Access to Spirooxindole-Fused Cyclopentanes via a Stereoselective Organocascade Reaction Using Bifunctional Catalysis

Abstract

The present study reports an asymmetric organocascade reaction of oxindole-derived alkenes with 3-bromo-1-nitropropane efficiently catalyzed by the bifunctional catalyst. Spirooxindole-fused cyclopentanes were produced in moderate-to-good isolated yields (15–69%) with excellent stereochemical outcomes. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spirooxindole compounds.

Introduction

Nowadays, cascade reactions (or domino reactions)¹ represent a formidable challenge for modern synthetic chemistry.² Those reactions are generally described as multicomponent one-pot processes involving two or more transformations. That strategy offers many advantages over classical “stop-and-go” sequences, for example, in avoiding protecting groups or isolation of reaction intermediates. Besides operational efficiency (step and pot economy),³ organocascade reactions showed significant advantages for constructing complex molecular frameworks with high selectivity levels (stereo-, chemo-). Not surprisingly, organocascade reactions were successfully used for the stereoselective preparation of valuable spirocyclic compounds,⁴ for example, the privileged scaffold—spirocyclic oxindole derivatives (spirooxindoles).⁵ The spirooxindole structural motif appears as part of various natural or synthetic compounds with remarkable biological activity, including medicinally relevant compounds (Figure 1).⁶

Figure 1.

Selected biologically active spirooxindoles.

Organocascade reactions initiated by the Michael reaction are highly efficient for the construction of spirooxindole-fused derivatives,⁷ using either oxindoles with nucleophilic C3 (Michael donors)⁸⁻¹⁰ or electrophilic methyleneindolinones (Michael acceptors).^11,12 Interestingly, a combination of both types of starting materials was applied by Wang for the preparation of highly rigid bispirooxindoles via a Michael/spirocyclization reaction promoted by a bifunctional organocatalyst (Scheme 1A).¹³ Recently, our group described the Michael/alkylation organocascade reaction of 3-(2-bromoethyl)oxindoles with α,β-unsaturated aldehydes efficiently catalyzed by a chiral secondary amine, producing valuable spirooxindole-fused cyclopentanes (Scheme 1B).¹⁴

Scheme 1. Examples of Organocascade Approaches toward Spirooxindole-Fused Cyclopentanes.

Considering the above, and in light of our ongoing interest in the enantioselective synthesis of spirocyclic compounds,¹⁵ we envisioned the construction of novel spirooxindole-fused cyclopentane derivatives having up to three stereocenters via a stereoselective organocascade Michael/spirocyclization reaction promoted by the bifunctional catalyst from 3-bromo-1-nitropropane and methyleneindolinones (Scheme 1C).

Results and Discussion

To verify our design strategy, we began our study by mixing easily accessible methyleneindolinone 1a with 3-bromo-1-nitropropane (2a), bifunctional organocatalyst, and base (Table 1). To our delight, a reaction conducted with commercially available Takemoto catalyst (C1) and K₂CO₃ produced spirooxindole derivative 3a as the main diastereomer. Moreover, compound 3a was readily separable on silica and isolated in good yield (58%) with high enantioselectivity (99% ee, entry 1). Besides, we observed the formation of 5a in traces as a product of base-induced HNO₂ elimination. Conversely, the diastereocontrol of the reactions catalyzed by Rawal’s and Soos’s catalysts was significantly diminished (entries 2 and 3). Apart from C1–C3, we tested other bifunctional organocatalysts (for details, please see the SI file), but no further improvement in reaction efficiency was observed. Interestingly, the reaction rate was significantly decreased when using Na₂CO₃ (entry 4) and NaHCO₃ (entry 5). Using organic bases, such as DIPEA (entry 6), significantly reduced the diastereocontrol. Then, the effect of solvent on reaction efficiency and the stereochemical outcome was evaluated. Using polar aprotic solvents (ethyl acetate or MTBE) resulted in the highest reaction rates. On the other hand, diastereoselectivities of those reactions were significantly lowered (entries 7 and 8). The model reaction conducted in chloroform (entry 8) produced spirooxindole 3a in high yield, with excellent stereochemical outcome. Additionally, we conducted the model reaction with a reduced amount of 3-bromo-1-nitropropane (2a) and organocatalyst C1 (1 mol %), producing 3a with the same efficiency and stereocontrol (entry 11). For complete optimization studies, please see the SI.

Table 1. Optimization Studies of Cascade Reaction.

entrya	cat.	base	time (h)	drb	yieldc (%)	eed (%)
1	C1	K2CO3	24	17/1	58	99
2	C2	K2CO3	24	3/1	39	92
3	C3	K2CO3	24	3/1	58	91
4	C1	Na2CO3	48	20/1	55	99
5	C1	NaHCO3	168	20/1	32	99
6	C1	DIPEA	24	2/1	49	98
7e	C1	K2CO3	2	3/1	38	91
8f	C1	K2CO3	3	8/1	23	99
9g	C1	K2CO3	24	>20/1	59	99
10h	C1	K2CO3	18	>20/1	57	99
11i	C1	K2CO3	45	>20/1	64	99

^aReactions were conducted with 1a (0.1 mmol), 2a (0.2 mmol), corresponding base (0.2 mmol), and catalyst (20 mol %) in DCM (1.0 mL) at room temperature. After the full disappearance of methyleneindolinone 1a (monitored by TLC), the reaction mixture was concentrated using rotavap. Crude product was purified using column chromatography.

^bDetermined by ¹H NMR of the crude reaction mixture (3a/4a).

^cIsolated yield of 3a after column chromatography.

^dDetermined by chiral HPLC analysis.

^eEtOAc was used.

^fMTBE was used.

^gCHCl₃ was used.

^hReaction was conducted with 1a (0.10 mmol), 3a (0.15 mmol), and C1 (20 mol %) in CHCl₃ (1.0 mL) at room temperature.

ⁱReaction was conducted with 1a (0.10 mmol), 3a (0.15 mmol), and C1 (1 mol %) in CHCl₃ (1.0 mL) at room temperature.

After optimizing the reaction conditions, we began exploring the scope of the organocascade reaction by varying N-protecting groups of methyleneindolinones 1 (Scheme 2A). We assessed the effect on reactivity and stereoselectivity of organocascade reactions using various N-protected methyleneindolinones. We identified oxycarbonyl-protecting groups as most effective in terms of stereocontrol. Corresponding spirocyclic compounds 3a,b were isolated in good yields (43–60%) with high stereoselectivity.

Scheme 2. Substrate Scope of Organocascade Reactions.

On the other hand, organocascade reactions of other N-protected methyleneindolinones did not give products with acceptable yields and stereochemical outcomes. For example, the organocascade reaction of unprotected methyleneindolinone 1f produced a mixture of products (3f/4f) with poor stereocontrol. Luckily, substrate 3f can be prepared in high yield by TFA-mediated deprotection of the N-Boc protecting group of 3a (for more details, please see late-stage transformations). Subsequently, the scope of the developed organocascade reaction was investigated by varying substituted methyleneindolinones 1 (Scheme 2B). In general, spirooxindoles 3 were obtained in moderate-to-good yields with excellent stereoselectivity, when oxindole derivatives 1 bearing electron-donating (3g, 3h) and weakly electron-withdrawing groups (3k–n) on the oxindole aromatic ring were used. The reaction of methyleneindolinones bearing a strong electron-withdrawing group, such as the nitro group, led to a complex mixture or to the decomposition of starting material. Additionally, we studied the process using various substituted alkenes of methyleneindolinone derivatives 1. Good efficiency of the developed method was shown in reactions of alkenes bearing various electron-withdrawing groups, especially in reactions of ester-derived alkenes producing spirocycles 3o–r in moderate-to-good yields (36–59%) and excellent stereochemical outcomes (Scheme 2C). Remarkably, other electron-withdrawing groups did not show similar efficiency. For example, the reaction between ketone-derived alkene 1t and 2a produced only elimination product 5t in moderate yield and low enantioselectivity.

The relative configuration of spirooxindole-fused cyclopentanes 3 was adopted on the basis of 1D NOE NMR spectroscopy of mixtures 3l/4l and 3n/4n (for details, please see the SI). In addition, the absolute configuration of 3a was ascertained using X-ray diffraction analysis, and the configuration of 3a was assigned as 2R, 9R, and 10R (Figure 2, for details, see the SI). Absolute configurations of other spirooxindole derivatives 3 were assigned by the analogy of chemical shifts and J values of the cyclopentane ring.

Figure 2.

X-ray single-crystal structure of 3a and the displacement ellipsoids at 30% probability level.

On the basis of the absolute configuration of products and the previous report,¹⁶ the transition state was proposed to rationalize the stereochemical outcome of the cascade process (Figure 3). The tertiary amine moiety of catalyst C1 deprotonates an acidic proton of nitroalkane 2a, generating the complex of nitronate noncovalently bonded to the tertiary amine. Simultaneously, the thiourea part of the catalyst activates methyleneindolinone 1a, prompting Si-face addition of nitronate to the electron-deficient alkene. As a result, the corresponding Michael adduct with 9R and 10R configuration is formed. Subsequently, the intramolecular α-alkylation proceeds with good diastereocontrol, forming spirocycle 3 with 2R configuration at the spiro atom. The observed diastereocontrol can be explained by kinetically favored spirocyclization in the presence of bifunctional organocatalyst C1,^11c which can participate in the spirocyclization step by H-bonding to a bromide anion. Noteworthy, the sterical hindrance of the tert-butyl moiety of the N-Boc group may increase the rigidity of the initially formed ternary complex, which seems crucial for high stereocontrol. That hypothesis is supported by lowered diastereocontrol, when methyleneindolinone 3b with a more planar N-CBz protecting group is used.

Figure 3.

Proposed bifunctional activation and subsequent spirocyclization.

To expand the developed organocatalytic process toward the construction of spiro compounds containing 3-, 4-, and 6-membered rings (Scheme 3), 1-bromonitroalkanes 2 with various lengths of alkyl moiety were subjected to the reaction with methyleneindolinone 1a. With respect to previously reported methods,¹⁷ we isolated the corresponding spirooxindole-fused cyclopropane 6 in good yield and stereochemical outcomes. Despite known examples of spirooxindole-fused cyclobutanes,^11b we did not observe any conversion of starting methyleneindolinone 1a in reaction with 1-bromo-2-nitroethane (2c). Interestingly, reaction of longer 1-bromo-2-nitrobutane produced an unseparable complex mixture of products with major uncyclized products of the Michael reaction.

Scheme 3. Substrate Scope with Diverse Bromonitroalkanes.

To demonstrate the synthetic utility of the developed organocascade reaction, we performed a reaction between 1a and 2a in gram scale, giving the product 3a in 61% yield with retained stereochemical outcomes (99% ee and dr > 20/1, Scheme 4A). To reduce reaction time, the reaction was performed with a slightly higher amount of C1 (3 mol %). This observation can be explained by the limited stability of C1 in the presence of an excess of 3-bromo-1-nitropropane (2a) and base (for more information, please see the SI). As an example of late-stage transformations, spirooxindole 3a was selectively converted to various derivatives (Scheme 4B). The N-Boc-protecting group was removed by treatment of 3a with an excess of TFA. The reaction provided the corresponding spirooxindole 3f in excellent yield with retained enantioselectivity. Noteworthy, the sequence of the developed organocascade followed by N-deprotection is more appropriate compared to the direct organocascade reaction starting from 1f. Next, DBU-mediated elimination of HNO₂ produced alkene 5a in excellent yield with retained optical purity. Noteworthy, the double bond of alkene 5a can be selectively reduced under catalytic hydrogenation conditions, producing cyclopentane derivative 9 with high diastereocontrol. The relative configuration of 9 was determined by 1D NOE NMR experiments (for more information, please see the SI). Furthermore, ethyl ester 5a can be chemoselectively reduced to the corresponding allylic alcohol 9 by treatment with DIBALH. Spirocyclic allylic alcohol 10 may be used as a valuable building block for synthesizing valuable complex molecules.¹⁸

Scheme 4. Gram-Scale Organocascade Reaction and Late-Stage Transformations.

Conclusion

In summary, we have developed an enantioselective organocascade Michael/spirocyclization reaction of readily available methyleneindolinone with 1-bromo-3-nitropropane. The reaction is efficiently catalyzed by a chiral bifunctional catalyst, affording chiral spirooxindole-fused cyclopentanes in moderate-to-good yields and excellent stereochemical outcomes. The developed synthetic protocol is suitable for late-stage functionalizations, as shown by a set of additional transformations.

Experimental Section

Chemicals and solvents were purchased from commercial suppliers and purified using standard techniques. For thin-layer chromatography (TLC), silica gel plates from Merck 60 F₂₅₄ were used, and compounds were visualized by irradiation with UV light and/or by treatment with a solution of phosphomolybdic acid (AMC) or vanillin followed by heating. Column chromatography was performed using silica gel Fluka (40–63 μm) or SiliCycle-SiliaFlash P60 (particle size: 40–63 μm, pore diameter: 60 Å). ¹H, ¹³C, and ¹⁹F NMR spectra were recorded with Bruker AVANCE III 400. Chemical shifts for protons are given in δ relative to tetramethylsilane (TMS), and they are referenced to residual protium in the NMR solvent (chloroform-d: δ_H = 7.26 ppm). Splitting patterns are stated as singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublet (dd), doublet doublet of doublet (ddd), doublet of triplet (dt), doublet triplet of doublet (dtd), doublet of quartet (dq), triplet of doublet (td), quartet of doublet (qd), m (multiplet), and broad singlet (br s). Splitting patterns that could not be easily interpreted were marked as multiplets. Chemical shifts for carbon are referenced to the carbon of NMR solvent (chloroform-d: δ_C = 77.16 ppm). The coupling constants J are given in hertz. IR DRIFT or ATR spectra were recorded with Nicolet AVATAR 370 FT-IR in cm^–1. Chiral HPLC was carried out using a LC20AD Shimadzu liquid chromatograph with SPD-M20A diode array detector with columns Daicel Chiralpak IA, Daicel Chiralpak IB, Daicel Chiralpak AD, and Daicel Chiralpak ODH. Samples for measurement of chiral HPLC were prepared by dissolving the corresponding sample in an n-heptane/i-PrOH (8/2, v/v) mixture. Optical rotations were measured on an AU-Tomatica polarimeter, and Autopol III and specific optical rotation are given in concentrations c [g/100 mL]. Samples for the measurement of specific optical rotation were prepared by dissolving the corresponding sample in chloroform in concentrations which are labeled for each compound. Melting points were measured using a Büchi melting point B-545 apparatus. All melting points were measured in an open glass capillary, and all values are uncorrected. High-resolution mass spectra were recorded with an LCQ Fleet spectrometer. The measurement of low-resolution mass spectra was performed on a GCMS-QP2010 Shimadzu spectrometer. Samples for mass spectrometry were prepared by dissolving the corresponding sample in methanol.

Preparation of Catalyst

Catalyst C1 was purchased from commercial suppliers. Ent-C1, C2, and C3 are known and prepared according to previously reported procedures.¹⁹

Preparation of Methyleneindolinones

Methyleneindolinones 1 are typically known (1i is a new compound), and they were prepared according to previously reported procedures.²⁰

tert-Butyl (E)-3-(2-Ethoxy-2-oxoethylidene)-2-oxo-5-(trifluoromethyl)indoline-1-carboxylate (1i)

Ethyl 2-(triphenyl-λ⁵-phosphanylidene)acetate (142 mg, 0.41 mmol, 1.1 equiv) was added in one portion to a stirred solution of 5-trifluoromethylisatin²¹ (80 mg, 0.37 mmol, 1.0 equiv) in THF (1 mL). The resulting mixture was stirred at room temperature for 3 h. After the consumption of starting isatin (monitored by TLC), solvent was removed under reduced pressure. Crude product was purified by column chromatography (eluting with hexane/EtOAc = 3/1–1/1). The resulting heterocyclic alkene (quantitative yield) was used in the next step without other purification. Heterocyclic alkene (116 mg, 0.41 mmol, 1.0 equiv) and di-tert-butyldicarbonate (98 mg, 0.45 mmol, 1.1 equiv) were added in one portion to a stirred solution of DMAP (3 mg, 0.02 mmol, 0.05 equiv) in THF (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 14 h. After the consumption of starting alkene (monitored by TLC), the reaction was quenched by adding water (5 mL) and diluted with EtOAc (5 mL). The organic phase was separated, and the water phase was extracted with EtOAc (3 × 10 mL). Collected organic phases were washed with brine (1 × 10 mL) and dried over MgSO₄. After filtration of drying agent, solvents were removed under reduced pressure. The crude product was purified by column chromatography with toluene as an eluent.

Yellow Amorphous Solid

Yield = 49% (70 mg, over two steps). ¹H NMR (400 MHz, chloroform-d): δ 9.04–8.97 (m, 1H), 8.04 (dt, J = 8.7, 0.7 Hz, 1H), 7.69 (ddd, J = 8.6, 2.0, 0.8 Hz, 1H), 6.98 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.65 (s, 9H), 1.38 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 165.2, 165.1, 148.6, 144.3, 135.2, 129.6 (q, J = 3.8 Hz, 1C), 127.0 (q, J = 33.0 Hz, 1C), 125.7 (q, J = 4.0 Hz, 1C), 125.4, 124.0 (q, J = 272.1 Hz), 120.4, 115.2, 85.6, 61.9, 28.1 (3C), 14.2 ppm. ¹⁹F NMR (376 MHz, chloroform-d): δ −62.27 (d, J = 0.9 Hz) ppm. IR (KBr): ν = 1765 (C=O, ester, amide), 1738 (C=O, ester, amide), 1711 (C=O, ester, amide), 1201 (C–CF₃) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₈H₁₈F₃NNaO₅ [M + Na]⁺: 408.1029, found: 408,1027.

Preparation of 1-Bromonitrolalkanes

Alkane 2b was purchased from commercial suppliers. 2d is known and was prepared according to a previously reported procedure.²²

General Procedure for the Appel Reaction (GP1)

NBS (1.3 equiv) and PPh₃ (1.3 equiv) were added portionwise to a stirred solution of nitroalcohol (1.00 g, 9.51 mmol, 1.0 equiv) in DCM (0.3 M solution of alcohol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the full consumption of starting 3-nitropropan-1-ol (monitored by TLC), solvent was removed under reduced pressure. The crude product was purified by column chromatography (eluting with hexane/EtOAc = 7/1).

1-Bromo-3-nitropropane (2a)

The title compound was synthesized according to general procedure GP1, using 3-nitropropan-1-ol²³ (1.00 g, 9.51 mmol).

Yellow Oil

Yield = 50% (780 mg). ¹H NMR (400 MHz, chloroform-d): δ 4.59 (t, J = 6.5 Hz, 2H), 3.50 (t, J = 6.2 Hz, 2H), 2.54 (p, J = 6.4 Hz, 2H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 73.3, 29.9, 28.7 ppm. GCMS (EI, 70 eV): t_R = 8.1 min. m/z (%): 89 (1), 72 (1), 57 (2), 42 (4), 41 (100), 39 (65), 27 (8). Our physical and spectroscopic data matched previously reported data.²⁴

1-Bromo-2-nitroethane (2c)

The title compound was synthesized according to general procedure GP1, starting from 2-nitroethan-1-ol²⁵ (1030 mg, 11.3 mmol).

Light yellow liquid. Yield = 92% (1600 mg). ¹H NMR (400 MHz, chloroform-d): δ 4.77 (t, J = 6.4 Hz, 2H), 3.81 (t, J = 6.3 Hz, 2H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 75.7, 23.8 ppm. GCMS (EI, 70 eV): t_R = 10.1 min. m/z (%): 89 (17), 75 (100), 59 (16), 47 (21), 31 (18). Our physical and spectroscopic data matched previously reported data.²⁴

General Procedure for the Michael/Alkylation Cascade Reaction (GP2)

The catalyst C1 (0.4 mg, 0.001 mmol, 0.01 equiv) was added to a solution of the corresponding methyleneindolinone 1 (0.1 mmol, 1.0 equiv) in anhydrous chloroform (0.5 mL) at room temperature. Then, 1-bromonitroalkane 2 (0.15 mmol, 1.5 equiv) and potassium carbonate (20.7 mg, 0.15 mmol, 1.5 equiv) were added. The reaction was stirred at room temperature for the indicated time (TLC monitoring). With complete conversion of methyleneindolinone 1, solvent was removed under reduced pressure. Crude product was purified by column chromatography.

Note: For racemic reactions, catalyst rac-C1 was used.

1′-(tert-Butyl) 2-Ethyl (1R,2R,3R)-3-Nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3a, ent-3a)

The title compound was synthesized according to the GP2, using methyleneindolinone 1a (31.8 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 45 h. The products were purified by column chromatography (hexane/EtOAc = 10/1), with a diastereomeric ratio of 3a/4a > 20/1.

Ent-3a was prepared according to the modified GP2, using catalyst ent-C1 instead of C1 and the same starting materials and purification method as 3a (reaction time: 60 h). The diastereomeric ratio of ent-3a/ent-4a = 20/1.

White crystalline solid, crystals suitable for X-ray analysis, were grown by the dissolution of 3a (20 mg) in a boiling i-PrOH (0.5 mL), followed by standing at rt overnight. Yield 3a = 60% (24 mg). Yield ent-3a = 53% (21 mg). mp (3a) = 78–80 °C (i -PrOH). 99% ee for 3a and 99% ee for ent-3a, and the enantiomeric excess of 3a was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 208 nm) at t_R = 4.4 min (minor) and 5.0 min (major). The enantiomeric excess of ent-3a was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 216 nm) at t_R = 4.4 min (major) and 5.0 min (minor). [α]_D²⁰ (3a) = +9.2 (c = 0.4, CHCl₃). [α]_D (ent-3a) = −6.0 (c = 1.4, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.88–7.81 (m, 1H), 7.42–7.29 (m, 2H), 7.28–7.20 (m, 1H), 5.69 (ddd, J = 9.5, 6.8, 3.6 Hz, 1H), 4.20 (d, J = 6.8 Hz, 1H), 4.09 (dq, J = 10.7, 7.1 Hz, 1H), 3.95 (dq, J = 10.8, 7.1 Hz, 1H), 3.08–2.89 (m, 1H), 2.47–2.21 (m, 3H), 1.64 (s, 9H), 1.06 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.5, 168.5, 149.1, 139.8, 129.7, 129.1, 125.1, 122.0, 115.3, 87.6, 84.8, 62.0, 57.9, 56.7, 37.6, 31.2, 28.2 (3C), 13.7 ppm. IR (KBr): ν =1759 (C=O, ester, amide), 1739 (C=O, ester, amide), 1549 (NO₂), 1350 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₀H₂₄N₂NaO₇ [M + Na]⁺: 427.1476, found: 427.1474.

Ethyl (1R,2R,3R)-3-Nitro-2′-oxo-1′-(2-oxo-2-phenyl-1λ²-ethyl)spiro[cyclopentane-1,3′-indoline]-2-carboxylate (3b)

The title compound was synthesized according to the GP2, using methyleneindolinone 1b (33.3 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 64 h. The product was purified by column chromatography (hexane/EtOAc = 3/1). The diastereomeric ratio of 3b/4b = 5/1.

Yellow oil. Yield = 43% (18 mg). 96% ee. The enantiomeric excess of product 3b was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 208 nm) at t_R = 11.1 min (minor) and 12.9 min (major). [α]_D²⁰ = +3.6 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.97–7.87 (m, 1H), 7.55–7.47 (m, 2H), 7.46–7.31 (m, 5H), 7.29–7.23 (m, 1H), 5.68 (ddd, J = 9.6, 6.9, 3.6 Hz, 1H), 5.51–5.39 (m, 2H), 4.22 (d, J = 6.9 Hz, 1H), 4.07–3.88 (m, 2H), 3.07–2.93 (m, 1H), 2.47–2.36 (m, 1H), 2.36–2.22 (m, 2H), 0.97 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.3, 168.4, 150.7, 139.4, 134.9, 129.6, 129.3, 128.84 (2C), 128.76, 128.5 (2C), 125.5, 122.1, 115.5, 87.6, 68.9, 62.2, 58.1, 56.7, 37.6, 31.2, 13.6 ppm. IR (KBr): ν 1765 (C=O, ester, amide), 1741 (C=O, ester, amide), 1724 (C=O, ester, amide), 1556 (NO₂), 1377 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₃H₂₂N₂NaO₇ [M + Na + H₂O]⁺: 461.1319, found: 461.1327.

Ethyl (1R,2R,3R)-3-Nitro-2′-oxo-1′-tosylspiro[cyclopentane-1,3′-indoline]-2-carboxylate (3c/4c)

The title compounds were synthesized according to the GP2, using methyleneindolinone 1c (37.1 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol), at a reaction time of 28 h. The product was purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3c/4c = 1/1. Products were obtained as an inseparable mixture of 4c/5c and pure 3c.

Ethyl (1R,2R,3R)-3-Nitro-2′-oxo-1′-tosylspiro[cyclopentane-1,3′-indoline]-2-carboxylate (3c)

Yellow oil. Yield = 28% (13 mg). 35% ee. The enantiomeric excess of product 3c was determined by HPLC (IB, n-heptane/i-PrOH = 90/10, flow rate = 1.0 mL/min, λ = 207 nm) at t_R = 10.6 min (minor) and 11.9 min (major). [α]_D²⁰ = −2.3 (c = 0.7, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 8.00–7.91 (m, 3H), 7.41–7.29 (m, 4H), 7.23 (dd, J = 7.5, 1.0 Hz, 1H), 5.58 (ddd, J = 9.7, 7.0, 3.5 Hz, 1H), 4.13 (d, J = 7.0 Hz, 1H), 3.85 (dq, J = 10.6, 7.1 Hz, 1H), 3.63 (dq, J = 10.6, 7.1 Hz, 1H), 2.95–2.84 (m, 1H), 2.42 (s, 3H), 2.40–2.03 (m, 3H), 0.91 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.3, 168.0, 145.8, 139.4, 135.0, 129.8 (2C), 129.6, 129.4, 128.3 (2C), 125.5, 122.4, 113.9, 87.1, 62.0, 57.6, 56.7, 37.2, 30.9, 21.8, 13.7 ppm. IR (KBr): ν = 1738 (C=O, ester, amide), 1552 (NO₂), 1371 (NO₂), 1336 (S=O, sulfonamide) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₂H₂₃N₂O₇S [M + H]⁺: 459.1220, found 459.1220.

Ethyl-3-nitro-2′-oxo-1′-tosylspiro[cyclopentane-1,3′-indoline]-2-carboxylate (4c)

Inseparable mixture of 4c/5c = 5/1. Yellow oil. NMR yield 4c = 18%. 12/12% ee (4c/5c). The enantiomeric excess of product 4c was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 207 nm) at t_R = 14.9 min (major) and 20.4 min (minor). The enantiomeric excess of product 5c was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 207 nm) at t_R = 8.5 min (minor) and 9.0 min (major). ¹H NMR (400 MHz, chloroform-d, 4c – H′, 5c – H): δ 8.03 (dd, J = 8.6, 2.0 Hz, 2H′), 8.01 (d, J = 6.6 Hz, 2H), 7.95 (dt, J = 8.2, 0.7 Hz, 1H′), 7.91 (dt, J = 8.2, 0.8 Hz, 1H), 7.38 (d, J = 1.3 Hz, 1H), 7.35 (dd, J = 8.2, 1.2 Hz, 3H′), 7.33–7.28 (m, 2H), 7.18–7.11 (m, 1H + 1H′, overlapped), 7.11–7.08 (m, 1H), 7.02 (dd, J = 7.5, 1.5 Hz, 1H), 6.99 (dd, J = 7.5, 1.4 Hz, 1H′), 5.58 (td, J = 8.8, 5.9 Hz, 1H′), 4.22 (d, J = 8.3 Hz, 1H′), 3.84 (dq, J = 10.8, 7.1 Hz, 1H), 3.64–3.55 (m, 1H + 1H′, overlapped), 3.44–3.32 (m, 1H + 1H′, overlapped), 2.78 (dtd, J = 8.3, 5.9, 2.6 Hz, 1H), 2.74–2.65 (m, 1H′), 2.65–2.54 (m, 1H′ + 1H, overlapped), 2.53–2.45 (m, 1H′), 2.43 (s, 3H′), 2.40 (s, 3H), 2.22–2.13 (m, 1H), 1.95 (ddd, J = 13.2, 7.4, 4.7 Hz, 1H′), 0.83 (t, J = 7.1 Hz, 3H′), 0.43 (t, J = 7.1 Hz, 3H′) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d, 4c – C′, 5c – C): δ 177.5 (1C), 176.3 (1C′), 167.8 (1C′), 162.4 (1C), 148.7 (1C′), 146.1 (1C′), 145.5 (1C), 139.0 (1C), 138.8 (1C′), 137.4 (1C), 135.5 (1C), 135.2 (1C′), 132.4 (1C), 129.9 (2C′ + 2C, overlapped), 129.8 (1C′), 129.7 (1C′), 129.2 (1C), 128.9 (1C), 128.2 (2C′ + 2C, overlapped), 125.2 (1C′), 125.0 (1C), 123.2 (1C′), 122.9 (1C), 113.9 (1C′), 113.5 (1C), 85.6 (1C′), 61.6 (1C′), 60.5 (1C), 57.0 (1C′), 56.4 (1C), 38.1 (1C), 37.3 (1C′), 32.2 (1C), 30.7 (1C′), 21.9 (1C′), 21.8 (1C), 13.8 (1C), 13.2 (1C′) ppm. IR (KBr): ν = 1761 (C=O, ester, amide), 1736 (C=O, ester, amide), 1550 (NO₂), 1373 (S=O, sulfonamide), 1317 (NO₂) cm^–1. HRMS (4c, ESI+) m/z: calcd. for C₂₂H₂₃N₂O₇S [M + H]⁺: 459.1220, found: 459.1216.

Ethyl 1′-Acetyl-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-2-carboxylate (3d/4d)

The title compounds were synthesized according to the GP2, using methyleneindolinone 1d (25.9 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 71 h. The products were purified by column chromatography (hexane/EtOAc = 7/1), and the diastereomeric ratio of 3d/4d = 1/1.

Ethyl (1R,2R,3R)-1′-Acetyl-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-2-carboxylate (3d)

Yellow oil. Yield = 21% (7 mg). 65% ee. The enantiomeric excess of product 3d was determined by HPLC (IB, n-heptane/i-PrOH = 98/2, flow rate = 1.0 mL/min, λ = 224 nm) at t_R = 17.2 min (minor) and 38.1 min (major). [α]_D²⁰ = +6.8 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 8.24 (dt, J = 8.1, 0.8 Hz, 1H), 7.43–7.35 (m, 2H), 7.32–7.26 (m, 1H), 5.66 (ddd, J = 9.5, 7.1, 3.8 Hz, 1H), 4.23 (d, J = 7.1 Hz, 1H), 4.11–3.91 (m, 2H), 3.05–2.83 (m, 1H), 2.64 (s, 3H), 2.51–2.18 (m, 3H), 1.06 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 180.0, 170.7, 168.5, 140.2, 129.4, 128.7, 125.9, 121.8, 116.9, 87.5, 62.2, 58.3, 56.7, 37.5, 31.2, 26.7, 13.8 ppm. IR (KBr): ν = 1739 (C=O, ester, amide), 1705 (C=O, ester, amide), 1552 (NO₂), 1273 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₇H₁₈N₂NaO₆ [M + Na]⁺: 369.1057, found: 369.1052.

Ethyl 1′-Acetyl-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-2-carboxylate (4d)

Yellow oil. Yield = 20% (7 mg). 64% ee. The enantiomeric excess of product 4d was determined by HPLC (IB, n-heptane/i-PrOH = 98/2, flow rate = 1.0 mL/min, λ = 216 nm) at t_R = 23.8 min (major) and 49.2 min (minor). [α]_D²⁰ = +4.4 (c = 0.3, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 8.27 (dt, J = 8.1, 0.9 Hz, 1H), 7.36 (ddd, J = 8.2, 7.6, 1.4 Hz, 1H), 7.19 (td, J = 7.6, 1.1 Hz, 1H), 7.07 (ddd, J = 7.6, 1.4, 0.6 Hz, 1H), 5.66 (ddd, J = 9.5, 8.4, 5.7 Hz, 1H), 4.32 (d, J = 8.4 Hz, 1H), 3.73 (qd, J = 7.2, 1.7 Hz, 2H), 2.88–2.71 (m, 1H), 2.74 (s, 3H), 2.73–2.53 (m, 2H), 2.06 (ddd, J = 13.0, 7.6, 4.3 Hz, 1H), 0.70 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 178.8, 170.9, 167.9, 139.8, 129.6, 129.3, 125.6, 122.6, 117.0, 85.7, 61.8, 57.8, 56.8, 37.2, 30.8, 26.8, 13.5 ppm. IR (KBr): ν = 1759 (C=O, ester, amide), 1738 (C=O, ester, amide), 1699 (C=O, ester, amide), 1554 (NO₂), 1309 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₇H₁₉N₂O₆ [M + H]⁺: 347.1243, found: 347.1240.

Ethyl 3-Nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-2-carboxylate (3f/4f́/4f)

The title compounds were synthesized according to the GP2, using methyleneindolinone 1f (21.7 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 168 h. The products were purified by column chromatography (hexane/EtOAc = 3/1). The diastereomeric ratio of 3f/4f′/4f = 3/1/4. Products were obtained as an inseparable mixture of diastereomers 3f/4f and diastereomer 4f′as an inseparable mixture with byproducts.

Inseparable mixture of diastereomers (3f/4f) = 1/1. Yellow oil. Combined yield (3f/4f) = 20% (8 mg). 2/0% ee (3f/4f). The enantiomeric excess of product 3f was determined by HPLC (IC, n-heptane/i-PrOH = 90/10, flow rate = 1.0 mL/min, λ = 208 nm) at t_R = 9.6 min (minor) and 12.6 min (major). The enantiomeric excess of product 4f was determined by HPLC (IC, n-heptane/i-PrOH = 90/10, flow rate = 1.0 mL/min, λ = 208 nm) at t_R = 13.6 min and 28.1 min. ¹H NMR (400 MHz, chloroform-d, 4f – H′, 3f – H): δ 8.35 (br s, 1H′), 7.99 (br s, 1H), 7.35 (dd, J = 7.5, 1.2 Hz, 1H), 7.29–7.21 (m, 1H′ + 1H, overlapped), 7.11 (td, J = 7.6, 1.0 Hz, 1H), 7.06–6.98 (m, 2H′), 6.94–6.89 (m, 1H′ + 1H, overlapped), 5.76–5.63 (m, 1H′ + 1H, overlapped), 4.27 (d, J = 8.1 Hz, 1H′), 4.19 (d, J = 7.2 Hz, 1H), 4.10–3.95 (m, 2H), 3.83 (dq, J = 10.8, 7.1 Hz, 1H′), 3.74 (dq, J = 10.7, 7.1 Hz, 1H′), 3.06–2.94 (m, 1H), 2.81–2.62 (m, 2H′), 2.53 (dt, J = 13.1, 9.0 Hz, 1H′), 2.47–2.16 (m, 3H), 2.00 (ddd, J = 13.1, 7.3, 4.8 Hz, 1H′), 1.08 (t, J = 7.1 Hz, 3H), 0.72 (t, J = 7.1 Hz, 3H′) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d, 4f – C′, 3f – C): δ 180.5 (1C), 179.4 (1C′), 168.7 (1C), 168.5 (1C′), 140.8 (1C), 140.6 (1C′), 131.2 (1C), 130.6 (1C′), 129.2 (1C′), 128.9 (1C), 123.5 (1C′), 123.2 (1C), 123.0 (1C′), 122.6 (1C), 110.2 (1C′), 110.0 (1C), 87.4 (1C), 86.1 (1C′), 61.9 (1C), 61.6 (1C′), 56.8 (1C), 56.5 (1C′), 36.5 (1C′ + 1C, overlapped), 30.9 (1C), 30.8 (1C′), 13.8 (1C), 13.5 (1C′) ppm. One qC′ and one qC were not found. IR (KBr): ν = 3192 (N–H), 1734 (C=O, ester, amide), 1707 (C=O, ester, amide), 1552 (NO₂), 1342 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₅H₁₆N₂NaO₅ [M + Na]⁺: 327.0951, found: 327.0948.

1′-(tert-Butyl) 2-Ethyl (1R,2R,3R)-5′-Methyl-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3g)

The title compound was synthesized according to the GP2, using methyleneindolinone 1g (33.1 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 66 h. The product was purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3g/4g = 13/1.

Yellow oil. Yield = 69% (29 mg). 99% ee. The enantiomeric excess of product 3g was determined by HPLC (IA, n-heptane/i-PrOH = 90/10, flow rate = 1.0 mL/min, λ = 204 nm) at t_R = 4.9 min (minor) and 6.0 min (major). [α]_D²⁰ = +19.9 (c = 0.7, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.71 (d, J = 8.3 Hz, 1H), 7.19–7.09 (m, 2H), 5.68 (ddd, J = 9.4, 6.8, 3.6 Hz, 1H), 4.18 (d, J = 6.8 Hz, 1H), 4.10 (dq, J = 10.7, 7.1 Hz, 1H), 3.94 (dq, J = 10.7, 7.1 Hz, 1H), 3.09–2.89 (m, 1H), 2.45–2.19 (m, 6H), 1.63 (s, 9H), 1.06 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.7, 168.5, 149.2, 137.4, 134.9, 129.61, 129.58, 122.6, 115.1, 87.6, 84.6, 62.0, 57.9, 56.7, 37.7, 31.2, 28.2 (3C), 21.3, 13.7 ppm. IR (KBr): ν 1786 (C=O, ester, amide), 1757 (C=O, ester, amide), 1732 (C=O, ester, amide), 1552 (NO₂), 1369 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₁H₂₆N₂NaO₇ [M + Na]⁺: 441.1632, found: 441.1626.

1′-(tert-Butyl) 2-Ethyl (1R,2R,3R)-5′-Methoxy-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3h)

The title compound was synthesized according to the GP2, using methyleneindolinone 1h (33.1 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction timeof 71 h. The product was purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3h/4h = 15/1.

Yellow oil. Yield = 56% (25 mg). 99% ee. The enantiomeric excess of product 3h was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 207 nm) at t_R = 6.5 min (minor) and 8.6 min (major). [α]_D²⁰ = +20.4 (c = 1.1, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.76 (d, J = 8.9 Hz, 1H), 6.92 (d, J = 2.6 Hz, 1H), 6.86 (dd, J = 8.8, 2.6 Hz, 1H), 5.69 (ddd, J = 10.1, 6.7, 3.7 Hz, 1H), 4.17 (d, J = 6.7 Hz, 1H), 4.10 (dq, J = 10.6, 7.1 Hz, 1H), 3.95 (dq, J = 10.5, 7.1 Hz, 1H), 3.84 (s, 3H), 2.99 (dq, J = 14.4, 9.4 Hz, 1H), 2.39 (ddt, J = 14.6, 7.5, 4.0 Hz, 1H), 2.33–2.21 (m, 2H), 1.62 (s, 9H), 1.07 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.5, 168.4, 157.5, 149.2, 133.1, 130.9, 116.3, 113.7, 108.3, 87.6, 84.6, 62.0, 57.9, 57.0, 55.9, 37.7, 31.3, 28.2 (3C), 13.7 ppm. IR (KBr): ν 1784 (C=O, ester, amide), 1755 (C=O, ester, amide), 1728 (C=O, ester, amide), 1552 (NO₂), 1369 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₁H₂₆N₂NaO₈ [M + Na]⁺: 457.1581, found: 457.1584.

1′-(tert-Butyl) 2-Ethyl 3-Nitro-2′-oxo-5′-(trifluoromethyl)spiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3i/4i)

The title compounds were synthesized according to the GP2, using methyleneindolinone 1i (38.5 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 22 h. The products were purified by column chromatography (hexane/EtOAc = 10/1) at a diastereomeric ratio of 3i/4i = 3/1. Products were obtained as an inseparable mixture of diastereomers 3i/4i with 5i.

Inseparable mixture (3i/4i/5i) = 14/1/5. Yellow oil. NMR yield 3i = 22%. 90% ee (3i). The enantiomeric excess of product 3i was determined by HPLC (IC, n-heptane/i-PrOH = 98/2, flow rate = 1.0 mL/min, λ = 222 nm) at t_R = 17.6 min (minor) and 36.6 min (major). ¹H NMR (400 MHz, chloroform-d, 3i – H″, 4i – H′, 5i – H): δ 8.06 (d, J = 8.6 Hz, 1H′), 8.02–7.96 (m, 1H″ + 1H, overlapped), 7.65–7.62 (m, 1H + 1H′, overlapped), 7.62–7.59 (m, 1H″), 7.57 (ddd, J = 8.6, 2.0, 0.9 Hz, 1H), 7.30–7.28 (m, 1H′ + 1H, overlapped), 7.25 (q, J = 2.6 Hz, 1H), 5.73–5.66 (m, 1H′), 5.63 (dd, J = 8.7, 6.4 Hz, 1H′), 4.58 (t, J = 6.5 Hz, 1H′), 4.34 (d, J = 8.4 Hz, 1H′), 4.24 (d, J = 6.8 Hz, 1H″), 4.10 (dq, J = 10.8, 7.2 Hz, 1H″), 4.04–3.91 (m, 1H″ + 2H, overlapped), 3.77 (q, J = 7.1 Hz, 1H′), 3.11–2.94 (m, 1H″), 2.91–2.86 (m, 2H), 2.83–2.75 (m, 1H′), 2.76–2.66 (m, 1H + 1H′, overlapped), 2.48–2.37 (m, 1H″ + 1H′, overlapped), 2.37–2.23 (m, 2H′), 2.12–2.00 (m, 1H′), 1.67 (s, 9H′), 1.65 (s, 9H), 1.64 (s, 9H″), 1.08 (t, J = 7.1 Hz, 3H″), 1.04 (d, J = 7.1 Hz, 3H), 0.76 (t, J = 7.1 Hz, 3H′) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d, 3i – C″, 4i – C′, 5i – C): δ 177.1 (1C), 176.7 (1C″), 168.1 (1C′′), 167.7 (1C), 162.4 (1C), 148.9, (1C′′) 148.7 (1C), 142.7 (1C′′), 137.4 (1C′′), 133.0 (1C), 130.2 (1C′′), 127.3 (q, J = 33.1 Hz, 1C″), 126.6 (q, J = 3.8 Hz, 1C″), 126.0 (q, J = 3.8 Hz, 1C), 123.9 (q, J = 272.1 Hz, 1C″), 119.3 (q, J = 3.6 Hz, 1C), 119.0 (q, J = 3.8 Hz, 1C″), 115.4 (1C′′), 115.1 (1C), 87.2 (1C′′ + 1C, overlapped), 85.4 (1C″), 62.2 (1C′′), 60.8 (1C), 57.8 (1C′′), 56.4 (1C), 38.0 (1C), 37.3 (1C′′), 32.2 (1C), 31.0 (1C′′), 28.1 (3C′′ + 3C, overlapped), 13.7 (1C), 13.6 (1C″) ppm. Four qC were not found. ¹⁹F NMR (376 MHz, chloroform-d, 3i – F″, 4i – F′, 5i – F): δ −61.83 (d, J = 0.8 Hz, 3F), −61.90 (d, J = 0.8 Hz, 3F″), −61.98 (s, 3F′) ppm. IR (KBr): ν = 1792 (C=O, ester, amide), 1766 (C=O, ester, amide), 1734 (C=O, ester, amide), 1556 (NO₂), 1371 (NO₂), 1120 (C–CF₃) cm^–1. HRMS (3i, ESI+) m/z: calcd. for C₂₁H₂₃F₃N₂NaO₇ [M + Na]⁺: 495.1350, found: 495.1357. Note:¹³C{¹H} NMR was determined for the mixture 3i/5i.

1′-(tert-Butyl) 2-Ethyl (1R,2R,3R)-5′-Fluoro-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3k)

The title compound was synthesized according to the GP2, using methyleneindolinone 1k (33.5 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 43 h. The product was purified by column chromatography (hexane/EtOAc = 10/1), and the diastereomeric ratio of 3k/4k > 20/1.

Yellow oil. Yield = 49% (21 mg). 99% ee. The enantiomeric excess of product 3k was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 208 nm) at t_R = 5.8 min (minor) and 6.4 min (major). [α]_D²⁰ = +5.8 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.84 (dd, J = 9.0, 4.5 Hz, 1H), 7.11 (dd, J = 7.6, 2.7 Hz, 1H), 7.04 (td, J = 8.9, 2.7 Hz, 1H), 5.68 (ddd, J = 9.5, 6.6, 3.5 Hz, 1H), 4.16 (d, J = 6.7 Hz, 1H), 4.10 (dq, J = 10.8, 7.2 Hz, 1H), 3.96 (dq, J = 10.7, 7.1 Hz, 1H), 3.07–2.91 (m, 1H), 2.47–2.35 (m, 1H), 2.32–2.22 (m, 2H), 1.63 (s, 9H), 1.07 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.0, 168.2, 160.4 (d, J = 244.6 Hz, 1C), 149.1, 135.8 (d, J = 2.7 Hz, 1C), 131.5 (d, J = 7.9 Hz, 1C), 116.8 (d, J = 7.9 Hz, 1C), 115.7 (d, J = 22.7 Hz, 1C), 109.7 (d, J = 24.6 Hz, 1C), 87.5, 85.0, 62.2, 57.9, 56.9 (d, J = 1.9 Hz, 1C), 37.6, 31.3, 28.2 (3C), 13.7 ppm. ³¹F NMR (376 MHz, CDCl₃): δ −116.68 (ddd, J = 9.0, 7.6, 4.6 Hz) ppm. IR (KBr): ν = 1788 (C=O, ester, amide), 1759 (C=O, ester, amide), 1732 (C=O, ester, amide), 1552 (NO₂), 1369 (NO₂), 1246 (C–F) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₀H₂₃FN₂NaO₇ [M + Na]⁺: 445.1382, found: 445.1380.

1′-(tert-Butyl) 2-Ethyl 5′-Chloro-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3l/4l)

The title compounds were synthesized according to the GP2, using methyleneindolinone 1l (35.2 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 70 h. The products were purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3l/4l = 3/1.

Inseparable mixture of diastereomers 3l/4l = 3/1. Yellow oil. Combined yield 3l/4l = 44% (19 mg). 88/37% ee (3l/4l). The enantiomeric excess of product 3l was determined by HPLC (IG, n-heptane/i-PrOH = 90/10, flow rate = 1.0 mL/min, λ = 209 nm) at t_R = 8.1 min (minor) and 11.7 min (major). The enantiomeric excess of product 4l was determined by HPLC (IG, n-heptane/i-PrOH = 90/10, flow rate = 1.0 mL/min, λ = 209 nm) at t_R = 10.0 min (minor) and 10.8 min (major). ¹H NMR (400 MHz, chloroform-d, 3l – H′, 4l – H): δ 7.88 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H′), 7.36 (d, J = 2.0 Hz, 1H′), 7.33–7.30 (m, 1H′ + 1H, overlapped), 7.01 (d, J = 2.2 Hz, 1H), 5.67 (ddd, J = 9.4, 6.7, 3.5 Hz, 1H′), 5.64–5.57 (m, 1H), 4.32 (d, J = 8.4 Hz, 1H), 4.18 (d, J = 6.7 Hz, 1H′), 4.10 (dq, J = 10.7, 7.1 Hz, 1H′), 3.97 (dq, J = 10.8, 7.1 Hz, 1H′), 3.80 (qd, J = 7.1, 4.6 Hz, 2H), 3.49–3.39 (m, 1H), 3.05–2.93 (m, 1H′), 2.88–2.62 (m, 1H), 2.57 (dt, J = 13.2, 8.9 Hz, 1H), 2.47–2.35 (m, 1H′), 2.35–2.23 (m, 2H′), 2.05–1.97 (m, 1H), 1.65 (s, 9H), 1.62 (s, 9H′), 1.07 (t, J = 7.1 Hz, 3H′), 0.80 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d, 3l – C′, 4l – C): δ 176.8 (1C′), 175.7 (1C), 168.2 (1C′), 167.9 (1C), 148.9 (1C′ + 1C, overlapped), 138.4 (1C′), 138.2 (1C), 131.4 (1C′), 130.8 (1C), 130.6 (1C′), 130.3 (1C), 129.4 (1C), 129.2 (1C′), 123.0 (1C), 122.5 (1C′), 116.8 (1C′ + 1C, overlapped), 87.4 (1C′ + 1C, overlapped), 85.5 (1C′), 85.4 (1C), 62.2 (1C′), 61.9 (1C), 57.9 (1C′), 57.6 (1C), 56.6 (1C′), 56.5 (1C), 37.5 (1C′), 37.1 (1C), 31.2 (1C′), 30.7 (1C), 28.2 (3C′ + 3C, overlapped) 13.7 (1C′), 13.5 (1C) ppm. IR (KBr): ν = 1790 (C=O, ester, amide), 1761 (C=O, ester, amide), 1732 (C=O, ester, amide), 1556 (NO₂), 1371 (NO₂), 752 (C–Cl) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₀H₂₃ClN₂NaO₇ [M + Na]⁺: 461.1086, found: 461.1088.

1′-(tert-Butyl) 2-Ethyl (1R,2R,3R)-5′-Bromo-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3m)

The title compound was synthesized according to the GP2, using methyleneindolinone 1m (39.6 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 22 h. The product was purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3m/4m > 20/1.

Yellow oil. Yield = 61% (29 mg). 99% ee. The enantiomeric excess of product 3m was determined by HPLC (IA, n-heptane/i-PrOH = 90/10, flow rate = 1.0 mL/min, λ = 205 nm) at t_R = 5.1 min (minor) and 6.3 min (major). [α]_D²⁰ = +24.1 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.76 (d, J = 8.5 Hz, 1H), 7.52–7.43 (m, 2H), 5.72–5.62 (m, 1H), 4.18 (d, J = 6.8 Hz, 1H), 4.10 (dq, J = 10.8, 7.1 Hz, 1H), 3.97 (dq, J = 10.7, 7.1 Hz, 1H), 3.07–2.90 (m, 1H), 2.47–2.20 (m, 3H), 1.62 (s, 9H), 1.08 (t, J = 7.2 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 176.7, 168.2, 148.9, 138.9, 132.1, 131.7, 125.3, 118.0, 117.0, 87.4, 85.2, 62.2, 57.9, 56.6, 37.5, 31.2, 28.2 (3C), 13.7 ppm. IR (KBr): ν 1790 (C=O, ester, amide), 1761 (C=O, ester, amide), 1730 (C=O, ester, amide), 1552 (NO₂), 1369 (NO₂), 538 (C–Br) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₀H₂₃BrN₂NaO₇ [M + Na]⁺: 505.0580, found: 505.0577.

1′-(tert-Butyl) 2-Ethyl 6′-Bromo-3-nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3n/4n)

The title compounds were synthesized according to the GP2, using methyleneindolinone 1n (39.6 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 42 h. The products were purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3n/4n = 3/1.

Inseparable mixture of diastereomers 3n/4n = 4/1. Yellow oil. Combined yield 3n/4n = 36% (17 mg). 97/97% ee (3n/4n). The enantiomeric excess of product 3n was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 221 nm) at t_R = 4.4 min (minor) and 5.6 min (major). The enantiomeric excess of product 4n was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 221 nm) at t_R = 5.2 min (major) and 6.2 min (minor). ¹H NMR (400 MHz, chloroform-d, 3n – H′, 4n – H): δ 8.15 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 1.8 Hz, 1H′), 7.39 (dd, J = 8.0, 1.8 Hz, 1H′), 7.31–7.28 (m, 1H), 7.25 (d, J = 8.1 Hz, 1H′), 6.91 (d, J = 8.1 Hz, 1H), 5.67 (ddd, J = 9.4, 6.7, 3.5 Hz, 1H′), 5.59 (td, J = 8.8, 6.1 Hz, 1H), 4.30 (d, J = 8.4 Hz, 1H), 4.17 (d, J = 6.6 Hz, 1H′), 4.15–4.07 (m, 1H′), 3.97 (dq, J = 10.8, 7.1 Hz, 1H′), 3.79 (q, J = 7.1 Hz, 2H), 3.07–2.86 (m, 1H′), 2.79–2.63 (m, 2H), 2.56 (dt, J = 13.1, 8.9 Hz, 1H), 2.45–2.35 (m, 1H′), 2.31–2.22 (m, 2H′), 1.99 (ddd, J = 12.7, 7.4, 4.8 Hz, 1H), 1.66 (s, 9H), 1.63 (s, 9H′), 1.08 (t, J = 7.2 Hz, 3H′), 0.82 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d, 3n – C′, 4n – C): δ 176.9 (1C′), 175.8 (1C), 168.3 (1C′), 168.0 (1C), 148.9 (1C′ + 1C, overlapped), 140.9 (1C′), 140.7 (1C), 128.6 (1C), 128.1 (1C′), 128.0 (1C), 127.8 (1C′), 123.9 (1C), 123.3 (1C′), 123.2 (1C), 122.8 (1C′), 119.0 (1C), 118.9 (1C′), 87.5 (1C′ + 1C, overlapped), 85.5 (1C), 85.4 (1C′), 62.2 (1C′), 61.9 (1C), 57.8 (1C′), 57.5 (1C), 56.5 (1C′), 56.3 (1C), 37.5 (1C′), 37.1 (1C), 31.3 (1C′), 30.7 (1C), 28.2 (3C′ + 3C, overlapped), 13.8 (1C′), 13.5 (1C) ppm. IR (KBr): ν = 1792 (C=O, ester, amide), 1763 (C=O, ester, amide), 1732 (C=O, ester, amide), 1552 (NO₂), 1369 (NO₂), 528 (C–Br) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₀H₂₃BrN₂NaO₇ [M + Na]⁺: 505.0580; found: 505.0580.

1′-(tert-Butyl) 2-Methyl (1R,2R,3R)-3-Nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3o)

The title compound was synthesized according to the GP2, using methyleneindolinone 1o (30.3 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 46 h. The product was purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3o/4o = 7/1.

Yellow oil. Yield = 59% (23 mg). 96% ee. The enantiomeric excess of product 3o was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 210 nm) at t_R = 4.6 min (minor) and 5.2 min (major). [α]_D²⁰ = +8.8 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.85 (dt, J = 8.0, 0.8 Hz, 1H), 7.41–7.31 (m, 2H), 7.24 (td, J = 7.5, 1.1 Hz, 1H), 5.69 (ddd, J = 9.5, 6.9, 3.6 Hz, 1H), 4.24 (d, J = 6.9 Hz, 1H), 3.58 (s, 3H), 3.07–2.93 (m, 1H), 2.41 (ddt, J = 14.3, 7.4, 3.7 Hz, 1H), 2.35–2.21 (m, 2H), 1.64 (s, 9H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.6, 169.0, 149.1, 139.9, 129.4, 129.2, 125.2, 122.0, 115.5, 87.6, 84.8, 58.0, 56.7, 52.9, 37.5, 31.3, 28.2 (3C) ppm. IR (KBr): ν 1763 (C=O, ester, amide), 1738 (C=O, ester, amide), 1724 (C=O, ester, amide), 1556 (NO₂), 1352 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₉H₂₂N₂NaO₇ [M + Na]⁺: 413.1319; found: 413.1321.

2-Benzyl 1′-(tert-Butyl) (1R,2R,3R)-3-Nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3p)

The title compound was synthesized according to the GP2, using methyleneindolinone 1p (37.9 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 70 h. The product was purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3p/4p = 6/1.

Yellow oil. Yield = 36% (17 mg). 99% ee. The enantiomeric excess of product 3p was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 217 nm) at t_R = 4.7 min (minor) and 6.5 min (major). [α]_D²⁰ = +7.1 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.76 (ddd, J = 8.1, 1.1, 0.6 Hz, 1H), 7.42–7.27 (m, 2H), 7.29–7.19 (m, 4H), 7.04–6.94 (m, 2H), 5.74 (ddd, J = 9.6, 6.9, 3.6 Hz, 1H), 5.06–4.91 (m, 2H), 4.28 (d, J = 7.0 Hz, 1H), 3.10–2.92 (m, 1H), 2.47–2.20 (m, 3H), 1.58 (s, 9H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.4, 168.3, 148.9, 139.8, 134.5, 129.3, 129.1, 128.6 (2C), 128.4, 127.7 (2C), 125.1, 122.0, 115.5, 87.5, 84.7, 67.7, 57.6, 56.8, 37.7, 31.0, 28.2 (3C) ppm. IR (KBr): ν 1780 (C=O, ester, amide), 1730 (C=O, ester, amide), 1709 (C=O, ester, amide), 1543 (NO₂), 1369 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₅H₂₆N₂NaO₇ [M + Na]⁺: 489.1632, found: 489.1630.

Di-tert-butyl (1R,2R,3R)-3-Nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3q)

The title compound was synthesized according to the GP2, using methyleneindolinone 1q (34.5 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 22 h. The product was purified by column chromatography (hexane/EtOAc - 10/1). The diastereomeric ratio of 3q/4q = 11/1.

Yellow oil. Yield = 39% (16 mg). 99% ee. The enantiomeric excess of product 3q was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 211 nm) at t_R = 4.0 min (minor) and 4.5 min (major). [α]_D²⁰ = +12.3 (c = 0.6, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.85 (dt, J = 8.2, 0.7 Hz, 1H), 7.38 (dt, J = 7.3, 0.9 Hz, 1H), 7.34 (td, J = 7.9, 1.5 Hz, 1H), 7.23 (dd, J = 7.5, 1.1 Hz, 1H), 5.68 (ddd, J = 9.5, 6.6, 3.5 Hz, 1H), 4.10 (d, J = 6.6 Hz, 1H), 3.03–2.90 (m, 1H), 2.44–2.34 (m, 1H), 2.33–2.20 (m, 2H), 1.63 (s, 9H), 1.21 (s, 9H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.3, 167.5, 149.2, 139.8, 130.2, 128.9, 125.1, 122.0, 115.2, 87.7, 84.7, 83.2, 58.6, 56.9, 37.9, 31.1, 28.2 (3C), 27.6 (3C) ppm. IR (KBr): ν 1782 (C=O, ester, amide), 1739 (C=O, ester, amide), 1726 (C=O, ester, amide), 1543 (NO₂), 1371 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₂H₂₈N₂NaO₇ [M + Na]⁺: 455.1789, found: 455.1786.

1′-(tert-Butyl) 2,2-Diethyl 3-Nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2,2-tricarboxylate (3r)

The title compound was synthesized according to the GP2, using methyleneindolinone 1r (38.9 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 168 h (no full conversion of 1r was observed). The product was purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3r/4r = 13/1.

Yellow oil. Yield = 53% (25 mg). 65% ee. The enantiomeric excess of product 3r was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 208 nm) at t_R = 4.8 min (minor) and 5.4 min (major). [α]_D²⁰ = −26.0 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.84 (d, J = 8.2 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.15 (dd, J = 11.2, 7.8 Hz, 1H), 4.37 (dq, J = 10.8, 7.1 Hz, 1H), 4.27 (dq, J = 10.8, 7.1 Hz, 1H), 4.14 (dq, J = 11.2, 7.2 Hz, 1H), 4.01 (dq, J = 10.8, 7.1 Hz, 1H), 3.01–2.91 (m, 1H), 2.90–2.80 (m, 1H), 2.69 (td, J = 12.7, 12.2, 7.3 Hz, 1H), 2.17 (ddd, J = 12.8, 9.2, 3.1 Hz, 1H), 1.62 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.5, 167.4, 166.7, 148.9, 140.3, 129.5, 127.0, 124.9, 123.4, 115.1, 88.3, 85.1, 68.2, 62.9, 62.4, 59.9, 34.4, 28.2 (3C), 27.7, 13.8, 13.4 ppm. IR (KBr): ν 1786 (C=O, ester, amide), 1728 (C=O, ester, amide), 1552 (NO₂), 1346 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₃H₂₈N₂NaO₉ [M + Na]⁺: 499.1687, found: 499.1683.

tert-Butyl 3-Nitro-2′-oxo-2-(trifluoromethyl)spiro[cyclopentane-1,3′-indoline]-1′-carboxylate (3s/4s)

The title compounds were synthesized according to the GP2, using methyleneindolinone 1s (31.3 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 64 h. The products were purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3s/4s = 2/1.

tert-Butyl (1R,2R,3R)-3-Nitro-2′-oxo-2-(trifluoromethyl)spiro[cyclopentane-1,3′-indoline]-1′-carboxylate (3s)

Yellow oil. Yield = 18% (7 mg). 9% ee. The enantiomeric excess of product 3s was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 208 nm) at t_R = 5.9 min (major) and 7.6 min (minor). [α]_D²⁰ = −7.9 (c = 0.4, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.95 (d, J = 8.2 Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 7.23–7.13 (m, 2H), 5.42 (td, J = 9.2, 4.4 Hz, 1H), 4.35–4.22 (m, 1H), 2.93–2.80 (m, 1H), 2.68 (ddd, J = 14.1, 7.8, 3.6 Hz, 1H), 2.61 (dt, J = 12.6, 9.8 Hz, 1H), 2.02 (ddd, J = 12.0, 7.5, 2.7 Hz, 1H), 1.66 (s, 9H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 175.1, 148.9, 139.2, 129.7, 126.9, 124.7, 124.6 (q, J = 279.3 Hz), 124.1, 115.8, 85.4, 84.9, 56.3 (q, J = 28.6 Hz), 55.8, 38.4, 31.6, 28.2 (3C) ppm. ¹⁹F NMR (376 MHz, chloroform-d): δ −65.46 (d, J = 8.8 Hz) ppm. IR (KBr): ν 1763 (C=O, ester, amide), 1732 (C=O, ester, amide), 1554 (NO₂), 1371 (NO₂), 1275 (C–CF₃) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₈H₁₉F₃N₂NaO₅ [M + Na]⁺: 423.1138, found: 423.1126.

tert-Butyl 3-Nitro-2′-oxo-2-(trifluoromethyl)spiro[cyclopentane-1,3′-indoline]-1′-carboxylate (4s)

Yellow oil. Yield = 15% (6 mg). 6% ee. The enantiomeric excess of product 4s was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 261 nm) at t_R = 4.8 min (minor) and 6.1 min (major). [α]_D²⁰ ∼ 0 (c = 0.3, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.86 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.2 Hz, 2H), 7.27 (d, J = 14.9 Hz, 1H), 5.66–5.57 (m, 1H), 4.03–3.98 (m, 1H), 3.26–3.14 (m, 1H), 2.47–2.35 (m, 2H), 2.28 (dd, J = 11.4, 8.3 Hz, 1H), 1.64 (s, 9H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 174.9, 148.9, 139.6, 129.8, 126.8, 125.4, 124.5 (q, J = 280.3 Hz), 122.1, 115.6, 85.3, 84.6, 56.9 (q, J = 28.6 Hz), 55.2, 37.3, 30.6, 28.2 (3C) ppm. ¹⁹F NMR (376 MHz, chloroform-d): δ −65.34 (d, J = 8.4 Hz) ppm. IR (KBr): ν 1790 (C=O, ester, amide), 1759 (C=O, ester, amide), 1732 (C=O, ester, amide), 1552 (NO₂), 1369 (NO₂), 1250 (C–CF₃) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₈H₁₉F₃N₂NaO₅ [M + Na]⁺: 423.1138, found: 423.1141.

tert-Butyl 2-benzoyl-2′-oxospiro[cyclopentane-1,3′-indolin]-2-ene-1′-carboxylate (5t)

The title compound was synthesized according to the GP2, using methyleneindolinone 1t (34.9 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 18 h. The products were purified by column chromatography (hexane/EtOAc = 10/1). Yellow oil. Yield = 47% (18 mg). 20% ee. The enantiomeric excess of product 5t was determined by HPLC (IA, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 216 nm) at t_R = 4.9 min (minor) and 6.6 min (major). [α]_D²⁰ ∼ 0 (c = 0.6, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.89 (dt, J = 8.1, 0.8 Hz, 1H), 7.71–7.65 (m, 2H), 7.54–7.48 (m, 1H), 7.43–7.35 (m, 2H), 7.27 (ddd, J = 8.2, 6.7, 2.3 Hz, 1H), 7.13–7.04 (m, 2H), 6.94 (t, J = 2.6 Hz, 1H), 3.11–2.83 (m, 2H), 2.69 (ddd, J = 13.3, 8.9, 5.1 Hz, 1H), 2.28 (ddd, J = 13.3, 8.6, 6.1 Hz, 1H), 1.67 (s, 9H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 191.0, 177.7, 150.0, 149.7, 145.8, 140.1, 137.9, 132.5, 132.1, 129.1 (2C), 128.5, 128.4 (2C), 124.6, 121.9, 115.4, 84.2, 61.3, 37.7, 33.3, 28.3 (3C) ppm. IR (KBr): ν 1778 (C=O, ester, amide) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₄H₂₃NNaO₄ [M + Na]⁺: 412.1519, found: 412.1520.

tert-Butyl 3-Nitro-2′-oxo-2-phenylspiro[cyclopentane-1,3′-indoline]-1′-carboxylate (3v)

The title compound was synthesized according to the GP2, using methyleneindolinone 1v (32.1 mg, 0.1 mmol) and 1-bromo-3-nitropropane (25.0 mg, 0.15 mmol) at a reaction time of 65 h. The product was purified by column chromatography (hexane/EtOAc = 7/1). The diastereomeric ratio of 3v/4v = 4/1.

Yellow oil. Yield = 45% (41 mg). 12% ee. The enantiomeric excess of product 3v was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 199 nm) at t_R = 5.2 min (major) and 5.9 min (minor). [α]_D²⁰ = +4.7 (c = 0.6, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.61–7.55 (m, 1H), 7.51–7.46 (m, 1H), 7.30–7.24 (m, 2H), 7.19–7.07 (m, 3H), 6.92 (dt, J = 8.6, 2.1 Hz, 2H), 5.99–5.91 (m, 1H), 4.09 (d, J = 10.5 Hz, 1H), 3.06 (dtd, J = 13.2, 8.9, 7.7 Hz, 1H), 2.66–2.55 (m, 1H), 2.50 (ddd, J = 13.6, 10.6, 7.6 Hz, 1H), 2.40 (ddd, J = 13.5, 8.8, 4.3 Hz, 1H), 1.52 (s, 9H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 177.4, 148.6, 139.8, 132.5, 129.1, 128.6, 128.5 (2C), 128.4, 127.7 (2C), 125.0, 122.4, 115.1, 87.7, 84.4, 61.4, 60.1, 34.1, 29.9, 28.1 (3C) ppm. IR (KBr): ν 1786 (C=O, amide), 1755 (C=O, amide), 1730 (C=O, amide), 1549 (NO₂), 1350 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₃H₂₄N₂NaO₅ [M + Na]⁺: 431.1577, found: 431.1573.

1′-(tert-Butyl) 2-Ethyl 3-nitro-2′-oxospiro[cyclopropane-1,3′-indoline]-1′,2-dicarboxylate (6/6′)

The title compounds were synthesized according to the GP2, using methyleneindolinone 1a (31.7 mg, 0.1 mmol) and commercially available bromonitromethane (21.0 mg, 0.15 mmol) at a reaction time of 72 h. The products were purified by column chromatography (hexane/EtOAc = 8/1). The diastereomeric ratio of 6/6′ = 4/1.

Inseparable mixture of diastereomers 6/6′ = 4/1. Light yellow oil. Combined yield 6/6′ = 59% (22 mg). 90/84% ee (6/6′). The enantiomeric excess of product 6 was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 227 nm) at t_R = 11.9 min (major) and 16.8 min (minor). The enantiomeric excess of product 6′ was determined by HPLC (IB, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 227 nm) at t_R = 12.7 min (major) and 24.0 min (minor). ¹H NMR (400 MHz, chloroform-d, diastereomer 6 – H′, diastereomer 6′ – H): δ 7.98 (dt, J = 8.2, 0.8 Hz, 1H), 7.94 (dt, J = 8.3, 0.8 Hz, 1H′), 7.44–7.38 (m, 1H′ + 1H, overlapped), 7.29 (ddd, J = 7.7, 1.4, 0.6 Hz, 1H), 7.22–7.17 (m, 2H′), 7.16 (dd, J = 2.5, 1.0 Hz, 1H), 5.30 (d, J = 6.2 Hz, 1H′), 5.27 (d, J = 6.3 Hz, 1H), 4.33–4.22 (m, 2H′ + 1H, overlapped), 4.22–4.11 (m, 1H), 3.83 (d, J = 6.2 Hz, 1H′), 3.80 (d, J = 6.3 Hz, 1H), 1.63 (s, 9H′), 1.63 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H′), 1.24 (t, J = 7.1 Hz, 3H) ppm. ¹³C{¹H} NMR (chloroform-d, diastereomer 6 – C′, diastereomer 6′ – C) δ 168.3 (1C′), 167.4 (1C), 164.4 (1C), 163.0 (1C′), 148.7 (1C), 148.5 (1C′), 141.1 (1C′), 140.8 (1C), 130.3 (1C′), 130.1 (1C), 125.1 (1C′), 124.9 (1C), 122.4 (1C), 122.0 (1C′), 121.1 (1C), 120.2 (1C′), 115.7 (1C′), 115.6 (1C), 85.6 (1C′ + 1C, overlapped), 70.1 (1C′), 68.8 (1C), 62.8 (1C′ + 1C, overlapped), 40.1 (1C′), 39.4 (1C), 38.2 (1C), 35.9 (1C′), 28.2 (3C′ + 3C, overlapped), 14.1 (1C′ + 1C, overlapped) ppm. IR (ATR): ν 1793 (C=O, ester, amide), 1765 (C=O, ester, amide), 1736 (C=O, ester, amide), 1554 (NO₂), 1350 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₈H₂₀N₂NaO₇ [M + Na]⁺, 399.1163; found, 399.1161.

Gram-Scale Organocascade Reaction and Late-Stage Transformations

1′-(tert-Butyl) 2-Ethyl (1R,2R,3R)-3-Nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (3a)

The catalyst C1 (12.4 mg, 0.001 mmol, 0.01 equiv) was added to a solution of the methyleneindolinone 1a (1000.0 mg, 3.14 mmol, 1.0 equiv) in anhydrous chloroform (16 mL) at room temperature. Then, 1-bromo-3-nitropropane (786 mg, 4.71 mmol, 1.5 equiv) and potassium carbonate (650 mg, 4.71 mmol, 1.5 equiv) were added. The reaction was stirred at room temperature for 48 h. Then catalyst C1 (12.4 mg, 0.001 mmol, 0.01 equiv) was added. The addition of C1 (12.4 mg, 0.001 mmol, 0.01 equiv) was repeated after the next 48 h. With complete conversion of the methyleneindolinone 1a (TLC monitored, reaction time: 161 h) solvent was removed under reduced pressure. Crude product was purified by column chromatography (hexane/EtOAc = 10/1). The diastereomeric ratio of 3a/4a > 20/1. Yield of 3a = 61% (771 mg). All analytical data matched the data of identical compounds prepared on a smaller scale

Ethyl (1R,2R,3R)-3-Nitro-2′-oxospiro[cyclopentane-1,3′-indoline]-2-carboxylate (3f)

TFA (38 μL, 0.5 mmol, 5.0 equiv) was dropwise added (during 1 min) to a stirred solution of spirocycle 3a (40 mg, 0.1 mmol, 1.0 equiv., 99% ee) in anhydrous DCM (2.0 mL) at rt. At this temperature, the reaction mixture was stirred for 2 h. After the full disappearance of starting material (monitored by TLC), the reaction was quenched by careful addition of a saturated solution of NaHCO₃ (5 mL). The resulting mixture was diluted with DCM (5 mL). The organic phase was separated, and the water phase was extracted with DCM (3 × 10 mL). Collected organic phases were washed with brine (1 × 10 mL) and dried over MgSO₄. After filtration of the drying agent, solvents were removed under reduced pressure. The crude product was purified by column chromatography with a mixture of hexane/EtOAc as an eluent (2/1).

Colorless oil. Yield = 90% (27 mg). 99% ee. The enantiomeric excess of product 3f was determined by HPLC (IC, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 209 nm) at t_R = 9.5 min (major) and 12.2 min (minor). [α]_D²⁰ = +28.6 (c = 1.1, CHCl₃). ¹H NMR (600 MHz, chloroform-d): δ 8.28 (br s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.30–7.23 (m, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 5.73 (ddd, J = 9.4, 7.2, 4.1 Hz, 1H), 4.18 (d, J = 7.2 Hz, 1H), 4.10–3.96 (m, 2H), 3.00 (dtd, J = 14.1, 10.1, 7.8 Hz, 1H), 2.46–2.37 (m, 1H), 2.32 (ddd, J = 13.4, 10.5, 8.8 Hz, 1H), 2.23 (ddd, J = 13.5, 7.8, 3.0 Hz, 1H), 1.07 (t, J = 7.1 Hz, 3H). ppm. ¹³C{¹H} NMR (151 MHz, chloroform-d): δ 180.9, 168.7, 140.9, 131.2, 128.9, 123.2, 122.5, 110.1, 87.4, 61.9, 56.8, 56.5, 36.4, 30.9, 13.8 ppm. IR (ATR): ν 3159 (N–H, secondary amide), 1726 (C=O, ester, amide), 1701 (C=O, ester, amide), 1728 (C=O, ester, amide), 1545 (NO₂), 1360 (NO₂) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₅H₁₆NO₃ [M + Na]⁺: 327.0951, found: 327.0956.

1′-(tert-Butyl) 2-Ethyl (S)-2′-Oxospiro[cyclopentane-1,3′-indolin]-2-ene-1′,2-dicarboxylate (5a)

DBU (30 μL, 0.2 mmol, 2.0 equiv) was added in one portion to a stirred solution of spirocycle 3a (40 mg, 0.1 mmol, 1.0 equiv, 99% ee) in DMSO (2.0 mL) at rt. At this temperature, the reaction mixture was stirred for 15 h. After the full disappearance of starting material (monitored by TLC), the reaction mixture was diluted with brine (10 mL). The resulting solution was extracted with EtOAc (3 × 10 mL). Collected organic phases were washed with brine (2 × 10 mL) and dried over MgSO₄. After filtration of the drying agent, solvents were removed under reduced pressure. The crude product was purified by column chromatography with a mixture of hexane/EtOAc as an eluent (7/1).

White semisolid. Yield = 92% (32 mg). 99% ee. The enantiomeric excess of product 5a was determined by HPLC (IB, n-heptane/i-PrOH = 98/2, flow rate = 1.0 mL/min, λ = 243 nm) at t_R = 10.5 min (major) and 14.7 min (minor). [α]_D²⁰ = −38.7 (c = 0.8, CHCl₃). ¹H NMR (600 MHz, chloroform-d): δ 7.84 (d, J = 8.2 Hz, 1H), 7.27 (td, J = 7.9, 1.6 Hz, 1H), 7.19 (t, J = 2.6 Hz, 1H), 7.10 (td, J = 7.5, 1.0 Hz, 1H), 7.06 (dd, J = 7.5, 1.5 Hz, 1H), 3.93 (qd, J = 7.2, 1.9 Hz, 2H), 2.92–2.76 (m, 2H), 2.67 (ddd, J = 13.4, 9.2, 6.4 Hz, 1H), 2.24 (ddd, J = 13.2, 8.3, 4.8 Hz, 1H), 1.64 (s, 9H), 1.01 (t, J = 7.2 Hz, 3H) ppm. ¹³C{¹H} NMR (151 MHz, chloroform-d): δ 177.9, 162.7, 149.5, 148.3, 139.5, 138.0, 132.4, 128.5, 124.6, 122.4, 115.0, 84.2, 60.6, 60.3, 38.2, 32.2, 28.2 (3C), 13.7 ppm. IR (ATR): ν 1793 (C=O, ester, amide), 1766 (C=O, ester, amide), 1707 (C=O, ester, amide) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₀H₂₃NNaO₅ [M + Na]⁺: 380.1468, found: 380.1469.

1′-(tert-Butyl) 2-Ethyl (1R,2S)-2′-Oxospiro[cyclopentane-1,3′-indoline]-1′,2-dicarboxylate (9)

A solution of spirocycle 5a (18 mg, 0.05 mmol, 1.0 equiv, 99% ee) in MeOH (1.0 mL) was degassed (flask was evacuated and refilled with Ar three times), and Pd/C (10%, 10.6 mg, 0.2 equiv) was added. The reaction flask was evacuated again and refilled with H₂ three times at rt. Under a hydrogen atmosphere (ballon), the reaction mixture was stirred for 15 h. After the full disappearance of starting material (monitored by TLC), the reaction mixture was filtered through a short pad of Celite (washed with a minimal amount of MeOH). The resulting filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography with a mixture of hexane/EtOAc as an eluent (8/1). The diastereomeric ratio 9/9′ = 9/1.

Colorless oil. Yield = 97% (17 mg). 98% ee. The enantiomeric excess of product 9 was determined by HPLC (IC, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 208 nm) at t_R = 7.6 min (minor) and 13.9 min (major). [α]_D²⁰ ∼ 0 (c = 1.0, CHCl₃). ¹H NMR (400 MHz, chloroform-d, only major diastereomer): δ 7.84 (dt, J = 8.2, 0.9 Hz, 1H), 7.31–7.25 (m, 1H), 7.21–7.08 (m, 2H), 4.03 (dq, J = 10.8, 7.1 Hz, 1H), 3.91 (dq, J = 10.8, 7.1 Hz, 1H), 3.23 (dd, J = 10.7, 8.6 Hz, 1H), 2.57–2.42 (m, 1H), 2.37–2.17 (m, 3H), 2.01–1.88 (m, 2H), 1.63 (s, 9H), 1.06 (t, J = 7.1 Hz, 3H). ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d, only major diastereomer): δ 178.5, 171.7, 149.6, 139.8, 132.9, 128.2, 124.6, 121.6, 115.0, 84.1, 60.9, 56.2, 55.8, 40.1, 28.9, 28.3 (3C), 24.2, 13.8 ppm. IR (ATR): ν 1790 (C=O, ester, amide), 1761 (C=O, ester, amide), 1724 (C=O, ester, amide) cm^–1. HRMS (ESI+) m/z: calcd. for C₂₀H₂₅NNaO₅ [M + Na]⁺: 382.1625, found: 382.1621.

tert-Butyl (S)-2-(Hydroxymethyl)-2′-oxospiro[cyclopentane-1,3′-indolin]-2-ene-1′-carboxylate (10)

A solution of DIBALH (25 wt.% in toluene, 150 μL, 0.22 mmol, 2.2 equiv) was dropwise added (during 3 min) to a stirred solution of spirocycle 5a (36 mg, 0.1 mmol, 1.0 equiv, 99% ee) in anhydrous DCM (2.0 mL) at 0 °C (water/ice cooling bath). At this temperature, the reaction mixture was stirred for 1 h. After the full disappearance of starting material (monitored by TLC), the reaction was quenched by careful addition of MeOH (1 mL) followed with Rochelle’s salt solution (5 mL). Resulting gelly solution was stirred until it became a clear biphasic solution (aprox. 2 h). Then the organic phase was separated and the water phase extracted with DCM (3 × 10 mL). Collected organic phases were washed with brine (1 × 10 mL) and dried over MgSO₄. After filtration of the drying agent, solvents were removed under reduced pressure. The crude product was purified by column chromatography with a mixture of hexane/EtOAc as an eluent (3/1 to 2/1).

Colorless oil. Yield = 84% (27 mg). 96% ee. The enantiomeric excess of product 10 was determined by HPLC (IC, n-heptane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ = 240 nm) at t_R = 8.0 min (minor) and 10.9 min (major). [α]_D²⁰ = −117.7 (c = 0.3, CHCl₃). ¹H NMR (400 MHz, chloroform-d): δ 7.98–7.61 (m, 1H), 7.26–7.14 (m, 2H), 6.99 (td, J = 7.5, 1.1 Hz, 1H), 5.75 (dd, J = 3.0, 1.5 Hz, 1H), 5.66 (s, 1H), 4.31 (d, J = 11.1 Hz, 1H), 3.89 (ddd, J = 7.4, 3.7, 1.9 Hz, 1H), 3.22–3.06 (m, 1H), 2.76 (ddd, J = 16.3, 8.7, 3.2 Hz, 1H), 2.41–2.23 (m, 2H), 1.60 (s, 9H) ppm. ¹³C{¹H} NMR (101 MHz, chloroform-d): δ 149.5, 148.4, 128.6, 128.5, 124.7, 123.3, 122.5, 122.1, 114.9, 95.7, 64.9, 38.0, 37.5, 32.3, 28.6 (3C), 28.3 ppm. IR (ATR): ν 3408 (O–H, alcohol) 1705 (C=O, aldehyde, amide) cm^–1. HRMS (ESI+) m/z: calcd. for C₁₈H₂₃NNaO₄ [M + Na]⁺: 340.1519, found: 340.1513.

Data Availability Statement

The data underlying this study are available in the published article and its online Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.2c02478.

• Reaction condition optimization, crystallographic data, copies of ¹H NMR, ¹³C NMR, and ¹⁹F NMR, and copies of chiral HPLC (PDF)

• FAIR data, including the primary NMR FID files, for compounds 3–10 (ZIP)

• FAIR data, including the primary NOE NMR FID files (ZIP)

Author Contributions

A.V. and V.D. performed the synthesis of all compounds. S.P. performed selected NMR experiments. I.C. performed X-ray analysis. V.D. and J.V. wrote the manuscript. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.