Dbu-Mediated Diastereoselective [3+2]-Cycloaddition of Isatin Ketonitrones and Coumarins to Construct Coumarin-Fused Spiropyrolidine Oxoindoles

1. Introduction

Coumarins, a class of naturally occurring benzopyrone derivatives, are widely present in medicinal plants and isolated from 1820 [1,2,3,4,5,6,7,8]. Many of these compounds have demonstrated significantly high biological activities (anticancer, anti-HIV, antibacterial, anti-pathogen, anticoagulant and antispasmodic activities…) [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. For examples, a famous compound warfarin (II), originated from dicoumarol (I) (Figure 1), exhibited an anticoagulant activity, and was subsequently used as a rodenticide and a drug for prevention of cerebral thrombosis [26,27]. Compounds III-V also displayed considerable chemotherapeutic efficacy against mammary cancer induced by polycyclic aromatic hydrocarbons, important soybean lipoxygenase (LOX) inhibitory activity, and significant anticancer activity against both bladder cancer and glioma, respectively [28,29,30,31]. In addition, versatile coumarin skeletons by facile chemical modification were served as key components in organic optical devices [32,33,34,35]. The chemical syntheses of coumarins have been well developed by various methods, including common condensations/lactonizations, transition-metal-catalyzed reactions, and photoinduced organocatalytic methods [36,37,38,39,40,41,42,43,44]. Meanwhile, as a kind of important synthons, coumarins could take part in various chemical reactions, which offered structurally more complex derivatives of coumarin [45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71]. Spirooxindoles, on the other hand, are a class of tricyclic organic molecules featuring multiple contiguous quaternary or tertiary stereocenters, commonly found in natural products and bioactive compounds [72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95]. Their unique structures and remarkable biological activities make them highly promising in the field of medicine, positioning them as one of the most potential drug candidates. For instance, the two compounds VI and VII inhibited an advanced glycation end (AGE) product formation activity (IC₅₀=11.37 nm) [96], and the α-amylase and α-glucosidase enzyme inhibitory activity (IC₅₀=0.28 and 0.31 mg mL^-1) [97], respectively. Furthermore, the tetrahydroisoquinolinyl oxindole VIII showed a highly effective and selective histone lysine-specific demethylase 1 (LDS1) inhibitory activity (IC₅₀= 42 nm) [98]. The spiropyrrolothiazolyl oxindole IX was discovered to exhibit in vitro activity against MCF-7 and K562-leukemia cancer cells, with IC₅₀ values of 15.32 and 14.74 μM, respectively [99].

Among many spirooxindoles, sipropyrolidine ones are the most common type of compound, and possess the diverse and important biological activities, which have attracted widespread attention and considerable interest from organic chemists all over the world [100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125]. In the various synthetic approaches of spiropyrrolidine oxindoles, 1,3-dipolar cycloaddition of isatin-derived dipoles (azomethine ylide, azomethine imine and nitrone etc.) with dipolarophiles has been shown to be the most practical and simplest method for constructing pyrrolidine ring [126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179]. As a versatile synthon, nitrone was widely used in various organic reactions for constructing complex molecules [180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211]. Recently, we have developed a rapidly [3+2]-cycloaddition of isatin ketonitrone 1,3-dipoles with chalcones to afford novel dicyclic spiropyrrolidine oxindole derivatives in 18-98% yields and >20:1 dr values under t-BuOK (Scheme 1) [212]. Meanwhile, Michael adducts were obtained under DBU, with 18-83% yields and 1:1->20:1 dr values. As an extension of our work on 1,3-dipolar cycloaddition of isatin [126–179ketonitrones, we attempted to treat isatin ketonitrone 1a using coumarin 2a as a partner in the presence of base, which expected to give pentacyclic spiropyrolidine oxoindoles.

2. Results and Discussion

Prior to starting this research, N-Bn isatin ketonitrone 1a and ethyl coumarin 3-carboxylate 2a were selected as model substrates, as illustrated in Table 1. Initially, the reaction was performed in the presence of DBU (25 mol%) in some protic and aprotic solvents, such as H₂O, EtOH, MTBE, DMF, THF and DCM. The result demonstrated that above all aprotic solvents could not afford the desired cycloadduct 3a at rt or under heating condition (entries 1-2). Fortunately, however, the protic polar solvent EtOH gave 70% yield of the desired product 3a (entry 4). The ¹H NMR spectrum for 3a showed that the shifts of two proton in pyrrolidine ring were 6.39 (singlet peak) and 4.70 (singlet peak) ppm, respectively, which could confirm α-C of isatin ketonitrone 1a nucleophilically attacked the electrophilic site of the electron-efficient C=C bond in coumarin 2a, to obtain α-selective cycloadduct. Furthermore, the stereochemistry (exo-configuration) of cycloadduct 3a were indirectly proved by the single crystal X-ray diffraction of compound 3b (Figure 3). Subsequently, various alcohols, for instance MeOH, IPA, nBuOH and tBuOH were screened for improving the yield of the reaction. Regrettably, the above all alcohols afford lower yields than one of ethanol. Next, other organic and inorganic bases were screened using ethanol as a solvent. The inorganic bases (for instance tBuOK, KOH, NaOH and NaHCO₃) did not work at all at rt and gave the complex results at heating or refluxing conditions. Although both EtONa and MeONa could smoothly proceed, the conversion rates of 1a were too low. In organic bases, such as DMAP, DABCO and Ph₃P, the reactions were also discovered to be not take place, while in other secondary and tertiary amines (Et₂NH, Bn₂NH, TEA, Bn₃N, nPr₃N, DIPEA, tri-n-amylamine and tri-n-octylamine), the conversion rates of 1a were equally low, even if the reaction temperature was increased. Changing the amount of coumarin 2a (2.1 equiv.), the yield was almost the same compared to 1.0 equivalent of 2a. Finally, the amount of DBU and the concentration of the reaction were investigated. The higher concentration (0.2 M) could slightly increase the yield (74%). Considering the above factors, the optimal reaction condition for 1,3-dipolar cycloaddition was established as isatin ketonitrone 1a (1 equiv.), maleimide 2a (1.05 equiv.) and base DBU (0.25 equiv.) in EtOH at rt for 5 h (entry 14).

Figure 2. X-ray crystal structure of 3b (CCDC: 2375731).

Figure 2. X-ray crystal structure of 3b (CCDC: 2375731).

Figure 3. Other unsuccessful like-coumarins 5.

Figure 3. Other unsuccessful like-coumarins 5.

After the optimal reaction conditions established, a wide range of different substituted isatin ketonitrones were explored for this 1,3-dipolar cycloaddition. As outlined in the Table 2, various substituent groups installed on isatin ketonitrones could be tolerated, which furnished the desired cycloadducts in 38-98% yields with >20:1 dr values, except for the cases of 3h-i, 3o and 3v. It was worth noting that the cycloaddition for the synthesis of 3a was scale up to 0.5 mmol or 5 mmol, which gave rise to the same yield. The substituent patterns on the benzene ring of isatin part of compounds 1 had a significant impact on the yields. All in all, the yields of the electron-donating groups were relative higher than that of the electron-withdrawing ones. For example, 5-methyl group installed on the benzene ring afforded the highest yield (98%) (entry 2), whereas, the strong electron-withdrawing groups (5-NO₂ and 7-CF₃) gave a complex mixture (entries 8 and 9). Changing the substituent groups (R= H, Me, Et, allyl and propargyl) on the nitrogen atom of isatin part of ketonitrones 1, the corresponding cycloadducts were also rendered consistently in satisfactorily yields (59-85%). Subsequently, when R² group (R²= Ph) was replaced by various substituent phenyl gourps, the products 3p-u were generated smoothly with moderate to good yields as a single isomer. However, only a trace amount of 3o was found when R² was a hydrogen atom possibly due to ketonitrone’s difficulty to form the active intermediate C-N-C type 1,3-dipole in the presence of DBU, even EtONa (entry 15). The similar result was also discovered in the case of 3v (entry 22). Next, in view of 3b obtained in the highest yield, these reactions were investigated using substituent phenyl instead of phenyl at the site of R², when R¹ was 5-methyl group. The results demonstrated that their yields were analogous to these of 3p-u (entries 23-29). Finally, the substrate bearing benzyl at nitrogen atom and aryl groups at the site of R² were also underwent the 1,3-dipolar cycloaddition, which afforded commonly the inferior outcomes to the above examples, in especial 3ad and 3ae. From the above results, the yields were seemingly irrelevant to the electronic effects of substituents at the site of R². However, when the steric bias existed on the substrate, the yield dynamically dropped off (entry 26).

In order to further explore the generality of the cycloaddition reaction, various substituted coumarins were studied. All results were illuminated in Table 3. Firstly, coumarins bearing various groups on benzene ring were employed to react with 1a, which showed that the electron effect and site of substituent played a critical impact on yields and diastereoselectivities of the reaction. For example, 8-ethoxyl coumarin could smoothly undergo the cycloaddition and obtain the yield of 86% with >20:1 dr, whereas, 7-methoxyl coumarin only gave the yield of 22%. Furthermore, when 7-methoxyl group was replaced by 7-diethylamino group, this reaction gave rise to a complex mixture. All coumarin bearing electron-withdrawing or electron-deficient group at 6-position afforded the desired products with yields of 67-82%. However, 6,8-dibromocoumarin only gave 30% yield, which was similar for the reaction result of 7-methoxylcoumarin. It was worth noting that 6-nitrocoumarin 2h was subjected to the cycloaddition with 1a in EtOH, and then the lactone ring of the cycloadduct was opened to yield the compound 4g’ with 24% yield. After many experiments, the reaction 2h with 1a was carried out in non-nucleophilic solvent t-BuOH, leading to the desired product 4g with good yield. Next, other coumarin 3-carboxylic esters 2k-n were investigated. Both i-propyl and n-butyl esters 2l-m were treated with 1a, leading to the same and slight low yield compared with 2a, whereas benzyl esters 2n could lead to a higher yield than 2a. Surprisingly, the yield for the reaction of methyl ester 2k sharply decreased, maybe because of the its unstability in the currently reactional condition. Thirdly, when the entire ethyl ester group of 2a was replaced by other groups, such as H, CN, X, Ac, Bz, carboxyl and amide, all reactions were very messy. In addition, the analogue 2-quinolinones 5 was also applied in this reaction, though the attempts were unsuccessful.

To achieve an asymmetric version of the present reaction, some chiral catalysts, such as quinine, quinidine, hydroquinidine, (S)-BINOL, (R)-BINAP, instead of DBU, were screened in the model reaction of 1a and 2a in EtOH at reflux. Unfortunately, all ligands were not suitable for this reaction (0–26% yields and 0% ee).

To show the synthetic utility of these spiropyrrolidine scaffolds, the derivatization of the model substrate 3a was took place. As shown in scheme 2, the hydroxyl group of 3a was protected by acetyl or benzoyl groups in the presence of DMAP, providing the compounds 6a and 6b, respectively, with 87% and 79% yields. Next, the saponification of 3a in the presence of NaOH could gave smoothly the desired carboxylic acid 7. Unexpectedly, the carboxylic acid was found to reconvert quickly into 3a by TLC, even if sodium salt of 7 was not acidified, needless to say the isolation of 7 via column chromatography (by silica gel using 0.5% TEA of EtOAc/Petroleum ether as an eluent). Exposed to DDQ in DCM, 3a was oxidized to the new nitrone 8 in 55% yield. The configuration of oxidation product 8 were undoubtedly proved by its single crystal X-ray diffraction.

Scheme 2. Transformation of 3a and X-ray crystal structure of the compound 8 (CCDC: 2518523).

Scheme 2. Transformation of 3a and X-ray crystal structure of the compound 8 (CCDC: 2518523).

3. Materials and Methods

3.1. General Methods

All reactions were carried out without strict water-free and oxygen-free conditions. All reagents were obtained from commercial suppliers unless otherwise stated. All solvents and reagents were directly used for reactions without further purification unless otherwise stated. When the reactions preformed at the condition of MeONa, EtONa and tBuONa, solvents (DCM, DCE, dioxane and MTBE) were pre-dried with CaH₂. Flash chromatography was performed using silica gel (200-300 mesh). Reactions were monitored by TLC or/and colour changes of reaction solution. Visualization was achieved under a UV lamp (254 nm and 365 nm), I₂ and by developing the plates with anisaldehyde. ¹H and ¹³C NMR were recorded on 400 and 600 MHz NMR spectrometers with tetramethylsilane (TMS) as the internal standard and were calibrated using residual undeuterated solvent as an internal reference (CHCl₃: ¹H NMR= 7.26, ¹³C NMR= 77.16; DMSO-d₆: ¹H NMR= 2.50, ¹³C NMR= 39.52). IR spectra were acquired on an FT-IR spectrometer and are reported in wavenumbers (cm^-1). High-resolution mass spectra were obtained using electrospray ionization (ESI). The following abbreviations are used for the multiplicities: s: singlet, d: doublet, t: triplet, sept: septet, m: multiplet, br s: broad singlet for proton spectra. Coupling constants (J) are reported in Hertz (Hz).

3.2. Preparation of Intermediates

All N-substituted isatins were prepared by isatin (1.0 equiv.) and alkyl halides (1.5 equiv.) under NaH (2.0 equiv.) in DMF at 0^oC-rt.¹ All O-substituted benzyl hydroxylamine hydrochlorides were prepared by two-step reactions, including the aldoxime reaction (1 equiv. aromatic aldehydes/1.2 equiv. hydroxylamine hydrochloride/2.0 equiv. NaOAc/1:1 EtOH:H₂O and the reduction of aldoxime (1.0 equiv. aromatic aldoxime/1.2 equiv. NaBH₃CN/10.0 equiv. con. HCl/MeOH/0^oC-rt).² All isatin ketonitrones 1 were prepared by isatin or substituted isatins (1.0 equiv.) and O-benzyl or substituted benzyl hydroxylamine hydrochlorides (1.1 equiv.) in the condition of HOAc (2.0 equiv.) in MeOH at rt.³

All coumarins 2 to the equimolar mixture of salicyladehyde (1.0 equiv.) and malonate ester (3.2 equiv) in absolute ethanol or tetrahydrofuran was added catalytic amount of piperidine (0.35 equiv.) and resulting homogeneous mixture was refluxed for 5-8 h. Completion of the reaction was confirmed by TLC, whole reaction mixture was dispensed into crushed ice and the resulting precipitate was filtered, dried and recrystallized from methanol.⁴ 2H-chromene-3 carbaldehydes 5 were prepared by salicyladehyde (1.0 equiv.) or acrolein (1.2 equiv.) under potassium carbonate (1.2 equiv.) in dioxane was refluxed. The mixture was stirred at rt for 27 h before it was quenched with a saturated NH₄Cl solution. The aqueous solution was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether: EtOAc = 100:1 to 50:1) to furnish 5.⁵

3.3. General Procedure for Condition Optimization

A 10 mL tube was charged with isatin ketonitrone 1a (0.2 mmol, 1.0 equiv.) coumarin 2a (0.21-0.22 mmol, 1.05-1.1 equiv.), base (0.05-0.2 mmol, 25-100 mol%) and solvent (1-4 mL). After the reaction mixture is directly concentrated under vacuum. The residue was purified by flash silica gel chromatography eluated with EtOAc:PE (1:12 to 1:2, v/v) to afford the corresponding product 3a.

3.4. General Procedure for Typical Procedure for Cycloaddition

A 25 mL tube was charged with isatin ketonitrone 1 (0.5 mmol, 1.0 equiv.), coumarin 2 (0.525 mmol, 1.05 equiv.), DBU (0.125 mmol, 25 mol%) and EtOH/t-BuOH (2.5 mL). The reaction mixture was stirred at rt and monitor by TLC plate. fter the reaction mixture is directly concentrated under vacuum.The residue was purified by flash silica gel chromatography eluated with EtOAc:PE (1:12 to 1:2, v/v) to afford the corresponding products 3.

3.5. The Phenomenon of the Reaction and TLC

Figure 4 showed the phenmenon of the reaction for 1a and 2a under DBU and TLC of starting materials 1a/2a and product 3a.

3.6. Deriverziation of 3a

To a solution of 3a (280 mg, 0.5 mmol, 1.0 equiv.) in DCM (3 mL) was added DMAP (18 mg, 0.15 mmol, 0.3 equiv.), Ac₂O (70 μL, 0.75 mmol, 1.5 equiv.) at rt. The mixture was stirred at rt for 18 h before it was quenched with a saturated NaHCO₃ solution (10 mL). The aqueous solution was extracted with EtOAc (3x10 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether: EtOAc = 8:1 to 2:1) to provide the acetate 6a in 87% yield.

To a solution of 3a (280 mg, 0.5 mmol, 1.0 equiv.) in DCM (3 mL) was added DMAP (112 mg, 1.0 mmol, 2.0 equiv.), BzCl (145 μL, 1.25 mmol, 2.5 equiv.) at rt. The mixture was stirred at rt for21 h before it was quenched with a saturated NaHCO₃ solution (10 mL). The aqueous solution was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether: EtOAc = 8:1 to 6:1) to furnish the benzoate 6b in 79% yield.

To a solution of 3a (280 mg, 0.5 mmol, 1.0 equiv.) in DCM (5 mL) was added DDQ (170 mg, 0.75 mmol, 1.5 equiv.). The mixture was stirred at rt for 3 h before it was quenched with a saturated Na₂SO₃ solution (15 mL). The aqueous solution was extracted with DCM (3 x 10 mL). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was washed with methanol to give the pure product 8 in 55% yield.

3.7. Data for All New Compounds

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3a)

207.4 mg, 74%, a white solid, >20:1 dr, mp: 182.9-184.1^oC; IR (thin film): ν_max 3470, 3061, 3032, 2977, 2911, 1760, 1732, 1615, 1491, 1369, 1228, 1212, 1179, 768, 732, 610, 532 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.40 (ψt, J = 7.4 Hz, 3H), 7.34-7.26 (m, 3H), 7.14-7.11 (m, 2H), 7.05 (ψt, J = 7.4 Hz, 2H), 6.90 (ψt, J = 7.4 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 7.2 Hz, 2H), 6.38 (d, J = 7.52 Hz, 1H), 5.76 (s, 1H), 4.88 (d, J = 16.4 Hz, 1H), 4.68 (s, 1H), 4.51 (d, J = 16.0 Hz, 1H), 3.61-3.49 (m, 2H), 0.65 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.2, 164.6, 150.8, 144.1, 138.2, 135.7, 130.6, 128.9, 128.4, 128.2, 128.1, 127.4, 126.7, 126.4, 125.0, 124.9, 123.7, 117.5, 115.2, 109.9, 77.4, 72.4, 63.0, 59.3, 47.0, 42.6, 13.5; HRMS (ESI): m/z calcd for C₃₄H₂₈N₂O₆Na [M+Na]⁺ 583.1845, found 583.1836.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-5’-methyl-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3b)

281.0mg, 98%, a white solid, >20:1 dr, mp: 185.3-186.6^oC; IR (thin film): ν_max 3479, 3377, 3065, 3032, 2982, 2919,1767, 1728, 1705, 1496, 1369, 1227, 1174, 808, 765, 527 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.84 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.40 (ψt, J = 7.6 Hz, 2H), 7.32 (t, J = 6.8 Hz, 1H), 7.27 (t, J = 7.4 Hz, 1H), 7.11 (ψt, J = 7.2 Hz, 1H), 7.09–7.06 (m, 2H), 7.04 (ψt, J = 7.8 Hz, 2H), 6.80 (ψt, J = 7.4 Hz, 1H), 6.56 (d, J = 7.8 Hz, 2H), 6.44 (d, J = 7.8 Hz, 2H), 6.11 (s, 1H), 5.01 (d, J = 16.2 Hz, 1H), 4.78 (s, 1H), 4.72 (s, 1H), 4.35 (d, J = 15.6 Hz, 1H), 3.69-3.64 (m, 1H), 3.60-3.55 (m, 1H), 2.46 (s, 3H), 0.76 (t, J = 7.2 Hz, 3H); ¹³C NMR (150 MHz, DMSO-d₆): δ 174.4, 167.0, 164.6, 151.1, 141.8, 137.4, 135.0, 133.0, 130.8, 129.6, 128.9, 128.6, 128.2 (2C), 128.1, 127.2, 126.7, 125.8, 124.8, 124.2, 117.6, 114.9, 109.6, 72.51, 63.0, 59.1, 46.9, 43.4, 21.3, 13.3; HRMS (ESI): m/z calcd for C₃₅H₃₀N₂O₆Na [M+Na]⁺ 597.2002, found 597.1976.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-5’-methoxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3c)

242.6 mg, 82%, a white solid, >20:1 dr, mp: 176.3-177.9^oC; IR (thin film): ν_max 3476, 3067,3026, 2920, 2841, 1770, 1707, 1495, 1435, 1353, 1247, 1171, 1019, 1005, 763, 704 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.40-7.38 (m, 4H), 7.31 (t, J = 7.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 2H), 7.05 (ψt, J = 7.2 Hz, 2H), 6.93 (ψt, J = 7.6 Hz, 1H), 6.88 (dd, J = 8.8, 1.6 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 7.6 Hz, 2H), 6.47 (d, J = 7.6 Hz, 1H), 5.74 (s, 1H), 4.85 (d, J = 16.0 Hz, 1H), 4.68 (s, 1H), 4.46 (d, J = 16.0 Hz, 1H), 3.85 (s, 3H), 3.62-3.46 (m, 2H), 0.65 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.8, 167.2, 164.6, 156.5, 150.8, 138.3, 137.4, 135.8, 130.6, 128.9, 128.8, 128.6, 128.2, 128.1, 127.7, 127.4, 126.7, 124.9, 117.4, 115.3, 114.9, 112.0, 110.4, 77.7, 72.4, 62.9, 59.3, 56.2, 47.0, 42.7, 13.5; HRMS (ESI): m/z calcd for C₃₅H₃₀N₂O₇Na [M+Na]⁺ 613.1951, found 613.1946.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-5’-fluoro-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3d)

236.3 mg, 82%, a white solid, >20:1 dr, mp: 188.1-189.0^oC; IR (thin film): ν_max 3469, 3065, 3039, 2921, 1767, 1708, 1492, 1370, 1355, 1249, 1172, 767, 705, 609, 557 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 7.77-7.71 (m, 3H), 7.42-7.38 (m, 3H), 7.32 (t, J = 6.8 Hz, 1H), 7.20-7.12 (m, 3H), 7.05 (ψt, J = 7.4 Hz, 2H), 6.94 (ψt, J = 7.4 Hz, 1H), 6.68 (dd, J = 8.2, 3.8 Hz, 1H), 6.51 (d, J = 7.6 Hz, 3H), 5.73 (s, 1H), 4.88 (d, J = 16.4 Hz, 1H), 4.73 (s, 1H), 4.50 (d, J = 16.0 Hz, 1H), 3.62-3.48 (m, 2H), 0.65 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.0, 164.6, 150.8, 140.3, 138.2, 135.5, 130.7, 128.9, 128.6, 128.4, 128.3, 128.2, 127.5, 126.7, 125.0, 117.5, 117.1, 116.8, 115.0, 113.4, 113.2, 110.8 (J = 31.6 Hz), 77.7 (J = 4.0 Hz), 72.4, 62.9, 59.3, 46.8, 42.7, 13.4; ¹⁹F NMR (376 MHz, DMSO-d₆): -119.7; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆FNa [M+Na]⁺ 601.1751, found 601.1757.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-5’-chloro-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3e)

221.1 mg, 74%, a white solid, >20:1 dr, mp: 189.7-191.1^oC; IR (thin film): ν_max 3469, 3067, 3037, 2985, 1765, 1734, 1486, 1354, 1256, 1170, 767, 704, 693, 550 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (s, 1H), 7.91 (s, 1H), 7.91 (s, 1H), 7.20 (d, J = 7.2 Hz, 2H), 7.43-7.38 (m, 4H), 7.20 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 7.15-7.12 (m, 2H), 7.06 (ψt, J = 7.4 Hz, 2H), 6.96 (ψt, J = 7.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.50 (ψd, J = 6.8 Hz, 3H), 5.72 (s, 1H), 4.88 (d, J = 16.0 Hz, 1H), 4.75 (s, 1H), 4.51 (d, J = 16.4 Hz, 1H), 3.62-3.49 (m, 2H), 0.64 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.9, 167.0, 164.6, 150.8, 143.0, 138.1, 135.4, 130.7, 130.6, 128.9, 128.6, 128.5, 128.2, 127.9, 127.5, 126.7, 125.4, 125.0, 117.5, 115.0, 111.4, 77.6, 72.4, 63.0, 59.3, 46.8, 42.7, 13.5; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆ClNa [M+Na]⁺ 617.1455, found 617.1447.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-6’-bromo-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3f)

185.8 mg, 58%, a white solid, >20:1 dr, mp: 193.7-194.5^oC; IR (thin film): ν_max 3367, 3067, 2924, 2995, 2852, 1754, 1716, 1615, 1491, 1454, 1228, 1183, 761, 701, 698, 651, 511 cm⁻¹; ¹H NMR (600 MHz, DMSO-d₆) δ 8.59 (s, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.48 (dd, J = 8.1, 1.5 Hz, 1H), 7.43-7.38 (m, 3H), 7.32 (t, J = 7.5 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.07 (ψt, J = 7.8 Hz, 2H), 6.98-6.95 (m, 2H), 6.53 (d, J = 7.8 Hz, 2H), 6.48 (d, J = 6.6 Hz, 1H), 5.71 (s, 1H), 4.87 (d, J = 16.2 Hz, 1H), 4.70 (s, 1H), 4.57 (d, J = 16.2 Hz, 1H), 3.60-3.45 (m, 2H), 0.65 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.0, 164.6, 150.8, 145.7, 138.0, 135.4, 130.8, 129.0, 128.9, 128.5, 128.2, 127.6, 127.1, 126.7, 126.5, 125.7, 125.1, 123.4, 117.6, 114.9, 112.9, 77.2, 72.4, 63.0, 59.3, 46.7, 42.6, 13.5; δ HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆BrNa [M+Na]⁺ 661.0950, found 661.0952.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-5’-iodo-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3g)

175.7 mg, 51%, a white solid, >20:1 dr, mp: 184.4-185.4^oC; IR (thin film): ν_max 3413, 3067, 2983, 2929, 2852, 1754, 1613, 1351, 1262, 1228, 1169, 1029, 808, 767, 701, 608, 534 cm⁻¹; ¹H NMR (600 MHz, DMSO-d₆) δ 8.61 (s, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.72 (d, J = 7.2 Hz, 2H), 7.68 (dd, J = 8.4, 1.8 Hz, 1H), 7.42 (dd, J = 7.2, 1.2 Hz, 1H), 7.40 (ψt, J = 7.8 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.05 (ψt, J = 7.5 Hz, 2H), 6.96 (td, J = 7.5, 0.9 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 7.2 Hz, 2H), 6.50 (ψt, J = 7.5 Hz, 1H), 5.72 (s, 1H), 4.87 (d, J = 16.2 Hz, 1H), 4.72 (s, 1H), 4.49 (d, J = 16.2 Hz, 1H), 3.59 (dq, J = 10.8, 7.2 Hz, 1H), 3.53 (dq, J = 10.8, 7.2 Hz, 1H), 0.64 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.6, 167.0, 164.6, 150.8, 143.9, 139.2, 138.1, 135.3, 133.4, 130.7, 128.9, 128.8, 128.5, 128.2, 127.5, 126.7, 125.0, 117.5, 115.0, 112.3, 87.1, 77.4, 72.4, 63.0, 59.3, 46.8, 42.6, 13.5; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆INa [M+Na]⁺ 709.0811, found 709.0793.

(±)-ethyl (1R,3R,3aS,9bR)-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3j)

178.7 mg, 76%, a white solid, >20:1 dr, mp: 186.3-187.4^oC; IR (thin film): ν_max 3367, 3283, 3057, 3043, 2995, 2935, 1778, 1714, 1620, 1498, 1351, 1257, 1228, 1181, 1019, 763, 741, 598, 567 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 8.40 (s, 1H), 7.71 (t, J = 8.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.40-7.21 (m, 6H), 7.07 (d, J = 8.0 Hz, 1H), 6.88 (ψt, J = 7.4 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 5.70 (s, 1H), 4.55 (s, 1H), 3.59-3.47 (m, 2H), 0.64 (t, J =7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 176.7, 167.3, 164.6, 150.8, 143.9, 138.4, 130.6, 130.3, 128.9, 128.2, 128.1, 128.0, 127.2, 125.0, 124.7, 122.9, 117.3, 115.6, 110.3, 77.5, 72.3, 62.9, 59.2, 47.0, 13.5; HRMS (ESI): m/z calcd for C₂₇H₂₂N₂O₆Na [M+Na]⁺ 493.1376, found 493.1339.

(±)-ethyl (1R,3R,3aS,9bR)-2-hydroxy-1’-methyl-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3k)

193.1 mg, 80%, a white solid, >20:1 dr, mp: 172.1-172.8^oC; IR (thin film): ν_max 3477, 3060, 3038, 2985, 2944, 1765, 1711, 1617, 1498, 1378, 1250, 1228, 1174, 1095, 771, 754, 699, 610, 540 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.45 (t, J = 7.6 Hz, 1H), 7.38 (ψt, J = 7.2 Hz, 2H), 7.32 (ψt, J = 7.4 Hz, 1H), 7.30 (ψt, J = 7.0 Hz, 1H), 7.24 (ψt, J = 7.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.85 (ψt, J = 7.4 Hz, 1H), 6.31 (d, J = 7.6 Hz, 1H), 5.70 (s, 1H), 4.60 (s, 1H), 3.59-3.47 (m, 2H), 2.82 (s, 3H), 0.64 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.8, 167.2, 164.6, 150.6, 145.3, 138.2, 130.7, 130.3, 128.9, 128.2, 128.1, 127.9, 126.4, 124.7, 124.6, 123.6, 117.4, 115.3, 109.2, 77.3, 72.3, 62.9, 59.2, 47.0, 26.0, 13.5; HRMS (ESI): m/z calcd for C₂₈H₂₄N₂O₆Na [M+Na]⁺ 507.1532, found 507.1527.

(±)-ethyl (1R,3R,3aS,9bR)-1’-ethyl-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3l)

195.4 mg, 78%, a white solid, >20:1 dr, mp: 170.4-171.0^oC; IR (thin film): ν_max 3449, 3063, 2981, 2931, 1764, 1732, 1711, 1616, 1491, 1468, 1455, 1373, 1258, 1229, 1178, 763, 750, 610, 551 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.44 (t, J = 7.6 Hz, 1H), 7.39 (ψt, J = 7.4 Hz, 2H), 7.31 (ψt, J = 7.2 Hz, 2H), 7.24 (ψt, J = 7.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.83 (ψt, J = 7.4 Hz, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.74 (s, 1H), 4.54 (s, 1H), 3.55-3.49 (m, 3H), 3.32-3.27 (m, 1H), 0.65 (t, J = 7.0 Hz, 3H), 0.49 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.6, 167.2, 164.6, 150.7, 144.0, 138.3, 130.7, 130.3, 128.9, 128.2, 128.1, 127.8, 126.7, 124.8, 124.5, 123.5, 117.1, 115.1, 109.3, 77.3, 72.5, 62.9, 59.2, 47.7, 34.0, 13.5, 12.0; HRMS (ESI): m/z calcd for C₂₉H₂₆N₂O₆Na [M+Na]⁺ 521.1689, found 521.1683.

(±)-ethyl (1R,3R,3aS,9bR)-1’-allyl-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3m)

217.6 mg, 85%, a white solid, >20:1 dr, mp: 168.4-169.9^oC; IR (thin film): ν_max 3448, 3092, 3059, 2982, 2915, 1762, 1734, 1715, 1618, 1492, 1469, 1369, 1257, 1234, 1181, 767, 749, 732, 702, 608, 527 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 8.2 Hz, 1H), 7.40 (ψt, J = 7.8 Hz, 2H), 7.31 (ψt, J = 6.8 Hz, 2H), 7.26 (ψt, J = 7.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.85 (ψt, J = 7.6 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 5.72 (s, 1H), 5.38-5.29 (m, 1H), 4.70 (d, J = 10.0 Hz, 1H), 4.61 (s, 1H), 4.27 (d, J = 17.2 Hz, 1H), 4.15 (d, J = 16.4 Hz, 1H), 3.95(t, J = 17.2 Hz, 1H), 3.60-3.47 (m, 2H), 0.65 (t, J =7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.7, 167.2, 164.6, 150.8, 144.3, 138.3, 131.2, 130.6, 130.4, 128.9, 128.2, 128.1, 126.3, 124.8, 124.7, 123.6, 117.4, 115.9, 115.2, 109.2, 77.4, 72.4, 62.9, 59.2, 47.2, 41.3, 13.5; HRMS (ESI): m/z calcd for C₃₀H₂₆N₂O₆Na [M+Na]⁺ 533.1689, found 533.1686.

(±)-ethyl (1R,3R,3aS,9bR)-2-hydroxy-2’,4-dioxo-3-phenyl-1’-(prop-2-yn-1-yl)-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3n)

148.9 mg, 59%, a white solid, >20:1 dr, mp: 176.3-168.4^oC; IR (thin film): ν_max 3270, 3067, 3041, 2975, 2923, 1775, 1730, 1711, 1615, 1491, 1369, 1245, 1226, 1163, 759, 700, 612,529 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.81 (ψd, J = 7.8 Hz, 3H), 7.47 (td, J = 7.8, 0.9 Hz, 1H), 7.39 (ψt, J = 7.8 Hz, 2H), 7.34 (t, J = 7.8 Hz, 1H), 7.31 (ψt, J = 7.2Hz, 1H), 7.16 (td, J = 7.1, 1.2 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.75 (ψt, J = 7.5 Hz, 1H), 6.32 (d, J = 7.8 Hz, 1H), 6.05 (s, 1H), 4.74 (s, 1H), 4.72 (s, 1H), 4.31 (dd, J = 17.4, 2.4 Hz, 1H), 4.12 (dd, J = 17.4, 2.4 Hz, 1H), 3.64 (dq, J = 10.8, 7.2 Hz, 1H), 3.56 (dq, J = 10.8, 7.2 Hz, 1H), 1.92 (t, J = 2.4 Hz, 1H), 0.74 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 173.5, 166.8, 164.5, 150.9, 143.2, 137.2, 130.5, 129.6, 128.8, 128.2, 128.1, 127.6, 125.9, 124.1, 124.0, 123.7, 117.5, 114.5, 109.7, 77.2, 76.1, 72.6, 71.8, 63.0, 58.0, 47.2, 28.8, 13.2; HRMS (ESI): m/z calcd for C₃₀H₂₄N₂O₆Na [M+Na]⁺ 531.1532, found 531.1511.

(±)-ethyl (1R,3R,3aS,9bR)-2-hydroxy-2’,4-dioxo-3-(p-tolyl)-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3p)

160.2 mg, 66%, a white solid, >20:1 dr, mp: 162.2-164.0^oC; IR (thin film): ν_max 3384, 3098, 3032, 2981, 2921, 2851, 1763, 1736, 1713, 1621, 1491, 1458, 1350, 1228, 1170, 754, 641, 583 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.37 (s, 1H), 7.71 (d, J = 7.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.27-7.17 (m, 4H), 7.06 (d, J = 8.4 Hz, 1H), 6.87 (ψt, J = 7.4 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.65 (s, 1H), 4.53 (s, 1H), 3.58-3.51 (m, 2H), 2.30 (s, 3H), 0.65 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 176.9, 167.3, 164.6, 150.8, 143.9, 137.2, 135.3, 130.5, 130.2, 128.8, 128.7, 128.0, 127.3, 125.0, 124.6, 122.8, 117.3, 115.6, 110.3, 77.4, 72.0, 62.8, 59.1, 46.9, 21.2, 13.4; HRMS (ESI): m/z calcd for C₂₈H₂₄N₂O₆Na [M+Na]⁺ 507.1532, found 507.1521.

(±)-ethyl (1R,3R,3aS,9bR)-2-hydroxy-3-(4-methoxyphenyl)-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3q)

135.5 mg, 54%, a white solid, >20:1 dr, mp: 150.5-151.3^oC; IR (thin film): ν_max 3422, 3189, 3086, 2917, 2848, 1778, 1736, 1716, 1619, 1512, 1471, 1247, 1166, 1026, 751, 637, 558 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (s, 1H), 8.36 (s, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.33 (ψt, J = 7.6 Hz, 1H), 7.27-7.19 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.87 (ψt, J = 7.4 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.34 (d, J = 7.6 Hz, 1H), 5.64 (s, 1H), 4.54 (s, 1H), 3.75 (s, 3H), 3.59-3.52 (m, 2H), 0.68 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 176.9, 167.3, 164.7, 159.4, 150.8, 143.8, 130.5, 130.2, 130.1, 130.0, 128.0, 127.3, 124.9, 124.6, 122.8, 117.3, 115.7, 113.6, 110.3, 77.4, 71.9, 62.9, 59.1, 55.6, 46.8, 13.5; HRMS (ESI): m/z calcd for C₂₈H₂₄N₂O₇Na [M+Na]⁺ 523.1481, found 523.10467.

(±)-ethyl (1R,3R,3aS,9bR)-3-(4-fluorophenyl)-2-hydroxy-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3r)

189.7 mg,78%, a white solid, >20:1 dr, mp: 205.6-206.3^oC; IR (thin film): ν_max 3350, 3096, 2980, 2840, 1760, 1737, 1711, 1621, 1509, 1472, 1458, 1226, 1177, 1158, 756, 643, 509 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H), 8.47 (s, 1H), 7.72 (m, 3H), 7.34 (t, J = 7.4 Hz, 1H), 7.28-7.21 (m, 4H), 7.07 (d, J = 8.4 Hz, 1H), 6.88 (ψt, J = 7.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 5.68 (s, 1H), 4.53 (s, 1H), 3.59 (q, J = 7.0 Hz, 2H), 0.69 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 176.8, 167.3, 164.7, 150.7, 143.9, 134.4 (d, J= 3.0 Hz), 130.9, 130.8 (d, J= 8.0 Hz), 130.6, 130.3, 128.0, 127.1, 125.0, 124.7, 122.9, 117.4, 115.5, 115.1, 114.9, 110.3, 77.4, 71.6, 63.0, 59.0, 46.9, 13.5; ¹⁹F NMR (376 MHz, DMSO-d₆): -115.0; HRMS (ESI): m/z calcd for C₂₇H₂₁N₂O₆FNa [M+Na]⁺ 511.1281, found 511.1279.

(±)-ethyl (1R,3R,3aS,9bR)-3-(4-chlorophenyl)-2-hydroxy-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3s)

218.2 mg, 86%, a white solid, >20:1 dr, mp: 166.7-167.4^oC; IR (thin film): ν_max 3368, 3088, 2983, 2836, 1766, 1736, 1709, 1621, 1490, 1457, 1227, 1177, 1017, 752, 670, 579 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.51 (s, 1H), 7.73-7.68 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H), 7.34 (ψt, J = 7.8 Hz, 1H), 7.26 (ψt, J = 7.6 Hz, 1H), 7.23 (ψt, J = 7.2 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.89 (ψt, J = 7.6 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.67 (s, 1H), 4.52 (s, 1H), 3.61 (q, J = 7.0 Hz, 2H), 0.68 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 176.4, 167.3, 164.7, 150.7, 143.9, 137.3, 132.8, 130.7, 130.3, 128.2, 128.0, 127.0, 125.0, 124.7, 122.9, 117.4, 115.4, 110.3, 77.4, 71.5, 63.0, 59.0, 47.0, 13.5; HRMS (ESI): m/z calcd for C₂₇H₂₁N₂O₆ClNa [M+Na]⁺ 527.0986, found 527.0984.

(±)-ethyl (1R,3R,3aS,9bR)-3-(4-bromophenyl)-2-hydroxy-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3t)

225.9 mg, 82%, a white solid, >20:1 dr, mp: 161.6-163.0^oC; IR (thin film): ν_max 3513, 3282, 2859, 1784, 1714, 1688, 1487, 1247, 1226, 1178, 1010, 858, 748, 665, 570 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 8.51 (s, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.34 (ψt, J = 7.6 Hz, 1H), 7.26 (ψt, J = 7.6 Hz, 1H), 7.22 (ψt, J = 7.6 Hz, 1H),7.08 (d, J = 8.0 Hz, 1H), 6.88 (ψt, J = 7.4 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.35 (d, J = 7.6 Hz, 1H), 5.66 (s, 1H), 4.52 (s, 1H), 3.61 (q, J = 7.1 Hz, 2H), 0.68 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 176.7, 167.3, 164.7, 150.7, 143.9, 137.7, 131.2, 131.0, 130.6, 130.3, 128.0, 126.9, 125.0, 124.7, 122.9, 121.3, 117.4, 115.4, 110.3, 77.4, 71.6, 63.0, 59.0, 47.0, 13.5; HRMS (ESI): m/z calcd for C₂₇H₂₁N₂O₆BrNa [M+Na]⁺ 571.0481, found 571.0471.

(±)-ethyl (1R,3R,3aS,9bR)-2-hydroxy-3-(4-nitrophenyl)-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3u)

122.1 mg, 47%, a white solid, >20:1 dr, mp: 170.4-171.8^oC; IR (thin film): ν_max 3360, 3288, 2941, 2345, 1782, 1735, 1605, 1523, 1492, 1347, 1256, 1174, 1112, 1017, 856, 745, 608, 573 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 8.69 (s, 1H), 8.30 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 7.2 Hz, 1H), 7.36 (ψt, J = 7.5 Hz, 1H), 7.28 (ψt, J = 7.6 Hz, 1H), 7.25 (ψt, J = 7.2 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.90 (ψt, J = 7.4 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.37 (d, J = 7.2 Hz, 1H), 5.80 (s, 1H), 4.53 (s, 1H), 3.60 (q, J = 7.0 Hz, 2H), 0.66 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 176.6, 167.3, 164.7, 150.6, 147.6, 146.1, 143.9, 130.8, 130.4, 130.0, 128.1, 126.6, 125.2, 124.8, 123.5, 123.0, 117.4, 115.2, 110.4, 77.6, 71.5, 63.2, 59.1, 47.3, 13.5; HRMS (ESI): m/z calcd for C₂₇H₂₁N₃O₈Na [M+Na]⁺ 538.1226, found 538.1215.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-5’-methyl-2’,4-dioxo-3-(p-tolyl)-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3w)

227.7 mg, 77%, a white solid, >20:1 dr, mp: 167.4-169.2^oC; IR (thin film): ν_max 3369, 3037, 2975, 2915, 2851, 1757, 1741, 1709, 1609, 1498, 1369, 1271, 1248, 1178, 801, 769, 623, 565 cm⁻¹;¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (s, 1H), 7.63 (s, 1H), 7.58 (d, J = 8.0 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 6.8 Hz, 2H), 7.04 (ψt, J = 7.2 Hz, 2H), 6.91 (ψt, J = 7.2 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 7.2 Hz, 2H), 6.42 (d, J = 7.2 Hz, 1H), 5.70 (s, 1H), 4.85 (d, J = 16.4 Hz, 1H), 4.64 (s, 1H), 4.46 (d, J = 16.4 Hz, 1H), 3.64-3.51 (m, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 0.66 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.2, 164.7, 150.8, 141.8, 137.2, 135.8, 135.2, 132.8, 130.8, 130.5, 128.8, 128.7, 128.5, 127.4, 126.7, 126.5, 125.5, 124.9, 117.4, 115.3, 109.7, 77.4, 72.2, 62.9, 59.3, 46.9, 42.6, 21.3, 13.5; HRMS (ESI): m/z calcd for C₃₆H₃₂N₂O₆Na [M+Na]⁺ 611.2158, found.611.2137.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-3-(4-methoxyphenyl)-5’-methyl-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3x)

149.9 mg, 50%, a white solid, >20:1 dr, mp: 147.1-147.7^oC; IR (thin film): ν_max 3440, 3069, 3032, 2983, 2935, 2836, 1776, 1736, 1694, 1612, 1514, 1498, 1370, 1244, 1163, 1134, 1022, 823, 754, 699, 567 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 1H), 7.63 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 7.39 (t, J = 7.6 Hz, 1H), 7.11 (ψd, J = 7.2 Hz, 3H), 7.04 (ψt, J = 7.4 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.90 (ψt, J = 7.6 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 7.2 Hz, 2H), 6.42 (d, J = 7.6 Hz, 1H), 5.69 (s, 1H), 4.85 (d, J = 16.2 Hz, 1H), 4.65 (s, 1H), 4.47 (d, J = 16.2 Hz, 1H), 3.76 (s, 3H), 3.66-3.53 (m, 2H), 2.42 (s, 3H), 0.69 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.2, 164.7, 159.4, 150.8, 141.8, 135.8, 132.8, 130.8, 130.5, 130.1, 128.8, 128.5, 127.4, 126.7, 126.5, 125.5, 124.9, 117.4, 115.3, 113.6, 109.7, 77.4, 72.1, 62.9, 59.2, 55.6, 46.8, 42.6, 21.3, 13.5; HRMS (ESI): m/z calcd for C₃₆H₃₂N₂O₇Na [M+Na]⁺ 627.2107, found.627.2096.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-3-(4-fluorophenyl)-2-hydroxy-5’-methyl-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3y)

205.6 mg, 69%, a white solid, >20:1 dr, mp: 185.6-186.5^oC; IR (thin film): ν_max 3478, 2989, 2960, 2918, 1774, 1737, 1710, 1613, 1516, 1496, 1158, 812, 765, 610, 503 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.65 (s, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.25 (ψt, J = 8.6 Hz, 2H), 7.12 (ψt, J = 7.2 Hz, 3H), 7.04 (ψt, J = 7.4 Hz, 2H), 6.92 (ψt, J = 7.6 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 7.6 Hz, 2H), 6.42 (d, J = 7.6 Hz, 1H), 5.73 (s, 1H), 4.85 (d, J = 16.4 Hz, 1H), 4.64 (s, 1H), 4.47 (d, J = 16.4 Hz, 1H), 3.68-3.55 (m, 2H), 2.42 (s, 3H), 0.70 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.9, 167.3, 164.7, 150.8, 141.8, 135.8, 134.3 (d, J = 2.8 Hz), 132.8, 130.9, 130.8, 130.6, 128.5, 127.4, 126.7, 126.3, 125.5, 124.9, 117.5, 115.2, 114.9, 109.7, 77.4, 71.8, 63.1, 59.2, 46.9, 42.7, 21.3, 13.5; ¹⁹F NMR (376 MHz, DMSO-d₆): -114.9; HRMS (ESI): m/z calcd for C₃₅H₂₉N₂O₆FNa [M+Na]⁺ 615.1907, found 615.1904.

(±)-ethyl (1R,3S,3aS,9bR)-1’-benzyl-3-(2-chlorophenyl)-2-hydroxy-5’-methyl-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3z)

147.3 mg, 48%, a white solid, >20:1 dr, mp: 155.0-156.2^oC; IR (thin film): ν_max 3447, 3069, 3030, 2979, 2921, 2867, 1782, 1717, 1605, 1497, 1457, 1370, 1259, 1226, 1152, 1007, 815, 756, 695, 532 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.44 (s, 1H), 7.89 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.43-7.33 (m, 3H), 7.14-7.12 (m, 5H), 6.92 (ψt, J = 7.2 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.47 (ψd, J = 6.4 Hz, 3H), 6.20 (s, 1H), 4.87 (d, J = 16.2 Hz, 1H), 4.80 (s, 1H), 4.46 (d, J = 16.2 Hz, 1H), 3.69-3.61 (m, 1H), 3.48-3.40 (m, 1H), 2.41 (s, 1H), 0.63 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.9, 166.1, 162.4, 151.0, 141.7, 137.3, 135.8, 135.1, 132.8, 131.7, 130.8, 130.5, 130.0, 129.5, 128.9, 128.4, 127.4, 127.1, 126.6, 126.5, 125.8, 124.7, 117.3, 115.5, 109.6, 77.4, 69.5, 63.1, 60.1, 46.9, 42.6, 21.1, 13.4; HRMS (ESI): m/z calcd for C₃₅H₂₉N₂O₆ClNa [M+Na]⁺ 631.1612, found 631.1602.

(±)-ethyl (1R,3S,3aS,9bR)-1’-benzyl-3-(4-chlorophenyl)-2-hydroxy-5’-methyl-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3aa)

276.5 mg, 85%, a white solid, >20:1 dr, mp: 192.4-193.7^oC; IR (thin film): ν_max 3454, 3067, 3018, 2983, 2925, 2859, 1774, 1729, 1705, 1607, 1497, 1455, 1374, 1349, 1262, 1225, 1165, 1015, 811, 755, 629, 544 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.65 (s, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 7.6 Hz, 1H), 7.13 (ψt, J = 7.8 Hz, 3H), 7.04 (ψt, J = 7.8 Hz, 2H), 6.92 (ψt, J = 7.4 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 7.2 Hz, 2H), 6.42 (d, J = 7.6 Hz, 1H), 5.72 (s, 1H), 4.85 (d, J = 16.0 Hz, 1H), 4.63 (s, 1H), 4.47 (d, J = 16.0 Hz, 1H), 3.70-3.58 (m, 2H), 2.42 (s, 3H), 0.70 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.9, 167.2, 164.7, 150.8, 141.8, 137.2, 135.7, 132.8, 130.9, 130.7, 128.8, 128.5, 128.3, 127.4, 126.7, 126.2, 125.6, 125.0, 117.5, 115.1, 109.7, 77.4, 71.4, 63.1, 59.1, 47.0, 42.7, 21.2, 13.5; HRMS (ESI): m/z calcd for C₃₅H₂₉N₂O₆ClNa [M+Na]⁺ 631.1612, found 631.1613.

(±)-ethyl (1R,3S,3aS,9bR)-1’-benzyl-3-(4-bromophenyl)-2-hydroxy-5’-methyl-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3ab)

204.7 mg, 66%, a white solid, >20:1 dr, mp: 193.1-194.8^oC; IR (thin film): ν_max 3370, 3032, 2977, 2929, 2902, 1753, 1741, 1708, 1497, 1369, 1250, 1225, 1182, 1013, 770, 806, 770, 612, 536 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 7.67-7.61 (m, 5H), 7.40 (t, J = 7.2 Hz, 1H), 7.12 (ψt, J = 7.4 Hz, 3H), 7.04 (ψt, J = 7.4 Hz, 2H), 6.92 (ψt, J = 7.6 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 7.6 Hz, 2H), 6.42 (d, J = 7.6 Hz, 1H), 5.71 (s, 1H), 4.84 (d, J = 16.0 Hz, 1H), 4.63 (s, 1H), 4.47 (d, J = 16.0 Hz, 1H), 3.70-3.59 (m, 2H), 2.42 (s, 3H), 0.70 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.9, 167.2, 164.7, 150.7, 141.8, 137.6, 135.7, 132.8, 131.2, 131.0, 130.9, 130.6, 128.8, 128.5, 127.4, 126.7, 126.2, 125.6, 125.0, 121.4, 117.5, 115.1, 109.7, 77.4, 71.8, 63.1, 59.1, 47.0, 42.6, 21.2, 13.5; HRMS (ESI): m/z calcd for C₃₅H₂₉N₂O₆BrNa [M+Na]⁺ 675.1107, found 675.1080.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-5’-methyl-3-(4-nitrophenyl)-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3ac)

157.8 mg, 52%, a white solid, >20:1 dr, mp: 194.1-195.5^oC; IR (thin film): v_max 3500, 3063, 3037, 2989, 2921, 1782, 1707, 1605, 1516, 1495, 1456, 1347, 1261, 1247, 1231, 1177, 765, 697, 544 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.31 (d, J = 7.6 Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 7.68 (s, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.12 (ψt, J = 7.2 Hz, 2H), 7.05 (ψt, J = 7.4 Hz, 2H), 6.94 (ψt, J = 7.2 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.51 (d, J = 7.2 Hz, 2H), 6.44 (d, J = 7.6 Hz, 1H), 5.84 (s, 1H), 4.86 (d, J = 16.2 Hz, 1H), 4.64 (s, 1H), 4.49 (d, J = 16.2 Hz, 1H), 3.67-3.59 (m, 2H), 2.43 (s, 3H), 0.67 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 174.8, 167.2, 164.7, 150.7, 147.6, 146.0, 141.8, 135.7, 132.9, 131.0, 130.7, 130.0, 128.9, 128.5, 127.4, 126.7, 125.9, 125.7, 125.1, 123.5, 117.6, 114.8, 109.8, 77.5, 71.7, 69.3, 59.2, 47.3, 42.7, 21.3, 13.5; HRMS (ESI): m/z calcd for C₃₅H₂₉N₃O₈Na [M+Na]⁺ 642.1852, found 642.1846.

(±)- ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-2’,4-dioxo-3-(p-tolyl)-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3ad)

133.6 mg, 46%, a white solid, >20:1 dr, mp: 164.5-166.5^oC; IR (thin film): ν_max 3852, 3678, 3649, 1712, 1460, 1369, 1231, 1176, 857, 738, 620, 554 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 7.81 (d, J = 6.8 Hz, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.32 (ψt, J = 7.2 Hz, 1H), 7.28 (ψt, J = 7.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.05 (ψt, J = 7.4 Hz, 2H), 6.89 (ψt, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 7.6 Hz, 2H), 6.37 (d, J = 7.6 Hz, 1H), 5.71 (s, 1H), 4.87 (d, J = 16.2 Hz, 1H), 4.66 (s, 1H), 4.50 (d, J = 16.2 Hz, 1H), 3.61-3.52 (m, 2H), 2.31 (s, 3H), 0.67 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.2, 164.7, 150.8, 144.1, 137.3, 135.7, 135.2, 130.6, 128.9, 128.8, 128.7, 128.4, 127.4, 126.7, 126.5, 125.0, 124.9, 123.7, 117.5, 115.2, 109.9, 77.3, 72.4, 62.9, 59.3, 47.0, 42.6, 21.2, 13.5; HRMS (ESI): m/z calcd for C₃₅H₃₀N₂O₆Na [M+Na]⁺ 597.2002, found 597.2014.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-3-(4-methoxyphenyl)-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3ae)

112.0 mg, 38%, a yellow solid, >20:1 dr, mp: 169.3-169.6^oC; IR (thin film): ν_max 3853, 3669, 3629, 3565, 1779, 1703, 1611, 1462, 1234, 1171, 1019, 855, 757, 668, 602, 516 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.32 (ψt, J = 7.8 Hz, 1H), 7.28 (ψt, J = 7.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 2H), 7.05 (ψt, J = 7.6 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 6.88 (ψt, J = 7.6 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.52 (d, J = 7.6 Hz, 2H), 6.37 (d, J = 7.6 Hz, 1H), 5.70 (s, 1H), 4.87 (d, J = 16.4 Hz, 1H), 4.67 (s, 1H), 4.50 (d, J = 16.4 Hz, 1H), 3.76 (s, 3H), 3.65-3.54 (m, 2H), 0.70 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.2, 164.7, 159.4, 150.8, 144.1, 135.7, 130.6, 130.1, 130.0, 128.9, 128.4, 126.7, 126.5, 124.9, 124.9, 123.7, 117.5, 115.3, 113.6, 109.9, 77.3, 72.1, 62.9, 59.3, 55.6, 46.8, 42.6, 13.5; HRMS (ESI): m/z calcd for C₃₅H₃₀N₂O₇Na [M+Na]⁺ 613.1951, found 613.1949.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-3-(4-fluorophenyl)-2-hydroxy-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3af)

181.3 mg, 63%, a yellow solid, >20:1 dr, mp: 161.1-163.6^oC; IR (thin film): ν_max 3852,3696, 3680, 3624, 3564, 3422, 1773, 1732, 1611, 1369, 1169, 858, 819, 757, 507 cm^{−1; 1}H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 8.4, 6.0 Hz, 2H), 7.40 (td, J = 8.4, 1.0 Hz, 1H), 7.32 (td, J = 7.6, 1.2 Hz, 1H), 7.32 (ψt, J = 8.0 Hz, 1H), 7.32 (ψt, J = 8.8 Hz, 2H), 7.13 (ψt, J = 7.4 Hz, 2H), 7.05 (ψt, J = 7.4 Hz, 2H), 6.90 (ψt, J = 7.4 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 2H), 6.38 (d, J = 7.6 Hz, 1H), 5.75 (s, 1H), 4.87 (d, J = 16.0 Hz, 1H), 4.66 (s, 1H), 4.51 (d, J = 16.0 Hz, 1H), 3.65-3.58 (m, 2 H), 0.71 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.2, 164.7, 150.8, 144.2, 135.7, 134.3 (d, J = 2.7 Hz), 130.9, 130.8, 130.7, 128.9, 128.4, 127.5, 126.7, 126.3, 125.0 (2C), 123.7, 117.5, 115.2, 115.1, 115.0, 109,9, 77.3, 71.8, 63.1, 59.1, 47.0, 42.6, 13.5; ¹⁹F NMR (376 MHz, DMSO-d₆): -114.9; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆FNa [M+Na]⁺ 601.1751, found 601.1740.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-3-(4-chlorophenyl)-2-hydroxy-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3ag)

225.5mg, 76%, a white solid, >20:1 dr, mp: 183.1-184.2^oC; IR (thin film): ν_max 3852, 3734, 3678, 3574, 3563, 2981, 2933, 1778, 1714, 1611, 1493, 1229,1165, 1009, 862, 754, 610, 544 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.32 (ψt, J = 7.8 Hz, 1H), 7.28 (ψt, J = 7.2 Hz, 1H), 7.13 (ψt, J = 8.2 Hz, 1H), 7.05 (ψt, J = 7.6 Hz, 2H), 6.90 (ψt, J = 7.6 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 7.6 Hz, 2H), 6.38 (d, J = 7.6 Hz, 1H), 5.74 (s, 1H), 4.87 (d, J = 16.0 Hz, 1H), 4.65 (s, 1H), 4.51 (d, J = 16.0 Hz, 1H), 3.63 (q, J = 7.0 Hz, 2H), 0.71 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.2, 164.7, 150.8, 144.1, 137.2, 135.7, 132.9, 130.7, 128.9, 128.4, 128.3, 127.5, 126.7, 126.2, 125.0 (2C), 123.7, 117.5, 115.0, 110.0, 77.3, 71.8, 63.1, 59.1, 47.0, 42.6, 13.5; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆ClNa [M+Na]⁺ 617.1455, found 617.1455.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-3-(4-bromophenyl)-2-hydroxy-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate (3ah)

218.2 mg, 68%, a white solid; >20:1 dr, mp: 190.0-191.3^oC; IR (thin film): ν_max 3854, 3729, 3668, 3633, 1740, 1712, 1617, 1498, 1376, 1232, 1180, 1004, 858, 804, 736, 620 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.32 (ψt, J = 7.6 Hz, 1H), 7.28 (ψt, J = 7.6 Hz, 1H), 7.13 (ψt, J = 8.4 Hz, 2H), 7.05 (t, J = 7.4 Hz, 2H), 6.90 (ψt, J = 7.0 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 6.8 Hz, 2H), 6.38 (d, J = 7.6 Hz, 1H), 5.72 (s, 1H), 4.87 (d, J = 16.2 Hz, 1H), 4.65 (s, 1H), 4.51 (d, J = 16.2 Hz, 1H), 3.64 (q, J = 7.0 Hz, 2H), 0.70 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.2, 164.7, 150.8, 144.1, 137.6, 135.7, 131.2, 131.0, 130.7, 128.9, 128.4, 127.5, 126.7, 126.2, 125.0, 124.9, 123.7, 121.4, 117.5, 115.0, 109.9, 77.3, 71.8, 63.1, 59.1, 47.1, 42.7, 13.5; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆BrNa [M+Na]⁺ 661.0950, found 661.0924.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-3-(4-nitrophenyl)-2’,4-dioxo-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(3ai)

182.1 mg, 60%, a white solid, >20:1 dr, mp: 202.1-203.2^oC; IR (thin film): ν_max 3854, 3736, 3639, 3612, 3396, 3070, 2987, 2931, 1728, 1610, 1348, 1235, 1178, 1009, 754, 699, 610, 551 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.00 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.12 (d, J = 6.8 Hz, 1H), 7.06 (ψt, J = 7.4 Hz, 2H), 6.92 (ψt, J = 7.4 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 2H), 6.40 (d, J = 7.6 Hz, 1H), 5.86 (s, 1H), 4.88 (d, J = 16.2 Hz, 1H), 4.66 (s, 1H), 4.53 (d, J = 16.2 Hz, 1H), 3.62 (q, J = 7.0 Hz, 2H), 0.69 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.2, 164.7, 150.7, 147.6, 146.0, 144.2, 135.6, 130.8, 130.0, 128.9, 128.4 127.5, 126.7, 125.9, 125.1, 125.0, 123.8, 123.5, 117.6, 114.8, 110.0, 77.5, 71.8, 63.3, 59.2, 47.3, 42.7, 13.5; HRMS (ESI): m/z calcd for C₃₄H₂₇N₃O₈Na [M+Na]⁺ 628.1696, found 628.1690.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-6-methyl-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4a)

188.6 mg, 65%, a white solid; >20:1 dr, mp: 182.6-183.9^oC; IR (thin film): ν_max 3460, 3061, 3035, 2981, 2915, 1755, 1733, 1615, 1468, 1366, 1273, 1207, 1184, 1031, 1006, 837, 782, 752, 631, 551, 530 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 7.6 Hz, 2H), 7.40 (ψt, J = 7.6 Hz, 2H), 7.34-7.23 (m, 4H), 7.13 (t, J = 7.4 Hz, 1H), 7.05 (ψt, J = 7.5 Hz, 2H), 6.76 (ψt, J = 7.4 Hz, 1H), 6.70 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 7.6 Hz, 2H), 6.19 (d, J = 7.2 Hz, 1H), 5.77 (s, 1H), 4.87 (d, J = 16.2 Hz, 1H), 4.65 (s, 1H), 4.51 (d, J = 16.2 Hz, 1H), 3.60-3.48 (m, 2H), 2.22 (s, 3H), 0.65 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.2, 164.6, 149.1, 144.2, 138.3, 135.8, 131.8, 130.6, 128.9, 128.8, 128.2, 128.1, 127.4, 126.7, 126.6, 126.1, 125.9, 124.9, 124.2, 123.6, 114.8, 109.8, 77.4, 72.5, 62.9, 59.2, 47.2, 42.7, 15.9, 13.5; HRMS (ESI): m/z calcd for C₃₅H₃₀N₂O₆Na [M+Na]⁺ 597.2002, found 597.2003.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-7-methoxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4b)

64.7 mg, 22%, a white solid, >20:1 dr, mp: 169.6-171.1^oC; IR (thin film): ν_max 3478, 2958, 2924, 2853, 1770, 1710, 1613, 1493, 1467, 1361, 1194, 1081, 1013, 955, 856, 747, 595, 643 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 7.79 (d, J = 6.4 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.39 (ψt, J = 7.4 Hz, 2H), 7.33-7.25 (m, 3H), 7.15 (ψt, J = 7.2 Hz, 1H), 7.03 (t, J = 7.6 Hz, 2H), 6.74 (d, J = 2.0 Hz, 1H), 6.71 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 7.6 Hz, 2H), 6.48 (dd, J = 8.6, 2.2 Hz, 1H), 6.24 (d, J = 8.8 Hz, 1H), 5.75 (s, 1H), 4.91 (d, J = 16.0 Hz, 1H), 4.59 (s, 1 H), 4.51 (d, J = 16.0 Hz, 1H), 3.74 (s, 3H), 3.59-3.52 (m, 2H), 0.65 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.2, 167.2, 164.8, 160.9, 151.8, 144.1, 138.3, 135.8, 130.5, 129.1, 128.8, 128.6, 128.2, 128.1, 127.5, 126.8, 126.5, 124.9, 123.6, 111.6, 109.8, 106.8, 102.4, 77.4, 72.3, 62.9, 59.3, 56.0, 46.7, 42.6, 13.5; HRMS (ESI): m/z calcd for C₃₅H₃₀N₂O₇Na [M+Na]⁺ 613.1952, found 613.1949.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-6-ethoxy-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4c)

261.0 mg, 86%, a white solid, >20:1 dr, mp: 143.2-145.1^oC; IR (thin film): ν_max 3471, 3068, 3039, 2981, 2927, 1774, 1715, 1615, 1587, 1369, 1243, 1181, 1069, 953, 866, 754, 700, 664, 604, 540 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 7.80 (d, J = 6.8 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.40 (ψt, J = 7.6 Hz, 2H), 7.31 (ψt, J = 7.8 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.14 (ψt, J = 7.2 Hz, 1H), 7.12-7.05 (m, 3H), 6.81 (ψt, J = 8.0 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 7.6 Hz, 2H), 5.91 (d, J = 7.6 Hz, 1H), 5.74 (s, 1H), 4.89 (d, J = 16.4 Hz, 1H), 4.67 (s, 1H), 4.52 (d, J = 16.4 Hz, 1H), 4.11-3.97 (m, 2H), 3.61-3.48 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H), 0.65 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.1, 164.4, 146.8, 144.2, 140.0, 138.3, 135.7, 130.6, 128.9, 128.8, 128.2, 128.1, 127.4, 126.6, 126.5, 124.9, 124.8, 123.7, 119.2, 115.9, 113.8, 109.9, 77.3, 72.5, 64.6, 63.0, 59.0, 47.1, 42.6, 15.0, 13.4; HRMS (ESI): m/z calcd for C₃₆H₃₂N₂O₇Na [M+Na]⁺ 627.2107, found 627.2110.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-8-fluoro-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4d)

236.4 mg, 82%, a yellow solid, >20:1 dr, mp: 177.4-178.2^oC; IR (thin film): ν_max 3471, 3068, 3018, 2977, 2909, 1770, 1731, 1615, 1495, 1467, 1369, 1250, 1183, 1007, 874, 753, 700, 623, 542 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.40 (ψt, J = 7.4 Hz, 2H), 7.35-7.26 (m, 4H), 7.22 (dd, J = 8.8, 4.8 Hz, 1H), 7.16 (ψt, J = 7.2 Hz, 1H), 7.09 (ψt, J = 7.4 Hz, 2H), 6.76 (d, J = 7.6 Hz, 1H), 6.60 (d, J = 7.6 Hz, 2H), 6.06 (d, J = 8.0 Hz, 1H), 5.74 (s, 1H), 4.90 (d, J = 16.0 Hz, 1H), 4.69 (s, 1H), 4.53 (d, J = 16.0 Hz, 1H), 3.62-3.49 (m, 2H), 0.65 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.0, 164.4, 147.2 (d, J = 2.0 Hz), 144.1, 138.1, 135.8, 130.8, 128.9, 128.2, 127.6, 126.8, 126.0, 125.1, 123.8, 119.5 (d, J = 9.6 Hz), 117.8, 117.6, 116.9, 116.8, 114.5, 114.2, 110.1, 77.3, 72.4, 63.0, 58.8, 46.8, 42.7, 13.4; ¹⁹F NMR (376 MHz, DMSO-d₆): -118.0; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆FNa [M+Na]⁺ 601.1751, found 601.1754.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-8-chloro-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4e)

204.2 mg, 67%, a white solid, >20:1 dr, mp: 168.8-170.0^oC; IR (thin film): ν_max 3448, 3098, 3059, 3022, 2977, 2913, 1774, 1725, 1707, 1489, 1468, 1381, 1255, 1255, 1161, 1138, 1007, 885, 750, 701, 615, 557, 534 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.46 (dd, J = 8.6, 2.6 Hz, 1H), 7.39 (ψt, J = 7.4 Hz, 2H), 7.36-7.24 (m, 3H), 7.19 (d, J = 8.8 Hz, 1H), 7.17 (ψt, J = 7.2 Hz, 1H), 7.10 (ψt, J = 7.6 Hz, 2H), 6.75 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 7.6 Hz, 2H), 6.32 (d, J = 2.4 Hz, 1H), 5.73 (s, 1H), 4.91 (d, J = 16.0 Hz, 1H), 4.69 (s, 1H), 4.53 (d, J = 16.0 Hz, 1H), 3.62-3.50 (m, 2H), 0.66 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 166.9, 164.2, 149.6, 144.1, 138.0, 135.7, 130.8, 130.6, 128.9, 128.8, 128.6, 128.2 (2C), 127.8, 127.6, 126.6, 125.9, 125.1, 123.8, 119.5, 117.2, 110.0, 77.3, 72.4, 63.1, 58.9, 46.6, 42.7, 13.4; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆ClNa [M+Na]⁺ 617.1455, found 617.1450.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-8-bromo-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4f)

214.3 mg, 67%, a white solid, >20:1 dr, mp: 159.1-161.2^oC; IR (thin film): ν_max 3453, 3064, 3026, 2983, 2930, 1776, 1725, 1615, 1467, 1227, 1163, 1075, 999, 824, 749, 700, 614, 535 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (s, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.58 (dd, J = 8.8, 2.0 Hz, 1H), 7.40 (ψt, J = 7.4 Hz, 2H), 7.37 (ψt, J = 8.0 Hz, 1H), 7.33-7.29 (m, 2 H), 7.17 (ψt, J = 7.2 Hz, 1H), 7.12 (s, 1 H), 7.11 (ψt, J = 7.2 Hz, 2H), 6.75 (d, J = 7.6 Hz, 1H), 6.57 (d, J = 7.6 Hz, 2H), 6.45 (d, J = 2.4 Hz, 1H), 5.73 (s, 1H), 4.91 (d, J = 16.0 Hz, 1H), 4.69 (s, 1H), 4.53 (d, J = 16.0 Hz, 1H), 3.62-3.50 (m, 2H), 0.66 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 166.9, 164.2, 150.1, 144.1, 138.0, 135.7, 133.4, 130.8, 130.7, 128.9, 128.8, 128.2 (2C), 127.5, 126.5, 125.9, 125.1, 123.8, 119.8, 117.7, 116.5, 110.0, 77.3, 72.4, 63.1, 58.9, 46.6, 42.7, 13.4; HRMS (ESI): m/z calcd for C₃₄H₂₇N₂O₆BrNa [M+Na]⁺ 661.0950, found 661.0933.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-8-nitro-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4g)

228.0 mg, 75%, a white solid, >20:1 dr, mp: 142.8-143.6^oC; IR (thin film): ν_max 3904, 3740, 3079, 1784, 1714, 1613, 1528, 1343, 1246, 1149, 996, 844, 742, 699 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.23 (dd, J = 9.2, 2.8 Hz, 1H), 7.89 (dd, J = 7.0, 1.0 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.44-7.31 (m, 6H), 7.14 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.02 (ψt, J = 7.6 Hz, 2H), 6.82 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 7.2 Hz, 2H), 5.76 (s, 1H), 4.85 (d, J = 16.0 Hz, 2H), 4.82 (s, 1 H), 4.51 (d, J = 16.0 Hz, 1H), 3.63-3.50 (m, 2H), 0.67 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 166.6, 163.7, 155.3, 144.0, 143.5, 137.8, 135.9, 131.0, 128.9, 128.7, 128.3, 127.7, 127.0, 126.4, 125.5, 125.3, 124.0, 123.9, 119.0, 116.6, 110.2, 77.3, 72.5, 63.2, 58.7, 46.4, 42.8, 13.4; HRMS (ESI): m/z calcd for C₃₄H₂₇N₃O₈Na [M+Na]⁺ 628.1696, found 6281.1693.

(±)-diethyl (3R,3’R,5’R)-1-benzyl-1’-hydroxy-3’-(2-hydroxy-5-nitrophenyl)-2-oxo-5’-phenylspiro[indoline-3,2’-pyrrolidine]-4’,4’-dicarboxylate(4g’)

77.4 mg, 24%, a white solid, >20:1 dr, mp: 178.1-180.0^oC; IR (thin film): ν_max 3852, 3732, 3676, 3649, 3622, 1725, 1618, 1496, 1339, 1289, 1195, 1098, 1020, 803, 753, 702, 611 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 8.32 (d, J = 2.8 Hz, 1H), 8.20 (s, 1H), 7.97 (dd, J = 9.2, 2.8 Hz, 1H), 7.71 (dd, J = 5.8, 2.2 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.35 (ψt, J = 7.4 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.18-7.11 (m, 3H), 7.05 (ψt, J = 7.4 Hz, 2H), 6.84 (d, J = 7.6 Hz, 2H), 6.75 (d, J = 9.2 Hz, 1H), 6.60 (dd, J = 6.8, 1.6 Hz, 1H), 6.46 (s, 1H), 5.85 (s, 1H), 4.90 (d, J = 15.8 Hz, 1H), 4.55 (d, J = 15.8 Hz, 1H), 3.88-3.80 (m, 1H), 3.72-3.64 (m, 1H), 3.60-3.52 (m, 1H), 3.22-3.14 (m, 1H), 0.67 (t, J = 7.0 Hz, 3H), 0.59 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 174.8, 169.2, 168.4, 162.7, 143.7, 139.3, 138.6, 136.3, 129.8, 128.6, 128.5, 128.1, 128.0, 127.9, 127.6, 127.1, 125.4, 125.1, 122.9, 122.8, 115.6, 109.0, 76.9, 70.7, 65.6, 61.7, 61.2, 43.3, 42.6, 13.5, 13.4; HRMS (ESI): m/z calcd for C₃₆H₃₃N₃O₉Na [M+Na]⁺ 674.2114, found 674.2107.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-6,8-di-tert-butyl-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4h)

246.1 mg, 73%, a white solid, >20:1 dr, mp: 145.1-146.8^oC; IR (thin film): ν_max 3065, 3035, 2962, 2907, 2867, 1774, 1720, 1615, 1468, 1365, 1225, 1163, 1124, 1007, 750, 699, 631, 546 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 7.82 (d, J = 6.8 Hz, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.40 (ψt, J = 7.2 Hz, 2H), 7.36-7.29 (m, 3H), 7.24 (s, 1H), 7.14 (ψt, J = 7.4 Hz, 1H), 7.01 (ψt, J = 7.4 Hz, 2H), 6.74 (d, J = 7.2 Hz, 1H), 6.45 (d, J = 7.6 Hz, 2H), 6.12 (s, 1H), 5.83 (s, 1H), 4.94 (d, J = 16.0 Hz, 1H), 4.52 (s, 1H), 4.35 (d, J = 16.0 Hz, 1H), 3.63-3.50 (m, 2H), 1.36 (s, 9H), 0.73 (s, 9H), 0.68 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 167.4, 126.6, 164.3, 147.1, 145.4, 144.3, 138.4, 136.4, 136.1, 130.4, 128.9, 128.7, 128.2, 128.0, 127.3, 126.7, 124.9, 124.0, 123.5, 123.3, 114.5, 109.6, 77.6, 72.4, 62.7, 58.6, 48.1, 42.9, 35.1, 34.1, 31.0, 30.0, 13.6; HRMS (ESI): m/z calcd for C₄₂H₄₄N₂O₆Na [M+Na]⁺ 695.3097, found 695.3082.

(±)-ethyl (1R,3R,3aS,9bR)-1’-benzyl-6,8-dibromo-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4j)

109.1 mg, 30%, a yellow solid; >20:1 dr, mp: 147.9-149.1^oC; IR (thin film): v_max 3472, 3070, 3035, 2983, 2940, 1789, 1714, 1614, 1495, 1369, 1238, 1155, 1125, 1000, 862, 752, 699, 546 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.69 (d, J = 7.2 Hz, 2H), 7.40 (ψt, J = 7.6 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.32 (ψt, J = 6.6 Hz, 1H), 7.31 (ψt, J = 7.0 Hz, 1H), 7.19 (ψt, J = 7.2 Hz, 1H), 7.13 (ψt, J = 7.4 Hz, 2H), 6.83 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 2H), 6.41 (d, J = 2.0 Hz, 1H), 5.73 (s, 1H), 4.91 (d, J = 16.0 Hz, 1H), 4.72 (s, 1H), 4.55 (d, J = 15.7 Hz, 1H), 3.63-3.50 (m, 2H), 0.66 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 175.0, 166.5, 163.5, 137.8, 136.0, 135.8, 130.9, 130.2, 128.9, 128.3, 127.7, 126.7, 125.6, 125.2, 123.9, 118.9, 116.5, 111.6, 110.1, 77.2, 72.5, 63.2, 58.9, 46.7, 42.8, 13.4; HRMS (ESI): m/z calcd for C₃₄H₂₆N₂O₆Br₂Na [M+Na]⁺ 741.0035, found 741.0034.

(±)-methyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4k)

81.3 mg, 30%, a white solid, >20:1 dr, mp: 158.8-159.6^oC; IR (thin film): ν_max 3854, 3555, 3474, 3185, 3068, 2915, 1744, 1709, 1610, 1491, 1460, 1253, 1178, 948, 756, 705, 604, 526 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 7.83 (d, J = 6.6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.40 (ψt, J = 7.4 Hz, 3H), 7.32 (ψt, J = 7.2 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 7.05 (ψt, J = 7.6 Hz, 2H), 6.90 (ψt, J = 7.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 2H), 6.38 (d, J = 7.6 Hz, 1H), 5.76 (s, 1H), 4.88 (d, J = 16.0 Hz, 1H), 4.68 (s, 1H), 4.51 (d, J = 16.0 Hz, 1H), 3.07 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.7, 164.5, 150.8, 144.1, 138.2, 135.7, 130.6, 128.9, 128.7, 128.4, 128.2, 128.1, 127.4, 126.7, 126.3, 125.0, 124.9, 123.7, 117.5, 115.1, 109.9, 77.4, 72.4, 59.5, 53.5, 46.9, 42.6; HRMS (ESI): m/z calcd for C₃₃H₂₆N₂O₆Na [M+Na]⁺ 569.1689, found 569.1700.

(±)-isopropyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4l)

193.2 mg, 67%, a white solid, >20:1 dr, mp: 182.0-183.0^oC; IR (thin film): ν_max 3474, 3065, 3030, 2989, 2907, 1748, 1731, 1617, 1492, 1371, 1261, 1230, 1261, 1181, 1100, 1004, 908, 753, 701, 610, 553 cm⁻¹; ¹H NMR (600 MHz, CDCl₃) δ 7.84 (d, J = 7.2 Hz, 2H), 7.79 (d, J = 6.6 Hz, 1H), 7.39 (ψt, J = 7.5 Hz, 2H), 7.31 (ψt, J = 7.2 Hz, 1H), 7.27 (td, J = 7.8, 1.2 Hz, 2H), 7.25 (td, J = 8.1, 0.9 Hz, 1H), 7.12 (ψt, J = 7.5 Hz, 1H), 7.09 (dd, J = 8.4, 0.6 Hz, 1H), 7.05 (ψt, J = 7.8 Hz, 2H), 6.79 (td, J = 7.5, 0.9 Hz, 1H), 6.58 (d, J = 7.2 Hz, 2H), 6.56 (dd, J = 7.2, 1.2 Hz, 1H), 6.42 (d, J = 7.2 Hz, 1H), 6.10 (s, 1H), 5.03 (d, J = 16.2 Hz, 1H), 4.80 (s, 1H), 4.72 (s, 1H), 4.46 (Sept, J = 6.0 Hz, 1H), 4.38 (d, J = 16.2 Hz, 1H), 0.95 (d, J = 6.0 Hz, 3H), 0.57 (d, J = 6.0 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃): δ 174.4, 166.4, 164.6, 151.1, 144.2, 137.3, 134.9, 130.4, 129.7, 129.1, 128.6, 128.2, 128.1, 127.2, 126.6, 126.0, 124.1, 124.0, 123.3, 117.6, 114.9, 109.8, 77.0, 72.4, 71.3, 59.0, 47.2, 43.4, 21.2, 20.5; HRMS (ESI): m/z calcd for C₃₅H₃₀N₂O₆Na [M+Na]⁺ 597.2002, found 597.1975.

(±)-n-butyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4m)

197.1 mg, 67%, a white solid, >20:1 dr, mp: 144.6-145.9^oC; IR (thin film): ν_max 3474, 3063, 3035, 2958, 2872, 1777, 1716, 1615, 1491, 1455, 1369, 1226, 1174, 1035, 753, 700, 610, 528 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.42-7.37 (m, 3H), 7.34-7.27 (m, 3H), 7.14 (d, J = 8.0 Hz, 1H), 7.13 (ψt, J = 7.2 Hz, 1H), 7.05 (ψt, J = 7.4 Hz, 2H), 6.90 (ψt, J = 7.4 Hz, 1H), 6.69 (d, J = 7.2 Hz, 1H), 6.53 (d, J = 7.2 Hz, 2H), 6.38 (d, J = 7.6 Hz, 1H), 5.76 (s, 1H), 4.88 (d, J = 16.4 Hz, 1H), 4.66 (s, 1H), 4.51 (d, J = 16.4 Hz, 1H), 3.57-3.51 (m, 1H), 3.47-3.41 (m, 1H), 1.10-0.99 (m, 4H), 0.73 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.2, 164.7, 150.3, 144.1, 138.2, 135.7, 130.6, 128.9, 128.8, 128.3, 128.2, 128.1, 127.4, 126.7, 126.4, 124.9, 124.9, 123.7, 117.5, 115.1, 109.9, 77.4, 72.4, 66.5, 59.4, 47.2, 42.6, 29.8, 18.7, 13.9; HRMS (ESI): m/z calcd for C₃₆H₃₂N₂O₆Na [M+Na]⁺ 611.2158, found 611.2149.

(±)-benzyl (1R,3R,3aS,9bR)-1’-benzyl-2-hydroxy-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(4n)

276.9 mg, 89%, a white solid, >20:1 dr, mp: 131.9-132.5^oC; IR (thin film): ν_max 3648, 3415, 3063, 3020, 1968, 1742, 1708, 1613, 1461, 1374, 1217, 1175, 1004, 910, 739, 695, 608, 528 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.37-7.30 (m, 4H), 7.29-7.27 (m, 4H), 7.13 (t, J = 8.4 Hz, 1H), 7.12 (t, J = 6.8 Hz, 1H), 7.05 (ψt, J = 7.6 Hz, 2H), 6.99-6.96 (m, 2H), 6.90 (ψt, J = 7.4 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.53 (d, J = 7.6 Hz, 2H), 6.39 (d, J = 7.6 Hz, 1H), 5.78 (s, 1H), 4.88 (d, J = 16.2 Hz, 1H), 4.70 (s, 1H), 4.64 (d, J = 12.4 Hz, 1H), 4.51 (d, J = 16.2 Hz, 1H), 4.37 (d, J = 12.4 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.1, 167.1, 164.6, 150.8, 144.1, 138.1, 135.7, 134.9, 130.7, 128.9, 128.8, 128.6, 128.4, 128.3, 128.2, 127.9, 127.4, 126.7, 126.3, 125.0, 124.9, 123.7, 117.5, 115.1, 109.9, 77.4, 72.5, 68.1, 59.4, 47.3, 42.6; HRMS (ESI): m/z calcd for C₃₉H₃₀N₂O₆Na [M+Na]⁺ 645.2002, found 645.1997.

(±)-ethyl (1R,3R,3aS,9bR)-2-acetoxy-1’-benzyl-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(6a)

260.7 mg, 87%, a white solid, mp: 194.2-196.0^oC; IR (thin film): ν_max 3523, 3445, 3210, 3059, 2931, 2859, 1773, 1737, 1707, 1610, 1492, 1367, 1165, 998, 758, 697, 596,495 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.43-7.31 (m, 5H),7.26 (t, J = 7.2 Hz, 1H), 7.17-7.08 (m, 4 H), 6.92 (td, J = 7.6, 0.8 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.63 (d, J = 7.2 Hz, 2H), 6.39 (d, J = 7.2 Hz, 1H), 6.03 (s, 1H), 4.86 (s, 1H), 4.84 (d, J = 16.0 Hz, 1H), 4.60 (d, J = 16.0 Hz, 1H), 3.64-3.50 (m, 2H), 1.53 (s, 3H), 0.67 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 173.5, 167.8, 166.5, 164.1, 150.8, 143.6, 136.0, 135.6, 131.4, 131.0, 129.0, 128.8, 128.4, 128.3, 127.7, 126.9, 126.5, 125.1, 123.9, 123.3, 117.7, 114.1, 110.2, 76.7, 71.3, 63.3, 59.2, 46.7, 42.8, 18.6, 13.4; HRMS (ESI): m/z calcd for C₃₆H₃₀N₂O₇Na [M+Na]⁺ 625.1951, found 625.1953.

(±)-ethyl (1R,3R,3aS,9bR)-2-(benzoyloxy)-1’-benzyl-2’,4-dioxo-3-phenyl-2,3-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline]-3a(9bH)-carboxylate(6b)

263.0 mg, 79%, a white solid, 10:1 dr, mp: 160.4-162.1^oC; IR (thin film): ν_max 3847, 3648, 3567, 3511, 3237, 2975, 2929, 1766, 1715, 1610, 1459, 1233, 1167, 1017, 753, 701, 554 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (dd, J = 6.4, 2.4 Hz, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.59-7.50 (m, 3H), 7.45-7.36 (m, 5H), 7.32-7.25 (m, 3H), 7.20 (d, J = 8.0 Hz, 1H), 7.11 (ψt, J = 7.4 Hz, 1H), 6.98-6.92 (m, 3 H), 6.67 (dd, J = 5.6, 3.2 Hz, 1H), 6.57 (d, J = 7.2 Hz, 2H), 6.25 (s, 1H), 4.95 (s, 1H), 4.88 (d, J = 16.0 Hz, 1H), 4.57 (d, J = 16.0 Hz, 1H), 3.67-3.54 (m, 2H), 0.69 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆): δ 173.5, 166.5, 164.2, 163.3, 150.8, 143.5, 135.9, 135.4, 134.4, 131.4, 131.2, 129.5, 129.3, 129.0, 128.9, 128.5, 128.4, 127.6, 127.3, 126.8, 126.5, 125.1, 124.0, 123.3, 117.7, 114.0, 110.2, 76.9, 71.6, 63.4, 59.2, 46.9, 42.8, 13.4; HRMS (ESI): m/z calcd for C₄₁H₃₂N₂O₇Na [M+Na]⁺ 687.2107, found 687.2106.

(±)-(1R,3aS,9bR)-1’-benzyl-3a-(ethoxycarbonyl)-2’,4-dioxo-3-phenyl-3a,9b-dihydro-4H-spiro[chromeno [3,4-c]pyrrole-1,3’-indoline] 2-oxide(8)

154.0 mg, 55%, a white solid, 10:1 dr, mp: 295.1-295.8^oC; IR (thin film): ν_max 3098, 3068, 2975, 2927, 1773, 1746, 1721, 1458, 1374, 1263, 1225, 1150, 1023, 990, 910, 860, 762, 697, 637, 544 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 8.43-8.40 (m, 2H), 7.76 (d, J = 7.2 Hz, 1H), 7.55-7.51 (m, 4H), 7.46 (t, J = 7.4 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.17 (ψt, J = 7.2 Hz, 1H), 7.10 (ψt, J = 7.4 Hz, 1H), 7.06 (ψt, J = 7.2 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.57 (ψd, J = 7.2 Hz, 3H), 4.93 (s, 1H), 4.86 (d, J = 16.2 Hz, 1H), 4.59 (d, J = 16.2 Hz, 1H), 4.29-4.23 (m, 1H), 4.20-4.12 (m, 1H), 0.98 (t, J = 7.0 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 170.7, 167.9, 161.3, 150.9, 140.4, 135.1, 132.5, 131.6, 131.4, 129.0, 128.7, 128.4, 127.8, 126.8, 126.4, 125.6, 124.5, 122.8, 117.6, 113.2,110.8, 85.9, 64.3, 60.3, 47.6, 43.3, 13.9; HRMS (ESI): m/z calcd for C₃₄H₂₆N₂O₆Na [M+Na]⁺ 581.1689, found 581.1683.

4. Conclusions

This section is not mandatory but can be added to the manuscript if the discussion is unusually long or complex. In summary, we have developed a rapidly [3+2]-cycloaddition of isatin ketonitrone 1,3-dipoles generated in situ with coumarins to access novel dicyclic spiropyrrolidine oxindole derivatives (45 examples) in moderate to excellent yields (22-98%). The reaction proceeded under mild conditions and were found to be high regio- and diastereoselectivities (>20:1 dr). All the synthesized exo-type spirooxindole derivatives 3/4 were confirmed by using ¹H and ¹³C NMR, IR and HMRS technologies. The relative stereochemistry of products was explained undoubtedly by the single crystal X-ray of 3b and 8. Additionally, the transformation of spiroxindole product was realized successfully, which exhibited their good value of synthetic applications. Further exploration and application of this reaction in organic synthesis is ongoing in our laboratory.