Enantioselective Synthesis of 2-Oxabicyclo[2.1.1]hexanes and Bicyclo[2.1.1]hexanes via Catalytic Asymmetric Intramolecular Photocycloadditions

Abstract

Due to the ubiquitous presence of ortho-disubstituted benzenes in pharmaceuticals and agrochemicals, the exploration of their bioisosteres incorporating three-dimensional bridged cyclic scaffolds has attracted significant interest among chemists in recent years. As a result, 4,5-disubstituted 2-oxabicyclo[2.1.1]hexanes have recently emerged as promising candidates owing to their enhanced pharmacological potency, improved metabolic stability, and, importantly, superior aqueous solubility. Herein, we report our recent progress on enantioselective synthesis of such compounds via an intramolecular [2 + 2] photocycloaddition enabled by cooperative photoinduced energy transfer (EnT) and chiral Brønsted acid catalysis. A broad range of valuable pyridine-functionalized 2-oxabicyclo[2.1.1]hexane derivatives have been obtained in high yields with good to excellent enantioselectivity and diastereoselectivity. In addition, this transition metal-free approach offers an efficient and modular route to pyridine-based bicyclo[2.1.1]hexanes, which contain a significant yet challenging structural motif—pyridine rings directly attached to the bridgehead carbon atoms. Mechanistic studies demonstrate that the photosensitizer and low reaction temperature are crucial for rendering the chiral catalyst indispensable in facilitating substrate activation to the triplet state, thereby enabling enantiocontrol in this highly reactive transformation.

Ortho-disubstituted benzene bioisosteres such as 4,5-disubstituted 2- oxabicyclo[2.1.1]hexanes are attractive scaffolds for improving drug-like properties but remain challenging to access enantioselectively. Here, the authors report a transition-metal-free enantioselective intramolecular [2 + 2] photocycloaddition using cooperative energy transfer and chiral Brønsted acid catalysis.

Introduction

In the pharmaceutical sciences, bioisostere design has become a cornerstone strategy for accelerating the discovery of new drug candidates with improved pharmacological profiles over their parent compounds^1,2. Among these approaches, three-dimensional bridged cyclic scaffolds have emerged as effective bioisosteres for phenyl rings, one of the most ubiquitous motifs in bioactive molecules^3–23. In particular, the search for suitable bioisosteres of ortho-disubstituted phenyl rings has gained momentum, driven by the widespread presence of this motif in over 300 approved drugs and agrochemicals²³. As a result, 1,5-disubstituted bicyclo[2.1.1]hexanes (BCHs) have been recognized as promising replacements (Fig. 1A)²³. Incorporation of BCH scaffolds in place of phenyl rings has been shown to enhance key molecular attributes, including pharmacological potency and metabolic stability. However, their aqueous solubility remains similar to that of the parent ortho-disubstituted benzenes, restricting the broader adoption of this bioisosteric strategy in drug design^13,23.

Fig. 1. Research background and our work.

A Bioisosteres of ortho-disubstituted benzenes; B Method to access the desired racemic 2-oxabicyclo[2.1.1]hexanes; C This work.

In 2023, Mykhailiuk and co-workers addressed this limitation by introducing 4,5-disubstituted 2-oxabicyclo[2.1.1]hexanes as superior bioisosteres that not only retain desirable pharmacological features but also display markedly enhanced aqueous solubility (Fig. 1B)²³. These scaffolds are readily accessible from simple dienes via photoinduced energy-transfer (EnT)–catalyzed processes. Nonetheless, the method exhibits only moderate stereoselectivity (dr ≤ 4:1). More critically, despite having three stereocentres—a feature not found in planar ortho-disubstituted benzenes—no enantioselective synthesis has been achieved from such easily modified substrates, although enantiomeric purity is crucial in chiral drug development. This difficulty likely arises from the high reactivity of triplet-state intermediates, which hampers effective enantiofacial discrimination by chiral catalysts, and from the competitive racemic background reaction^{15,17,18,20,22,24–28}. Notably, Bach and colleagues introduced a photoexcitation method to overcome the latter challenge, wherein in situ formed complexes through the interactions of two oxygen atoms of 2-(alkenyloxy)cyclohex-2-enone substrates with a chiral rhodium catalyst, rather than the substrates themselves, are directly excited by visible light²⁹. In addition, Zi and collaborators reported a chiral palladium-catalyzed intermolecular [2 + 2] cycloaddition between bicyclo[1.1.0]butanes (BCBs) and aldehydes³⁰. However, these products do not exhibit the structural features necessary for ortho-disubstituted benzene bioisosterism, as demonstrated in Mykhailiuk’s studies comparing the bioactivity of 2-oxabicyclo[2.1.1]hexanes with distinct substituent patterns to the corresponding ortho-disubstituted benzene-based molecules^13,23. Thus, the development of efficient and practical enantioselective routes to these specific bioisosteres remains a pressing and unresolved challenge.

Inarguably, intramolecular cycloadditions of simple dienes can offer a promising route to valuable enantioenriched 2-oxabicyclo[2.1.1]hexanes with diverse 4- and 5-position substituents, thanks to readily available substrates and superior chemo- and regioselectivity over intermolecular variants. In recent years, this approach has notably enabled access to other benzene ring bioisosteres. For example, Rigotti, Tortosa, and co-workers developed an attractive photo-driven asymmetric intramolecular [2 + 2] cycloaddition using Λ-RhS as a chiral Lewis acid catalyst to synthesize enantioenriched 5-amide-functionalized bicyclo[2.1.1]hexanes³¹. This method relies on Λ-RhS interacting with the diene’s amide moiety to form a light-sensitive species that generates a triplet state upon irradiation. To access enantioenriched 2-azabicyclo[2.1.1]hexanes (aza-BCHs), our group developed a dual catalytic system with DPZ as a photosensitizer and a chiral Sc(III) complex for asymmetric intramolecular [2 + 2] photocycloaddition³². Here, racemic background reactions are suppressed due to the low reactivity of the triplet-state olefin, caused by the electron-donating amine substituent. The chiral Sc(III) complex acts as a Lewis acid to provide sufficient activation energy for efficient cyclization. These findings suggest that different olefin types in diene substrates may require distinct catalytic strategies, posing a significant challenge.

Building on our efforts to develop asymmetric photocatalytic methods for aryl ring bioisosteres^32,33, we report a solution to the asymmetric intramolecular [2 + 2] photocycloaddition for synthesizing enantioenriched 4,5-disubstituted 2-oxabicyclo[2.1.1]hexanes. Using an attractive transition metal-free dual-catalyst system—a chiral Brønsted acid^34–39 and a photosensitizer as an energy transfer (EnT) photocatalyst—we achieve a broad range of products with diverse bridgehead pyridine substituents in high yields and good to excellent enantio- and diastereoselectivity (Fig. 1C). These scaffolds are pharmaceutically significant as bioisosteres of clinically and agriculturally relevant compounds (e.g., I–VI)^40–47. Critically, stereocontrol depends on the precise pairing of the photosensitizer and chiral Brønsted acid. 4CzIPN, as the photosensitizer, has a triplet energy level similar to that of the substrate olefin, which is otherwise unreactive at low temperatures without activation. The chiral phosphoric acid (CPA) activates the olefin by slightly lowering its triplet energy, enabling the EnT process. This synergy allows efficient enantiofacial discrimination during the formation of three stereocenters while suppressing racemic background reactions. Importantly, the method’s high efficiency and versatility enable a precise synthesis of enantioenriched bicyclo[2.1.1]hexanes (BCHs) with pyridines at bridgehead positions.

Results and Discussion

Considering the pharmaceutical relevance of the targeted scaffolds (as exemplified by molecules IV–VI, Fig. 1C), methyl (E)−3-((2-(pyridin-2-yl)allyl)oxy)acrylate (1a) was chosen as a model substrate to probe reactivity and identify an optimal chiral catalytic system (Table 1 and Table S1 in the Supplementary Information (SI)). Density functional theory (DFT) calculations revealed that the terminal olefin (E_T ≈ 56.0 kcal/mol, E_p = ‒2.27 V) possesses a lower triplet energy than the ester-substituted double bond (E_T ≈ 62.7 kcal/mol) (Fig. S21 in the Supplementary Information for details). Moreover, irradiation of 1a using a 3 W blue LED (λ^em_max = 455 nm) did not induce any reaction, indicating that direct photoexcitation of the substrate is not feasible due to the mismatch between the substrate’s absorption characteristics and the emission profile of the light source. We therefore employed 4CzIPN (E_T = 59.7 kcal/mol, E*_ox = ‒1.07 V vs. SCE)⁴⁸ as a photosensitizer to promote EnT to generate the triplet state of the terminal olefin. As a result, the desired racemic product 2a was obtained in 92% yield and 6:1 dr when the reaction was conducted with 1.0 mol% 4CzIPN in toluene at 25 °C for 16 h (entry 1, Table S1). Although 20 mol% diphenylphosphate as a Brønsted acid was ineffective in promoting the reaction (entry 2, Table S1), pointing to a pronounced racemic background process in the reaction system, we continued to challenge the enantioselective variant by evaluating a broad range of CPAs (Table S1). Gratifyingly, when the reaction was performed in chloroform at –70 °C for 72 h with 5.0 mol% 4CzIPN and 20 mol% SPINOL-derived CPA C1, the chiral product 2a was obtained in 78% yield, 91% ee, and >19:1 dr (entry 1, Table 1). In this context, CPA C1 not only achieved excellent enantiocontrol at the three stereocenters but also markedly enhanced diastereoselectivity. It should be noted that a broad range of chiral Lewis acid complexes were evaluated during the investigation of reaction conditions; these catalysts are known to effectively lower the triplet energy of such azaarene-based olefins and promote cycloaddition reactions³². Nevertheless, no enantioselectivity was observed for product 2a.

Table 1.

Control experiments.^a

Entry	Alteration to conditions	yield (%)b	ee (%)c	drd	Entry	Alteration to conditions	yield (%)b	ee (%)c	drd
1	none	78	91	>19:1	7	C2 instead of C1	51	43	6:1
2	Rose Bengal instead of 4CzIPN	N.R.	N.A.	N.A.	8	C3 instead of C1	45	46	5:1
3	Eosin Y instead of 4CzIPN	N.R.	N.A.	N.A.	9	No 4CzIPN	N.R.	N.A.	N.A.
4	DPZ instead of 4CzIPN	N.R.	N.A.	N.A.	10	No C1	N.R.	N.A.	N.A.
5	fac-Ir(ppy)3 instead of of 4CzIPN	N.R.	N.A.	N.A.	11	In the dark	N.R.	N.A.	N.A.
6	IrIII instead of of 4CzIPN[e]	90	0	5:1	12	Under air	N.R.	N.A.	N.A.

N.R. no reaction, N.A. not applicable.

^aThe reaction was performed on a 0.1 mmol scale.

^bYield of isolated product.

^cDetermined by high-performance liquid chromatography analysis on a chiral stationary phase.

^dDetermined by ¹H-NMR analysis of the crude reaction mixture.

^eIr^III = Ir(dF(CF)₃ppy)₂(dtbbpy).

We subsequently evaluated a series of alternative photosensitizers, including Rose Bengal (E_T = 40.9 kcal/mol, E *_ox = −0.96 V vs. SCE), Eosin Y (E_T = 44.0 kcal/mol vs. SCE, E *_ox = −1.11 V vs. SCE), DPZ (E_T = 47.5 kcal/mol, E*_ox = −1.07 V vs. SCE), fac-Ir(ppy)₃ (E_T = 55.2 kcal/mol, E*_ox = ‒1.88 V vs. SCE), and Ir(dF(CF)₃ppy)₂(dtbbpy) (E_T = 60.1 kcal/mol, E*_ox = ‒1.21 V vs. SCE) (entries 2–6)^32,48,49. The results indicated that photosensitizers with triplet energies lower than that of 4CzIPN failed to generate product 2a (entries 2–5). Although Ir(dF(CF)₃ppy)₂(dtbbpy) enabled the formation of 2a in 90% yield, no enantioselectivity was observed, and the dr of 2a decreased to 5:1 (entry 6). This outcome most likely arises from a racemic background pathway (Fig. S17 in the Supplementary Information), consistent with the higher triplet energy of this Ir^III complex relative to 4CzIPN, thereby underscoring the pivotal role of the photosensitizer in enantioselective control. The substituents at the 6,6′-positions of SPINOL were found to have a significant influence on both the enantioselectivity and diastereoselectivity of the reaction. For instance, catalysts C2 and C3 afforded product 2a in 43% ee with a 6:1 dr and 46% ee with a 5:1 dr, respectively (entries 7–8). The reaction was then evaluated in the absence of 4CzIPN, and no conversion was observed, confirming the photosensitizer's essential role (entry 9). Notably, in the absence of the chiral catalyst C1, no reaction was observed, demonstrating that racemic background transformations do not occur under the current reaction conditions (entry 10). Additional control experiments demonstrated that both photoirradiation and an oxygen-free atmosphere are essential for the reaction to proceed (entries 11–12).

With the optimal reaction conditions established, the substrate scope of this asymmetric intramolecular [2 + 2] photocycloaddition for constructing valuable pyridine-functionalized 4,5-disubstituted 2-oxabicyclo[2.1.1]hexanes was evaluated. As shown in Fig. 2, we first examined the compatibility of various ester groups on the molecular scaffold. In addition to simple methyl and ethyl groups (2a–b), cyclic alkyl (2c), highly bulky alkyl (2 d), benzyl (2e), silyl-functionalized alkyl (2 f), and aryl esters (2g–h) were well tolerated, affording the corresponding products 2a–h in 56% to 78% yields, with ees ranging from 85% to 91% and excellent diastereoselectivity (>19:1). We then introduced diverse substituents onto the 2-pyridyl ring to expand the structural diversity of accessible pyridine derivatives, given that pyridine is one of the most prevalent heterocyclic motifs in marketed pharmaceuticals worldwide. The results showed that substitution at either the 4- or 5-position with electron-withdrawing or electron-donating groups generally afforded satisfactory outcomes, particularly in terms of stereoselectivity, as all products (2i–r) were obtained in over 90% ee and >19:1 dr. It should be noted that substituents at the 3- or 6-position significantly influence reactivity and enantioselectivity, despite extensive efforts devoted to screening various catalysts and catalytic systems (Fig. S18 in the Supplementary Information). We hypothesize that this may arise from steric effects, which could interfere with the effective interaction between the chiral catalyst and the pyridyl ring. We next investigated whether ketones could be used directly as substituents on internal olefins, as the resulting products constitute bioisosteric derivatives of the anti-tumor drug III (Fig. 1C). To our delight, product 2 s was obtained in 75% yield with 95% ee and >19:1 dr, highlighting both the breadth of the substrate scope and the promise of this transition-metal-free protocol for drug-discovery applications. Encouraged by these results, we further examined alkyl substituents. Notably, substrates bearing sensitive functionalities—including OBn (2t), OTBS (2 u), and an azide (2 v)—were well tolerated, delivering 2t–v in high yields with excellent enantio- and diastereoselectivity. We also probed the pharmaceutical utility of this approach by appending drug-derived fragments (for example, oxaprozin, isoxepac, and adapalene) to the substrates, thereby providing streamlined access to derivatives featuring a pyridine-functionalized 2-oxabicyclo[1.1.0]hexane motif as a bioisostere of 2-pyridyl benzene. Gratifyingly, products 2w–y were formed in high yields and stereoselectivity. Of note, pyridine-substituted inner olefin–based dienes were also synthesized and tested; however, no reaction was observed, likely because such triplet olefins are not competent to undergo intramolecular [2 + 2] photocycloaddition.

Fig. 2. Substrate scope with respect to the synthesis of enantioenriched 2-oxabicyclo[2.1.1]hexanes.

Reaction conditions: 4CzIPN (0.005 mmol, 0.05 equiv.), 1 (0.10 mmol, 1.0 equiv.), C1 (0.02 mmol, 0.2 equiv.), CHCl₃ (4.0 mL). Isolated yield.

The success of this approach also prompted us to extend the strategy to the synthesis of pyridine-based BCHs by replacing the oxygen atom with a methylene group. Notably, beyond reactivity, enantioselectivity represents a significant challenge in this work, as the inner olefins in these substrates are expected to be less electron-rich than those in substrates 1. Nevertheless, the important structural motif of the target products—featuring a pyridine moiety at the bridgehead carbons—strongly motivated active efforts to address these challenges. Consequently, we were pleased to find that the catalytic platform was effective for the transformation of the corresponding substrates 3, affording products 4a–q in 69% to 86% yields, with enantioselectivities ranging from 64% to 93% ee and excellent diastereoselectivity (>19:1 dr) in all cases (Fig. 3). The scope of compatible substrates mirrors that of substrates 1, as diverse substituents on the 2-pyridyl ring or different alkyl groups on the inner olefin can be accommodated while maintaining high yields and excellent stereoselectivity. Furthermore, the method enables the synthesis of derivatives incorporating various drug molecules, such as 2,4-D (4p) and probenecid (4q). However, a limitation of the current system was observed in the construction of aryl-substituted tertiary carbon stereocenters in BCHs, as exemplified by the challenging formation of 4 m. Based on these results, we were prompted to directly synthesize bioisostere derivatives of several pharmaceutically relevant molecules, further highlighting the utility of this method. As a representative example, product 4r, designed as a bioisostere of the known NLRP3 inhibitor II (Fig. 1C), was obtained in 65% yield with 80% ee and 5:1 dr.

Fig. 3. Substrate scope with respect to the synthesis of enantioenriched pyridine-containing BCHs.

Reaction conditions: 4CzIPN (0.005 mmol, 0.05 equiv.), 3 (0.10 mmol, 1.0 equiv.), C1 (0.02 mmol, 0.2 equiv.), CHCl₃ (4.0 mL). Isolated yield.

To further enhance the applicability of this method in drug discovery, product 2a was subjected to direct reduction with DIBAL-H, affording alcohol 5 in 87% yield with excellent retention of enantiomeric excess and diastereomeric ratio (Fig. 4). It should be noted that repeated attempts were made to access 5 via the intramolecular [2 + 2] cycloaddition approach; however, the enantioselectivity was consistently low, underscoring the necessity of the reductive modification strategy. Notably, alcohol 5 reacted efficiently with carboxylic acid-containing pharmaceuticals such as indomethacin and bezafibrate under EDCI/HOBT activation, yielding the corresponding adducts 6 and 7 in satisfactory yields and with preserved enantiopurity. Furthermore, treatment of 5 with DPPA in the presence of DBU afforded the attractive phosphate derivative 8 in 86% yield, with 90% ee and >19:1 dr. Thus, a convenient and cost-effective route for generating novel drug candidates featuring improved solubility has been successfully established. Moreover, compound 2 s, which serves as a bioisostere of the anti-tumor agent III, could be further modified to alkyne 9 in satisfactory yield using TMSCHN₂ and LDA. The synthetically versatile alkyne group enables broader utility, including applications in bioconjugation reactions.

Fig. 4. Chemical transformations of products to access pharmaceutically valuable molecules.

A Modifications of 2a to bioactive molecules; B Modifications of 2 s to bioactive molecules.

We subsequently explored the plausible mechanism of this transformation, focusing on the initiation pathway and the underlying basis for the CPA catalyst to exert enantiocontrol. Indeed, the results summarized in Table 1 (entries 2–6), alongside the comparison of triplet energies and redox potentials of the substrates and photosensitizers, provide compelling evidence for an EnT pathway as the key activation mechanism. Specifically, photosensitizers with triplet energies lower than that of 4CzIPN (entries 2–5) were unable to promote the reaction, consistent with the requirement for exergonic energy transfer. To further validate this hypothesis, the transformation of 1a was tested under standard conditions in the presence of 1.0 equivalent of pyrene or anthracene as an additive (Fig. 5A)³⁷. As expected, no reaction occurred due to quenching by these polycyclic aromatic hydrocarbons, which possess triplet energies lower than that of the substrate. Additionally, when TEMPO was employed as an additive, the reaction was completely suppressed, suggesting the involvement of radical intermediates in the process. Notably, product 2a was obtained when Ir(dF(CF)₃ppy)₂(dtbbpy) was used as the photosensitizer, albeit without enantioselectivity (entry 6, Table 1). Control experiments using this photosensitizer in the absence of CPA C1 (Fig. 5B) still afforded 2a in 90% yield, confirming that the [2 + 2] cycloaddition proceeds efficiently via EnT even without the chiral Brønsted acid catalyst. These results demonstrate that the reaction occurs efficiently when the photosensitizer possesses a sufficiently higher triplet energy than the olefin substrate, allowing the excited triplet-state species to undergo smooth intramolecular [2 + 2] cycloaddition. In contrast, CPA C1 likely plays a modulatory role by slightly lowering the triplet energy of the terminal olefin through ion-pair formation and associated hydrogen-bonding interactions²⁸, thereby facilitating selective activation. Importantly, density functional theory (DFT) calculations further support this catalyst-induced attenuation (Figure. S21 in the Supplementary Information). Consistent with this trend, Stern–Volmer quenching studies and transient UV–vis absorption measurements provide additional experimental evidence (Figs. S5–S8 and S11–S16 in the Supplementary Information). It should be noted that no reaction was observed in the absence of chiral catalyst C1 under standard conditions (entry 10, Table 1). However, the transformation proceeded upon raising the temperature to 25 °C (Table S1). Therefore, the combination of low reaction temperature and the closely matched triplet energy between 4CzIPN and the substrate is crucial for suppressing the racemic background reaction, enabling the chiral Brønsted acid catalyst to effectively participate in the transformation and deliver high enantiocontrol over stereocenter formation.

Fig. 5. Mechanism study.

A Control experiments B Control experiment without C1;C the mechanism.

On the basis of these findings, we propose a plausible mechanism for the intramolecular [2 + 2] photocycloaddition, using 1a as a representative substrate. As depicted in Fig. 5C, association of 1a with the chiral catalyst C1 furnishes ion pair 10, which lowers the triplet energy of the terminal olefin. This lowering is crucial for initiation because it enables efficient energy transfer (EnT) from triplet-excited 4CzIPN to the terminal olefin, generating the triplet intermediate. A subsequent cascade—comprising intramolecular radical addition via intermediate 11, in which the pyridine moiety is positioned away from the 6,6′-substituents of C1 to create an efficient chiral control environment, followed by intersystem crossing (ISC) and radical recombination—then proceeds within the chiral environment imposed by C1, ultimately delivering enantioenriched 2a. By contrast, in the absence of C1, the triplet energy of 4CzIPN is insufficient at low temperature to populate the reactive triplet state of the substrate, and the reaction does not progress.

In summary, the catalytic asymmetric synthesis of 4,5-disubstituted 2-oxabicyclo[2.1.1]hexanes—highly effective bioisosteres of ortho-disubstituted benzenes exhibiting enhanced aqueous solubility—has been successfully developed. The dual catalytic system has proven effective, combining a photosensitizer to generate triplet-state substrates via EnT with a chiral Brønsted acid catalyst that enables enantiocontrol during stereocenter formation via a highly reactive radical-based intramolecular cyclization. A broad range of 2-oxabicyclo[2.1.1]hexanes bearing structurally diverse and pharmaceutically relevant pyridine moieties at the bridgehead positions were obtained in high yields with good to excellent enantioselectivity and diastereoselectivity. The method’s versatility is demonstrated by the facile incorporation of various functional groups, including complex drug molecules, at the stereogenic carbon centers. The protocol’s robustness is demonstrated by its successful application to the highly enantioselective synthesis of pharmaceutically relevant pyridine-based BCHs. Mechanistic studies show that low reaction temperatures and a photosensitizer with a triplet energy level closely matching that of the substrate’s olefin moiety are essential for effective enantiocontrol, representing an important catalytic mode of chiral Brønsted acids in excited-state synthesis. In addition to suppressing racemic background pathways, this methodology provides a practical and efficient approach to accessing diverse enantioenriched drug candidates featuring bioactive pyridine-functionalized bioisosteres of ortho-disubstituted benzenes, which also exhibit enhanced aqueous solubility. This advancement holds significant promise for accelerating innovation in pharmaceutical research and development.

Methods

General experimental procedures of 2

For products 2a-2y: 4CzIPN (0.005 mmol, 0.05 equiv.), 1 (0.10 mmol, 1.0 equiv.), C1 (0.02 mmol, 0.2 equiv.), CHCl₃ (4.0 mL) were sequentially added, degassed three times by the freeze-pump-thaw method. The reaction mixture was stirred under an argon atmosphere at −70 ^oC, then irradiated by a 3 W blue LED (λ = 450 − 455 nm) from a 3.0 cm distance for 72 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (hexane/EtOAc, 10/1‒3/1 ratio) afford product.

General experimental procedures of 4

For products 4a-4r: 4CzIPN (0.005 mmol, 0.05 equiv.), 3 (0.10 mmol, 1.0 equiv.), C1 (0.02 mmol, 0.2 equiv.), CHCl₃ (4.0 mL) were sequentially added, degassed three times by the freeze-pump-thaw method. The reaction mixture was stirred under an argon atmosphere at −70 ^oC, then irradiated by a 3 W blue LED (λ = 450 − 455 nm) from a 3.0 cm distance for 72 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (hexane/EtOAc, 30/1‒10/1 ratio) afford product.

Author contributions

Z.J. conceived and designed the study. D.T. and C.Q. performed the experiments. D.T., C.Q., S.C., B.Y., X.Z. and J.Z. analyzed and interpreted the data. S.C. carried out the DFT calculations. D.T., J.Z., and Z.J. prepared the Supplementary Information. Z.J. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Peer review

Peer review information

Nature Communications thanks Shunxi Dong, liang yi and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Data availability

All data are available from the corresponding author. The authors declare that all data supporting the findings of this study are available in the paper and its Supplementary Information files. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers (CCDC 2496083) (2 g). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-026-71590-x.