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. 2024 Oct 29;15:9307. doi: 10.1038/s41467-024-53767-4

Ligand-controlled regiodivergent arylation of aryl(alkyl)alkynes and asymmetric synthesis of axially chiral 9-alkylidene-9,10-dihydroanthracenes

Chao Sun 1, Ting Qi 2, Faiz-Ur Rahman 1, Tamio Hayashi 3,✉, Jialin Ming 1,✉
PMCID: PMC11519556  PMID: 39468097

Abstract

Transition metal-catalyzed addition of organometallics to aryl(alkyl)alkynes has been well known to proceed with the regioselectivity in forming a carbon–carbon bond at the alkyl-substituted carbon (β-addition). Herein, the reverse regiochemistry with high selectivity in giving 1,1-diarylalkenes (α-addition) was realized in the reaction of arylboronic acids with aryl(alkyl)alkynes by use of a rhodium catalyst coordinated with a chiral diene ligand, whereas the arylation of the same alkynes proceeded with the usual regioselectivity (β-addition) in the presence of a rhodium/DM-BINAP catalyst. The regioselectivity can be switched by the choice of ligands on the rhodium catalysts. This reverse regioselectivity also enabled the catalytic asymmetric synthesis of phoenix-like axially chiral alkylidene dihydroanthracenes with high enantioselectivity through an α-addition/1,4-migration/cyclization sequence.

Subject terms: Asymmetric catalysis, Synthetic chemistry methodology, Synthetic chemistry methodology

Transition-metal-catalysed additions of carbon species to aryl(alkyl)alkynes is an established and useful methodology for building towards useful molecular complexity. Here, the authors present rhodium-catalysed regiodivergent additions to aryl(alkyl)alkynes, which allows access to the uncommonly found α-addition products through modulation of the ligand choice.

Introduction

Transition metal-catalyzed addition of organometallics to alkynes is undoubtedly among the most important tools for the synthesis of trisubstituted/tetrasubstituted alkenes1–7. For aryl(alkyl)alkynes, the reaction has been well documented to proceed with the regioselectivity in forming a carbon–carbon bond at the alkyl-substituted carbon (β-addition), and this regiochemistry is supported by both kinetic and thermodynamic factors (Fig. 1a)1–25. Sahoo and his coworkers reported a palladium-catalyzed regioselective 1,2-diarylation of aryl(alkyl)alkynes using acetate as the directing group, in which the addition of arylpalladium species to alkynes proceeded with excellent β-selectivity26–28. On the other hand, the reverse regiochemistry (α-addition) with high selectivity at the addition to aryl(alkyl)alkynes is still a significant challenge and has been rarely reported29–34. All of these previous examples of α-addition based on substrate control, involving electronic property tuning29–31 and directing group strategy (Fig. 1b)32–34. In addition to α-addition of organometallics to alkynes, there are also some other methods to synthesize 1,1-diarylalkenes35–38.

Fig. 1. Regiochemistry at transition metal-catalyzed addition of organometallics to aryl(alkyl)alkynes.

Fig. 1

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a Regiochemistry at addition of organometallics to aryl(alkyl)alkynes. b Previous work of α-addition relying on substrate control. c This work: ligand-controlled regiodivergent rhodium-catalyzed addition to aryl(alkyl)alkynes. d Axially chiral compounds with perpendicular geometry of two pairs of substituents.

Herein, we report a ligand-controlled regiodivergent addition of organometallics to aryl(alkyl)alkynes (Fig. 1c). The reverse regioselectivity in giving 1,1-diarylalkenes (α-addition) was realized in the reaction of arylboronic acids with aryl(alkyl)alkynes by use of a rhodium catalyst coordinated with a chiral diene ligand, whereas the arylation of the same alkynes proceeded with the usual regioselectivity (β-addition) in the presence of a rhodium/DM-BINAP catalyst. The regioselectivity can be completely switched by the choice of ligands on the rhodium catalysts, representing a more convenient and economical method. Density functional theory (DFT) calculations were performed to elucidate the origins of ligand-controlled regiodivergence. This reverse regioselectivity also enabled the catalytic asymmetric synthesis of phoenix-like axially chiral alkylidene dihydroanthracenes with high regio- and enantioselectivity through an α-addition/1,4-migration/cyclization sequence. Axially chiral compounds are widely present in natural products, biologically active molecules, ligands, and catalysts39–43. In the most recent decade, the asymmetric synthesis of axially chiral allenes has received significant research attention (Fig. 1d)44–50. However, asymmetric synthesis of axially chiral alkylidene cycloalkanes has been less developed, and there are mainly by two pathways: asymmetric functionalization of cyclic carbonyl functionalities51–56 and transition metal-catalyzed desymmetrization of functionalized cycloalkanes57–61. In particular, the asymmetric synthesis of axially chiral alkylidene dihydroanthracenes has not been reported to the best of our knowledge. During the review process of our article, a related study, the asymmetric synthesis of alkylidene dihydroanthracenes, was published62.

Results and Discussion

Optimization of reaction conditions

As a first set of experiments, the reaction of phenyl(alkyl)alkyne 1a with 4-MeOC6H4B(OH)2 (2a, 2.0 equiv. to 1a) was performed in the presence of 5.0 mol% of rhodium catalysts bearing several types of bisphosphine and diene ligands and 0.5 equiv. of KOH in toluene/H2O at 100 °C for 12 h (Table 1). The reaction with BINAP as a ligand gave a 95% yield of a mixture of the β-addition product 3aa and α-addition product 4aa in a 91:9 ratio, this β-selectivity being normal and as expected (entry 1). The yields and regioselectivity with SEGPHOS and T-BINAP were similar to those with BINAP for the reaction of 1a (entries 2 and 3). A high yield and excellent β-selectivity (3aa:4aa = >98:2) were obtained with the bulky phosphine ligand DM-BINAP63 (entry 4). The reaction in dioxane/H2O, which is a homogeneous solvent system commonly used for rhodium-catalyzed arylation reactions, also gave 3aa in high yield with excellent β-selectivity (entry 5). A rhodium/diene complex, [RhCl(COD)]2, gave a 95% yield of a mixture of 3aa and 4aa with a ratio of 55:45 (entry 6). The use of a bicyclic diene ligand, Ph-bod, resulted in reverse regioselectivity to give 4aa as the major product (3aa:4aa = 28:72) in a low yield (entry 7). The moderate α-selectivity was also observed with some other diene ligands, L1 and L2 (entries 8 and 9). The diene ligand substituted with a bulky ester group, L3, gave a high yield of 4aa with high α-selectivity (3aa:4aa = 7:93, entry 10). The best result was obtained by use of diene ligand diene*64, which bears a bulkier ester group, for the reaction of 1a giving rise to a 91% yield of 4aa with excellent α-selectivity (3aa:4aa = <2:98, entry 11). The reaction in dioxane/H2O gave 4aa in moderate yield due to a low conversion of 1a (entry 12).

Table 1.

Rh-catalyzed addition to aryl(alkyl)alkyne 1a: evaluation of ligandsa

graphic file with name 41467_2024_53767_Taba_HTML.gif
entry Rh catalyst yield (%)b 3aa + 4aa ratioc of 3aa/4aa
1 [RhCl(COE)2]2 + BINAP 95 91:9
2 [RhCl(COE)2]2 + SEGPHOS 94 88:12
3 [RhCl(COE)2]2 + T-BINAP 95 93:7
4 [RhCl(COE)2]2 + DM-BINAP 95 >98:2
5 d [RhCl(COE)2]2 + DM-BINAP 93 >98:2
6 [RhCl(COD)]2 95 55:45
7 [RhCl(Ph-bod)]2 32 28:72
8 [RhCl(COE)2]2 + L1 76 39:61
9 [RhCl(COE)2]2 + L2 75 35:65
10 [RhCl(COE)2]2 + L3 94 7:93
11 [RhCl(COE)2]2 + diene* 91 <2:98
12 d [RhCl(COE)2]2 + diene* 58 <2:98
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aReaction conditions: 1a (0.10 mmol), 2a (0.20 mmol), [RhCl(COE)2]2 (2.5 mol% dimer, 5.0 mol% Rh), ligand (6.0 mol%), KOH (0.05 mmol), H2O (0.1 mL), and toluene (1.0 mL) at 100 °C (oil bath) for 12 h. COE = cis-cyclooctene. COD = 1,5-cyclooctadiene.

bIsolated yield.

cDetermined by 1H NMR spectra.

dDioxane instead of toluene.

Substrate scope

With the optimized reaction conditions allowing for the reverse regioselectivity (entry 11 in Table 1), we studied the scope and limitations of the α-addition to aryl(alkyl)alkynes in the presence of Rh/diene* catalyst. The results obtained for various substituents on the alkyl group of the phenyl(alkyl)alkynes are summarized in Fig. 2, which also includes the results with the Rh/DM-BINAP catalyst for comparison. α-Addition of 4-methoxyphenylboronic acid (2a) to various propargylmalonates bearing different functional groups, namely benzyl, cyclobutyl, methoxyethyl, acetoxyethyl, and morpholino, at the α-position, proceeded well in the presence of the Rh/diene* catalyst to give the desired products 4ba–4fa in high yields with excellent regioselectivity (3:4 = < 2:98). Alkyne 1 g, bearing a bulky tertiary alkyl, exclusively gave α-addition product 4ga in high yield with excellent α-selectivity. High regioselectivity was also observed in the Rh/diene*-catalyzed α-addition of 2a to various other 1-phenylpropynes, bearing -NHTs (1 h), diethyl phosphonate (1i), silyl (1j and 1k), and t-butyl groups (1 l) at the 3-position. Thus, the α-addition products 4ha–4la were obtained as the main products in high yields. On the other hand, addition to the same alkynes in the presence of the Rh/DM-BINAP catalyst gave the β-addition products 3ba–3la in high yields with excellent usual regioselectivity (3:4 = > 98:2).

Fig. 2. Ligand-controlled Rh-catalyzed regiodivergent addition to phenyl(alkyl)alkynes: scope of the alkyl moietya,b.

Fig. 2

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a Reaction conditions: 1 (0.10 mmol), 2a (0.20 mmol), [RhCl(COE)2]2 (2.5 mol% dimer, 5.0 mol% Rh), ligand (6.0 mol%), KOH (0.05 mmol), H2O (0.1 mL), and toluene (1.0 mL) at 100 °C (oil bath) for 12 h. b Isolated yield. c A trace amount (ca. 5%) of the anti-addition isomer was detected.

Figure 3a summarizes the effects of the aryl group on the alkyne. Using the Rh/diene* catalyst, reversal of regioselectivity was also achieved in the addition of 2a to various aryl(alkyl)alkynes, with the aryl moieties being phenyl rings bearing -OMe, -Cl, -Br, -CO2Me, and -CF3 substituents at the para, meta, or ortho positions, irrespective of the electronic properties of the substituents. Thus, the α-addition products 4B–4 K were obtained in high yields with excellent regioselectivity (3:4 = < 2:98). α-Addition of 2a to heteroaryl(alkyl)alkynes also proceeded smoothly to give the corresponding products 4L–4 N with excellent regioselectivity (3:4 = < 2:98). The Rh-catalyzed α-addition was also successfully accomplished with several other organoboron reagents (Fig. 3b). In the presence of the Rh/diene* catalyst, α-addition to 1a proceeded well for arylboronic acids 2b–2k, in which the aryl groups were phenyl rings bearing -OMe, -Cl, -Br, -SiMe3, -CF3, and -CO2Me substituents at the para or meta positions. The corresponding α-addition products 4ab–4ak were obtained in high yields with excellent regioselectivity (3:4 = < 2:98). In the presence of the Rh/diene* catalyst, α-addition also took place in the reaction of ortho-substituted arylboronic acid 2 l with 1a, albeit in a lower. High yields and excellent regioselectivity towards α-addition products 4am–4ap (3:4 = < 2:98) were also achieved in the reactions of heteroarylboronic acids and cyclopentenylboronic acid with 1a. On the other hand, the use of Rh/DM-BINAP catalyst instead of Rh/diene* gave β-addition products 3B–3 N and 3ab–3ap in high yields with excellent usual regioselectivity (3:4 = > 98:2) for all the reactions shown in Fig. 3.

Fig. 3. Ligand-controlled Rh-catalyzed regiodivergent addition of organoboronic acids to aryl(alkyl)alkynes: substrates scopea–c.

Fig. 3

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a Reaction conditions: 1 (0.10 mmol), 2 (0.20 mmol), [RhCl(COE)2]2 (2.5 mol% dimer, 5.0 mol% Rh), ligand (6.0 mol%), KOH (0.05 mmol), H2O (0.1 mL), and toluene (1.0 mL) at 100 °C (oil bath) for 12 h. b Isolated yield. c rr (regioisomeric ratio) was determined by 1H NMR of the crude reaction mixture. Considering the accuracy of 1H NMR, the ratio of 3:4 is >98:2 using DM-BINAP, while the ratio of 3:4 is <2:98 using diene*. d A trace amount (ca. 5%) of anti-addition isomer was detected.

DFT calculations

To shed light on the origins of ligand-controlled regioselectivity, DFT calculations were performed on the ligand-controlled regiodivergent addition transition states for the Rh-catalyzed arylation of aryl(alkyl)alkyne 1a with 2a (Fig. 4). As illustrated in Fig. 4b, with the involvement of BINAP ligand, the difference of relative Gibbs free energy (ΔΔG) of α-TS1(BINAP) is 3.0 kcal mol–1 higher than that of β-TS1(BINAP), which indicates that β-addition is more favourable than α-addition. While, with the involvement of diene* ligand, the ΔΔG of α-TS1(diene*) is lower than that of β-TS1(diene*) by the 10.6 kcal mol–1 (Fig. 4c). It indicates that the diene* ligand is in favour of α-addition. To better elucidate how ligands affect the inversion of regioselectivity, the independent gradient model based on Hirshfeld partition (IGMH)65 together with atom-in-molecule (AIM)66 analyses were performed to investigate the non-covalent interactions of ligand-controlled α- or β-addition transition states. The δg value at bond critical point (δg(BCP)), Laplacian electron density values (∇2ρ, eÅ–3), and the electron density at the bond critical point (ρBCP) could be useful in quantitatively measuring the strength of the weak interaction. The structure of each transition state is divided into three fragments (Fig. 4a), i.e. L*-Rh (Fragment 1), 4-methoxyphenyl (Ar, Fragment 2), and substrate 1a (Fragment 3). As shown in Fig. 4b, the wider green surfaces among the three fragments, which represent the stronger weak interactions, are observed in β-TS1(BINAP), compared to α-TS1(BINAP). Notably, one more pair of π···π stacking and three more pairs of C–H···C–H interactions exist in β-TS1(BINAP) than in α-TS1(BINAP). Moreover, the obvious C = O···H hydrogen bonding interaction between the CMe(COOtBu)2 group of the substrate and the Ph group of the catalyst is observed in β-TS1(BINAP), which does not occur in case of α-TS1(BINAP). Thus, the high β-selectivity using BINAP stems from the stronger π···π stacking and favorable C = O···H hydrogen bonding interactions.

Fig. 4. DFT calculations for the origins of ligand-controlled regioselectivity.

Fig. 4

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a The structural models of α- and β-addition transition states. b 3D-optimized structures with the difference of relative Gibbs free energy (ΔΔG, kcal mol–1), IGMH together with AIM analyses of the non-covalent interactions, illustration of the numbers of major weak interaction pairs, and the δg value at bond critical point (BCP) (δg(BCP)) for the involvement of BINAP ligand. c Ditto items for the involvement of diene* ligand. The distances are given in Ångstrom (Å). The isosurface was visualized using VMD with the isovalue of 0.007 and the color scale range is from –0.05 to 0.05 atomic units (a.u.).

As displayed in Fig. 4c, α-TS1(diene*) and β-TS1(diene*) transition states exhibited strong π-σ interactions among the alkyne moiety of the substrate, Ar moiety, and the diene*-Rh moiety of the catalyst and C = O···H hydrogen-bonding interactions between the CO2R (R = 2,6-iPr2C6H3) group of the catalyst and the C–H moiety of the substrate. However, it’s worth noting that the δg(BCP) of C = O···H interaction in the structure of α-TS1(diene*) is 0.0347 higher than that of in the β-TS1(diene*) (0.0315). Based on the electron density at the bond critical point (ρBCP), the predicted binding energies of C = O···H interactions are 3.1 and 2.8 kcal mol–1, respectively. These were implied the strength of the C = O···H interaction in the α-TS1(diene*) is notably stronger than that in β-TS1(diene*). Moreover, compared with α-TS1(diene*), β-TS1(diene*) also exhibited a clear steric repulsion between the CO2R group of the catalyst and the CMe(COOtBu)2 group of the substrate, resulting in a higher activation energy. The above analysis indicates that the steric repulsion, the hydrogen bonding, and dispersion interactions between the ligand and the substrates were found to collectively contribute to the observed high α-selectivity using the diene* ligand.

Thus, different ligands on the rhodium catalysts enable different weak interactions between the ligands and the reacting partners, which are found to be the key controlling factors for the observed regioselectivity switch. Furthermore, the Rh-catalyzed arylation of 1 l, having a CH2tBu group, was also investigated by using DFT calculations (see Supplementary Fig. 2). The computed results of 1 l are similar to those of 1a. In the arylation of 1 l, the stronger π···π stacking and the more dispersion interactions lead to high β-selectivity in the reaction using BINAP, whereas the C = O···H hydrogen-bonding interaction in the reaction using diene* results in high α-selectivity. It also indicates that the ligand, rather than the substrate, mainly dictates the regioselectivity pattern.

Applications

For the rhodium-catalyzed arylative cyclization of malonate-tethered 1,6-enynes with arylboronic acids, it has been reported that a bicyclo[2.2.1]heptanone derivative or a tetralone derivative is formed depending on the regiochemistry at the aryl-rhodation of alkyne67–72 and the regioselectivity has been controlled mainly by the substituents at the alkyne terminus73. The use of Rh/DM-BINAP catalyst for the reaction of 1,6-enyne 5a, where the substituent at the alkyne terminus is phenyl, gave a high yield of the tetralone 6 (Fig. 5a). The formation of 6 through the normal β-addition is not surprising while its exclusive formation and high enantioselectivity with DM-BINAP ligand are remarkable. The reaction with the Rh/diene* catalyst, where the reverse a-addition is expected at the addition to the phenyl-substituted triple bond, proceeded with the reverse regioselectivity to produce bicyclic compound 7 of high % ee (98% ee). The arylative cyclization shown in Fig. 5b73–76 demonstrates another example of the utility of Rh/diene* catalyst. The perfect reverse regioselectivity at the aryl-rhodation step realized the catalytic asymmetric transformation of 1,6-enyne 5b into 8 in 98% yield with 98% ee. The reaction of alkynyl 1,3-diketone 5c with PhB(OH)2 in the presence of the Rh/(R)-DM-BINAP catalyst produced a 93% yield of compound 9 with excellent β-selectivity through an addition/1,4-Rh migration/cyclization sequence (Fig. 5c)69–72,77,78. By contrast, the use of Rh/diene* catalyst instead of Rh/DM-BINAP gave a 93% yield of tetrasubstituted alkene 10c, in which the acetyl group 1,3-migrates from the alkyl carbon to the alkenyl carbon. The proposed mechanism involves arylative cyclization of 5c with excellent α-selectivity giving a cyclobutanol intermediate79,80, followed by ring opening via a retro-aldol reaction81–84. Alkynyl cyclic 1,3-diketones 5 d and 5e also underwent the ring-expansion reactions using diene*, giving seven-membered ring 10 d and eight-membered ring 10e in high yields.

Fig. 5. Rh-catalyzed tandem reactions triggered by α-addition.

Fig. 5

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a Rh-catalyzed asymmetric arylative bis-cyclization of 1,6-enyne 5a. b Rh-catalyzed asymmetric arylative cyclization of 1,6-enyne 5b. c Rh-catalyzed regiodivergent addition of phenylboronic acid to alkynyl 1,3-diketones.

The reverse regioselectivity in producing 1,1-diarylalkenes enabled the catalytic asymmetric synthesis of axially chiral alkylidene dihydroanthracenes 12 by use of Rh/diene* catalyst and aryl(alkyl)alkynes 11, which are substituted with electron deficient olefins at the ortho position of the aryl moiety (Fig. 6a). The catalytic cycle consists of three key steps, α-addition of Ar-Rh species to aryl(alkyl)alkyne to generate alkenyl-Rh intermediate, 1,4-migration of Rh from alkenyl to ortho-position of the aryl group85–95, and intramolecular conjugate addition to form alkylidene dihydroanthracene skeleton. Thus, the reactions of aryl(alkyl)alkynes 11a–11 d with PhB(OH)2 in the presence of the Rh/diene* catalyst and KOH (0.5 equiv) in toluene/MeOH at 100 °C produced high yields of alkylidene dihydroanthracenes 12a–12 d with high enantioselectivity (89–92% ee, entries 1–4). Asymmetric synthesis of axially chiral alkylidene dihydroanthracenes 12e–12 h, whose benzene rings are substituted with Me or Cl at the symmetrical positions, were also achieved under the same conditions (entries 5–8). In the reactions giving 12 g and 12 h, 1,4-Rh migration took place exclusively to the sterically less hindered site, para to the substituents (entries 7 and 8). The alkylidene dihydroanthracenes 12i–12q, which possess both central and axial chirality, were also obtained with high enantioselectivity (82–96% ee) and perfect diastereoselectivity ( > 50:1 dr) (entries 9–17). The high diastereoselectivity is reasonable, considering that the arylrhodation of alkyne takes place with high syn selectivity8–10. As expected, both diastereoisomers with opposite central chiralities, (Sa,SC)-12r and (Sa,RC)-12s, were obtained selectively through the corresponding substrate-pair combinations (entries 18 and 19). An allylic ether can be also use as an electrophile at the cyclization (Fig. 6b). Thus, the reaction of arylalkyne 11t, which has 3-methoxy-1-propenyl group at the ortho-position, with arylboronic acids gave axially chiral alkylidene dihydroanthracenes 12t and 12 u bearing a vinyl group at the sp3 carbon (entries 20 and 21). The catalytic cycle may involve addition of the aryl-Rh intermediate, formed by the 1,4-shift, to the olefin of allyl ether followed by β-methoxy elimination. Bromo, cyano, and cyanomethyl substituents at the ortho position also serve as electrophilic acceptors to trap the aryl-Rh intermediates (Fig. 6c). Their reactions in the presence of Rh/diene* catalyst gave high yields of the corresponding cyclization products, alkylidene-fluorene 12 v, anthracenone 12w, and dibenzoannulenone 12x, respectively (entries 22–24).

Fig. 6. Rh-catalyzed arylative cyclization of 1,5-enynes giving alkylidene dihydroanthracenes triggered by α-additiona–d.

Fig. 6

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a Reaction conditions: 11 (0.10 mmol), 2 (0.20 mmol), [RhCl(COE)2]2 (2.5 mol% dimer, 5.0 mol% Rh), diene* (6.0 mol%), KOH (0.05 mmol), MeOH (0.1 mL), and toluene (1.0 mL) at 100 °C (oil bath) for 12 h. b Isolated yield. c The % ee was determined by HPLC on a chiral stationary phase column. d dr (diastereomeric ratio) was determined by 1H NMR of the crude reaction mixture. Considering the accuracy of 1H NMR, the dr is >50:1. e L2 instead of diene*.

The potential synthetic utility of above method is exemplified by synthetic transformations, a large-scale experiment, and displaying the ability of 12 to generate reactive oxygen species (ROS) in Fig. 7. Palladium-catalyzed cross-coupling of 12 m, whose ee value was enhanced by preparative HPLC with Chiralpak IA, with FcB(OH)2 gave the corresponding product 12 y, whose absolute configuration was determined to be (Sa,RC) by X-ray crystallographic analysis (Fig. 7a). Moreover, its coupling with 1-pyrenylboronic acid and phenylacetylene proceeded well to give the corresponding products 12z and 12aa without loss of enantioselectivity. The asymmetric synthesis on the gram scale was carried out successfully to give the target product 12n in 80% yield with 94% ee (Fig. 7b). Furthermore, two ester groups (COOMe) of 12n were then reduced to alcohol using NaBH4, whereas the stable ester group (COOtBu) remained unchanged. To identify the potential applications of these chiral 9-alkylidene-9,10-dihydroanthracenes96–98, the photophysical properties of 12e and 12k were studied by UV-vis and photoluminescence (PL) spectroscopy (Fig. 7c left). The absorption maxima of 12e peaked at 338, 358, 385 and 405 nm, and 12k peaked at 334, 357, 376 and 397 nm, respectively. The maximal emission peaks were located at 441 nm and 433 nm for 12e and 12k, respectively. Subsequently, the reactive oxygen species (ROS) generation abilities of the two luminogens were further investigated under white light irradiation (Fig. 7c right and S1). Their overall ROS generation in CH3CN/PBS (v/v, 1/10) was investigated using a ROS indicator 2′,7′-dichlorodihydrofluorescein (DCFH), which was converted to 2′,7′-dichlorofluorescin (DCF) with green fluorescence after being activated by ROS. The fluorescence emission of DCFH alone varied negligibly under continuous exposure to white light, whereas the PL intensity of DCFH increased swiftly with 12e or 12k, indicating these luminogens can efficiently generate ROS. Thus, compounds 12 are promising candidates as photosensitizers in photodynamic therapy (PDT), which is a modern therapy with non-invasiveness, high specificity, controllable spatio-temporal selectivity, and low side effects, and shows great potential in clinical applications99–102.

Fig. 7. Synthetic applications.

Fig. 7

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a Cross-coupling reactions of 12 m. b Large-scale experiment. c Photophysical properties of 12e and 12k. Left: Normalized absorption spectra (dash line) and PL spectra (solid line) of 12e and 12k in CH3CN solution. Right: ROS generation of 12e and 12k after being irradiated with white light: Relative changes in PL intensity of DCFH in the presence of 12e and 12k (10 μM) in CH3CN/PBS (v/v, 1/10) upon white light irradiation (50 mW cm–2) for different times.

Proposed mechanism and mechanistic studies

Figure 8a illustrates a plausible catalytic cycle for the reaction producing 12a. Of the five steps shown, the syn-α-addition of Ph–Rh A to the triple bond of 11a forming the 1,1-diarylalkenyl-Rh intermediate B is the most important key step realizing the present asymmetric synthesis of alkylidene dihydroanthracenes. Subsequent 1,4-migration of Rh from intermediate B to C makes the location of rhodium ready for the cyclization. Insertion of the olefin into the aryl-Rh bond in C forms α-rhodioester D or rhodium enolate103–107, which undergoes protonolysis giving the product 12a. At the cyclization of aryl-rhodium intermediate C, re-face of the acrylate double bond is attacked by the aryl-rhodium with the chiral ligand diene* to lead to the product 12a with S axial chirality. The results obtained for deuterium labelling studies shown in Fig. 8b and c are consistent with the catalytic cycle. Thus, the reaction with C6D5B(OH)2 gave the product 12a-d5 where the deuterium is incorporated at the alkenyl carbon, demonstrating that the 1,4-rhodium migration is involved in the catalytic cycle. In the reaction of PhB(OD)2 in toluene/D2O, deuterium was found at the α-position to ester, which supports the presence of intermediate D before protonolysis releasing the product.

Fig. 8. Mechanism studies.

Fig. 8

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a A catalytic cycle for the reaction producing 12a. b and c Deuterium labelling experiments.

In summary, we have disclosed that a rhodium-catalyzed addition of arylboronic acids to aryl(alkyl)alkynes proceeds with reversed regioselectivity (α-addition) to produce 1,1-diarylalkenes with high selectivity by use of a chiral diene ligand, whereas the arylation of the same alkynes proceeded with the usual regioselectivity (β-addition) in the presence of a rhodium/DM-BINAP catalyst. The reverse regioselectivity enabled the catalytic asymmetric synthesis of axially chiral alkylidene dihydroanthracenes with high enantioselectivity through the α-addition/1,4-migration/cyclization sequence.

Methods

A typical procedure for Rh-catalyzed arylative cyclization of 1,5-enynes giving alkylidene dihydroanthracenes triggered by α-addition (Fig. 6, entry 1)

An oven-dried Schlenk tube was charged with [RhCl((COE)2]2 (1.80 mg, 2.5 μmol dimer, 5.0 mol% Rh), diene* (2.20 mg, 6.0 μmol, 6.0 mol%), 11a (34.4 mg, 0.10 mmol), phenylboronic acid (2b, 24.4 mg, 0.20 mmol), KOH (2.80 mg, 0.05 mmol), toluene (1.0 mL), and MeOH (0.1 mL) under argon. The tube was placed in a preheated oil bath at 100 °C. The mixture was stirred at 100 °C for 12 h before extracted with ethyl acetate. The organic layers were dried over anhydrous MgSO4, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel to give compound (Sa)-12a (88%, 37.1 mg, 0.088 mmol) as a pale yellow oil. Rf = 0.30 (hexane/ethyl acetate (20/1)).

Supplementary information

Supplementary information (46.1MB, pdf)
41467_2024_53767_MOESM2_ESM.docx (13.2KB, docx)

Description of Additional Supplementary Files

Supplementary Data 1 (43.1KB, xlsx)
Peer Review file (15.3MB, pdf)

Acknowledgements

J.M. is thankful for financial support from the National Natural Science Foundation of China (22261039) and the Program for Innovative Research Team in Universities of Inner Mongolia Autonomous Region (NMGIRT2324). F.R. is thankful for financial support from the Inner Mongolia University China funding under the title Academic Backbone (No. 10000-21311201/092). T.H. thanks the Taiwan Ministry of Education for support through the Yushan Fellow Program. We are also very grateful to Dr. Jianguo Wang and He Meng (both at IMU) for ROS experiments and NMR, respectively.

Author contributions

J.M. and T.H. conceived the idea and guided the project. C.S. performed the experiments and analyzed the data. J.M. directed the part of computational study. T.Q. and F.R. carried out the computational study. J.M. and T.H. wrote the manuscript. All authors approved the submission of the manuscript.

Peer review

Peer review information

Nature Communications thanks Mengchun Ye, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.

Data availability

Detailed experimental procedures, characterization data, NMR spectra of new compounds, HPLC spectra for chiral compounds, detailed computational results, X-ray structural analysis, and calculated structures are available within Supplementary Information. Cartesian coordinates of the calculated structures are available from Supplementary Data 1. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2328320 (3I), 2328318 (4ai), 2328317 (4an), 2328319 ((1S,4 R)-7), and 2328316 ((Sa,RC)-12y). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/ data_request/cif. Data supporting the findings of this manuscript are also available from the corresponding authors upon request.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Tamio Hayashi, Email: hayashi@ntnu.edu.tw.

Jialin Ming, Email: mingjialin@imu.edu.cn.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-024-53767-4.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary information (46.1MB, pdf)
41467_2024_53767_MOESM2_ESM.docx (13.2KB, docx)

Description of Additional Supplementary Files

Supplementary Data 1 (43.1KB, xlsx)
Peer Review file (15.3MB, pdf)

Data Availability Statement

Detailed experimental procedures, characterization data, NMR spectra of new compounds, HPLC spectra for chiral compounds, detailed computational results, X-ray structural analysis, and calculated structures are available within Supplementary Information. Cartesian coordinates of the calculated structures are available from Supplementary Data 1. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2328320 (3I), 2328318 (4ai), 2328317 (4an), 2328319 ((1S,4 R)-7), and 2328316 ((Sa,RC)-12y). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/ data_request/cif. Data supporting the findings of this manuscript are also available from the corresponding authors upon request.

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