Synthesis of chiral spiro-heterocyclic azides via asymmetric [4 + 2]-cycloaddition of conjugated vinyl azides

Abstract

Chiral spiro-heterocyclic scaffolds are prevalent in numerous bioactive molecules and pharmaceuticals, yet their asymmetric synthesis remains rare. In this study, we achieved a highly enantioselective and diastereoselective [4 + 2]-cycloaddition reaction of 1-(1-azidovinyl)-cyclohex-1-ene with aurones and (E)-alkenyloxindoles mediated by chiral N,N′-dioxide/metal complexes. This approach efficiently delivered enantioenriched [6,5] spiro-heterocyclic azides with three contiguous stereocenters in good yields and excellent stereoselectivities. The derivatization of the products yielded valuable functional groups and structures, such as seven-membered lactams, diols, and ketones, underscoring the utility and versatility of this methodology. Possible transition state models were proposed to elucidate the observed stereo-induction.

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Introduction

As an important subset of spiro-heterocyclic scaffolds, spiro-benzofuran–cyclohexanes are the cores that recur across numerous biologically active molecules, natural products, and pharmaceutical agents,¹ such as the antifungal agent griseofulvin, filifolinol, stachybotrylactam and spirodesertol B (Fig. 1). Despite their high significance and the considerable attention paid to racemate synthesis,² studies on constructing chiral spiro-benzofuran–cyclohexane skeletons have been limited over the past decades.³ Catalytic asymmetric cycloaddition and cyclization are powerful strategies for building chiral cyclic compounds.⁴ Cheng and coworkers reported a chiral primary amine-catalyzed asymmetric tandem Michael-aldol reaction of 2-substituted benzofuran-3-ones with enones, which represents a powerful protocol to synthesize enantioenriched spiro-benzofuran–cyclohexane analogues.^3b Subsequently, Katsuki's group realized an enantioselective tandem spiro-cyclization of 1,3-dimethyl-2-naphthol with phenol mediated by an iron–salen complex, providing straightforward access to such chiral frameworks.^3c Very recently, Brimble and coworkers reported the asymmetric total synthesis of (+)-spiroapplanatumine G, featuring the formation of a key spirobenzofuranone intermediate through a chiral diboronate-mediated catalytic enantioselective Diels–Alder reaction between an aurone ester and a silyloxydiene (Scheme 1a).^3e

Fig. 1 Representative bioactive molecules containing spiro-benzofuran–cyclohexane scaffolds.

Scheme 1 Asymmetric synthesis of chiral spiro-benzofuran–cyclohexane analogues and spirocyclic azides.

Azide compounds are versatile synthetic hubs,⁵ enabling divergent downstream functionalization to streamline the synthesis of high-value functionalized molecules. The asymmetric [4 + 2]-cycloaddition of conjugated vinyl azides⁶ as 4π partners with benzofuran-3-one-based exocyclic alkenes could afford chiral benzofuran–cyclohexanes bearing an azide group. In this context, the resulting azide-based spiro-cyclohexane would be a promising functional group for late-stage modification. As a continuation of our interest in the transformations of vinyl azides,⁷ we herein report the asymmetric [4 + 2]-cycloaddition of 1-azidovinyl-cyclohex-1-ene with both sluggish aurones and reactive 3-alkenyl-oxindoles as 2π donors (Scheme 1b), by using easy-to-obtain chiral N,N′-dioxide/metal complex⁸ catalysts. The desired chiral spiro-benzofuran–cyclohexanes and spiro-oxindole-cyclohexane azides with three consecutive stereocenters were obtained in good yields, leading to multiple functionalizations and ring modifications.

Results and discussion

2-Benzylidenebenzo-furan-3(2H)-ones, known as aurones,⁹ are usually recognized as 4π partners in hetero-Diels–Alder reactions, but have been largely overlooked as dienophiles for constructing carbocyclic frameworks.¹⁰ Our investigation began with the asymmetric [4 + 2]-cycloaddition of aurone A1 with 1-(1-azidovinyl)-cyclohex-1-ene B (Table 1). The exploration of metal salts revealed that Ni(OTf)₂ coordinated with the chiral N,N′-dioxide ligand L₃-PiPr₂, serving as a Lewis acid catalyst to deliver the desired product C1 with 67% ee, but the yield (4%) was poor (entry 1). By contrast, rare earth metal salts exhibited high reactivity, albeit with lower enantioselectivity (entries 2–5). Among them, 93% yield with 39% ee of C1 was obtained with the use of Sc(OTf)₃. The chiral ligands had a significant influence on the enantioselectivity. L-Tetrahydroisoquinoline-carboxylic-acid-derived L₃-TqPr₂ outperformed those from other amino acids (entries 6–8). Furthermore, L₃-TqCPh₃, containing bulky triphenylmethanamine motifs instead of aniline groups, further enhanced the enantioselectivity to 95% ee with 94% yield (entry 10). Lowering the reaction temperature to 10 °C resulted in a slight decrease of yield (90%) and an increase of the ee value (entry 11). The investigation of the ratio of metal salt and ligand showed that the yield of C1 was improved to 99% with 96% ee using a slightly excessive ligand (entry 12). Notably, no reaction occurred without a catalyst (entry 13), indicating the important role of Lewis acid in enhancing the reactivity. The diastereoselectivity was constantly over 19 : 1 dr, regardless of the presence of the chiral ligand (entry 14), suggesting a concerted [4 + 2] cycloaddition process, and a ligand acceleration effect¹¹ was observed.

Table 1 Optimization of the reaction conditions using 2-benzylidenebenzofuran-3(2H)-one^a

Entry	Ligand	Metal salt	Yield^b (%)	ee^c (%)
a Unless otherwise noted, all reactions were carried out with A1 (0.1 mmol), B (0.1 mmol), metal salt (10 mol%), ligand (10 mol%), and DCM (0.1 M) under an Ar atmosphere at 35 °C for 16 h. b Yield of the isolated product. c Determined by HPLC analysis. d At 10 °C. e L3-TqCPh3 (11 mol%). NR = no reaction.
1	L3-PiPr2	Ni(OTf)2	4	67
2	L3-PiPr2	Sc(OTf)3	93	39
3	L3-PiPr2	Y(OTf)3	62	13
4	L3-PiPr2	Dy(OTf)3	52	8
5	L3-PiPr2	Yb(OTf)3	77	13
6	L3-RaPr2	Sc(OTf)3	99	59
7	L3-PrPr2	Sc(OTf)3	91	0
8	L3-TqPr2	Sc(OTf)3	95	65
9	L3-TqCHPh2	Sc(OTf)3	96	65
10	L3-TqCPh3	Sc(OTf)3	94	95
11^d	L3-TqCPh3	Sc(OTf)3	90	97
12^d^,^e	L3-TqCPh3	Sc(OTf)3	99	96
13^d^,^e	—	—	NR	—
14^d^,^e	—	Sc(OTf)3	87	—

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With the optimal reaction conditions established, the substrate scope was investigated. As shown in Table 2, aurones bearing various groups on the benzofuran were transformed into the corresponding products C2–C8 with good enantioselectivity. Both the position and electronic properties of the substituents had an influence on the reaction. For example, the substrate containing a 4-F-substituent afforded C2 with a low yield (15%) and 82% ee; by contrast, 5-F substituted C3 was isolated with an excellent yield and enantioselectivity (95% yield, 94% ee). However, when electron-withdrawing groups of larger size were introduced at the C5-position, lower reactivities were observed (C5–C7). Subsequently, the 2-benzylidenebenzofuran-3(2H)-ones derived from different aldehydes were examined. Regardless of the electronic properties or steric hindrance of the substituents at the 4-position of the phenyl ring, products C10–C23 were afforded with excellent yields and enantio- and diastereoselectivities (86%–99% yields, 93%–97% ee). A series of functional groups were tolerated in this reaction, including halo, cyan, trifluoromethyl, and alkynyl groups. Product C22 bearing an amino group exhibited a lower yield (34%), probably due to the poor solubility of A22. Substrates with substituents at the ortho- or meta-position on the phenyl ring were also suitable for this system, and C9 was obtained with a moderate yield and ee value, probably due to steric hindrance. Additionally, heteroaromatic rings could be incorporated into C24 and C25 with excellent results. Alkyl and allyl substituents were also examined, resulting in corresponding products with moderate to excellent yields and ee values (C26–C27).

Table 2 The scope of aurones^a

a All reactions were performed with A (0.1 mmol), B (0.1 mmol), and Sc(OTf)₃/L₃-TqCPh₃ (1 : 1.1, 10 mol%) in DCM (0.1 M) under an Ar atmosphere at 10 °C for 16 h.

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Encouraged by the above results, we next aimed to expand the scope to 3-alkenyl-oxindoles, producing chiral spiro-oxindole-cyclohexanes that are also privileged frameworks.¹² Compared to aurones, (E)-alkenyloxindole (D) exhibited higher reactivity and reacted with vinyl azide B smoothly in the absence of a catalyst, giving the desired product E1 with 92% yield and 70 : 30 dr (see the SI for details), indicating a strong background reactivity. The addition of Lewis acids, such as Mg(OTf)₂ had little influence on the result, but the presence of the Mg(OTf)₂/L₃-RaPr₂ complex significantly increased the diastereoselectivity to 96 : 4 dr. Under the rescreening reaction conditions (see the SI for details), the scope of (E)-alkenyloxindoles was examined. As shown in Table 3, the ester group of the (E)-alkenyloxindoles had an important effect on this reaction. Using smaller sterically hindered substituents, such as methyl and ethyl, the corresponding products (E2 and E3) were obtained with slightly lower yields and ee values compared to that of E1 bearing a tert-butyl group. Dienophiles bearing other electron-withdrawing groups, such as cyano and aroyl, were evaluated, yielding E4 and E5. Regardless of the electronic properties or steric hindrance of the substituents on the phenyl ring, the corresponding products (E6–E25) were obtained with good yields (78–99%) and excellent ee values (91–99%). Among them, 4-fluoro substituted product E22 was obtained in a relatively low yield (78%) due to steric hindrance. In most cases, the diastereoselectivities are excellent, except for E10, E11, E13, E14, and E24 with strong electron-withdrawing substituents, possibly as a result of the competitive background reaction.

Table 3 The scope of (E)-alkenyloxindoles^a

a All reactions were carried out with D (0.1 mmol), B (0.1 mmol), and Mg(OTf)₂/L₃-RaPr₂ (1 : 1, 10 mol%) in DCM (0.1 M) under Ar at 0 °C for 4 h.

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To evaluate the synthetic potential of this protocol, gram-scale synthesis was carried out. Vinyl azide B (3.0 mmol) reacted smoothly with A1 (3.0 mmol) or D1 (3.0 mmol) under the standard conditions, respectively, producing C1 (1.08 g, 97% yield) and E1 (1.38 g, 93% yield) with excellent stereoselectivity (Scheme 2a). Next, further transformations of C1 and E1 were performed (Scheme 2b). The vinyl azide group could be converted into an amide group (F, 43% yield and 96% ee) upon treatment of C1 with the trifluoromethanesulfonic acid and potassium hydroxide sequence. Ketone G1 was obtained with 78% yield with 97% ee under Staudinger reaction conditions. Likewise, derivative G2 from C4 was isolated and its absolute configuration was determined by X-ray diffraction analysis.¹³ Therefore, the three contiguous stereocenters generated during cycloaddition were assigned the same configuration. A click reaction was conducted to afford triazole product H with 70% yield and 97% ee. Interestingly, oxidation with m-chloroperbenzoic acid (m-CPBA) led to product I (84% yield, 96% ee) via epoxidation-ring opening steps with high diastereoselectivity. For the transformations of E1, mixed click reaction products J1 and J2 were obtained. The ketone product K was formed in 54% yield with 92% ee via reduction of the azide group by hydrogen gas in the presence of Pd/C.

Scheme 2 Gram-scale synthesis and further transformations.

Based on the experimental results and the assigned configuration of the products according to the X-ray crystal structure of the ketone derivatives (G2 and K), possible catalytic cycles were proposed to elucidate the reaction process and stereo-induction (Scheme 3). The chiral Sc(III)/L₃-TqCPh₃ complex coordinates with A1 to generate INT1, which undergoes exo-[4 + 2]-cycloaddition with vinyl azide B through TS1. The formed INT2 releases the catalyst to yield the (2S,2′S,8a′S)-product C1. Different from the concerted process, INT3 generated from D1 and the Mg(OTf)₂/L₃-RaPr₂ complex via bidentate coordination undergoes a stepwise [4 + 2]-cycloaddition involving Re-face vinyl nucleophilic addition followed by cyclization to yield the major (2′R,3R,8a′S)-exo-product E1.

Scheme 3 Plausible catalytic cycles.

Conclusions

In conclusion, we have successfully developed an efficient catalytic asymmetric [4 + 2]-cycloaddition reaction of vinyl azides with 2-benzylidenebenzo-furan-3(2H)-ones or (E)-alkenyloxindoles. This strategy provided a facile route to chiral spiro-heterocyclic azides containing three contiguous stereocenters under mild reaction conditions with excellent yields, enantioselectivity and diastereoselectivity (up to 99% yield, 96% ee and >19 : 1 dr). The scale-gram synthesis and diverse derivations of the azide group further underscored the utility and versatility of this methodology.

Author contributions

Y. C. L. performed the experiments, analyzed the results, and wrote the SI and manuscript. Y. H. Q. participated in the synthesis of substrates. B. Q. Y. repeated some experiments. H. L. Z. participated in the article discussions. W. D. C. and X. M. F. supervised the project. W. D. C. and X. M. F. co-wrote the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

Supplementary information: ¹H, ¹³C{¹H} and ¹⁹F{¹H} NMR, MS, and HPLC spectra. See DOI: https://doi.org/10.1039/d5qo01290b.

CCDC 2449940 (K) and 2449941 (G2) contain the supplementary crystallographic data for this paper.^13a,b

Acknowledgements

We appreciate the National Natural Science Foundation of China (92256302) for financial support. We thank Dr Yuqiao Zhou (Sichuan University) for assistance with X-ray analysis.

References

1. (a) A. Bartoli, F. Rodier, L. Commeiras, J. L. Parrain and G. Chouraqui, Construction of spirolactones with concomitant formation of the fused quaternary centre application to the synthesis of natural products, Nat. Prod. Rep., 2011, 28, 763–782; (b) A. B. Petersen, M. H. Rønnest, T. O. Larsen and M. H. Clausen, The Chemistry of Griseofulvin, Chem. Rev., 2014, 114, 12088–12107; (c) C. Chen and L. He, Advances in research of spirodienone and its derivatives: Biological activities and synthesis methods, Eur. J. Med. Chem., 2020, 203, 112577.
2. (a) B. J. Bradbury, P. Bartyzel, T. S. Kaufman, M. J. Nieto, R. D. Sindelar, S. M. Scesney, B. R. Gaumond and H. C. Marsh, Synthesis and Complement Inhibitory Activity of B/C/D-Ring Analogues of the Fungal Metabolite 6,7-Diformyl-3′,4′,4a′,5′,6′,7′,8′,8a′-octahydro-4,6′,7′-trihydroxy 2′,5′,5′,8a′-tetramethylspiro[1′(2′H)-naphthalene-2(3H)-benzofuran], J. Med. Chem., 2003, 46, 2697–2705; (b) X. S. Wang, Y. Lu, H. X. Dai and J. Q. Yu, Pd(II)-Catalyzed Hydroxyl-Directed C-H Activation/C-O Cyclization: Expedient Construction of Dihydrobenzofurans, J. Am. Chem. Soc., 2010, 132, 12203–12205; (c) T. Pang, Y. Sun, W. J. Xue, Y. P. Zhu, G. A. Yu and A. X. Wu, Selective Synthesis of Six-Membered and Five-Membered Spiro Compounds by Controlling the Molar Ratio of Ternary Gallium/Indium/Copper (Ga/In/2(Cu) Catalysts, Adv. Synth. Catal., 2013, 355, 2208–2216; (d) C. H. Liu, Y. L. Xu, S. Y. Niu, L. Q. Wei, Y. Liu, Y. B. Wang, J. Y. Zhu, J. Y. Fu and J. F. Yuan, Functional Ionic Liquids Promoted Double Michael Reaction of Benzofuran-3-one or 1-Indone and Symmetric Dienones: Construction of Spiro[benzofuran-2,1′-cyclohexane]-3-one or Spiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione Derivatives, Chin. J. Chem., 2017, 35, 1231–1238; (e) M. B. Ruiz, A. Galdámez, B. Modak and M. V. Herrera, Diastereoselective Synthesis of Spirodihydrobenzofuran Analogues of the Natural Product Filifolinol, ChemistrySelect, 2020, 5, 15175–15179; (f) W. Y. Shi, Y. Ren, H. R. Zhao, Y. Tang, S. X. Piao, B. M. Mao, W. Wang, Y. J. Wu, B. Wang and H. C. Guo, Phosphine-Catalyzed [4 + 2] Annulation of Allenoates with Benzofuran-Derived Azadienes and Subsequent Thio-Michael Addition, Org. Lett., 2022, 24, 3747–3752; (g) Y. F. Huang, M. T. Tan, N. Z. Wang, Y. F. Zhang, H. Yao, X. Xiao, N. Y. Huang and K. Zou, Highly Regio- and Diastereoselective Phosphine-Catalyzed [2 + 4] Annulation of Benzofuran-Derived Azadienes with Allyl Carbonates: Access to Spiro[benzofuran-cyclohexanes], J. Org. Chem., 2023, 88, 13030–13041; (h) M. Q. Geng, J. Q. Kuang, M. Z. Miao and Y. M. Ma, Cu(II)-catalyzed domino construction of spironaphthalenones by dearomatization of β-naphthols and using N,N-dimethylaminoethanol as a C1 synthon, Org. Biomol. Chem., 2023, 21, 3101–3104.
3. (a) M. C. Pirrung, W. L. Brown, S. Rege and P. Laughton, Total Synthesis of (+)-Griseofulvin, J. Am. Chem. Soc., 1991, 113, 8561–8562; (b) N. Dong, X. Li, F. Wang and J. P. Cheng, Asymmetric Michael-Aldol Tandem Reaction of 2-Substituted Benzofuran-3 ones and Enones: A Facile Synthesis of Griseofulvin Analogues, Org. Lett., 2013, 15, 4896–4899; (c) T. Ogumaab and T. Katsuki, Iron-catalysed asymmetric tandem spiro-cyclization using dioxygen in air as the hydrogen acceptor, Chem. Commun., 2014, 50, 5053–5056; (d) J. Xiao, J. Zhao, Y. W. Wang, G. Luo and Y. Peng, Total syntheses of (+)-adunctins C and D: assignment of their absolute configurations, Org. Biomol. Chem., 2021, 19, 9840–9843; (e) Y. Q. Lin, F. F. Li and M. A. Brimble, Asymmetric Total Synthesis of (+)-Spiroapplanatumine G, Org. Lett., 2025, 27, 10390–10394.
4. (a) L. Klier, F. Tur, P. H. Poulsen and K. A. Jørgensen, Asymmetric cycloaddition reactions catalysed by diarylprolinol silyl ethers, Chem. Soc. Rev., 2017, 46, 1080–1102; (b) X. H. Liu, H. F. Zheng, Y. Xia, L. L. Lin and X. M. Feng, Asymmetric Cycloaddition and Cyclization Reactions Catalyzed by Chiral N,N-Dioxide–Metal Complexes, Acc. Chem. Res., 2017, 50, 2621–2631; (c) A. G. Woldegiorgis, M. Suleman and X. F. Lin, Asymmetric Cycloaddition/Annulation Reactions by Chiral Phosphoric Acid Catalysis: Recent Advances, Eur. J. Org. Chem., 2022, e202200624; (d) W. Tan, J. Y. Zhang, C. H. Gao and F. Shi, Progress in organocatalytic asymmetric (4 + 3) cycloadditions for the enantioselective construction of seven-membered rings, Sci. China:Chem., 2023, 66, 966–992; (e) Z. Q. Zhu, T. Z. Li, S. J. Liu and F. Shi, Advances in organocatalytic asymmetric [3 + 3] cycloadditions: synthesis of chiral six-membered (hetero)cyclic compounds, Org. Chem. Front., 2024, 11, 5573–5604.
5. (a) K. Banert, The Chemistry of Unusually Functionalized Azides, Synthesis, 2016, 2361–2375; (b) J. K. Fu, G. Zanoni, E. A. Anderson and X. H. Bi, α-Substituted vinyl azides: an emerging functionalized alkene, Chem. Soc. Rev., 2017, 46, 7208–7228; (c) M. Balci, Acyl Azides: Versatile Compounds in the Synthesis of Various Heterocycles, Synthesis, 2018, 1373–1401; (d) A. S. Carlson and J. J. Topczewski, Allylic azides: synthesis, reactivity, and the Winstein rearrangement, Org. Biomol. Chem., 2019, 17, 4406–4429; (e) A. A. Nayl, A. A. Aly, W. A. A. Arafa, I. M. Ahmed, A. I. Abd-Elhamid, E. M. El-Fakharany, M. A. Abdelgawad, H. N. Tawfeek and S. Bräse, Azides in the Synthesis of Various Heterocycles, Molecules, 2022, 27, 3716; (f) F. Gholami, F. Yousefnejad, B. Larijanib and M. Mahdavi, Vinyl azides in organic synthesis: an overview, RSC Adv., 2023, 13, 990–1018; (g) K. B. Mishra, Ene–azide chemistry in the synthesis of 1,2,3-triazoline/triazole and the corresponding mechanistic aspects, Org. Biomol. Chem., 2025, 23, 5483–5526.
6. (a) N. Thirupathi, F. Wei, C. H. Tung and Z. H. Xu, Divergent synthesis of chiral cyclic azides via asymmetric cycloaddition reactions of vinyl azides, Nat. Commun., 2019, 10, 3158; (b) S. N. Li, H. F. Lu, Z. H. Xu and F. Wei, Ni-Catalyzed asymmetric hetero-Diels–Alder reactions of conjugated vinyl azides: synthesis of chiral azido polycycles, Org. Chem. Front., 2021, 8, 1770–1774; (c) N. Li, W. J. Li, X. Y. Chen, H. X. Wang, M. S. Xie and H. M. Guo, Cu(II)-Catalyzed Asymmetric All-Carbon-Based Diels–Alder Reaction of Conjugated Vinyl Azides: Synthesis of Chiral Fused and Spiro-Cyclohexenes, Adv. Synth. Catal., 2025, 367, e202500089; (d) M. H. Shen, X. C. Liang, L. Chen, H. Wu, H. Y. Qu, F. M. Wang and H. D. Xu, Rhodium promoted intramolecular [4 + 2] cycloaddition of 2-azidodiene with alkyne: A transition metal catalysis approach to challenging fused bicyclic vinyl azide, Tetrahedron Lett., 2019, 60, 1025–1028.
7. (a) Z. W. Zhong, Z. J. Xiao, X. H. Liu, W. D. Cao and X. M. Feng, Catalytic asymmetric synthesis of 3,2′-pyrrolinyl spirooxindoles via conjugate addition/Schmidt type rearrangement of vinyl azides and (E)-alkenyloxindoles, Chem. Sci., 2020, 11, 11492–11497; (b) Z. W. Zhong, L. C. Ning, Y. C. Lu, J. Q. Tan, L. L. Lin and X. M. Feng, Asymmetric catalytic alkylation of vinyl azides with 3-bromo oxindoles: water-assisted chemo- and enantiocontrol, Sci. China:Chem., 2023, 66, 799–807.
8. (a) X. H. Liu, L. L. Lin and X. M. Feng, Chiral N,N′-Dioxides: New Ligands and Organocatalysts for Catalytic Asymmetric Reactions, Acc. Chem. Res., 2011, 44, 574–587; (b) S. X. Dong, X. H. Liu and X. M. Feng, Asymmetric Catalytic Rearrangements with α-Diazocarbonyl Compounds, Acc. Chem. Res., 2022, 55, 415–428; (c) D. F. Chen and L. Z. Gong, Feng chiral N,N′-dioxide ligands: uniqueness and impacts, Org. Chem. Front., 2023, 10, 3676–3683; (d) Z. Wang, X. H. Liu and X. M. Feng, Asymmetric Catalysis Enabled by Chiral N,N′-Dioxide–Nickel(II) Complexes, Aldrichimica Acta, 2020, 53, 3–10; (e) W. D. Cao, X. H. Liu and X. M. Feng, Asymmetric Catalytic Radical Reactions Enabled by Chiral N,N′-Dioxide–Metal Complexes, Acc. Chem. Res., 2025, 58, 2496–2510; (f) D. Ye, M. J. Ying, L. C. Ning, W. Y. R. Li, L. L. Lin and X. M. Feng, Chiral Magnesium(II)-Catalyzed Asymmetric Hydroalkylation of Imine-Containing Vinylazaarenes through Conjugate Addition, Org. Lett., 2025, 27, 3601–3606; (g) K. X. Wang, Z. C. Yu, Z. Tan, S. Y. Li, X. H. Liu, M. P. Pu and X. M. Feng, Catalytic Asymmetric Rearrangement of Azoalkene-Derived Sulfonium Ylides via Remote Chirality Control, Org. Lett., 2025, 27, 3409–3413; (h) L. K. Yang, L. C. Ning, H. Yu, S. Y. Li, M. Yang, L. H. Yang, F. Wang, X. H. Liu, W. D. Cao and X. M. Feng, Catalytic Asymmetric Photocycloaddition of Triplet Aldehydes with Benzocyclobutenones, CCS Chem., 2025, 7, 573–581; (i) Y. L. Song, D. Y. Liu, S. X. Dong and X. M. Feng, Asymmetric Synthesis of 3-Alkyl 3-Alkyloxy-2-oxindoles by Enantioconvergent Alkoxylation with Alcohols, Synthesis, 2025, 2241–2251; (j) F. L. Wu, H. K. Wang, Z. W. Wu, Y. B. Liu and X. M. Feng, Solvent-Controlled Enantioselective Allylic C–H Alkylation of 2,5 Dihydrofuran via Synergistic Palladium/Nickel Catalysis, J. Am. Chem. Soc., 2025, 147, 16237–16247; (k) H. K. Wang, L. J. Song, J. Huang, F. L. Wu, Z. Yang, Y. B. Liu, Y. D. Wu and X. M. Feng, Regiodivergent and Enantioselective Allylic C–H Alkylation of Allyl Ethers: Optimization, Scope, Mechanism and Application, Angew. Chem., Int. Ed., 2025, 64, e202500125.
9. (a) X. P. Li, J. Z. Yan, J. L. Qin, S. L. Lin, W. W. Chen, R. T. Zhan and H. C. Huang, Enantioselective Synthesis of Benzofuran-Fused N-Heterocycles via Chiral Squaramide Catalyzed [4 + 2] Cyclization of Azadienes with Azlactones, J. Org. Chem., 2019, 84, 8035–8045; (b) V. L. Martín, J. H. Martín, R. M. Ballesté, J. A. F. Salas and J. Alemán, Enantioselective Inverse-Electron Demand Aza-Diels–Alder Reaction: ipso,α-Selectivity of Silyl Dienol Ethers, ACS Catal., 2021, 11, 12133–12145; (c) W. K. Koay, G. J. Mei and Y. X. Lu, Facile access to benzofuran-fused tetrahydropyridines via catalytic asymmetric [4 + 2] cycloaddition of aurone-derived 1-azadienes with 3-vinylindoles, Org. Chem. Front., 2021, 8, 968–974; (d) F. Wang, C. Luo, Y. Y. Shen, Z. D. Wang, X. Li and J. P. Cheng, Highly Enantioselective [4 + 2] Cycloaddition of Allenoates and 2-Olefinic Benzofuran-3-ones, Org. Lett., 2015, 17, 338–341; (e) I. Mazziotti, G. Petrarolo and C. L. Motta, Aurones: A Golden Resource for Active Compounds, Molecules, 2022, 27, 2.
10. (a) R. Mose, M. E. Jensen, G. Preegel and K. A. Jørgensen, Direct Access to Multi-functionalized Norcamphor Scaffolds by Asymmetric Organocatalytic Diels–Alder Reactions, Angew. Chem., Int. Ed., 2015, 54, 13630–13634; (b) L. C. Yang, Z. Y. Tan, Z. Q. Rong, R. Y. Liu, Y. N. Wang and Y. Zhao, Palladium-Titanium Relay Catalysis Enables Switch from Alkoxide-π-Allyl to Dienolate Reactivity for Spiro-Heterocycle Synthesis, Angew. Chem., Int. Ed., 2018, 57, 7860–7864.
11. S. X. Dong, W. D. Cao, M. P. Pu, X. H. Liu and X. M. Feng, Ligand Acceleration in Chiral Lewis Acid Catalysis, CCS Chem., 2023, 5, 2717–2735.
12. (a) G. S. Singh and Z. Y. Desta, Isatins as Privileged Molecules in Design and Synthesis of Spiro-Fused Cyclic Frameworks, Chem. Rev., 2012, 112, 6104–6155; (b) G. Bencivenni, L. Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaioli, M. P. Song, G. Bartoli and P. Melchiorre, Targeting Structural and Stereochemical Complexity by Organocascade Catalysis: Construction of Spirocyclic Oxindoles Having Multiple Stereocenters, Angew. Chem., Int. Ed., 2009, 48, 7200–7203; (c) Q. Wei and L. Z. Gong, Organocatalytic Asymmetric Formal [4 + 2] Cycloaddition for the Synthesis of Spiro[4-cyclohexanone-1,3′-oxindoline] Derivatives in High Optical Purity, Org. Lett., 2010, 12, 1008–1011; (d) L. L. Wang, L. Peng, J. F. Bai, Q. C. Huang, X. Y. Xu and L. X. Wang, Highly organocatalytic asymmetric Michael–ketone aldol–dehydration domino reaction: straightforward approach to construct six-membered spirocyclic oxindoles, Chem. Commun., 2010, 46, 8064–8066; (e) L. L. Wang, L. Peng, J. F. Bai, L. N. Jia, X. Y. Luo, Q. C. Huang, X. Y. Xu and L. X. Wang, A highly organocatalytic stereo selective double Michael reaction : efficient construction of optically enriched spirocyclic oxindoles, Chem. Commun., 2011, 47, 5593–5595; (f) L. Yao, K. Liu, H. Y. Tao, G. F. Q, X. Zhou and C. J. Wang, Organocatalytic asymmetric desymmetrization: efficient construction of spirocyclic oxindoles bearing a unique all-carbon quaternary stereogenic center via sulfa-Michael addition, Chem. Commun., 2013, 49, 6078–6080; (g) J. Wang, X. Z. Zheng, J. A. Xiao, K. Chen, H. Y. Xiang, X. Q. Chen and H. Yang, Enantioselectivity-Switchable Organocatalytic [4 + 2]-Annulation to Access the Spirooxindole–Norcamphor Scaffold, Org. Lett., 2021, 23, 963–968; (h) C. S. Sankara, S. Bhagat, A. Chandra and I. N. N. Namboothiri, Enantioselective Desymmetrization of Curcumins with 3-Olefinic Oxindoles for the Synthesis of Spirocyclohexanoneoxindoles, Eur. J. Org. Chem., 2023, e202300069.
13. (a) CCDC 2449940: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2n7cbm; (b) CCDC 2449941: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2n7ccn.

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