, J = 14.8 Hz, 1H), 1.44 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.2, 170.3, 169.5, 160.4, 143.6, 142.8, 134.7, 134.5, 130.1, 129.5, 128.6, 128.4, 127.7, 127.6, 126.9, 126.0, 125.9, 125.1, 124.7, 122.8, 122.5, 122.3, 109.8, 109.6, 90.5, 73.0, 63.3, 58.0, 44.7, 44.3, 43.8, 14.1 ppm; HRMS (ESI) m/z calcd for C36H31N3NaO6 [M + Na]+ 624.2105, found 624.2110. Ethyl (3S,3′S,5′R)-1′′-Benzyl-1′-formyl-5′-hydroxy-1-methyl2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ba): white solid (39.6 mg, 75% yield); mp 177−178 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 43.0 min (minor), tR = 23.6 min (major), minor diastereomer tR = 14.4, 16.5 1 min; 83% ee; [α]20 D +108.6 (c 1.79, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.19 (s, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.33− 7.32 (m, 3H), 7.30−7.24 (m, 3H), 7.08−7.00 (m, 2H), 6.61 (t, J = 8.0 Hz, 1H), 6.57 (d, J = 8.0 Hz, 2H), 6.42 (d, J = 7.6 Hz, 1H), 5.19 (d, J = 15.6 Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 3.53 (d, J = 14.8 Hz, 1H), 2.97 (s, 3H), 2.74 (d, J = 14.4 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.9, 170.6, 169.5, 160.6, 143.6, 143.2, 134.8, 130.1, 129.5, 128.7, 127.8, 127.7, 125.9, 124.9, 124.7, 123.1, 122.23, 122.21, 109.4, 108.4, 90.5, 73.1, 63.3, 58.1, 44.6, 44.3, 26.5, 14.1 ppm; HRMS (ESI) m/z calcd for C30H27N3NaO6 [M + Na]+ 548.1792, found 548.1790. Ethyl (3S,3′S,5′R)-1′′-Benzyl-1′-formyl-5′-hydroxy-2,2′′-dioxo-1propyldispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ca): white solid (67.4 mg, 82% yield); mp 121−122 °C; HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 26.4 min (minor), tR = 40.0 min (major), minor diastereomer tR = 9.6, 15.1 1 min; 86% ee; [α]20 D +68.5 (c 2.55, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.29 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.08−7.01 (m, 2H), 6.62−6.56 (m, 3H), 6.33 (d, J = 7.6 Hz, 1H), 5.14 (d, J = 15.6 Hz, 1H), 4.61 (d, J = 15.2 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 3.67−3.60 (m, 1H), 3.54 (d, J = 14.4 Hz, 1H), 3.25−3.18 (m, 1H), 2.73 (d, J = 14.4 Hz, 1H), 1.43 (t, J = 7.0 Hz, 3H), 1.21−1.07 (m, 2H), 0.50 (t, J = 7.4 Hz, 3H) ppm; 13 C NMR (100 MHz, CDCl3) δ 178.1, 170.0, 169.5, 160.5, 143.4, 143.2, 134.8, 130.0, 129.5, 128.7, 128.0, 127.8, 126.0, 124.9, 124.8, 123.0, 122.2, 122.0, 109.3, 108.6, 90.6, 73.0, 63.3, 58.1, 44.7, 44.1, 41.8, 20.2, 14.1, 10.8 ppm; HRMS (ESI) m/z calcd for C32H31N3NaO6 [M + Na]+ 576.2105, found 576.2096. Ethyl (3S,3′S,5′R)-1-Allyl-1′′-benzyl-1′-formyl-5′-hydroxy-2,2′′dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3da): white solid (41.9 mg, 76% yield); mp 136−137 °C; HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 37.5 min (minor), tR = 31.1 min (major), minor diastereomer tR = 10.9, 17.6 1 min; 85% ee; [α]20 D +126.7 (c 1.20, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.28 (s, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.34− 7.21 (m, 6H), 7.08 (t, J = 8.2 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.62− 6.52 (m, 3H), 6.36 (d, J = 7.6 Hz, 1H), 5.42−5.33 (m, 1H), 5.17 (d, J = 15.6 Hz, 1H), 4.68 (d, J = 10.4 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 4.49−4.44 (m, 3H), 4.18 (d, J = 17.2 Hz, 1H), 3.86 (dd, J1 = 16.8 Hz, J2 = 2.4 Hz, 1H), 3.57 (d, J = 14.4 Hz, 1H), 2.74 (d, J = 14.4 Hz, 1H), 1.44 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (176 MHz, CDCl3) δ 178.1, 170.0, 169.5, 160.5, 143.6, 142.8, 134.7, 130.13, 130.07, 129.6, 128.7, 127.73, 127.69, 125.9, 125.0, 124.7, 122.9, 122.3, 122.2, 116.1, 109.6, 109.4, 90.6, 73.1, 63.3, 58.1, 44.7, 44.2, 42.3, 14.1 ppm; HRMS (ESI) m/z calcd for C32H30N3O6 [M + H]+ 552.2129, found 552.2138. Ethyl (3S,3′S,5′R)-1′′-Benzyl-1′-formyl-5′-hydroxy-2,2′′dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ea): white solid (44.1 mg, 86% yield); mp 107−108 °C; HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 16.5 min (minor), tR = 25.7 min (major), minor diastereomer tR = 13.1, 38.9

1 min; 85% ee; [α]20 D +83.5 (c 0.81, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.30−7.27 (m, 4H), 7.25−7.22 (m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 2H), 6.59 (t, J = 8.6 Hz, 2H), 6.54 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 4.98 (d, J = 15.6 Hz, 1H), 4.79 (d, J = 15.6 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 3.53 (d, J = 14.8 Hz, 1H), 2.72 (d, J = 14.4 Hz, 1H), 1.43 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.2, 171.8, 169.4, 160.7, 143.3, 141.0, 134.8, 130.2, 129.6, 128.8, 127.8, 127.5, 126.2, 124.9, 124.8, 122.7, 122.3, 122.1, 110.7, 109.7, 90.6, 73.2, 63.3, 58.0, 44.6, 44.2, 14.1 ppm; HRMS (ESI) m/z calcd for C29H26N3O6 [M + H]+ 512.1816, found 512.1816. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-5-fluoro-1′-formyl-5′-hydroxy2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3fa): white solid (48.6 mg, 78% yield); mp 96−97 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 43.4 min (minor), tR = 22.5 min (major), minor diastereomer tR = 17.1 min; 1 87% ee; [α]20 D +89.0 (c 1.89, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.31 (s, 1H), 7.50 (dd, J1 = 8.2 Hz, J2 = 2.6 Hz, 1H), 7.29−7.27 (m, 2H), 7.15−7.05 (m, 5H), 6.97 (t, J = 7.6 Hz, 2H), 6.83 (td, J1 = 8.6 Hz, J2 = 2.6 Hz 1H), 6.69−6.64 (m, 2H), 6.50 (d, J = 7.6 Hz, 2H), 6.45 (d, J = 7.6 Hz, 1H), 6.25 (dd, J1 = 8.6 Hz, J2 = 4.2 Hz, 1H), 5.10 (t, J = 15.2 Hz, 2H), 4.60 (d, J = 15.6 Hz, 1H), 4.47 (dq, J1 = 7.2 Hz, J2 = 1.6 Hz, 2H), 4.42 (d, J = 16.4 Hz, 1H), 3.54 (d, J = 14.4 Hz, 1H), 2.75 (d, J = 14.8 Hz, 1H), 1.45 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.9, 170.2, 169.5, 160.4, 158.7 (d, 1JC−F = 240.2 Hz), 143.6, 138.84, 138.82, 134.4 (d, 4JC−F = 4.1 Hz), 129.7, 128.6, 128.5, 127.74, 127.66, 127.3 (d, 3J = 7.8 Hz), 127.1, 126.0, 125.0, 122.6, 122.5, 116.4 (d, 2JC−F = 23.2 Hz), 113.1 (d, 2 JC−F = 25.6 Hz), 110.2 (d, 3JC−F = 7.9 Hz), 109.9, 90.5, 73.1, 63.5, 58.0, 44.7, 44.3, 43.9, 14.1 ppm; HRMS (ESI) m/z calcd for C36H30FN3NaO6 [M + Na]+ 642.2011, found 642.2012. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-5-chloro-1′-formyl-5′-hydroxy2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ga): faint yellow solid (50.3 mg, 79% yield); mp 52−53 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 39.4 min (minor), tR = 21.0 min (major), minor diastereomer tR = 14.5, 1 18.6 min; 87% ee; [α]20 D +161.6 (c 1.12, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.32 (s, 1H), 7.71 (d, J = 1.2 Hz, 1H), 7.29−7.27 (m, 2H), 7.17−7.06 (m, 6H), 6.98 (t, J = 7.6 Hz, 2H), 6.69 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 7.6 Hz, 2H), 6.45 (d, J = 7.6 Hz, 1H), 6.26 (d, J = 8.4 Hz, 1H), 5.12 (d, J = 15.6 Hz, 1H), 5.08 (d, J = 16.8 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 4.49 (q, J = 7.2 Hz, 2H), 4.43 (d, J = 16.4 Hz, 1H), 3.56 (d, J = 14.4 Hz, 1H), 2.76 (d, J = 14.4 Hz, 1H), 1.47 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (176 MHz, CDCl3) δ 177.8, 170.0, 169.3, 160.4, 143.6, 141.4, 134.4, 134.2, 130.0, 129.8, 128.6, 128.5, 127.81, 127.77, 127.7, 127.6, 127.1, 126.0, 125.2, 125.1, 122.7, 122.4, 110.6, 109.9, 90.4, 72.9, 63.6, 58.0, 44.7, 44.3, 43.9, 14.1 ppm; HRMS (ESI) m/z calcd for C36H31ClN3O6 [M + H]+ 636.1896, found 636.1915. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-5-bromo-1′-formyl-5′-hydroxy2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ha): yellow solid (53.1 mg, 78% yield); mp 54−55 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 38.7 min (minor), tR = 21.3 min (major), minor diastereomer tR = 12.2, 14.8 1 min; 85% ee; [α]20 D +100.3 (c 2.77, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.30 (s, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.28− 7.24 (m, 3H), 7.17−7.06 (m, 5H), 6.98 (t, J = 7.4 Hz, 2H), 6.70 (t, J = 7.8 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 7.6 Hz, 2H), 6.45 (d, J = 7.6 Hz, 1H), 6.21 (d, J = 8.4 Hz, 1H), 5.12 (d, J = 15.6 Hz, 1H), 5.06 (d, J = 16.4 Hz, 1H), 4.59 (d, J = 15.6 Hz, 1H), 4.49 (d, J = 7.2 Hz, 2H), 4.43 (d, J = 16.4 Hz, 1H), 3.55 (d, J = 14.4 Hz, 1H), 2.76 (d, J = 14.4 Hz, 1H), 1.47 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.8, 169.9, 169.3, 160.4, 143.6, 141.8, 134.4, 134.2, 132.9, 129.8, 128.6, 128.5, 128.0, 127.9, 127.8, 127.7, 127.1, 126.0, 125.1, 122.7, 122.4, 115.0, 111.0, 109.9, 90.4, 72.8, 63.6, 58.1,

7746

DOI: 10.1021/acs.joc.8b00632 J. Org. Chem. 2018, 83, 7741−7750

Article

The Journal of Organic Chemistry 44.7, 44.3, 43.9, 14.1 ppm; HRMS (ESI) m/z calcd for C36H31BrN3O6 [M + H]+ 680.1391, found 680.1397. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-1′-formyl-5′-hydroxy-5-methyl2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ia): white solid (47.1 mg, 73% yield); mp 87−88 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 35.7 min (minor), tR = 19.9 min (major), minor diastereomer tR = 13.2, 14.9 1 min; 85% ee; [α]20 D +124.0 (c 1.66, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.33 (s, 1H), 7.42 (s, 1H), 7.28−7.26 (m, 2H), 7.13−7.04 (m, 5H), 6.97−6.92 (m, 3H), 6.66−6.61 (m, 2H), 6.52 (d, J = 7.6 Hz, 2H), 6.38 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 8.0 Hz, 1H), 5.10 (t, J = 15.6 Hz, 2H), 4.61 (d, J = 15.6 Hz, 1H), 4.50−4.42 (m, 3H), 3.61 (d, J = 14.4 Hz, 1H), 2.74 (d, J = 14.4 Hz, 1H), 2.35 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.2, 170.3, 169.4, 160.5, 143.6, 140.5, 134.8, 134.5, 131.8, 130.5, 129.5, 128.6, 128.4, 127.7, 127.6, 126.9, 126.0, 125.9, 125.4, 125.2, 123.0, 122.5, 109.8, 109.4, 90.6, 73.2, 63.3, 58.0, 44.7, 44.2, 43.8, 21.3, 14.1 ppm; HRMS (ESI) m/z calcd for C37H33N3NaO6 [M + Na]+ 638.2262, found 638.2264. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-6-chloro-1′-formyl-5′-hydroxy2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ja): white solid (43.3 mg, 68% yield); mp 77−78 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 75:25, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 49.1 min (minor), tR = 21.5 min (major), minor diastereomer tR = 17.0, 20.5 1 min; 90% ee; [α]20 D +122.5 (c 1.30, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.26 (br s, 2H), 7.15−7.04 (m, 6H), 6.99 (t, J = 7.4 Hz, 2H), 6.71 (t, J = 7.4 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 7.2 Hz, 2H), 6.44 (d, J = 7.6 Hz, 1H), 6.35 (s, 1H), 5.10 (dd, J1 = 15.8 Hz, J2 = 5.4 Hz, 2H), 4.61 (d, J = 15.6 Hz, 1H), 4.49−4.39 (m, 3H), 3.50 (d, J = 14.4 Hz, 1H), 2.76 (d, J = 14.8 Hz, 1H), 1.44 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.8, 170.4, 169.6, 160.5, 144.1, 143.6, 135.9, 134.4, 134.1, 129.7, 128.62, 128.58, 127.8, 127.6, 127.2, 125.9, 125.8, 125.1, 124.4, 122.7, 122.6, 122.4, 110.1, 109.9, 90.5, 72.6, 63.5, 58.0, 44.7, 44.4, 43.9, 14.1 ppm; HRMS (ESI) m/z calcd for C36H31ClN3O6 [M + H]+ 636.1896, found 636.1918. Ethyl (3S,3′S,5′R)-1′-Acetyl-1,1′′-dibenzyl-5′-hydroxy-2,2′′dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ka): faint yellow solid (49.4 mg, 80% yield); mp 90−91 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 18.5 min (minor), tR = 13.0 min (major), minor diastereomer tR = 4.8, 5.5 min; 1 90% ee; [α]20 D +56.6 (c 2.23, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.02 (d, J = 6.4 Hz, 1H), 7.30 (s, 2H), 7.09−7.03 (m, 7H), 6.96 (t, J = 7.2 Hz, 2H), 6.62 (d, J = 8.0 Hz, 1H), 6.58 (t, J = 7.6 Hz, 1H), 6.47 (d, J = 7.6 Hz, 2H), 6.33−6.28 (m, 2H), 5.12 (d, J = 16.8 Hz, 1H), 5.11 (d, J = 15.2 Hz, 1H), 4.59 (d, J = 15.2 Hz, 1H), 4.52−4.47 (m, 2H), 4.39 (d, J = 16.4 Hz, 1H), 3.37 (d, J = 13.6 Hz, 1H), 2.78 (d, J = 14.0 Hz, 1H), 2.19 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (176 MHz, CDCl3) δ 178.3, 171.1, 170.9, 169.6, 143.6, 142.9, 135.0, 134.5, 129.7, 129.3, 128.5, 128.3, 127.8, 127.7, 126.8, 126.7, 125.9, 125.3, 125.0, 122.9, 122.3, 121.9, 109.6, 109.3, 90.4, 75.1, 63.2, 57.8, 46.5, 44.7, 43.7, 22.0, 14.2 ppm; HRMS (ESI) m/z calcd for C37H34N3O6 [M + H]+ 616.2442, found 616.2450. Ethyl (3S,3′S,5′R)-1-Benzyl-1′-formyl-5′-hydroxy-1′′-methyl2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ab): white solid (43.7 mg, 83% yield); mp 93−94 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 61.4 min (minor), tR = 39.3 min (major), minor diastereomer tR = 15.1 min; 1 90% ee; [α]20 D +87.8 (c 1.96, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.41 (s, 1H), 7.64 (d, J = 6.8 Hz, 1H), 7.23 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 7.17−7.06 (m, 5H), 6.72 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 7.2 Hz, 2H), 6.37 (d, J = 7.6 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 5.06 (d, J = 16.4 Hz, 1H), 4.45 (dq, J1 = 7.2 Hz, J2 = 2.0 Hz, 2H), 4.40 (d, J = 16.4 Hz, 1H), 3.60 (d, J = 14.8 Hz, 1H), 3.15 (s, 3H), 2.66 (d, J = 14.4 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.3, 170.0, 169.4, 160.3, 144.2, 142.7, 135.1, 130.1, 129.6, 128.5, 127.0, 126.2,

126.0, 125.1, 124.7, 122.5, 122.4, 122.3, 109.4, 108.5, 90.5, 73.1, 63.3, 58.0, 43.8, 43.6, 26.7, 14.1 ppm; HRMS (ESI) m/z calcd for C30H27N3NaO6 [M + Na]+ 548.1792, found 548.1784. Ethyl (3S,3′S,5′R)-1′′-Allyl-1-benzyl-1′-formyl-5′-hydroxy-2,2′′dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ac): faint yellow solid (46.9 mg, 85% yield); mp 46−47 °C; HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 37.0 min (minor), tR = 30.1 min (major), minor diastereomer tR = 10.5, 13.4 1 min; 90% ee; [α]20 D +54.3 (c 2.18, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.32 (s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.17−7.13 (m, 2H), 7.08 (t, J = 7.4 Hz, 3H), 6.76 (d, J = 7.6 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H), 6.59 (d, J = 7.2 Hz, 2H), 6.37 (d, J = 7.6 Hz, 2H), 5.73−5.63 (m, 1H), 5.16 (d, J = 17.2 Hz, 1H), 5.10−5.06 (m, 2H), 4.52−4.40 (m, 4H), 4.08 (dd, J1 = 16.0 Hz, J2 = 6.4 Hz, 1H), 3.61 (d, J = 14.8 Hz, 1H), 2.69 (d, J = 14.4 Hz, 1H), 1.43 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.9, 170.0, 169.4, 160.4, 143.5, 142.8, 135.0, 130.6, 130.2, 129.5, 128.5, 127.0, 126.1, 125.9, 125.1, 124.7, 122.6, 122.4, 122.3, 118.5, 109.5, 109.4, 90.5, 73.1, 63.3, 57.8, 43.8, 43.0, 14.1 ppm; HRMS (ESI) m/z calcd for C32H30N3O6 [M + H]+ 552.2129, found 552.2125. Ethyl (3S,3′S,5′R)-1-Benzyl-1′′-(4-bromobenzyl)-1′-formyl-5′-hydroxy-2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]5′-carboxylate (3ad): white solid (51.0 mg, 75% yield); mp 94−95 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 50.7 min (minor), tR = 29.8 min (major), minor diastereomer tR = 16.7, 1 24.4 min; 91% ee; [α]20 D +90.9 (c 2.97, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.24 (s, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.18− 7.04 (m, 8H), 6.96 (t, J = 7.6 Hz, 2H), 6.65 (t, J = 7.6 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.43 (d, J = 7.6 Hz, 2H), 6.38 (t, J = 7.8 Hz, 2H), 5.16 (t, J = 15.8 Hz, 2H), 4.49−4.39 (m, 4H), 3.62 (d, J = 14.8 Hz, 1H), 2.75 (d, J = 14.4 Hz, 1H), 1.44 (d, J = 7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.2, 170.3, 169.4, 160.4, 143.4, 142.9, 134.5, 133.4, 131.6, 130.3, 129.6, 129.4, 128.5, 127.0, 125.9, 125.6, 125.3, 124.8, 122.8, 122.7, 122.4, 121.7, 109.7, 109.5, 90.5, 73.0, 63.4, 58.0, 44.3, 44.1, 43.6, 14.1 ppm; HRMS (ESI) m/z calcd for C36H30BrN3NaO6 [M + Na]+ 704.1195, found 704.1196. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-1′-formyl-5′-hydroxy-5′′-methoxy-2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]5′-carboxylate (3ae): faint yellow solid (46.1 mg, 73% yield); mp 54−55 °C; HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 75:25, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 124.5 min (minor), tR = 73.0 min (major), minor diastereomer tR = 21.3, 35.4 min; 86% ee; [α]20 D +28.8 (c 2.07, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.46 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.26 (br s, 2H), 7.17−7.06 (m, 6H), 6.99 (t, J = 7.4 Hz, 2H), 6.66 (d, J = 8.8 Hz, 1H), 6.54−6.50 (m, 3H), 6.37 (d, J = 7.6 Hz, 1H), 5.95 (s, 1H), 5.15−5.08 (m, 2H), 4.60 (d, J = 15.6 Hz, 1H), 4.50−4.44 (m, 3H), 3.58 (d, J = 14.8 Hz, 1H), 3.31 (s, 3H), 2.75 (d, J = 14.4 Hz, 1H), 1.44 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.8, 170.2, 169.5, 160.4, 155.5, 143.0, 136.8, 134.7, 134.5, 130.2, 128.6, 128.5, 127.7, 127.6, 127.0, 126.04, 126.01, 124.7, 123.7, 122.2, 115.8, 111.3, 110.4, 109.8, 90.6, 73.0, 63.4, 58.2, 55.7, 44.7, 44.4, 43.8, 14.1 ppm; HRMS (ESI) m/z calcd for C37H34N3O7 [M + H]+ 632.2391, found 632.2391. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-1′-formyl-5′-hydroxy-5′′-methyl-2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′carboxylate (3af): white solid (48.0 mg, 78% yield); mp 123−124 °C; HPLC (Daicel Chiralpak IA, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 50.3 min (minor), tR = 38.2 min (major), minor diastereomer tR = 12.8, 1 17.7 min; 90% ee; [α]20 D +78.6 (c 1.84, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.40 (s, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.26 (s, 2H), 7.15−7.06 (m, 6H), 6.99 (t, J = 7.2 Hz, 2H), 6.90 (d, J = 7.6 Hz, 1H), 6.52−6.49 (m, 3H), 6.33 (d, J = 7.2 Hz, 1H), 6.13 (s, 1H), 5.10 (d, J = 16.0 Hz, 1H), 5.06 (d, J = 14.8 Hz, 1H), 4.62 (d, J = 15.6 Hz, 1H), 4.48−4.44 (m, 3H), 3.57 (d, J = 14.4 Hz, 1H), 2.73 (d, J = 14.4 Hz, 1H), 1.89 (s, 3H), 1.44 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 178.1, 170.3, 169.5, 160.4, 142.8, 141.1, 134.7, 134.6, 132.2, 130.0, 129.6, 128.5, 128.4, 127.6, 126.9, 126.1, 126.04, 126.01, 7747

DOI: 10.1021/acs.joc.8b00632 J. Org. Chem. 2018, 83, 7741−7750

Article

The Journal of Organic Chemistry

J = 14.4 Hz, 1H), 1.44 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (176 MHz, CDCl3) δ 178.2, 170.0, 169.3, 160.4, 144.7, 142.8, 135.6, 134.6, 133.9, 130.4, 128.7, 128.4, 127.9, 127.6, 127.2, 126.1, 126.0, 125.7, 124.6, 122.5, 122.3, 121.1, 110.4, 109.7, 90.5, 72.9, 63.4, 57.7, 44.8, 44.1, 43.8, 14.1 ppm; HRMS (ESI) m/z calcd for C36H31ClN3O6 [M + H]+ 636.1896, found 636.1915. (3S,3′S,5′R)-1′-Acetyl-1,1′′-dibenzyl-5′-hydroxy-5′(trifluoromethyl)dispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]2,2′′-dione (3ak): faint yellow solid (49.3 mg, 83% yield); mp 90−91 °C; HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 13.4 min (minor), tR = 15.0 min (major); 88% ee; [α]20 D −10.1 (c 1.17, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.20 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.22−7.07 (m, 9H), 6.91 (t, J = 7.8 Hz, 1H), 6.83 (t, J = 7.6 Hz, 3H), 6.72 (d, J = 7.6 Hz, 2H), 6.48 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 8.0 Hz, 1H), 5.00 (d, J = 16.0 Hz, 1H), 4.80 (d, J = 16.0 Hz, 1H), 4.69 (d, J = 16.0 Hz, 1H), 4.54 (d, J = 16.0 Hz, 1H), 3.66 (d, J = 14.0 Hz, 1H), 2.54 (d, J = 14.0 Hz, 1H) ppm; 13C NMR (176 MHz, CDCl3) δ 178.6, 172.5, 159.7, 143.13, 143.06, 134.5, 133.7, 130.1, 129.9, 128.8, 128.6, 127.7, 127.2, 126.7, 126.5, 125.7, 124.6, 124.2, 123.20, 123.19 (q, JC−F = 285.1 Hz), 123.10, 123.0, 110.2, 109.9, 90.3 (q, JC−F = 33.1 Hz), 73.1, 57.3, 44.1, 43.8, 40.6 ppm; HRMS (ESI) m/z calcd for C34H27F3N3O4 [M + H]+ 598.1954, found 598.1956. Ethyl (3S*,3′R*,5′S*)-1,1′′-Dibenzyl-1′-formyl-5′-hydroxy-5′′methoxy-2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3af′). 3-Aminoxindole 1a (0.12 mmol), isatinderived β,γ-unsaturated α-keto ester 2f (0.1 mmol), and catalyst C8 (5.2 mg, 0.01 mmol) were dissolved in CH3CN (0.5 mL), and the mixture was stirred at room temperature for 0.5 h. After completion of the reaction, the crude product was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate = 4:1 to 2:1) to afford the pure minor isomer 3af′ as a solid: 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.77 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.29 (s, 1H), 7.22−7.05 (m, 7H), 6.93 (d, 1H), 6.84−6.78 (m, 5H), 6.39−6.37 (m, 2H), 4.94 (t, J = 14.8 Hz, 2H), 4.62 (t, J = 15.6 Hz, 2H), 4.45−4.42 (m, 2H), 3.74 (d, J = 14.4 Hz, 1H), 2.60 (d, J = 14.0 Hz, 1H), 2.07 (s, 3H), 1.42 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (176 MHz, CDCl3) δ 178.5, 173.1, 168.3, 161.3, 143.3, 140.6, 134.7, 134.0, 133.9, 130.1, 129.6, 128.7, 128.5, 127.6, 127.1, 126.7, 126.22, 126.16, 124.5, 123.5, 123.4, 122.9, 109.8, 90.8, 72.6, 62.9, 58.1, 44.0, 43.6, 43.3, 20.9, 14.1 ppm; HRMS (ESI) m/z calcd for C37H34N3O6 [M + H]+ 616.2442, found 616.233.

124.8, 122.7, 122.2, 109.6, 109.4, 90.6, 73.1, 63.3, 58.1, 44.6, 44.3, 43.8, 29.7, 20.7, 14.1 ppm; HRMS (ESI) m/z calcd for C37H34N3O6 [M + H]+ 616.2442, found 616.2439. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-5′′-fluoro-1′-formyl-5′-hydroxy2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]-5′-carboxylate (3ag): orange solid (42.1 mg, 68% yield); mp 39−40 °C; HPLC (Daicel Chiralpak IB, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 43.0 min (minor), tR = 22.7 min (major), minor diastereomer tR = 13.8, 19.2 1 min; 71% ee; [α]20 D +30.2 (c 2.14, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.25 (s, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.26 (br s, 2H), 7.20−7.07 (m, 6H), 7.00 (t, J = 7.4 Hz, 2H), 6.80 (t, J = 8.6 Hz, 1H), 6.61 (d, J = 7.2 Hz, 2H), 6.53−6.52 (m, 1H), 6.42 (d, J = 7.6 Hz, 1H), 6.09 (d, J = 8.4 Hz, 1H), 5.09 (t, J = 16.2 Hz, 2H), 4.59 (d, J = 15.6 Hz, 1H), 4.51−4.44 (m, 3H), 3.57 (d, J = 14.4 Hz, 1H), 2.76 (d, J = 14.4 Hz, 1H), 1.44 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.8, 170.1, 169.3, 160.4, 158.5 (d, 1JC−F = 240.9 Hz), 142.7, 139.5 (d, 4JC−F = 2.0 Hz), 134.7, 134.2, 130.5, 128.7, 128.4, 127.8, 127.6, 127.1, 126.2, 125.5, 124.7, 124.6, 122.6, 115.9 (d, 2JC−F = 23.3 Hz), 113.4 (d, 2JC−F = 26.3 Hz), 110.2 (d, 3JC−F = 8.0 Hz), 109.8, 90.5, 72.9, 63.4, 58.09, 50.07, 44.8, 44.3, 43.9, 14.1 ppm; HRMS (ESI) m/z calcd for C36H31FN3O6 [M + H]+ 620.2197, found 620.2197. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-5′′-chloro-1′-formyl-5′-hydroxy-2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]5′-carboxylate (3ah): faint yellow solid (42.0 mg, 66% yield); mp 75−76 °C; HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 83.4 min (minor), tR = 64.6 min (major); 63% 1 ee; [α]20 D +19.1 (c 0.79, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.15 (s, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.25−7.18 (m, 3H), 7.15−7.05 (m, 6H, ArH), 7.02 (t, J = 8.0 Hz, 2H), 6.63 (d, J = 7.6 Hz, 2H), 6.50 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 7.6 Hz, 1H), 6.31 (s, 1H), 5.05 (t, J = 14.8 Hz, 2H), 4.61 (d, J = 15.2 Hz, 1H), 4.53 (d, J = 16.8 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.57 (d, J = 14.8 Hz, 1H), 2.76 (d, J = 14.4 Hz, 1H), 1.45 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (176 MHz, CDCl3) δ 177.7, 170.1, 169.3, 160.5, 142.7, 142.0, 134.7, 134.1, 130.5, 129.4, 128.7, 128.5, 128.0, 127.9, 127.6, 127.1, 126.2, 125.7, 125.5, 124.63, 124.57, 122.6, 110.5, 109.9, 90.5, 73.0, 63.5, 58.0, 44.8, 44.2, 43.9, 14.1 ppm; HRMS (ESI) m/z calcd for C36H31ClN3O6 [M + H]+ 636.1896, found 636.1915. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-5′′-bromo-1′-formyl-5′-hydroxy-2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]5′-carboxylate (3ai): faint yellow solid (45.6 mg, 67% yield); mp 87− 88 °C; HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 87.6 min (minor), tR = 68.4 min (major); 64% 1 ee; [α]20 D +11.5 (c 1.29, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.14 (s, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.25−7.20 (m, 4H), 7.15−7.09 (m, 5H), 7.03 (t, J = 7.2 Hz, 2H), 6.63 (d, J = 7.6 Hz, 2H), 6.46−6.43 (m, 3H), 5.05 (d, J = 15.6 Hz, 1H), 5.03 (d, J = 16.4 Hz, 1H), 4.61 (d, J = 15.6 Hz, 1H), 4.53 (d, J = 16.4 Hz, 1H), 4.47 (q, J = 7.2 Hz, 2H), 3.56 (d, J = 14.4 Hz, 1H), 2.75 (d, J = 14.4 Hz, 1H), 1.45 (t, J = 7.2 Hz, 3H) ppm; 13C NMR (176 MHz, CDCl3) δ 177.6, 170.0, 169.3, 160.5, 142.7, 142.5, 134.7, 134.0, 132.3, 130.5, 128.7, 128.52, 128.48, 127.9, 127.6, 127.1, 126.2, 125.4, 124.8, 124.6, 122.5, 115.2, 111.0, 109.9, 90.5, 73.0, 63.4, 58.0, 44.7, 44.1, 43.9, 14.1 ppm; HRMS (ESI) m/z calcd for C36H31BrN3O6 [M + H]+ 680.1391, found 680.1389. Ethyl (3S,3′S,5′R)-1,1′′-Dibenzyl-6′′-chloro-1′-formyl-5′-hydroxy-2,2′′-dioxodispiro[indoline-3,2′-pyrrolidine-3′,3′′-indoline]5′-carboxylate (3aj): pink solid (40.1 mg, 63% yield); mp 97−98 °C; HPLC (Daicel Chiralpak AD-H, n-hexane/2-propanol = 70:30, flow rate 1.0 mL/min, detection at 254 nm) major diastereomer tR = 78.4 min (minor), tR = 50.2 min (major), minor diastereomer tR = 33.0, 1 35.8 min; 79% ee; [α]20 D +103.5 (c 1.53, CH2Cl2); H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.15 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.28−7.27 (m, 2H), 7.18−7.08 (m, 6H), 7.04 (t, J = 7.2 Hz, 2H), 6.59−6.54 (m, 4H), 6.41 (d, J = 8.0 Hz, 1H), 6.23 (d, J = 8.0 Hz, 1H), 5.13 (d, J = 16.4 Hz, 1H), 5.05 (d, J = 15.6 Hz, 1H), 4.60 (d, J = 15.6 Hz, 1H), 4.49−4.41 (m, 3H), 3.58 (d, J = 14.8 Hz, 1H), 2.72 (d,

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00632. Single-crystal X-ray crystallography data for product 3ab, H−H NOESY spectra of 3af and 3af′ diastereomers, and copies of 1H and 13C NMR and HPLC spectra for the products (PDF) Single-crystal X-ray crystallography data for product 3ab (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: (+86)-010-68914985. ORCID

Da-Ming Du: 0000-0002-9924-5117 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21272024) and the Graduate 7748

DOI: 10.1021/acs.joc.8b00632 J. Org. Chem. 2018, 83, 7741−7750

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Technology Innovation Project of Beijing Institute of Technology (2018CX20015) . We also thank the Analysis & Testing Center of Beijing Institute of Technology for the measurement of NMR and mass spectrometry.

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