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Phase-transfer-catalyst enabled enantioselective C–N coupling to access chiral boron-stereogenic BODIPYs

Abstract

Tetracoordinate boron-based fluorescent materials have shown extensively applications in chemistry, biology and materials science owing to their unique optoelectronic properties. However, constructing chiral boron-stereogenic fluorophores through practical and universal strategies remains rare and challenging. Herein, as a proof of concept, we report an enantioselective postfunctionalization of boron dipyrromethene dyes (BODIPYs), to acess boron-stereogenic BODIPYs in moderate to good yields with commendable enantioselectivity. Chiral BODIPYs have attracted increasing attention owing to not only their distinctively photophysical properties and applications in circularly polarized luminescence (CPL) materials, but also diversely structural modification. In this·work, we present a phase-transfer-catalyst enabled enantioselective C–N coupling reaction of BODIPYs with diverse nucleophiles. This method serves as a practical SNAr (nucleophilic aromatic substitution reaction) route to achieve a series of boron-stereogenic amido/amino BODIPYs as well as demonstrates their promising CD and·CPL·activities, excellent biocompatibility, and high specificities, showing potential applications as chiral fluorescent imaging agents.

Introduction

Boron-containing compounds are widely used as dyes in medicinal research and materials science. Boron dipyrromethene dyes (BODIPYs), as a family of representative tetracoordinate boron molecules, have grown as one of the most popular organic fluorophores during the past few decades, owing to their excellent photophysical properties, including high photostability, molar absorption coefficients, and fluorescence quantum yields1,2,3,4,5. Furthermore, their abundant reaction sites provide diverse structural modification to achieve distinctly photophysical properties6,7,8,9,10,11. Among them, the construction of chiral BODIPYs attracts particular attention because of the great potential of circularly polarized luminescence (CPL) in optical displays12,13,14,15, information storage and processing16,17, and bioprobes18,19. Recently, couple of chiral BODIPYs were exploited by synthetic chemists, while most of them relied on resolution by HPLC or asymmetric synthesis induced by chiral substrates (Fig. 1a)20,21,22,23,24,25,26,27,28,29,30. Asymmetric catalysis has been regarded as one of the most efficient strategies for the construction of chiral compounds31,32,33,34,35, while introducing asymmetric catalysis to achieve chiral BODIPYs remains rare. Considering the excellent atom economy, generality, and efficiency, it is highly desirable to access chiral BODIPYs via asymmetric catalysis as a versatile tool.

Fig. 1: The representative examples and strategies for the construction of chiral boron-stereogenic BODIPYs.

figure 1

a Representative examples of boron-stereogenic BODIPYs. b Current strategies and challenges to synthesize boron-stereogenic BODIPYs. c Representative examples of enantioselective SNAr reactions. d Our approach to achieve boron-stereogenic amido/amino BODIPYs.

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The Pioneering work was disclosed through palladium-catalyzed enantioselective intramolecular C–H arylation in 202336. Very recently, an intermolecular Suzuki coupling reaction was developed, exhibiting excellent functional group tolerance as well as stereoselectivity37. Remarkably, an enantioselective carbene insertion with rhodium catalyst was doable to construct both axial and boron-stereogenic chirality38. Despite great success achieved, significant challenges are remained to be conquered. Firstly, all these examples were limited in C–C coupling, whereas the construction of C–X bonds remained unknown (After submission of this manuscript, Zhang, He et al. reported a Pd-catalyzed enantioselective C–N coupling of α,α-dichloro BODIPYs39). Furthermore, the usage of Pd/Rh catalysts might narrow the potential applications as imaging probes, as the residual transition metals probably caused bio-toxicity in vivo40.

Actually, BODIPY scaffolds have shown diverse reactivities, offering sufficient candidates for the organo-catalysis in the absence of transition metals. For instance, the β-position often exhibits electron-rich property, which might react with electrophiles through electrophilic aromatic substitution (SEAr)41,42,43. Another delicate pathway involves in nucleophilic aromatic substitution (SNAr) at the α-position of BODIPYs, representing facile reactivity under mild conditions (Fig. 1b)44,45,46,47.

In the past decades, a variety of phase-transfer-catalysts (PTCs) enabled enantioselective nucleophilic substitutions were disclosed, constructing point, axial, and planar chirality48,49,50. Thus, we considered it would be great to access chiral BODIPYs through PTC-enabled enantioselective SNAr reactions. Furthermore, most of the current enantioselective SNAr reactions employed 1,3-dicarbonyl compounds51,52,53, phenols54,55, and thiophenols56,57,58 as the nucleophiles, leading to the exploitation of novel nucleophiles in SNAr being urgent to enrich C–X coupling (Fig. 1c).

In this work, we develop a chiral PTC-enabled enantioselective α-amidation/amination of BODIPYs through SNAr with diverse nitrogen nucleophiles. This strategy represents an efficient route to achieve a series of boron-stereogenic amido/amino BODIPYs under mild conditions. Moreover, the amide group as a weak nucleophile might bring up new opportunities in enantioselective SNAr reactions (Fig. 1d).

Results

Reaction design and optimization

Initially, we started from α,α-dichloro BODIPY (1a) and benzamide (2a) to explore the PTC enabled enantioselective α-amidation of BODIPYs. PTC 1 was employed as the catalyst in the presence of Cs2CO3 (2.0 equiv.) in dichloromethane (DCM, 0.6 mL) at 30 °C. To our delight, 33% yield and 55% ee of desired product was obtained at the initial attempt (Table 1, entry 1). Different solvents were screened, and 1,4-dioxane was proven to be the best solvent, providing 3aa in 63% yield with 72% ee (Table 1, entries 2–4). Interestingly, when dimethyl formamide (DMF) was employed as a polar solvent, the stereoselectivity dramatically decreased to 33% ee with opposite configuration (Table 1, entry 4). Then we tested different PTC catalysts. Chiral PTC catalyst bearing a phenyl group (PTC 2) reacted smoothly, providing 3aa in 61% yield with 87% ee (Table 1, entry 5). Different aryl groups were then installed to the PTC catalysts, and all these catalysts offered 3aa in good selectivity (Table 1, entries 6–8). Notably, when we employed PTC 6 with a -OMe group at the 6-position of quinoline moiety as the catalyst, the desired product 3aa was obtained in 84% yield with 89% ee (Table 1, entry 9). Though PTC 7 and PTC 8 showed similar catalytic performance, we selected PTC 6 to pursue the optimization since it was a commercial catalyst (Table 1, entries 10 and 11). As solvent often played an important role in phase-transfer catalysis, we added DCM as cosolvent in this protocol (Table 1, entries 12–15). To our delight, 3aa was formed in 83% yield with 96% ee when we used a mixed solvent of 1,4-dioxane and DCM (0.7: 0.3 mL) at 30 °C (Table 1, entry 14). Different bases were evaluated as well, and a 74% yield with 90% ee of 3aa was obtained when we employed KOtBu as the base (Table 1, entry 17). Similar enantioselectivity was observed when DBU (1,8-diazabicyclo [5.4.0]undec-7-ene) was used as the base, while the yield decreased dramatically (Table 1, entry 18). Unfortunately, we did not observe any desired product in the presence of either Na2CO3 or Et3N as well as in the absence of base (Table 1, entries 16, 19, and 20). Lowering the reaction temperature to 0 °C improved the enantioselectivity to 97% ee, while the yield dramatically decreased to 42% (Table 1, entry 21). Surprisingly, no desired product was obtained in the absence of the catalyst, exhibiting significant role of PTC in reactivity (Table 1, entry 22). It was worth noting that we did not observe any di-amido BODIPYs during the optimization, which might due to the electron-donating property of amido group likely lowered the electrophilicity of the mono-substituted product and disfavored further substitution.

Table 1 The optimization of PTC enabled enantioselective amidation through SNAra

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Substrate scope

With optimal conditions in hand, we then examined different amides to evaluate the generality of our method. As shown in Fig. 2, amides bearing both electron-donating and withdrawing groups reacted smoothly, producing the corresponding products in 66–91% yields with 79–99.5% ee (Fig. 2). Interestingly, 4-aminobenzamide 2b was compatible to provide the desired product 3ba in 78% yield with 93% ee, showing excellent chemo- and enantioselectivity (Fig. 2, 3ba). Electron-donating groups, such as -OMe and -Me groups were tested as well, and the corresponding products 3ca and 3da were isolated in 75 and 83% yields with 96 and 90% ee, respectively. Amides 2e and 2 f with F and Br atoms at the para-position were feasible, offering the desired products in 76 and 79% yields with 97 and 94% ee (3ea and 3fa). Electron-deficient groups substituted at the para-position were examined, and the corresponding products were obtained in 77 and 74% yields with excellent selectivity (3ga and 3ha). Compound 3ia bearing a -OMe group at the meta-position was produced smoothly in 81% yield with 93% ee, and the absolute R-configuration of 3ia was confirmed by X-ray crystallography. Amide 2j was also compatible to afford 3ja in 79% yield with 94% ee. It is gratifying that 2-aminobenzamide 2k was converted to the desired product smoothly in 71% yield, whereas the selectivity decreased to 79% ee (3ka). Not only that, different substituents, including -OMe, -Me, -Br, -I, and -CF3 groups, substituted at the ortho-position were assessed, and the corresponding products were isolated in 86–91% yields with 91–97% ee (3la–3pa). Interestingly, 2-naphthylamide was tolerant as well, producing the desired 3qa in 90% yield with 93% ee. It is worthy to note that heteroaryl amides worked well, obtaining the corresponding products in 77, 76, and 71% yields with 90, 98 and 99.5% ee, respectively (3ra, 3sa, and 3ta). Remarkably, when acetamide and isobutyl amide were employed as the nucleophiles, the corresponding products 3ua and 3va were formed in 66 and 73% yields with 95 and 92% ee, respectively. To our delight, this protocol could be applied to late-stage transformation of drugs, installing levetiracetam to the α-position of BODIPY in 82% yield with 93% de (3wa). We then evaluated different nitrogen nucleophiles under modified conditions by modifying the solvent ratio. Different nucleophiles, including carbamate, urea, and sulfoximine were compatible, and the desired products were isolated in 37, 83, 77, and 39% yields with 96, 99.5, 94, and 99% ee, respectively (3xa, 3ya, 3za, and 3zaa). The promising results inspired us to further investigate amines as the nucleophiles. Unfortunately, both aniline 2zb and 4-chloroaniline 2zc only gave the desired products 3zba and 3zca in moderate yields (56 and 30% yields) with very poor selectivity (0 and 10% ee), respectively. Remarkably, anilines bearing strong electron-withdrawing groups reacted smoothly, producing the corresponding products 3zda–3zga in 53, 50, 65, and 61% yields with 96, 88, 92, and 96% ee, respectively. It was worthy to note that BODIPY dimer (3zha) was obtained in 81% yield with 95% ee when we employed α-amino BODIPY (2zh) as the nucleophile, representing an efficient route to access boron-stereogenic BODIPY dimers. When alkyl amine 2zi was utilized in this method, only racemic product (3zia) was obtained in 71% yield.

Fig. 2: The substrate scope of nucleophiles (2) for the PTC enabled enantioselective C–N coupling through SNAr.a.

figure 2

aReaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2 (0.11 mmol, 1.1 equiv.), PTC 6 (0.01 mmol, 10 mol%), Cs2CO3 (0.2 mmol, 2.0 equiv.), 1,4-dioxane: DCM (1.4: 0.6 mL), 30 °C, N2, 10 h. Isolated yield. b1,4-dioxane: DCM (1.0: 1.0 mL).

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Then, we turned our attention to examine the scope of BODIPYs (Fig. 3). Substrate 1b bearing a -Me group at the para-position of benzene ring attaching to the boron center reacted smoothly, affording the corresponding product in 78% yield with 90% ee (3ab). A halogen atom or -CN group installed at the same position were also feasible, and the desired products were obtained in 81 or 77% yield with 91% ee (3ac and 3ad). Not only para-position, functional groups (-OMe, -Me, -Br, and -CN) substituted at the meta-position were compatible to provide the corresponding products (3ae, 3af, 3ag, and 3ah) in good yields with excellent selectivity (82, 71, 70, and 78% yields with 91, 92, 90, and 89% ee, respectively). It is worth noting that the naphthyl group on the boron center was tolerant to produce 3ai in 72% yield with 90% ee. Interestingly, 1j could be applied to our method, forming the corresponding product in 73% yield with 94% ee (3aj). Moreover, 1k was selected as the representative, exhibiting structural diversity at the meso-position of BODIPY (3ak, 76% yield with 93% ee).

Fig. 3: The substrate scope of BODIPYs (1) for the PTC enabled enantioselective amidation through SNAr.a.

figure 3

aReaction conditions: 1 (0.1 mmol, 1.0 equiv.), 2a (0.11 mmol, 1.1 equiv.), PTC 6 (0.01 mmol, 10 mol%), Cs2CO3 (0.2 mmol, 2.0 equiv.), 1,4-dioxane: DCM (1.4: 0.6 mL), 30 °C, N2, 10 h. Isolated yield.

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Synthetic application and mechanistic studies

A 1.0 mmol scale experiment was conducted, and the desired 3aa was obtained in 81% yield with 96% ee (Fig. 4a). Compound 3aa was then selected as the representative to explore the transformations of these chiral BODIPYs. Firstly, nucleophilic substitutions were achieved by using phenol and dimethyl malonate as the nucleophiles, affording 4 and 5 in 51 and 57% yields with 93 and 92% ee, respectively. Compound 6 was also obtained in 79% yield with 98% ee through Suzuki coupling reaction. Not only aryl group, but also alkenyl group was installed at the α-position of chiral amido BODIPY, forming the desired product (7) in 54% yield with 94% ee, respectively (Fig. 4b).

Fig. 4: Representative transformations of BODIPY 3aa and the proposed asymmetric induction model.

figure 4

a Half-gram scale experiment of 1a and 2a. b Representative Transformations of 3aa. c Control experiments with different catalysts. d Postulated asymmetric induction model.

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To get insight of the asymmetric induction model, we conducted couple of control experiments. Firstly, quinine was employed as the catalyst to evaluate the role of the ammonium group, leading to dramatical decrease in both reactivity and enantioselectivity (Fig. 4c). In contrast, when the hydroxyl group of PTC 6 was substituted with an acetyl group (Cat 2), the desired product was obtained in 77% yield with 89% ee under identical conditions. These results strongly suggest that the ammonium group is critical for achieving reactivity and stereoselectivity, while the hydroxyl group might be less important towards the reaction.

Finally, a postulated asymmetric induction model was proposed based on the previous literature and our results59, which relied on the hydrogen bond interactions between substrates and phase-transfer-catalyst. We hypothesized the enantioselective SNAr reaction might undergo a SN2 pathway. The amide group and leaving group (Cl-) might interact with the chiral phase-transfer-catalyst through hydrogen bond and ion pair interactions, respectively. When the amide attacked to the α,α-dichloro BODIPY (1a), the phenyl group attached to the boron atom preferred to keeping away from the benzyl group of chiral catalyst due to the steric hindrance. Therefore, TS-1 might be the favored transition state based on the postulated model. Noticeably, the configuration of our product was in line with the proposed asymmetric induction model, implying rationality of our hypothesis (Fig. 4d).

Photophysical properties

Photophysical properties of BODIPYs 3 and their derivatives were investigated in DCM to evaluate potential applications as novel chiral fluorophores (Table 2). In general, most of the selected compounds 3 showed maxima absorption ranged at 523–536 nm and emission ranged at 541–553 nm with moderate yields (0.10–0.57) (Table 2). For instance, the absorption/emission maxima for 3aa and 3sa are 532/549 and 533/548 nm, respectively. Installing a -OPh at the α-position led to 10 and 11 nm red-shifts for 4 in absorption (542 vs 532 nm) and emission spectra (560 vs 549 nm), respectively. Interestingly, compound 5 showed very similar absorption maxima at 533 nm, while the emission maxima red-shifted to 593 nm with a shoulder peak at 545 nm. Notably, 6 and 7 showed obvious red-shifts both in absorption (556 nm for 6 and 570 nm for 7) and emission (597 nm for 6 and 589 nm for 7) (Fig. 5a, b). All these derivatives (4, 5, 6, and 7) showed moderate to excellent fluorescence quantum yields (0.65, 0.25, 0.25, and 0.95, respectively). Then, we studied the photophysical properties of 3sa in different solvents. Nonpolar solvents (hexane, toluene, and THF) showed very similar absorption (532, 535, and 531 nm vs 533 nm) and emission maxima (546, 551, and 547 nm vs 548 nm) with DCM. A slight blue shift of absorption was observed in CH3CN (527 nm), whereas the emission maxima showed a slight red shift (545 nm). Interestingly, obvious blue-shift in absorption and red-shift in emission were observed when DMF was employed as the solvent (508 and 565 nm, respectively) (Fig. 5c, d). The observed changes in DMF can be attributed to the disruption of intramolecular hydrogen bonding (N–H⋯F) between the amido and BF units. This phenomenon is analogous to the solvatochromic behavior observed in BODIPY-Schiff dyes60, where solvent interactions significantly alter electronic and structural properties.

Table 2 Photophysical properties of selected compounds in DCM

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Fig. 5: Photophysical properties of representative compounds.

figure 5

a Absorption and b fluorescence spectra of representatives in DCM (1.0 × 10−5 M). c Absorption and d fluorescence spectra of 3sa in different solvents (1.0 × 10−5 M). e CD and f CPL spectra of 3sa in toluene (1.0 × 10−5 M).

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Then, R-3sa/S-3sa were employed as representative to investigate the chiral photophysical properties through circular dichroism (CD) and circular polarized luminescence (CPL) spectroscopies. Enantiomers R-3sa/S-3sa showed clearly mirror images as well as Cotton effects both in CD and CPL spectra ranged at about 535 and 570 nm, respectively (Fig. 5e, f). The luminescence dissymmetry factor (glum) values of R-3sa/S-3sa were measured as −5.94 × 10−5 and +1.08 × 10−4, respectively (Fig. S3).

Considering the remarkably photophysical characteristics of our enantiopure BODIPYs, 3ta (strong green emission) and 7 (strong red emission) were selected to evaluate the potential applications of these BODIPYs as fluorescent imaging agents in living cells. Strong green (Fig. 6a) and red emission (Fig. 6d) were observed in the cytoplasm of treated HeLa cells, respectively, indicating effective cell uptake of both 3ta and 7 and their high brightness in cell imaging. Interestingly, the fluorescence signal of 3ta and 7 presented bright pellets, which were similar to LDs. Encouraged by this phenomena, cellular colocation experiments were conducted, and the results indicated that 3ta overlapped well with our previously reported LD-tracker TPAB61 with a Pearson’s correlation coefficient of 0.87 (Fig. 6a–c) and 7 overlapped well with the commercial LD-tracker BODIPY 493/503 with a Pearson’s correlation coefficient of 0.94 (Fig. 6d–f). The corresponding enantiomers S-3ta and S-7 also showed similar imaging behaviors in cells (Fig. S4, SI). Furthermore, cytotoxicities of 3ta and 7 were evaluated by using standard CCK-8 assay under different dye concentrations. To our delight, compounds 3ta and 7 were not cytotoxic even under ultrahigh concentrations (100 μM), and more than 90% HeLa cells remained alive after being incubated for 24 h (Figs. S5 and S6, SI). Importantly, both dyes exhibited no noticeable phototoxic effects on cells during imaging studies. Moreover, under strong light irradiation (light dose above 12 J cm⁻²), no cytotoxicity was observed up to 2 µM for 3ta and 5 µM for 7 (Figs. S7 and S8, SI). These findings demonstrated the excellent biocompatibility and high specificities of these chiral BODIPY derivatives for staining lipid droplet. Taking together with their promising CD and CPL activities, these chiral boron-sereogenic BODIPYs, therefore, may represent a simple and readily accessible scaffold for advancing efficient CPL probes for bioimaging by CPL Laser-Scanning Confocal Microscopy62.

Fig. 6: Fluorescent imaging studies of 3ta and 7.

figure 6

a LD co-localization studies of 3ta (0.5 µM) in HeLa cells. b Intensity profiles within the regions of interests of 3ta and TPAB across HeLa cells, Pearson’s correlation Rr = 0.87 ± 0.01. c Correlation scatter diagram of TPAB and 3ta intensities, Pearson’s correlation Rr = 0.94 ± 0.01; overlap coefficient R = 0.94 ± 0.01. d LD co-localization studies of 7 (0.5 µM) in HeLa cells. e Intensity profiles within the regions of interests of BODIPY 493/503 and 7 across HeLa cells, Pearson’s correlation Rr = 0.94 ± 0.02. f Correlation scatter diagram of BODIPY 493/503 and 7 intensities, Pearson’s correlation Rr = 0.92 ± 0.01; overlap coefficient R = 0.92 ± 0.01. Scale bars = 10 μm. Each experiment was repeated independently with similar results (n = 3).

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Discussion

In summary, we have developed a practical and universal strategy to access boron-stereogenic amido/amino BODIPYs through phase-transfer-catalyst-enabled enantioselective SNAr reaction. With a commercial catalyst, a series of chiral fluorophores were synthesized in moderate to good yields with excellent enantioselectivity. Further transformations of 3aa as well as their photophysical properties, excellent biocompatibility and high specificities of these chiral BODIPYs exhibited great potential to be chiral fluorescent materials. Interestingly, the usage of amides as weak nucleophiles in SNAr reaction might bring up new opportunities to achieve enantioselective C–N bond formation.

Methods

General

The 1H NMR and 13C NMR spectra were acquired over Bruker Avance 400 spectrometers. High-resolution mass spectra (HRMS) were performed on Shimadzu LCMS-9030, using a quadrupole time-of-flight mass spectrometer equipped with an ESI source. Analytical HPLC was performed on Angilent 1260 instrument using Daicel Chiralcel® columns as noted. The UV-Vis absorption spectra were acquired using a Shimadzu UV-2450 spectrophotometer and the fluorescence spectra were acquired with a Edinburgh FS5 spectrometers. Absolute fluorescence quantum yields were determined using a Hamamatsu Quantaurus spectrofluorometer equipped with an integrating sphere. Circular dichroism (CD) spectra were measured on a BioLogic MOS-500 CD Spectrometer. Circularly polarized luminescence (CPL) measurements were performed on an OLIS CPL SOLO spectrometer. The X-ray crystal diffraction data were collected using a Bruker APEX-II CCD diffractometer. The 1H NMR and 13C NMR spectra were processed using MestReNova. The spectral data were processed using Origin 2024b. The microscopy images were analyzed with Image J 1.48. The X-ray crystal diffraction data (cif file) were analyzed using Mercury 3.8, CCDC. HeLa cells were purchased from Cell Bank of Type Culture Collection of Chinese Academy of Sciences. Sheep red blood cells were purchased from SenBeiJia Biological Technology Co., Ltd.

General procedure for the PTC-enabled C–N coupling to access racemic *α-*amido/amino BODIPYs

To a 10 mL of Schlenk tube equipped with a magnetic stirring bar were added substrates 1 (0.05 mmol), 2 (0.06 mmol, 1.2 equiv.), tetrabutylammonium iodide (0.01 mmol, 20 mol%), and Cs2CO3 (0.1 mmol, 2.0 equiv.) under air. The mixture was then evacuated and backfilled with nitrogen for three times. After that, 1,4-dioxane (0.7 mL) and DCM (0.3 mL) were added subsequently. After stirring at 60 °C in an oil bath for 10 h, the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel with petroleum ether/ethyl acetate as the eluent to give the corresponding products 3.

General procedure for the PTC-enabled enantioselective C–N coupling to access boron-stereogenic BODIPYs

To a 10 mL of Schlenk tube equipped with a magnetic stirring bar were added substrates 1 (0.1 mmol), 2 (0.11 mmol, 1.1 equiv.), PTC 6 (0.01 mmol, 10 mol%), and Cs2CO3 (0.2 mmol, 2.0 equiv.) under air. The mixture was then evacuated and backfilled with nitrogen for three times. After that, 1,4-dioxane and DCM (1.4: 0.6 mL or 1.0: 1.0 mL) were added subsequently. After stirring at 30 °C in an oil bath for 10 h, the reaction mixture was cooled to room temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel with petroleum ether/ethyl acetate/DCM as the eluent to give the corresponding products 3.

Data availability

The data that support the findings of this study are available within the article and its Supplementary Information files. All other data are available from the corresponding author upon request. The X-ray crystallographic coordinates for structures 3ia reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2403966 (for 3ia). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

References

Loudet, A. & Burgess, K. BODIPY dyes and their derivatives: syntheses and spectroscopic properties. Chem. Rev. 107, 4891–4932 (2007).

CASPubMedMATHGoogle Scholar

Shi, Z. et al. Bioapplications of small molecule aza-BODIPY: from rational structural design to in vivo investigations. Chem. Soc. Rev. 49, 7533–7567 (2020).

CASPubMedMATHGoogle Scholar

Lu, H., Mack, J., Yang, Y. & Shen, Z. Structural modification strategies for the rational design of red/NIR region BODIPYs. Chem. Soc. Rev. 43, 4778–4823 (2014).

CASPubMedMATHGoogle Scholar

Xiao, X., Tian, W., Imran, M., Cao, H. & Zhao, J. Controlling the triplet states and their application in external stimuli-responsive triplet-triplet-annihilation photon upconversion: from the perspective of excited state photochemistry. Chem. Soc. Rev. 50, 9686–9714 (2021).

CASPubMedGoogle Scholar

Li, K. et al. J-aggregates of meso-[2.2]paracyclophanyl-BODIPY dye for NIR-II imaging. Nat. Commun. 12, 2376 (2021).

ADSCASPubMedPubMed CentralMATHGoogle Scholar

Boens, N., Verbelen, B., Ortiz, M. J., Jiao, L. & Dehaen, W. Synthesis of BODIPY dyes through postfunctionalization of the boron dipyrromethene core. Coord. Chem. Rev. 399, 213024 (2019).

CASGoogle Scholar

Lakshmi, V., Rao, M. R. & Ravikanth, M. Halogenated boron-dipyrromethenes: Synthesis, properties and applications. Org. Biomol. Chem. 13, 2501–2517 (2015).

CASPubMedMATHGoogle Scholar

Sheng, W., Lv, F., Tang, B., Hao, E. & Jiao, L. Toward the most versatile fluorophore: direct functionalization of BODIPY dyes via regioselective C–H bond activation. Chin. Chem. Lett. 30, 1825–1833 (2019).

CASGoogle Scholar

Bañuelos, J. BODIPY dye, the most versatile fluorophore ever? Chem. Rec. 16, 335–348 (2016).

PubMedMATHGoogle Scholar

Mendive-Tapia, L. et al. Spacer-free BODIPY fluorogens in antimicrobial peptides for direct imaging of fungal infection in human tissue. Nat. Commun. 7, 10940 (2016).

ADSCASPubMedPubMed CentralMATHGoogle Scholar

Zhu, H. et al. Synthesis of an ultrasensitive BODIPY-derived fluorescent probe for detecting HOCl in live cells. Nat. Protoc. 13, 2348–2361 (2018).

CASPubMedMATHGoogle Scholar

Schadt, M. Liquid crystal materials and liquid crystal displays. Annu. Rev. Mater. Sci. 27, 305–379 (1997).

ADSCASMATHGoogle Scholar

Liu, Z.-F. et al. Circularly polarized laser emission from homochiral superstructures based on achiral molecules with conformal flexibility. Angew. Chem. Int. Ed. 62, e202214211 (2023).

ADSCASGoogle Scholar

Maeda, C., Nagahata, K., Shirakawa, T. & Ema, T. Azahelicene-fused BODIPY analogs showing circularly polarized luminescence. Angew. Chem. Int. Ed. 59, 7813–7817 (2020).

CASGoogle Scholar

Wang, L.-Y., Liu, Z.-F., Teng, K.-X., Niu, L.-Y. & Yang, Q.-Z. Circularly polarized luminescence from helical N,O-boron-chelated dipyrromethene (BODIPY) derivatives. Chem. Commun. 58, 3807–3810 (2022).

CASGoogle Scholar

Sherson, J. F. et al. Quantum teleportation between light and matter. Nature 443, 557–560 (2006).

ADSCASPubMedMATHGoogle Scholar

Wagenknecht, C. et al. Experimental demonstration of a heralded entanglement source. Nat. Photonics 4, 549–552 (2010).

ADSCASMATHGoogle Scholar

Jorissen, A. & Cerf, C. Asymmetric photoreactions as the origin of biomolecular homochirality: a critical review. Orig. Life Evol. Biosph. 32, 129–142 (2002).

ADSCASPubMedMATHGoogle Scholar

Xu, Y. et al. Helical β-isoindigo-based chromophores with B-O-B bridge: facile synthesis and tunable near-infrared circularly polarized luminescence. Angew. Chem. Int. Ed. 62, e202218023 (2023).

CASGoogle Scholar

Li, X., Zhang, G. & Song, Q. Recent advances in the construction of tetracoordinate boron compounds. Chem. Commun. 59, 3812–3820 (2023).

CASMATHGoogle Scholar

Abdou-Mohamed, A. et al. Stereoselective formation of boron-stereogenic organoboron derivatives. Chem. Soc. Rev. 52, 4381–4391 (2023).

CASPubMedMATHGoogle Scholar

Guo, Y., Zu, B., Chen, C. D. & He, C. Boron-stereogenic compounds: synthetic developments and opportunities. Chin. J. Chem. 42, 2401–2411 (2024).

CASGoogle Scholar

Lu, H., Mack, J., Nyokong, T., Kobayashi, N. & Shen, Z. Optically active BODIPYs. Coord. Chem. Rev. 318, 1–15 (2016).

CASGoogle Scholar

Braun, M. Boron-based enantiomerism. Eur. J. Org. Chem. 27, e202400052 (2024).

CASMATHGoogle Scholar

Sanchez-Carnerero, E. M. et al. Unprecedented induced axial chirality in a molecular BODIPY dye: strongly bisignated electronic circular dichroism in the visible region. Chem. Commun. 49, 11641–11643 (2013).

CASMATHGoogle Scholar

Sánchez-Carnerero, E. M. et al. Circularly polarized luminescence by visible-light absorption in a chiral O-BODIPY dye: Unprecedented design of CPL organic molecules from achiral chromophores. J. Am. Chem. Soc. 136, 3346–3349 (2014).

PubMedPubMed CentralMATHGoogle Scholar

Bruhn, T. et al. Axially chiral BODIPY DYEmers: an apparent exception to the exciton chirality rule. Angew. Chem. Int. Ed. 53, 14592–14595 (2014).

CASMATHGoogle Scholar

Haefele, A., Zedde, C., Retailleau, P., Ulrich, G. & Ziessel, R. Boron asymmetry in a BODIPY derivative. Org. Lett. 12, 1672–1675 (2010).

CASPubMedGoogle Scholar

Ray, C. et al. Dissimilar-at-boron N-BODIPYs: from light-harvesting multichromophoric arrays to CPL-bright chiral-at-boron BODIPYs. Org. Chem. Front. 10, 5834–5842 (2023).

CASMATHGoogle Scholar

Saikawa, M., Nakamura, T., Uchida, J., Yamamura, M. & Nabeshima, T. Synthesis of figure-of-eight helical bisBODIPY macrocycles and their chiroptical properties. Chem. Commun. 52, 10727–10730 (2016).

CASGoogle Scholar

Forbes, K. C. & Jacobsen, E. N. Enantioselective hydrogen-bond-donor catalysis to access diverse stereogenic-at-P(V) compounds. Science 376, 1230–1236 (2022).

ADSCASPubMedPubMed CentralGoogle Scholar

Formica, M. et al. Catalytic enantioselective nucleophilic desymmetrization of phosphonate esters. Nat. Chem. 15, 714–721 (2023).

CASPubMedPubMed CentralMATHGoogle Scholar

Huang, S. et al. Organocatalytic asymmetric deoxygenation of sulfones to access chiral sulfinyl compounds. Nat. Chem. 15, 185–193 (2023).

CASPubMedMATHGoogle Scholar

Deng, T. et al. Organocatalytic asymmetric α-C–H functionalization of alkyl amines. Nat. Catal. 7, 1076–1085 (2024).

CASMATHGoogle Scholar

Han, J. T., Tsuji, N., Zhou, H., Leutzsch, M. & List, B. Organocatalytic asymmetric synthesis of Si-stereogenic silacycles. Nat. Commun. 15, 5846 (2024).

CASPubMedPubMed CentralGoogle Scholar

Zu, B., Guo, Y., Ren, L.-Q., Li, Y. & He, C. Catalytic enantioselective synthesis of boron-stereogenic BODIPYs. Nat. Synth. 2, 564–571 (2023).

ADSCASMATHGoogle Scholar

Ren, L.-Q. et al. Modular enantioselective assembly of multi-substituted boron-stereogenic BODIPYs. Nat. Chem. 17, 83–91 (2025).

ADSCASPubMedMATHGoogle Scholar

Gao, Y. et al. Catalytic enantioselective synthesis of boron-stereogenic and axially chiral BODIPYs via rhodium(II)-catalyzed C–H (hetero) arylation with diazonaphthoquinones and diazoindenines. Angew. Chem. Int. Ed. 64, e202418888 (2024).

Zhan, B., Ren, L.-Q., Zhao, J., Zhang, H., & He, C. Catalytic asymmetric C–N cross-coupling towards boron-stereogenic 3-amino-BODIPYs. Nat. Commun. 16, 438 (2025).

Economidou, M., Mistry, N., Wheelhouse, K. M. P. & Lindsay, D. M. Palladium extraction following metal-catalyzed reactions: Recent advances and applications in the pharmaceutical industry. Org. Process Res. Dev. 27, 1585–1615 (2023).

CASGoogle Scholar

Krumova, K. & Cosa, G. Bodipy dyes with tunable redox potentials and functional groups for further tethering: Preparation, electrochemical, and spectroscopic characterization. J. Am. Chem. Soc. 132, 17560–17569 (2010).

CASPubMedGoogle Scholar

Zhang, W. et al. One-pot synthesis and properties of well-defined butadiynylene-BODIPY oligomers. Chem. Commun. 53, 5318–5321 (2017).

CASMATHGoogle Scholar

Bozdemir, Ö. A., Büyükcakir, O. & Akkaya, E. U. Novel molecular building blocks based on the boradiazaindacene chromophore: Applications in fluorescent metallosupramolecular coordination polymers. Chem. Eur. J. 15, 3830–3838 (2009).

CASPubMedGoogle Scholar

Zhou, X. et al. Highly regioselective α-chlorination of the BODIPY chromophore with copper(II) chloride. Org. Lett. 17, 4632–4635 (2015).

CASPubMedMATHGoogle Scholar

Wang, L. et al. Nucleophilic aromatic substitution (SNAr) as an approach to challenging nitrogen-bridged BODIPY oligomers. Org. Lett. 26, 3026–3031 (2024).

CASPubMedMATHGoogle Scholar

Leen, V., Gonzalvo, V. Z., Deborggraeve, W. M., Boensa, N. & Dehaen, W. Direct functionalization of BODIPY dyes by oxidative nucleophilic hydrogen substitution at the 3- or 3,5-positions. Chem. Commun. 46, 4908–4910 (2010).

CASGoogle Scholar

Baruah, M. et al. A highly potassium-selective ratiometric fluorescent indicator based on BODIPY azacrown ether excitable with visible light. Org. Lett. 7, 4377–4380 (2005).

CASPubMedMATHGoogle Scholar

Patel, N., Sood, R. & Bharatam, P. V. NL2+ Systems as new-generation phase-transfer catalysts. Chem. Rev. 118, 8770–8785 (2018).

CASPubMedMATHGoogle Scholar

Lee, H.-J. & Maruoka, K. Asymmetric phase-transfer catalysis. Nat. Rev. Chem. 8, 851–869 (2024).

CASPubMedGoogle Scholar

Zong, L. & Tan, C.-H. Phase-transfer and ion-pairing catalysis of pentanidiums and bisguanidiniums. Acc. Chem. Res. 50, 842–856 (2017).

CASPubMedMATHGoogle Scholar

Bella, M., Kobbelgaard, S. & Jørgensen, K. A. Organocatalytic regio- and asymmetric C-selective SNAr reactions-stereoselective synthesis of optically active spiro-pyrrolidone-3,3’-oxoindoles. J. Am. Chem. Soc. 127, 3670–3671 (2005).

CASPubMedGoogle Scholar

Shirakawa, S., Koga, K., Tokuda, T., Yamamoto, K. & Maruoka, K. Catalytic asymmetric synthesis of 3,3’-diaryloxindoles as triarylmethanes with a chiral all-carbon quaternary center: Phase-transfer-catalyzed SNAr reaction. Angew. Chem. Int. Ed. 53, 6220–6223 (2014).

CASGoogle Scholar

Ma, T. et al. Pentanidium-catalyzed enantioselective phase-transfer conjugate addition reactions. J. Am. Chem. Soc. 133, 2828–2831 (2011).

CASPubMedMATHGoogle Scholar

Guo, F., Fang, S., He, J., Su, Z. & Wang, T. Enantioselective organocatalytic synthesis of axially chiral aldehyde-containing styrenes via SNAr reaction-guided dynamic kinetic resolution. Nat. Commun. 14, 5050 (2023).

ADSCASPubMedPubMed CentralGoogle Scholar

Ding, Q., Wang, Q., He, H. & Cai, Q. Asymmetric synthesis of (−)-Pterocarine and (−)-Galeon via chiral phase transfer-catalyzed atropselective formation of diarylether cyclophane skeleton. Org. Lett. 19, 1804–1807 (2017).

CASPubMedMATHGoogle Scholar

Fang, S., et al. Cationic foldamer-catalyzed asymmetric synthesis of inherently chiral cages. Angew. Chem. Int. Ed. 63, e202411889 (2024).

Armstrong, R. J. & Smith, M. D. Catalytic enantioselective synthesis of atropisomeric biaryls: a cation-directed nucleophilic aromatic substitution reaction. Angew. Chem. Int. Ed. 53, 12822–12826 (2014).

CASGoogle Scholar

Cardenas, M. M., Toenjes, S. T., Nalbandian, C. J. & Gustafson, J. L. Enantioselective synthesis of pyrrolopyrimidine scaffolds through cation-directed nucleophilic aromatic substitution. Org. Lett. 20, 2037–2041 (2018).

CASPubMedPubMed CentralGoogle Scholar

Martins, E. F. & Pliego, J. R. Jr. Unraveling the mechanism of the cinchoninium ion asymmetric phase-transfer-catalyzed alkylation reaction. ACS Catal. 3, 613–616 (2013).

MATHGoogle Scholar

Filarowski, A. et al. Solvatochromism of BODIPY-schiff dye. J. Phys. Chem. B 119, 2576–2584 (2015).

CASPubMedMATHGoogle Scholar

Guo, X. et al. Engineering BODIPY-based near-infrared nanoparticles with large Stokes shifts and aggregation-induced emission characteristics for organelle specific bioimaging. J. Mater. Chem. B 10, 5612–5623 (2022).

CASPubMedMATHGoogle Scholar

Stachelek, P., Serrano-Buitrago, S., Maroto, B. L., Pal, R. & de la Moya, S. Circularly polarized luminescence bioimaging using chiral BODIPYs: a model scaffold for advancing unprecedented CPL microscopy using small full-organic probes. ACS Appl. Mater. Interfaces 16, 67246–67254 (2024).

CASPubMedGoogle Scholar

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Acknowledgements

We acknowledge the National Natural Science Foundation of China (Grant 22201011 (Z.Y.L.) and 22271002 (L.J.)), Anhui Provincial Natural Science Foundation (2308085J14 (E.H.)), and Start-up fund of Anhui Normal University (114-022304 (Y.H.)) for financial support.

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Authors and Affiliations

Anhui Laboratory of Molecule-Based Materials, School of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui, China

Xue-Qing Zhang, Xiao-Juan Lv, Luying Guo, Juan Ma, Bin Su, Yuefei Hu, Lijuan Jiao, Zhong-Yuan Li & Erhong Hao

Key Laboratory of Functional Molecular Solids of Ministry of Education, Anhui Normal University, Wuhu, Anhui, China

Xue-Qing Zhang, Xiao-Juan Lv, Luying Guo, Juan Ma, Bin Su, Yuefei Hu, Lijuan Jiao, Zhong-Yuan Li & Erhong Hao

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Xue-Qing Zhang

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