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. 2026 Jun 25;17:7978. doi: 10.1038/s41467-026-74663-z

Catalytic Enantioselective Construction of Planar Chiral Heterocyclic [2.2]Paracyclophanes Enabled by Copper-Catalyzed Desymmetric Azide-Alkyne Cycloaddition

Zhuang-Zhuang Li 1,2, Yuan-Mei Feng 1,2, Ke-Feng Zhang 1,2,✉
PMCID: PMC13448697  PMID: 42350408

Abstract

The construction of planar chiral [2.2]paracyclophanes (PCPs) is of great importance due to their intriguing photophysical and optoelectronic properties. However, catalytic asymmetric approaches to access valuable heterocyclic PCPs directly remain underexplored. Herein, we present the enantioselective synthesis of planar chiral triazole-based PCPs via a desymmetrizing copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. A diverse range of functionalized optically enriched heterocyclic PCPs is obtained in a highly enantioselective manner under mild conditions. Moreover, this protocol showcases the versatility and efficiency of applying the desymmetric CuAAC reaction in the successful construction of planar chirality.

Subject terms: Synthetic chemistry methodology, Asymmetric catalysis

Catalytic asymmetric approaches to access valuable heterocyclic [2.2]paracyclophanes directly remain underexplored. Herein, the authors present the enantioselective synthesis of planar chiral triazole-based [2.2]paracyclophanes via a desymmetrizing copper-catalyzed alkyne-azide cycloaddition reaction.

Introduction

[2.2]Paracyclophane (PCP), discovered by Brown and Farthing in 1949, consists of two stacked and strongly interacting benzene rings that are held together by two ethylene bridges1. This distinctive structure has drawn tremendous interest and found widespread applications in material science2–7, polymer chemistry8–15, and asymmetric catalysis16–25. Remarkable progress has been achieved in the regioselective functionalization of PCPs over the past decades26–28. However, the synthesis of enantiopure PCP derivatives is a challenge in synthetic organic chemistry29. In this regard, chiral high-performance liquid chromatography (HPLC) separation or chemical resolution is still the dominant method for obtaining enantiopure PCPs. In recent years, catalytic asymmetric synthetic strategies have been developed to enable the efficient synthesis of optically enriched PCPs via kinetic resolution30–39, desymmetrization40–44 or strained dehydro[2.2]paracyclophane45. Among these strategies, catalytic enantioselective desymmetrization of prochiral or meso-compounds is a promising and powerful approach in asymmetric catalysis and has found great potential for the efficient synthesis of architecturally complex scaffolds46–50. This attractive method utilizes symmetric substrates that are usually easily accessible and provides at least one functionality for downstream diversification. Moreover, the theoretical yield of the desymmetrization reaction is 100%, while the yield of the kinetic resolution process cannot exceed 50%. Despite these elegant advances, the desymmetrizing construction of planar chiral PCPs is limited to selective transformations of aldehyde groups via transition-metal or organocatalysis, thereby restricting their applications. The development of easily accessible substrates and practical asymmetric approaches to access structurally diverse enantioenriched planar chiral PCP derivatives51–54, especially heterocyclic PCPs, remains a highly desirable and appealing goal in organic synthesis. For instance, the triazole and alkyne-based PCP scaffolds were previously demonstrated to exhibit versatile functionalities. They have been utilized not only as ligands55,56, but also as both promising cytostatics57 and circularly polarized luminescence (CPL) emitters (Fig. 1a)58.

Fig. 1. Background and strategies for the construction of planar chiral heterocyclic [2.2]paracyclophanes (PCPs).

Fig. 1

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a Selected PCPs with triazoles and alkynes; b Copper-catalyzed asymmetric azide-alkyne cycloaddition; c Only report in planar chirality: Desymmetric CuAAC of bisalkynylferrocenes; d This work: enantioselective construction of planar chiral heterocyclic PCPs via desymmetric CuAAC.

Catalytic enantioselective copper-catalyzed azide-alkyne cycloadditions (CuAACs) has become a highly powerful tool for generating a library of chiral triazoles59–62. Building upon the foundational contributions from the groups of Finn and Fokin, Zhou, and Topczewski, the asymmetric CuAAC has been extensively developed over the past decades to address the central63–72 and axial stereogenicity73–81. In sharp contrast, the construction of planar chirality via CuAACs is largely lagging behind and rarely explored (Fig. 1b). The only example was reported by Stephenson and co-workers in 2019, who pioneered the induction of planar chirality through a desymmetrization of 1,3-bisalkynyl ferrocenes82. Nevertheless, the reported method is quite limited to a narrow substrate scope. The high enantioselectivity of the reaction is only achieved by a suitable substituent (R = CH2OH) at the C2 position of the ferrocenyl framework, yet still with essentially equal amounts of mono- and bis-cycloaddition products (Fig. 1c). Therefore, there remains an urgent need for practical methodology development to achieve the efficient synthesis of planar chiral triazoles. With our continuous interest in the enantioselective synthesis of planar chiral PCPs via desymmetrization reactions44, we envisioned that the unique 3D structure and high steric of PCP would be a promising solution. However, several difficulties and challenges need to be addressed: (1) The unusual chemical reactivity of the PCP framework poses a challenge to the incorporation of heteroaromatic units in synthetic chemistry83–85. Despite the fact that heterocyclic [2.2]paracyclophanes have been documented since the 1960s, the direct access to their enantiopure forms from easily accessible compounds via asymmetric catalysis remains elusive. (2) A suitable catalytic system needs to be discovered not only to suppress the foreseeable double cycloaddition product, but to achieve precise control of the planar chirality.

Herein, we report a desymmetric CuAAC reaction that enables the catalytic asymmetric synthesis of planar chiral PCP-based triazoles (Fig. 1d). Our approach not only tackles the challenges of CuAAC reaction in the construction of planar chirality but also provides a general and direct route to access enantioenriched heterocyclic PCP compounds.

Results

Reaction design and optimization

To evaluate the feasibility of this desymmetrization reaction, we commenced our study by selecting prochiral pseudo-para PCP 1a, bearing two ethynyl groups, as the model substrate (Table 1. For details, see Tables S1–S4). In the presence of Cu(CH3CN)4PF6 (10 mol%) and indane-fused BOX ligand L1 (10 mol%), the reaction between 1a and benzyl azide 2a afforded the desired monotriazole product 3 successfully, with moderate yield (48%) but excellent enantioselectivity (98%). Encouraged by this promising result, various commercially available BOX-type ligands were further examined. It was disclosed that the two substituents at the bridged carbon atom of the BOX skeleton have a great influence on the yield. Among these, L2 stands out in terms of both yield and enantioselectivity (Table 1, entry 1). In sharp contrast, Indane-fused PHOX ligand L9 resulted in lower yield and enantioselectivity. With L2 as the optimal ligand, we next turned our attention to study the effect of different solvents and bases, with tetrahydrofuran (THF) and Et3N being the best choice (Table 1, entries 2–5). The examination of copper salts, such as CuI, CuBr, and Cu(CH3CN)4BF4, did not give better results (Table 1, entries 6–8). Interestingly, slightly modification of the ratio between Cu(CH3CN)4PF6 (10 mol%) and L2 (12 mol%) improved the yield to 90% (Table 1, entry 9). Control experiment demonstrated the important role of base in this reaction (Table 1, entry 10). Finally, the optimized conditions for constructing planar chiral PCP-based triazole 3 involved treating 1a and 2a in the presence of Cu(CH3CN)4PF6 (10 mol%) and L2 (12 mol%) in THF with Et3N as the base at room temperature for 12 h.

Table 1.

Optimization of the Reaction Conditions[a]

graphic file with name 41467_2026_74663_Taba_HTML.gif
entry Variations from the above Yield[b] ee[c]
1 None 84% 97%
2 DMF 66% 51%
3 CH3CN 60% 88%
4 Toluene 48% 92%
5 DCE 73% 94%
6 CuI 66% 97%
7 CuBr 63% 97%
8 Cu(CH3CN)4BF4 52% 97%
9 L2 (12 mol%) 90% (77%)[d] 98%
10 Without Et3N trace N.D.
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[a]Conditions: 1a (0.1 mmol), 2 (1.2 equiv.), Cu(CH3CN)4PF6 (10 mol%), L2 (10 mol%), Et3N (1.2 equiv.), THF (1.0 mL) at rt (around 25 oC) for 12 h. N.D.: Not Determined.

[b] Yield was determined by 1H-NMR analysis of the crude mixture with CH2Br2 as the internal standard.

[c] ee was determined by HPLC analysis on a chiral stationary phase.

[d] Isolated yield is given in parentheses.

Substrate scope

With the optimized reaction conditions in hand, we investigated the versatility of the enantioselective CuAAC reaction with pseudo-para derivative 1a for the synthesis of planar chiral heterocyclic PCPs (Fig. 2, condition A). A range of structurally different azides was examined first. In general, this desymmetric CuAAC reaction performed satisfactorily with benzyl azides containing electronically diverse substituents at the para and meta positions, affording the corresponding planar chiral PCPs in good yields (58%-79%) and excellent enantioselectivities (92%-99%). It should be noted that the steric hindrance had a negligible influence on the reaction, as ortho-substituted substrate delivered the desired product 13 in 60% yield and 93% ee. Functional groups, including ester, azide, and different halides, were all tolerated, which provides handles for downstream structure modification. In addition, more substituted aryl groups (14-16) were also compatible under the established conditions. We were pleased to find that benzylic azides containing polycyclic aromatic hydrocarbons, such as naphthalene (17) and pyrene (18), could be employed with similar levels of efficiency and enantioselectivity. Benzylic azides with heteroaromatic frameworks, such as pyridine (19, 20) and thiophene (21), were also suitable substrates, giving rise to the corresponding enantioenriched PCPs with good results. In addition to benzylic azides, alkyl azides also reacted successfully, as illustrated with products 22-24, albeit with slightly lower enantioselectivities (88%-92% ee). Of particular note, the reaction with phenyl azide proceeded smoothly with L6 to deliver the expected product 25 in 75% yield and 98% ee, which further expanded the scope and potential application of this methodology.

Fig. 2. Substrate scope of the pseudo-para and pseudo-gem derivatives.

Fig. 2

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Standard condition A for 1a: 1a (0.2 mmol), 2 (1.2 equiv.), Cu(CH3CN)4PF6 (10 mol%), L2 (12 mol%), Et3N (1.2 equiv.), THF (2.0 mL) at 25 oC for 12 h; Standard condition B for 1b: 1b (0.15 mmol), 2 (2.0 equiv.), CuCl (10 mol%), NaBArF (12 mol%), L2 (12 mol%), Et3N (2.0 equiv.), 1,2-dichloroethane (1.5 mL) at 25 oC for 24 h. [a] With ent-L2; [b] 2 (1.5 equiv.) with L6, 15 h.

The robustness and excellent functional-group tolerance of the developed CuAAC reaction prompted us to further examine some complex alkyl azides. For instance, reactions with azides containing a tetraphenylethylene (TPE) group (28) and a boron dipyrromethene (BODIPY) group (29) proceeded well with 57% yield, 98% ee, and 46% yield, 90% ee, respectively. As the TPE and BODIPY groups are known to exhibit promising optical properties and have found wide applications in the field of aggregation-induced emission (AIE), molecules with these two moieties would be particularly interesting candidates in the field of chiral functional materials and AIE. Furthermore, the late-stage functionalization of a complex azide derived from estrone worked smoothly with excellent diastereoselectivity.

We then turned our attention to further assess pseudo-gem-diethynylPCPs 1b. Encouragingly, under slightly modified conditions (For details, see Table S5), a range of enantioenriched pseudo-gem PCPs were afforded with good yields and excellent enantioselectivties, even through the two ethynyl groups were located spatially close (Fig. 2, condition B). The success of the involvement of pseudo-gem substrates further enriched the diversity of PCP-based heterocycles.

Encouraged by the above results, the power of this protocol was further demonstrated in the kinetic resolution of racemic ethynyl [2.2]paracyclophanes (Fig. 3). Satisfyingly, the reaction with racemic ethynyl [2.2]paracyclophanes worked well, including mono- and pseudo-para derivatives. The desired cycloaddition products were obtained with 96% to 98% ee (38, 40), and the remaining ethynyl [2.2]paracyclophane derivatives were recovered with excellent enantioselectivities (1c, 1 d), corresponding to a selectivity factor (s) of up to 460. Under the established reaction conditions, the kinetic resolution between mono-ethynyl [2.2]paracyclophane 1c and 1-(azidomethyl)−4-methylbenzene also proceeded smoothly, albeit with a moderate s value. The configuration of 38 and recovered 1c were determined by comparing the retention time of HPLC peaks and the sign of optical rotation to that reported in the literature45. Those of other substrates and products were assigned by analogy.

Fig. 3. Kinetic resolution of racemic ethynyl [2.2]paracyclophane derivatives.

Fig. 3

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Standard condition: 1 (racemic, 0.10 mmol, 1.0 equiv.), 2 (0.8 equiv.), Cu(CH3CN)4PF6 (10 mol%), L2 (12 mol%), Et3N (0.8 equiv.), 2-Me THF (1.0 mL) at rt (25 oC) for 48 h. Calculated conversion, C = eSM/(eeSM+eePR); selectivity (s) = ln[(1 − C)(1−eeSM)]/ln[(1 − C)(1+eeSM)].

Synthetic applications

With the enantioenriched planar chiral heterocyclic PCPs in hand, several synthetic transformations were then explored to demonstrate their practical utilities (Fig. 4). Benefiting from the remaining terminal alkyne group, a second copper-catalyzed Click reaction with an aryl azide gave rise to the PCP derivative 41 bearing two different triazole frameworks. In addition, Pd-catalyzed alkyne homocoupling and Sonogashira coupling readily afforded the π-extended conjugated systems 42 and 43 in good yields, with the stereoselectivities maintained. Besides, the alkyne group could also be completely reduced by Pd/C-catalyzed hydrogenation, leaving the benzylic group untouched. Moreover, a planar chiral analog of the precursors of mesoionic carbenes 45 could be accessed easily through a sequential hydrogenation/methylation process.

Fig. 4. Synthetic applications. Reaction conditions.

Fig. 4

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a ArN3, CuI, sodium ascorbate, Et3N, CH2Cl2/H2O, TBAB, 80 oC; b PdCl2(PPh3)2, CuI, Et3N/CH2Cl2, RT; c 1-iodopyrene, PdCl2(PPh3)2, CuI, iPr2NH/THF, 90 oC; d Pd/C (10%), H2 (balloon), MeOH, RT; e CH3I; f PdCl2(PPh3)2, CuI, THF/Et3N, 0 oC to RT.

Additionally, considering the interesting (chir)optical properties of both planar chiral PCP skeletons and BODIPY86, the Sonogashira cross-coupling between simple 8-chloroBODIPY and PCP 25 was conducted, leading to meso-[2.2]paracycloalkyne-BODIPY dye 46 in high enantioselectivity. Furthermore, the photophysical properties of 29 and 46 were studied in THF (Fig. 5). The ultraviolet−visible (UV−vis) absorption showed maxima absorption at 501 nm for 29 and at 542 nm for 46 (Fig. 5a). Upon excitation at 365 nm, the fluorescence emission spectra showed peaks at 517 nm and 559 nm, respectively (Fig. 5b). However, these two compounds indicated relatively poor circular polarized luminescence (CPL) performance in THF solution. Previous studies demonstrated that the doping of liquid crystal (LC) can enhance the chiroptical properties of chiral luminescent materials87–89. Inspired by this, two doped LC systems (R)- and (S)-29 were prepared by doping (R)- and (S)-29 into the room temperature nematic LC 4-cyano-4-pentylbiphenyl (5CB). While CPL signals were not detected in the solution state, we were delighted to find that significant CPL signals were observed for the resulting doped LC systems, with luminescence dissymmetry factors (glum) of 0.042 and -0.046 (Fig. 5c, d). Therefore, these easily accessible planar chiral PCP-BODIPY derivatives could be promising candidates in the development of interesting chiral fluorescent materials in the future.

Fig. 5. Photophysical properties of representative compounds.

Fig. 5

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a Absorption and b fluorescence spectra of representatives in THF (around 10-5 M); c CPL spectra of doped LC systems of (S)- and (R)−29; d glum values-wavelength curves of doped LC systems of (S)- and (R)−29.

All in all, these reactions highlight the numerous synthetic potential of the developed method for the construction of structurally diverse planar chiral PCP derivatives, which would find wide applications across different fields.

Mechanistic investigations

Control experiments were then conducted to gain some insights into the reaction mechanism. First, the yields and enantioselectivities of product 3 were tracked over different time (Fig. 6a). It was shown that product 3 was delivered in 34% yield and 48% yield with 94%-95% ee when the reaction was performed in 2 h and 6 h, respectively. In these two cases, no bis-triazole product was detected. 3 was formed in 90% yield and 98% ee under the standard reaction time (12 h), and the bis-triazole product began to appear. Further prolonging the reaction time to 24 h gave rise to a decreased yield of 3, together with more 3-bis product. In addition, the reaction between racemic-3 and azide 2 under the standard conditions was then studied (Fig. 6b). The selectivity factor (s-factor) for this kinetic resolution process is calculated to be 7.7. These results indicate that the desymmetrization step is the key to controlling the enantioselectivity. The effect of the kinetic resolution process on the enantioselectivity improvement is limited in this system. Moreover, a positive nonlinear effect was observed between the ee values of optically active ligand L2 and product 3. This nonlinear effect is inconsistent with a mechanism involving a mononuclear copper catalyst, thereby precluding it as the active species in this CuAAC transformation (For details, see supplementary information Section 5.2)90,91.

Fig. 6. Mechanistic investigations.

Fig. 6

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a Studies on the enantioselectivity control of 3 over time; b Selectivity factor for the kinetic resolution process: s = 7.7. [a] Yield was determined by 1H-NMR analysis of the crude mixture with CH2Br2 as the internal standard.

Discussion

In summary, the enantioselective construction of planar chiral PCP derivatives bearing both terminal alkyne and triazole frameworks has been successfully developed via copper-catalyzed alkyne-azide cycloaddition. This desymmetric method exhibits a broad substrate scope and diverse substitution patterns, yielding a wide range of planar-chiral heterocyclic PCPs with excellent enantioselectivities. Preliminary mechanistic investigations indicated that a sequential enantioselective desymmetrization−kinetic resolution process is involved, with desymmetrization playing a predominant role in enantioselectivity control. Moreover, the synthetic utility of this protocol was demonstrated by downstream transformations of the alkynyl group, thereby further enriching structural diversity. We believe that this methodology not only highlights the potential of desymmetrizing CuAAC chemistry in the construction of planar chirality but also opens innovative avenues for advancing cyclophane chemistry.

Methods

General procedure for the synthesis of planar chiral heterocyclic [2.2]Paracyclophanes with 1a (Condition A)

To a flame-dried 10 mL vial equipped with a magnetic stirrer bar, 1a (0.2 mmol) and alkyl azide 2 (0.24 mmol, if solid) were added sequentially. The vial was then transferred into the glovebox. Chiral bisoxazoline ligand L2 (0.024 mmol) and Cu(CH3CN)4PF6 (0.02 mmol) were added successively. The vial was sealed and removed from the glovebox. Under nitrogen protection, tetrahydrofuran (THF, 2 mL) was added to the reaction mixture, followed by the addition of triethylamine (0.24 mmol) and alkyl azide (0.24 mmol, if liquid). The mixture was stirred at room temperature for approximately 12 hours. After that, the concentrated reaction residue was purified by flash column chromatography on silica gel using petroleum ether/ethyl acetate (5:1, v/v) as the eluent, affording the target product.

General procedure for the synthesis of planar chiral heterocyclic [2.2]Paracyclophanes with 1b (Condition B)

To a flame-dried 10 mL vial equipped with a magnetic stirrer bar, 1b (0.15 mmol) and alkyl azide 2 (0.30 mmol, if solid) were added sequentially. The vial was then transferred into the glovebox. CuCl (10 mol%), NaBArF (12 mol%), and Chiral bisoxazoline ligand L2 (12 mol%) were added successively. The vial was sealed and removed from the glovebox. Under nitrogen protection, 1,2-dichloroethane (1.5 mL) was added to the reaction mixture, followed by the addition of triethylamine (0.3 mmol) and alkyl azide (0.3 mmol, if liquid). The mixture was stirred at room temperature for approximately 24 h. After that, the concentrated reaction residue was purified by flash column chromatography on silica gel using petroleum ether/ethyl acetate (5:1, v/v) as the eluent, affording the target product.

General Procedure for the preparation of liquid crystal systems

Sp-29 (0.002 mmol, 90% ee) and 4-cyano-4-pentylbiphenyl (5CB, 0.2 mmol) were dissolved in DCM (1 mL). The mixture was heated to 40 °C while stirring to evaporate the DCM. After the solvent was evaporated, the resulting liquid crystal (LC) Sp-29-LC was melted to an isotropic state at 50°C and filled into a LC cell with 9 μm thickness (purchased from JCOPTIX, LVE-ECB-9). Rp-29-LC was prepared following a similar procedure with Rp-29 (90% ee).

Supplementary information

Supplementary Information (15.7MB, pdf)
Transparent Peer Review file (261.8KB, pdf)

Acknowledgements

Prof. Erhong Hao (Anhui Normal University) is acknowledged for suggestions and help on the photophysical properties investigation. We thank Prof. Olivier Baudoin (University of Basel), Prof. Jérôme Lacour (University of Geneva), and Prof. Feng Li (Zaozhuang University) for fruitful discussions on this manuscript.

Author contributions

Z.-Z.L. and Y.-M.F. performed the experiments, analyzed experimental data, and prepared the Supplementary Information. K.-F.Z. directed the investigations and prepared the manuscript.

Peer review

Peer review information

Nature Communications thanks Long Li and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Funding

K.-F.Z. discloses support for the research of this work from the Natural Science Foundation of Anhui Province [grant number 2308085QB43], the Independent Research Project of Key Laboratory of Green and Precise Synthetic Chemistry and Applications, Ministry of Education, Huaibei Normal University [grant number KLGPSCA202305], the Natural Science Foundation of Anhui Education Department [grant number 2023AH030076], and the start-up funding from Huaibei Normal University.

Data availability

Data supporting the findings of this study are available in the Supplementary Information or from the corresponding author upon request. The Supplementary Information contains full details on the synthesis and characterization of compounds. CCDC 2489850 (compound 11) and 2491175 (compound 30) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre at http://www.ccdc.cam.ac.uk/data_request/cif.

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.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-026-74663-z.

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Supplementary Materials

Supplementary Information (15.7MB, pdf)
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Data Availability Statement

Data supporting the findings of this study are available in the Supplementary Information or from the corresponding author upon request. The Supplementary Information contains full details on the synthesis and characterization of compounds. CCDC 2489850 (compound 11) and 2491175 (compound 30) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre at http://www.ccdc.cam.ac.uk/data_request/cif.

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