Introduction

Owing to their widespread occurrence in natural products and drug molecules, as well as their demonstration of diverse and significant biological activities, such as anticancer, anti-inflammatory, and anti-HIV properties (Fig. 1)1,2,3,4,5,6, 2-substituted 2H-chromenes as core scaffolds have garnered substantial interest from organic chemists and biochemists, and numerous protocols have been established to facilitate their synthesis during the past decades. However, their catalytic asymmetric synthesis, especially for the 2-substituted 2H-chromenes bearing a quaternary carbon stereocenter, remains highly challenging7,8,9,10,11. More importantly, the development of new strategies for constructing such chiral units from commercially available benzofurans via asymmetric single-atom skeletal editing represents an underexplored yet highly promising and urgently needed area of research.

Fig. 1: Selected examples of pharmaceuticals and bioactive compounds based on 2H-chromene scaffolds.
figure 1

Some of representative molecules are listed.

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In recent years, molecular editing has proven to be a very attractive protocol for establishing high-throughput libraries in drug discovery due to its power to modify the scaffold economically during the late-stage modification of pharmaceutical molecules12,13,14,15,16,17,18,19,20,21,22,23,24. Among numerous skeletal editing strategies, ring expansion reactions, especially the one-carbon ring expansion of heteroarenes, have unique applied potency because of their ability to construct a variety of valuable complex molecules from simple precursors. Nevertheless, the utilization of one-carbon ring expansion of these aromatic ring systems is a formidable challenge due to the high energy barriers associated with dearomatization and cleavage of carbon–carbon bonds. Although significant progress on the one-carbon ring expansion of benzofurans25,26,27, indoles28,29,30,31,32,33, benzothiophenes34,35,36 and other typical heteroarenes37,38,39,40,41,42 has been achieved (Fig. 2a), most of them are restricted to dearomative cyclopropanation via metal carbenes by employing diazo compounds or hydrazones as one-carbon reagents, and a catalytic asymmetric version is still struggling with only one successful example28. Very recently, Bi and co-workers illustrated an elegant protocol of Rh-catalyzed asymmetric carbon-atom insertion involving an initial cyclopropanation step to achieve enantiodivergent dearomative skeletal editing of indoles and pyrroles by the use of trifluoromethyl N-triftosylhydrazones as carbene precursors, leading to chiral six-membered N-heterocycles containing a trifluoromethylated quaternary stereocenter with high efficiency and stereoselectivity28. Therefore, the development of novel strategies for asymmetric one-carbon ring expansion reactions of heteroarenes, particularly those involving non-dearomative cyclopropanation, utilizing alkynes as one-carbon reagents, and non-noble metal catalysis, is an underexplored yet highly desirable area (Fig. 2a).

Fig. 2: One-carbon ring expansion reactions of heteroarenes.
figure 2

a One-carbon ring expansion of heteroarenes via metal carbenes. b One-carbon ring expansion of benzofuran for synthesis of 2H-chromene. c This work: asymmetric one-carbon ring expansion of benzofurans via vinyl cations for synthesis of chiral 2H-chromenes.

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On account of their unique carbene-like reactivity, vinyl cations have emerged as an essential reactive intermediate in organic synthesis and have attracted wide attention in recent years43,44. However, relevant examples of asymmetric catalysis have been rarely reported, probably due to the lack of catalytic methods for their generation and their high reactivity once formed45. In the past several years, we disclosed that the vinyl cations could be generated via a facile copper-catalyzed diyne cyclization, allowing the establishment of a series of asymmetric transformations of vinyl cations via a remote control of enantioselectivity46,47,48,49,50,51,52,53,54,55,56,57,58. Nevertheless, intermolecular such asymmetric transformations were still very scarce54,57, and only one example of asymmetric one-carbon ring expansion of N-heterocycles via vinyl cations was limited to the intramolecular protocol49. Inspired by the above results and by our recent progress on ynamide chemistry in N-heterocycle synthesis59,60,61,62,63,64, we envisioned that the vinyl cations generated from diyne cyclization might be intermolecularly trapped by the benzofurans, eventually furnishing the ring-expanded chiral 2H-chromenes. It is notable that there was only one example on the synthesis of 2H-chromene from benzofuran via one-carbon ring expansion to the best of our knowledge, where a multistep synthesis was involved, and its asymmetric synthesis has not been explored yet (Fig. 2b)27. However, realizing this dearomative one-carbon ring expansion in an orderly manner is highly challenging: (i) how to prevent the competing background hydroarylation65,66 and cyclopropanation of the benzofurans67,68,69; (ii) due to the inherent high stability and low reactivity of the aromatic systems, whether the vinyl cation is electrophilic enough to be trapped by the heterocycles; and (iii) how to control the enantioselectivity in the context of the formation of expanded ring. Herein, we report the realization of such an intermolecular enantioselective one-carbon ring expansion reaction via vinyl cations by chiral copper-catalyzed dearomative insertion rather than previous cyclopropanation (Fig. 2c)67,68,69. This strategy enables the practical and atom-economical synthesis of a wide array of valuable chiral 2H-chromenes bearing a quaternary carbon stereocenter in generally good to excellent yields with excellent enantioselectivities (up to 96% ee). Importantly, this protocol not only features an asymmetric one-carbon ring expansion reaction of heteroarenes based on alkynes and an intermolecular asymmetric transformation of vinyl cations in ring expansion, but also represents an example of enantioselective dearomative single-atom skeletal editing of benzofurans.

Results

Screening of reaction conditions

In our initial attempts, the 3-methyl-substituted benzofuran 1a was chosen as the model substrate to react with diyne 2a in the presence of copper(I) catalysts, and the selected results are listed in Table 1 (see the Supplementary Table 1). Of note, the 2,6-dimethylphenyl-substituted N-propargyl ynamide 2a was used to prohibit the background aromatic C–H insertion reaction58. To our delight, the use of typical chiral bisphosphine ligands L1–L2 could afford the desired 2H-chromene derivative 3a in good yields, albeit with low enantioselectivities (Table 1, entries 1 and 2). Subsequently, Tang’s side-armed bisoxazoline (SaBOX) ligands L3–L10 were examined and led to dramatically increased enantioselectivities (Table 1, entries 3–10). Gratifyingly, the use of 9-phenanthrenyl-substituted L10 led to the formation of the expected 2H-chromene 3a in 74% yield with 88% ee (Table 1, entry 10). Next, a survey of several typical solvents failed to give better results (Table 1, entries 11–13). Finally, an apparent temperature influence was observed (Table 1, entries 14 and 15), and the desired 3a was formed in 92% ee by decreasing the reaction temperature to 5 °C (Table 1, entry 15). The use of 15 mol % of catalyst resulted in a significantly increased reaction speed, furnishing 3a in 75% yield with 92% ee (Table 1, entry 16).

Table 1 Optimization of reaction conditions for asymmetric dearomative single-atom skeletal editing of benzofuran 1a with diyne 2aa
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Reaction scope study

Having established the optimized reaction conditions, we then explored the reaction scope of this asymmetric dearomative ring-expansion. As depicted in Fig. 3, various 1,5-diynes 2 with different typical N-protecting groups, including Ts, Mbs, SO2Ph, 4-tBu-C6H4SO2 and Bs groups, were well tolerated, providing the desired chiral pyrrolyl 2H-chromenes 3a–3e bearing a chiral quaternary carbon stereocenter in 70–96% yields with 87–92% ees. In addition, different aryl-substituted diynes (R1 = Ar) bearing both electron-withdrawing and -donating groups on the benzene ring were suitable substrates to afford the corresponding products 3f–3k in moderate to good yields with 80–92% ees. Notably, the ynamide 2k bearing a single methyl group at the phenyl ring was also compatible in this dearomative insertion, with less than 10% of C–H insertion byproduct58. Moreover, a wide array of mono-substituted aryl of N-propargyl ynamides (R2 = Ar) were found to be suitable substrates, delivering the target products from 3l to 3p in good yields (50–71%) with 91–96% ees. The reaction of 4-MeC6H4-substituted diyne afforded the desired product 3q in 46% yield with 90% ee, but attempts to extend the reaction to the diynes with non-electron-rich aromatic groups only led to a trace of the desired 2H-chromenes (see the Supplementary Fig. 1), which is similar to our previous protocols46,47,48,49,50,51,52,53,54,55,56,57,58. Besides, diynes with disubstituted aryl groups could be readily transformed into the desired products 3r–3t in 64–76% yields with 92–96% ees. Of note, attempts to extend the reaction to CN-substituted diyne substrate 2v under the related conditions only led to the formation of complicated mixtures. When the chiral ligand with opposite configuration was employed, the expected 2H-chromene ent-3a was also obtained smoothly in 68% yield with 93% ee. Encouraged by our previous studies on chiral copper-catalyzed atroposelective annulation47,48,52,53, the reaction of sterically hindered diyne 2u under optimized conditions could lead to the desired atropisomer 3u containing central chirality in 90% yield with 90% ee and 13:1 dr. It is notable that due to the steric hindrance of the naphthyl group, compound 3u is actually very stable and does not rotate at room temperature, which is similar to our previously reported protocol53. The absolute configuration of product 3 s was confirmed by X-ray diffraction analysis (see the Supplementary Fig. 5). Thus, this strategy provides an efficient and practical route for the construction of valuable chiral 2H-chromenes.

Fig. 3: Reaction of benzofuran 1a with different N-propargyl ynamides 2.
figure 3

Reaction conditions: 1a (0.3 mmol), 2 (0.1 mmol), CuOAc (0.015 mmol), NaBArF4 (0.018 mmol), L10 (0.018 mmol), toluene (2 mL), 5 °C, 36–130 h, in vials; yields were those for the isolated products; ees were determined by HPLC analysis. aEnt-L10 was used instead of L10. b(S)-BINAP was used instead of L10, − 20 °C. PG = protecting group, Mbs = 4-methoxybenzenesulfonyl, Bs = 4-bromobenzenesulfonyl.

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Motivated by the above results, this skeleton editing reaction was also extended to other C3-substituted benzofurans, as outlined in Fig. 4. Under the optimized reaction conditions, the reaction of 3-ethyl and 3-phenyl substituted benzofurans proceeded smoothly to generate the expected products 3aa (61%, 93% ee) and 3ab (52%, 87% ee), respectively. In particular, this one-carbon ring expansion reaction could be applied to a wide range of diverse benzofurans with electron-donating and -withdrawing substituents, and even bearing substituents at sterically hindered positions, delivering the desired chiral 2H-chromenes 3ac–3an in moderate to good yields with generally excellent enantioselectivities (83–95% ees). Of note, it was shown that the positions of substituents have no significant effect on the reactivity and stereoselectivity. Interestingly, the benzofuran with an unprotected hydroxy group at the C5 position was also a viable substrate, affording the target product 3ae in 44% yield with 93% ee. In addition, it was found that the 5,6-dimethyl substituted benzofuran was also tolerated, and transformed into the expected 3ao in 84% yield with 85% ee. To get further insight into the potential pharmaceutical utility of this skeletal editing insertion, various benzofuran derivatives from complex scaffolds, such as anti-inflammatory or antifungal drugs and natural perfume molecules, were tested, generating the corresponding products 3ap–3as in 36–55% yields with high enantioselectivities, which might find potential applications in medicinal chemistry. It is notable that our attempts to extend this one-carbon ring expansion reaction to CF3-, CN- and NO2-substituted benzofurans 1u–1w only gave a complicated mixture.

Fig. 4: Reaction of N-propargyl ynamide 2a with different benzofurans 1.
figure 4

Reaction conditions: 1 (0.3 mmol), 2a (0.1 mmol), CuOAc (0.015 mmol), NaBArF4 (0.018 mmol), L10 (0.018 mmol), toluene (2 mL), 5 °C, 48 h-13 d, in vials; yields were those for the isolated products; ees were determined by HPLC analysis. des were determined by crude 1H NMR. a0.5 mmol of 1 was used.

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Of note, attempts to expand this chemistry to the 3-methyl-substituted benzothiophene, 2-methyl-substituted benzofuran and unsubstituted benzofuran only resulted in the formation of the corresponding cyclopropanation products (see the Supplementary Fig. 2). In the case of the indole substrates, the reaction also proceeded through the typical cyclopropanation process under the relevant conditions70.

Synthetic applications

To demonstrate the reliability of the present protocol, a preparative scale reaction was first performed (Fig. 5a). When 1 mmol of substrate 2a was used, 2H-chromene 3a was prepared without the erosion of yield and enantiopurity. Motivated by the valuable structural motif of 2H-chromenes, a set of downstream transformations of 3a was then studied. For instance, 3a could be smoothly reduced into valuable chromane 4a in 94% yield with 91% ee and 7:1 dr. In addition, simple Riley oxidation of 3a led to the corresponding aldehyde 4b in 41% yield with 88% ee.

Fig. 5: Synthetic transformations and applications.
figure 5

a Reagents and conditions: (i) H2 (4 atm), AcOH (5 mol %), Pd(OH)2/C (20 mol %), EA:MeOH = 1:1, rt, 24 h; (ii) SeO2 (10 equiv), 1,4-dioxane, 50 °C, 42 h. b Some products 3 with anti-neuroinflammatory activity against BV-2 cells.

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Furthermore, to evaluate the potential biological activity of the newly prepared chiral 2H-chromenes, the anticancer and anti-inflammatory activities of these compounds were investigated (see the Supplementary Tables 2 and 3, the Supplementary Figs. 3 and 4), as shown in Fig. 5b. Particularly, we were pleased to find that chiral 2H-chromene 3ae not only effectively inhibits the proliferation of cancer cell SK-OV-3 (IC50 = 22.31 ± 0.31 μM)71, but also exhibits significant anti-neuroinflammatory activity against BV-2 cells (IC50 = 10.31 ± 0.41 μM)72, suggesting a potential application of these chiral 2H-chromenes in pharmaceutically relevant realm.

Mechanistic investigations

To further understand the reaction mechanism, several control experiments were then conducted. First, the reaction of diyne 2a with benzofuran 1a in the presence of 10 equiv of D2O under standard conditions led to the desired product 3a with 30% deuterium incorporation into one of the α-position of the pyrrole moiety (Fig. 6a). In addition, when [D2]-2a was subjected to the standard conditions and in the presence of 10 equiv of H2O, it was found that only 20% deuterium and 7% deuterium were retained on one of the α-position of the formed pyrrole partner, respectively (Fig. 6b). Moreover, the reaction of 2a with [D]-1a under standard conditions could afford the desired 3a with deuterium atom completely retained (Fig. 6c). Interestingly, the Cu-catalyzed reaction of 2a with 3-methylfuran under the standard or related conditions resulted in the formation of furan ring-opening 1,3-diene product 5, which did not undergo further oxa-6π electrocyclization (Fig. 6d). Finally, we performed several radical control experiments and found that the addition of radical scavengers such as TEMPO (2,2,6,6-tetramethyl-1-piperinedinyloxy), BHT (butylated hydroxytoluene) and DDNU (1,1-diphenylethylene) under standard conditions almost did not affect the reaction, suggesting that the radical pathway is quite unlikely. Thus, these results are well consistent with our previous work on such a copper-catalyzed diyne cyclization46,47,48,49,50,51,52,53,54,55,56,57,58, and the vinyl cation and copper carbene intermediate are presumably involved in this one-carbon ring expansion reaction.

Fig. 6: Control experiments.
figure 6

a Cu-catalyzed reaction of 2a with 1a in the presence of 10 equiv of D2O. b Cu-catalyzed reaction of [D2]-2a with 1a under the standard conditions or in the presence of 10 equiv of H2O. c Cu-catalyzed reaction of 2a with [D]-1a under the standard conditions. d Cu-catalyzed reaction of 2a with 2-methylfuran under the standard conditions.

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Based on the above experimental observations, our previously published results46,47,48,49,50,51,52,53,54,55,56,57,58, and detailed density functional theory (DFT) calculations, the reaction mechanism of the CuI-catalyzed cyclization to form the 2H-chromene 3a is depicted in Fig. 7. Initially, the CuI catalyst, due to its distinct electronic properties, selectively activates the electron-rich C ≡ C bond adjacent to the amide group in N-propargyl ynamide 2a, thereby forming the crucial precursor A. Subsequently, the C ≡ C bond activated by CuI, undergoes an intramolecular electrophilic cyclization with the alkynyl group in precursor A. This step proceeds through the transition state TSA and requires overcoming a free energy barrier of 13.8 kcal/mol to generate the vinyl cation intermediate B. Thereafter, the 3-methyl-substituted benzofuran 1a attacks the vinyl cation intermediate B, surmounting a free energy barrier of 8.8 kcal/mol to form intermediate C, with a release of free energy of 9.7 kcal/mol. Intermediate C then undergoes a back-donation electron transfer, leading to the cleavage of the intramolecular five-membered ring and the formation of 1,3-diene intermediate D, releasing a free energy amounting to 12.3 kcal/mol. We speculate that this ring-opening process, instead of the direct cyclopropanation process, may be attributed to the steric hindrance of the methyl group, as the use of unsubstituted benzofuran only resulted in the formation of the cyclopropanation product (see the Supplementary Fig. 2). In addition, the fused cyclopropane can not be the intermediate on the way to the final product 3a. Of note, a similar 1,3-diene has been isolated as 5 in the case of 3-methylfuran as substrate (Fig. 6d). Subsequently, intermediate D undergoes an aromatization-driven oxa-6π electrocyclization to form intermediate E, with a release of free energy of 16.4 kcal/mol, which is also the enantio-determining step. To our best knowledge, a successful asymmetric oxa-6π electrocyclization reaction remains unrealized73. Finally, formal 1,4-H shift46,47,48,49,50,51,52,53,54,55,56,57,58 and demetallation yield the target product 3a. The entire reaction process is highly exergonic, with a total free energy release of 56.3 kcal/mol, highlighting the significant thermodynamic advantage of this reaction.

Fig. 7: Plausible reaction mechanism.
figure 7

Relative free energies (ΔG, in kcal/mol) of all the transition states and intermediates were computed at the SMD-M06/6-311 + G(d,p)/SDD//SMD-M06/6-31 G(d,p)/Lanl2Dz.

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The origin of the enantioselective synthesis of 3a is also computationally investigated by utilizing the chiral ligand L10 coordinated to the CuI center during the oxa-6π electrocyclization step. As shown in Fig. 8, upon further structural analysis of the two enantio-determining transition states, [CuL10]-R-TSD and [CuL10]-S-TSD, a significant steric repulsion is observed between the substrate and the bulky chiral ligand L10 in [CuL10]-S-TSD, thereby leading to a free energy difference of 4.0 kcal/mol compared to [CuL10]-R-TSD. This finding aligns remarkably well with the experimentally measured enantiomeric excess (ee) value. Consequently, this unique chiral ligand plays a pivotal role in maintaining stereochemistry by remotely controlling the stereoselectivity.

Fig. 8: DFT calculations on the origin of enantioselectivity.
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The geometries, relative free energies (ΔG, in kcal/mol), and key bond lengths (in Å) of the transition states [CuL10]-R-TSD and [CuL10]-S-TSD.

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Discussion

In summary, we disclose an enantioselective dearomative one-carbon ring expansion of benzofurans via copper-catalyzed cyclization of diynes, leading to the practical and atom-economic assembly of an array of valuable 2H-chromenes bearing a quaternary carbon stereocenter in generally good to excellent yields with excellent enantioselectivities. Further synthetic applications and biological tests demonstrate the reliability of the present protocol. Importantly, this protocol not only represents an example of asymmetric one-carbon ring expansion reaction of heteroarenes based on alkynes, but also constitutes an enantioselective dearomative single-atom skeletal editing of benzofurans and a successful asymmetric oxa-6π electrocyclization. Moreover, theoretical calculations are employed to elucidate the reaction mechanism involving non-dearomative cyclopropanation and the origin of enantioselectivity. We envision that these findings will offer a new perspective and further explorations for both one-carbon ring expansion reactions and vinyl cation chemistry, especially those based on asymmetric catalysis.

Methods

General

For 1H, 13C and 19F nuclear magnetic resonance (NMR) spectra of compounds in this manuscript and details of the synthetic procedures, as well as more reaction conditions screening, see Supplementary Information.

General procedure for the synthesis of chiral 2H-chromenes 3

The powered CuOAc (1.9 mg, 0.015 mmol), L10 (15.6 mg, 0.018 mmol) and NaBArF4 (16.0 mg, 0.018 mmol) were introduced into a 10 mL vial. After toluene (1.0 mL) was injected into the vial, the solution was stirred at 35 °C for 2 h. Then, the mixture was cooled to 5 °C, and benzofuran 1 (0.3 mmol) and diyne 2 (0.1 mmol) in toluene (1.0 mL) was introduced into the system. The reaction mixture was stirred at 5 °C, and the progress of the reaction was monitored by TLC. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE/EtOAc = 15:1) to give the desired chiral 2H-chromene derivative 3.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.