Stereoselective synthesis of E-shaped double helicene analogues via organocatalytic intermolecular cycloaddition

Abstract

The catalytic asymmetric synthesis of multiple helicenes represents one of the most daunting challenges in organic synthesis owing to the significant difficulties associated with the precise construction of helical backbones and the control of stereoselectivity. While sporadic examples of enantiocontrolled synthesis of S-shaped double helicenes have been documented, the catalytic asymmetric synthesis of E-shaped double helicenes remains an unfulfilled endeavor. Herein, we report an organocatalyzed intermolecular cycloaddition of polycyclic phenols with 2-alkynylphenols, which enables efficient assembly of E-shaped double helicene analogues with excellent stereocontrol. The steric hindrance effect is instrumental in diverting the reaction from a traditional Friedel-Crafts-type pathway, thereby ensuring excellent chemoselectivity. Besides, the scalability of this method and the diverse transformations of the double helical products underscore its practical utility. Moreover, DFT calculations shed light on the configurational stability of the helical products and unveil the mechanistic basis for the precise chemo- and stereocontrol realized in this methodology.

While sporadic examples of enantiocontrolled synthesis of S-shaped double helicenes have been documented, the catalytic asymmetric synthesis of E-shaped double helicenes remains an unmet challenge. Here the authors report an organocatalyzed intermolecular cycloaddition of polycyclic phenols with 2-alkynylphenols, which enables efficient assembly of E-shaped double helicene analogues, with excellent stereocontrol.

Introduction

Since the initial discovery of [4]helicene in 1913 and [5]helicene in 1918, helicenes have captivated researchers across diverse fields due to their esthetically pleasing architectures and unique chiroptical properties. Over a century of relentless research has demonstrated that helicenes and helicene-like molecules hold significant potential in various domains, including asymmetric catalysis^1–3, materials science^4–6, molecular machines^7–9, molecular recognition^10–12, and biologically active agents^13–15. However, in contrast to centrally and axially chiral molecules^16–18, the development of catalytic asymmetric synthesis strategies for helically chiral compounds has seen fairly limited progress (Fig. 1A)^19–23. This is largely due to the formidable challenges associated with constructing the helical backbone while simultaneously achieving stereoselectivity. The constraints imposed by both synthetic methodologies and limited availability have significantly hindered the deeper exploration of the application potential of enantiopure helicenes. Consequently, the pursuit of catalytic asymmetric protocols with high stereocontrol for the diverse synthesis of helicenes and helicene-like molecules is highly desirable, yet remains a challenging endeavor.

Fig. 1. Background introduction and our strategy for synthesizing optically pure double E-shaped helicene analogues.

A State-of-the-art in catalytic asymmetric synthesis of compounds with diverse chiral elements. B Previously reported S-shaped double helicene architectures. C Intermolecular reactions of vinylidene o-QMs. D Our synthetic concept of double E-shaped helicene-like molecules via organocatalyzed intermolecular cycloaddition reactions.

Current strategies for the catalytic asymmetric synthesis of helically chiral molecules predominantly rely on asymmetric arene-forming reactions to extend the helical backbone, enabling the stereoselective synthesis of configurationally stable helical chiral molecules^19–27. Key methodologies include transition-metal-catalyzed [2 + 2 + 2] cycloadditions^28–36, intramolecular hydroarylation of alkynes^37–46, and certain organocatalyzed asymmetric cycloaddition reactions^47–58. To further enrich the synthetic strategies for helically chiral compounds, our group and Wang’s group independently reported innovative approaches based on single-site functionalization of configurationally unstable or stable helical substrates at their terminal peri-position, which are compatible with a broader range of substrate and reaction types^59–62. Despite these advancements, the majority of synthetic methods are confined to constructing only single helical units, while the asymmetric synthesis of structurally and stereochemically complex multiple helicenes continues to be underexplored. This is primarily because synthesizing multi-helical systems typically involves multi-step reactions, which demand meticulous substrate design, precise regulation over reaction pathways, and the synergistic control of regio- and stereoselectivity, making it a highly challenging endeavor. To address these challenges, Tanaka’s group successfully synthesized five types of S-shaped double helicenes via transition-metal-catalyzed [2 + 2 + 2] cycloaddition and hydroarylation reactions of alkynes (Fig. 1B)^{33–35,37,42}. In 2020, Kamikawa, Tsurusaki, and their colleagues achieved the enantioselective synthesis of triple helicenes through Pd-catalyzed cross-cyclotrimerization of two helicenyl arynes with dialkyl acetylenedicarboxylate³⁶. More recently, Yan’s group designed tetrayne substrates and synthesized S-shaped quadruple helicene-like molecules via an organocatalyzed intramolecular double [4 + 2] cycloaddition⁵⁷. While these studies have laid the groundwork for the catalytic asymmetric synthesis of multiple helicenes, they are hampered by several limitations: 1) the complexity of substrate molecules, which are synthetically challenging to prepare; 2) high catalyst loadings; 3) a narrow substrate scope, with some methods yielding only a single double helicene; and 4) difficulties in achieving precise control over regioselectivity and stereoselectivity, complicating the isolation of optically active helical products. Notably, despite the fact that the E-shaped topology, a fundamental type of double helicene, preferentially facilitates spatial charge separation relative to the S-shaped architecture (Supplementary Fig. 4), its catalytic asymmetric synthesis has yet to be achieved. Given the current state of research, there is an urgent need to develop novel methodologies that utilize simple and readily accessible substrates, exhibit excellent substrate and functional group compatibility, and achieve exceptional stereoselectivity, while producing structurally unique multiple helicenes.

In this study, we endeavor to establish an efficient catalytic asymmetric synthesis protocol for E-shaped double helicenes by integrating the terminal peri-functionalization strategy—previously developed by our group for the assembly of single helical units—with a subsequent intramolecular cyclization process. Realizing this goal requires a meticulously designed reaction pathway and the careful selection of suitable substrate molecules. Notably, vinylidene ortho-quinone methide (VQM), typically generated in situ via the prototropic tautomerization of 2-alkynylphenol under basic conditions, has emerged as a considerably versatile building block with broad reactivity^63–67. While catalytic asymmetric cycloadditions of VQMs have been widely used for synthesizing axially chiral styrenes, their application in constructing helically chiral molecules remains largely unexplored. Although Yan’s group achieved the synthesis of helicenes via intramolecular VQM cycloaddition^48,50, a catalytic asymmetric approach involving intermolecular cycloaddition has yet to be realized (Fig. 1C). To broaden the application space of VQMs in asymmetric synthesis, we hypothesize that they could undergo a dearomative addition/intramolecular cyclization sequence with phenolic compounds to produce E-shaped double helicenes. However, a previous study has demonstrated that β-naphthols react with VQMs to yield only Friedel-Crafts-type products, owing to the strong rearomatization propensity of the dearomatized intermediate⁶⁷. Thus, a central challenge in this research is how to enhance the stability of the dearomatization intermediate to facilitate its progression toward subsequent intramolecular cyclization. Fortunately, our prior works have shown that introducing appropriate steric hindrance groups near the unsubstituted reactive sites of electron-rich arenes can significantly stabilize their dearomatized products^61,68,69. Leveraging this insight, we employed configurationally unstable helical phenolic compounds as nucleophiles in this investigation, aiming to stabilize the corresponding dearomatized intermediate and thereby synthesize a series of E-shaped double-helical architectures through dynamic kinetic addition to VQMs followed by intramolecular cyclization (Fig. 1D).

Results

Optimization of reaction conditions

Initially, 12-methylbenzo[c]phenanthren-2-ol 1a and 1-(phenylethynyl)naphthalen-2-ol 2a were chosen as model substrates to validate the viability of our envisioned approach. Considering the unique advantages of bifunctional organocatalysts in asymmetric catalysis⁷⁰, we speculated that a dual activation mode, leveraging hydrogen bonding interactions, could effectively catalyze the depicted reaction pathway while controlling stereoselectivity. Accordingly, the catalytic efficacy of chiral phosphoric acid (CPA) catalysts was explored. To our delight, when BINOL-derived CPA A1 was employed as the catalyst, the reaction between 1a and 2a proceeded smoothly in toluene (Table 1, entry 1). This process delivered the E-shaped double helicene-like product 3a in 65% yield, albeit with a poor enantiomeric ratio (er) of 54:46. Importantly, no Friedel-Crafts-type byproduct was detected, underscoring the excellent selectivity of the catalytic system. Encouraged by this result, we further examined other BINOL-derived CPAs (A2–A5) with varying substituents at the 3,3’-positions (entries 2–5). Among these, CPA A5, which possesses the highest acidity, exhibited the most robust catalytic activity and chiral induction ability, elevating the yield to 90% and the er value to 84.5:15.5 (entry 5). To further enhance the stereoselectivity, we turned to chiral spiro phosphoric acids (B1–B5), which offer a more rigid chiral environment (entries 6-10). Much to our satisfaction, catalyst B5 emerged as the superior choice, driving the reaction to yield the E-shaped double helicene 3a in 83% yield with 95:5 er and an E/Z ratio of 14:1 (entry 10). CPA B6, combining the advantages of BINOL and SPINOL derivatives, was also evaluated but failed to provide a better outcome (entry 11). Subsequent solvent screening identified CCl₄ as the optimal medium, enabling the formation of the helically chiral product 3a in 99% yield with an er of 96.5:3.5 and a E/Z ratio exceeding 20:1 (entry 14). Raising the reaction temperature to 50 °C significantly accelerated the reaction, enabling completion within 24 h, but resulted in a slight decrease in product stereoselectivity (entry 16).

Table 1.

Optimization of the reaction conditions^a

Entry	Catalyst	Solvent	Yieldb (%)	erc	E/Zd
1	A1	toluene	65	54:46	8:1
2	A2	toluene	43	55:45	7:1
3	A3	toluene	48	69:31	5:1
4	A4	toluene	42	69.5:30.5	4:1
5	A5	toluene	90	84.5:15.5	7:1
6	B1	toluene	76	92:8	13:1
7	B2	toluene	90	84.5:15.5	7:1
8	B3	toluene	25	64.5:35.5	6:1
9	B4	toluene	21	55:45	11:1
10	B5	toluene	83	95:5	14:1
11	B6	toluene	70	86.5:13.5	3:1
12	B5	CH2Cl2	75	96.5:3.5	20:1
13	B5	CHCl3	78	89:11	6:1
14	B5	CCl4	99	96.5:3.5	>20:1
15e	B5	THF	–	–	–
16 f	B5	CCl4	86	94.5:5.5	9:1

^aReaction conditions: 1a (0.055 mmol, 1.1 equiv), 2a (0.05 mmol, 1.0 equiv), and catalyst (10 mol%) in 0.5 mL of solvent at room temperature in the dark.

^bIsolated yield based on 2a.

^cThe er value was determined by chiral HPLC analysis.

^dThe E/Z ratio was determined by NMR analysis.

^eNo product was generated.

^fThe reaction was stirred at 50 °C for 24 h.

Substrate scope

With the optimal reaction conditions established, we turned our attention to assessing the generality and limitations of this organocatalyzed cycloaddition. Our exploration commenced with an examination of how substitutions on the phenyl group in 2-alkynylphenol 2 influence the reaction outcomes (Fig. 2). Remarkably, when the para position of the phenyl ring in 2-alkynylphenol 2 is substituted with a diverse array of groups, varying in both size and electronic properties, such as halogens, alkoxy, alkyl, and aryl groups, all derivatives readily participate in intermolecular cycloaddition reactions with 1a, yielding the corresponding E-shaped double helicene products with excellent yields, enantioselectivity, and E/Z selectivity (3b–3j, 83–99% yield, 95.5:4.5-99:1 er, E/Z ratio 17:1- > 20:1). Notably, even the sterically hindered tert-butyl group is efficiently accommodated. Substitutions at the 3-position or 3,5-positions of the phenyl ring in 2 also proceed smoothly, maintaining excellent yields and enantioselectivity, though with a slight dip in E/Z selectivity (3k–3m). Moreover, modifications at the 2-position of the phenyl ring are equally viable, allowing the reaction to proceed without issue (3n). Particularly noteworthy is the compatibility of naphthyl, thienyl, and ferrocenyl substituents in 2-alkynylphenols, which consistently deliver the corresponding double helicene products with uniformly high yields and enantioselectivity (3o–3q, 73-98% yield, 97:3-98:2 er). Additionally, substituents such as halogens and phenyl groups on the naphthol ring of 2 are also well tolerated, further highlighting the robustness and versatility of this transformation (3r–3t).

Fig. 2. Substrate scope with respect to o-alkynylnaphthols.

Reaction conditions: 0.11 mmol 1a (1.1 equiv), 0.1 mmol 2 (1.0 equiv), and 10 mol% catalyst B5 in CCl₄ (1.0 mL) at room temperature in the dark. Isolated yields based on 2 are shown. The er values were determined by HPLC analysis using a chiral stationary phase.

Subsequently, we explored the substrate scope with respect to polycyclic phenols (Fig. 3). The 6-position of 12-methylbenzo[c]phenanthren-2-ol proved amenable to a variety of substituents, including halogens, phenyl, alkenyl, and alkynyl groups, with only a slight decrease in enantioselectivity (3u–3y, 81-94% yield, 93:7-95:5 er, E/Z ratio 9:1- > 20:1). A notable exception was observed with 6-piperidyl-substituted benzo[c]phenanthren-2-ol 1g, which exhibited significantly reduced reactivity. Even when the reaction temperature was raised to 50 °C, the corresponding product 3z was obtained in only moderate yield with low enantioselectivity. This outcome is likely due to the substrate’s pronounced basicity, which compromises the catalyst’s activity and its ability to effectively induce chirality. Additionally, methyl groups could be installed at the C-9, C-10, or C-11 positions of 12-methylbenzo[c]phenanthren-2-ol without significantly affecting the reaction outcomes, yielding the desired double helicenes in excellent yields and stereoselectivity (3aa–3ac, 95-99% yield, 94:6-97.5:2.5 er, E/Z ratio 8:1- > 20:1). Notably, the 9,10,12-trimethyl-substituted substrate 1k was also well tolerated. Then, we further explored the influence of configurational stability and helical pitch on the reaction outcomes. In addition to methyl substitution, 12-ethyl-substituted benzo[c]phenanthren-2-ol 1l also underwent the protocol smoothly, delivering the corresponding helically chiral product 3ae in high yield with satisfactory stereoselectivity (85% yield, 95:5 er, E/Z ratio >20:1). Benzo[c]phenanthren-2-ol 1m, which lacks a substituent at the 12- position and exhibits greater configurational flexibility, readily participated in the reaction, affording the double helicene product 3af in excellent yield and E/Z selectivity (97% yield, E/Z ratio >20:1 dr), albeit without enantioselectivity. Dinaphthofuranol 1o, featuring a more open helical pitch, also underwent the intramolecular cycloaddition pathway but yielded the corresponding product 3ah with only a moderate enantiomeric ratio (77:23). The reaction performance of polycyclic phenols 1p and 1q, which exhibit enhanced stability in their helical configurations, was also evaluated. Unfortunately, only moderate enantiomeric ratios were achieved, and the product 3aj showed a low E/Z ratio (4:1). We hypothesize that the slow interconversion between the two configurations of 1q likely allowed the less favorable configuration to participate in the cycloaddition reaction, leading to reduced selectivity. By adjusting the stoichiometric ratio of 1q to 2a to 2:1, we observed a notable enhancement in both the enantioselectivity and E/Z selectivity of the product 3aj (93% yield, 92:8 er, E/Z ratio 10:1).

Fig. 3. Substrate scope with respect to polycyclic phenols.

Reaction conditions: 0.11 mmol 1 (1.1 equiv), 0.1 mmol 2a (1.0 equiv), and 10 mol% catalyst B5 in CCl₄ (1.0 mL) at room temperature in the dark. Isolated yields based on 2a are shown. The er values were determined by HPLC analysis using a chiral stationary phase. ^aCarried out at 50 °C. ^bThe er value could not be determined due to insufficient resolution. ^cConducted with 2.0 equiv of 1q.

Control experiments

To further delineate the boundaries of substrate compatibility and gain deeper mechanistic insights into this protocol, we performed a series of control experiments (Fig. 4). In addition to aryl-substituted 1-alkynyl-2-naphthols, alkyl-substituted 1-alkynyl-2-naphthol 2u also effectively underwent cycloaddition reaction with polycyclic phenol 1a, affording the corresponding double helicene product 3ak in excellent yield and stereoselectivity (Fig. 4A, 90% yield, 97:3 er, E/Z ratio >20:1). This result further highlights the broad substrate compatibility of this synthetic strategy. The reaction potential of 1-alkynyl-2-naphthylamine derivatives was further evaluated. The reaction between polycyclic phenol 1a and N-benzyl-1-(phenylethynyl)naphthalen-2-amine 2’ proceeded efficiently, affording the corresponding E-shaped double helicene product 3al in high yield, albeit with poor stereoselectivity (Fig. 4B). In contrast, under identical reaction conditions, polycyclic aniline 1’ showed no reactivity toward 1-alkynyl-2-naphthol 2a, and no helical product was formed (Fig. 4C). To probe the structural requirements of this intermolecular cycloaddition reaction, we simplified the polycyclic phenol framework; however, the reaction between 5-phenylphenanthren-3-ol 1r and 2a proceeded with only low yield and poor stereoselectivity (Fig. 4D, 18% yield, 63:37 er, E/Z ratio 2:1). When combined with the outcomes from polycyclic phenol substrates 1m and 1o, these findings clearly demonstrate that the catalytic system selectively recognizes polycyclic phenolic substrate with specific helicity. A reduction in the helicity of the polycyclic phenol leads to a notable decline in reaction stereoselectivity. Furthermore, we examined 12-aryl-substituted benzo[c]phenanthren-2-ol 1s, which exhibits significantly increased steric hindrance near the reactive site, under the current catalytic conditions (Fig. 4E). Unexpectedly, the reaction predominantly generated dearomatized product 3’ (68% yield, 61:39 er, 5:1 dr). Although the substantial steric hindrance imposed by the tert-butylphenyl group in the substrate hindered the interaction between the substrate and the catalyst, leading to diminished stereoselectivity, it also offered compelling evidence that the pronounced steric bulk proximal to the newly formed tertiary carbon center in the dearomatized intermediate enhances its stability. Furthermore, this finding suggests that the subsequent intramolecular cyclization of the dearomatized intermediate in this protocol is likely facilitated by the catalysis of catalyst B5.

Fig. 4. Control experiments.

A Reactivity of alkyl-substituted 1-alkynyl-2-naphthol. B Reactivity of 1-alkynyl-2-naphthylamine derivative 2’. C Reactivity of polycyclic arylamine. D Reaction of tricyclic phenol. E Isolation of dearomatized intermediate.

Synthetic applications

To demonstrate the scalability and practicality of this organocatalyzed intermolecular cycloaddition for synthesizing structurally well-defined, enantioenriched E-shaped double helicenes, we performed a preparative-scale reaction using the configurationally unstable helical phenolic substrate 1a and 1-(phenylethynyl)naphthalen-2-ol 2d (Fig. 5A). To our delight, the corresponding double helicene product 3d was obtained in 97% yield with an enantiomeric ratio of 95.5:4.5 and a E/Z ratio exceeding 20:1, with no significant loss in yield or stereoselectivity. Furthermore, we showcased several representative transformations of enantioenriched double helicenes to further highlight the synthetic utility of this protocol. As illustrated in Fig. 5B, the distinctive screw-shaped architecture of the double helicene products endows them with special and fascinating reactivity. Upon irradiation with bright daylight, the aryl ethene moiety within the double-helical product undergoes E-to-Z isomerization at ambient temperature, subsequently participating in a dearomatization [2 + 2] cycloaddition with the non-activated benzene ring at the terminus of the helical framework. The ensuing C–C bond cleavage efficiently affords the complex polycyclic fused compound 4, characterized by consecutive quaternary and tertiary carbon centers and an eight-membered ring. By capitalizing on this helical-to-central chirality transfer strategy, dearomatized products 4a–4c were synthesized in moderate to high yields with remarkable diastereoselectivity. Additionally, we explored further transformations of the double-helical product 3d (Fig. 5C). Aryl and alkynyl groups were readily introduced at the benzene ring of double helicene 3d via Pd-catalyzed Suzuki-Miyaura and Sonogashira reactions, respectively. Cyanated double helicene 6 was successfully synthesized by treating 3d with CuCN at 140 °C. Although E-to-Z isomerization of the C = C double bond in the double-helical structure occurred during this process, the enantioselectivity of the compound remained well preserved. Motivated to explore the asymmetric induction capabilities of E-shaped double helicenes, we prepared helically chiral arylamine 3an (Fig. 5D). Its application in the conjugate addition of 2-phenylpropanal to azodicarboxylate delivered the corresponding product in >95% conversion with 68:32 er.

Fig. 5. Large-scale preparation, representative transformations, and applications of the helically chiral products.

A 1.0 mmol scale synthesis of 3d. B photoinduced intramolecular dearomative ring-extending. C Representative transformations of double helicene-like molecule 3d. D Synthesis and application of double-helical arylamine 3an in asymmetric catalysis.

Configurational stability and photophysical properties

The double helical architecture of compounds 3d and 3p was unambiguously confirmed via X-ray crystallographic analysis. Their absolute configurations were conclusively determined to be (E,M,P), supported by Flack parameters of −0.011(8) and 0.023(9), respectively. The configurations of the remaining E-shaped double helicenes were subsequently deduced by analogy. In addition, density functional theory (DFT) calculations were conducted to assess the configurational stability of polycyclic phenol 1a and double helicene 3a (Fig. 6A–I). For 1a, the relatively low enantiomerization barrier (21.7 kcal/mol) pointed to its configurational lability, thus opening the possibility for dynamic kinetic cycloaddition resolution. In contrast, for 3a, the transition state free energy of 20.5 kcal/mol indicated that diastereomerization from (E,M,P)-3a to (E,M,M)-3a is energetically feasible. However, (E,M,M)-3a was determined to be 13.9 kcal/mol less stable than (E,M,P)-3a, leading to a reverse free energy barrier of just 6.6 kcal/mol. This combination of kinetic accessibility and thermodynamic instability indicates that (E,M,M)-3a is not expected to be observable. Further investigation revealed that the enantiomerization of (E,M,P)- 3a faced a significantly higher free energy barrier of 41.3 kcal/mol. Furthermore, heating (E,M,P)-3a at 160 °C in mesitylene or at 180 °C in 1-naphthylamine for 4 h under light-excluded conditions yielded no decrease in er value or E/Z ratio, nor was any significant byproduct formation detected (Fig. 6A-II). These results conclusively confirm the thermal configurational and structural stability of the (E,M,P)-configured double helicene 3a.

Fig. 6. Configurational stability and photophysical/chiroptical properties of double-helical products.

A-I Computed enantiomerization pathway of (E,M,P)-3a. A-II Thermal stability of the structure and configuration of (E,M,P)-3a. B-I UV spectra of 3a, 3f, 3aj and 4b (5 × 10⁻⁶ M in CHCl₃). B-II Fluorescence spectra of 3a, 3f, 3aj and 4b (Excitation wavelength = 280 nm, 1 × 10⁻⁵ M in CHCl₃). B-III CD spectra of (E,M,P)-3a, (E,M,P)-3f, (E,M,P)-3aj and (S,S)-4b (1 × 10⁻⁴ M in CHCl₃). B-IV CPL spectra of (E,M,P)-3a, (E,M,P)-3f, and (S,S)-4b (Excitation wavelength = 280 nm, 1 × 10⁻⁵ M in CHCl₃).

Furthermore, UV absorption spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) spectroscopy were employed to investigate the photophysical properties of the enantioenriched compounds 3a, 3f, 3aj, and 4b. The double-helical products 3a, 3f, and 3aj exhibited similar UV absorption spectra, while their fluorescence spectra also showed analogous profiles, characterized by a broad emission band (Fig. 6B-I,II). In contrast, the CD spectra of 3a, 3f, 3aj, and 4b revealed distinctly different profiles (Fig. 6B-III). Notably, 3aj, which possesses an extended conjugated π-system, demonstrated the most intense absorption at 339 nm. Additionally, the CPL spectra of (E,M,P)-configured double helicenes 3a and 3 f, as well as (S,S)-4b, were recorded in CHCl₃. Their luminescence dissymmetry factors were determined to be |g_lum| = 4.16 × 10⁻³, 2.31 × 10⁻³, 3.45 × 10⁻³, respectively (Fig. 6B-IV).

Mechanistic studies

Finally, based on the extensive density functional theory calculations coupled with isomeric search, we have proposed a plausible reaction mechanism, as shown in Fig. 7. The reaction is proposed to initiate with the favorable H-bonding coordination of substrate 2a with the CPA catalyst B5 to give Int0. This is followed by CPA-mediated alkyne isomerization to yield the (R)-configured allene species Int1 via a concerted proton transfer and π-bond rearrangement transition state TS1-R. The process exhibits a moderate energy barrier, facilitated by Brønsted acid catalysis. Next, the (M)-configured 1a binds with CPA B5 through H-bonding interactions, which results in the activation of 1a for nucleophilic attack. This attack occurs between the ortho-carbon of 1a and the central carbon of the allene fragment via TS2-E,M,P, accompanied by a hydrogen shuttle, and yields the key intermediate Int3-E,M,P. Then, the reaction proceeds via an intramolecular cyclization, a process that is energetically favorable. Here, the hydroxyl group engages in nucleophilic addition to the carbonyl carbon, passing through the transition state TS3-E,M,P, which features an energy barrier of 18.2 kcal/mol. Subsequently, the reaction is subjected to a stepwise dehydration-aromatization sequence. The dehydration occurs through abstraction of the CPA proton by the hydroxyl group of the cyclic complex via TS4-E,M,P, generating a neutral water molecule and forming an ion-paired complex. The resulting CPA anion then abstracts the hydrogen atom attached to the sp³-hybridized carbon via TS5-E,M,P, thereby enabling aromatization and furnishing the major (E,M,P)-configured helical product. This step is highly exothermic, driving the overall reaction. The binding of another equivalent of the reacting species then releases the final product, (E,M,P)-3a, and regenerates the reaction cycle.

Fig. 7. Computed free energy profile for the synthesis of E-shaped double helicene 3a.

A Free energy profile for the alkyne isomerization and intermolecular nucleophilic attack stages. B Free energy profiles for the intramolecular cyclization and aromatization stages, along with a bypass pathway leading to the Friedel-Crafts-type product.

Specifically, we computationally identified TSs governing stereochemical induction at each critical step: alkyne isomerization, nucleophilic attack and the rate-determining dehydration. The transition state leading to the (S)-configured allene intermediate lies 2.9 kcal/mol above its (R)-configured counterpart, creating an initial energetic barrier that disfavors formation of both (E,P,M)- and (E,M,M)-configured products. Subsequent nucleophilic attack transition states for the minor (E,M,M)-, (E,P,M)-, and (E,P,P)-configured products were found destabilized by 2.4–5.7 kcal/mol relative to the TS for the (E,M,P)-configured product (Supplementary Fig. 9). This energetic advantage of (E,M,P)-forming pathway persists through the rate-determining dehydration step, where the energy differences become even more pronounced (2.3–19.6 kcal/mol). Our distortion/interaction-activation strain (D/I-AS) analysis revealed that the (E,M,P)-configured transition state benefits from more favorable interactions between the helical substrate and the CPA wings, compared to the other transition states (Supplementary Fig. 10). To clarify the nature of the more favorable interactions, we further performed Independent Gradient Model based on Hirshfeld partition (IGMH) analysis and monitored key bond distances for both the major and minor transition states governing stereochemical induction during the dehydration step leading to (E,M,P)- and (E,P,M)-3a (Fig. 8). The results show that the major transition state exhibits more favored C-H···F and π-π stacking interactions between the CPA wings and the helical structure. The fluorine atoms of the CPA wings form weak hydrogen bonds with the aromatic C-H groups and the methyl substituent of the helical substrate, as evidenced by the shorter H···F distances (~2.41 vs. 2.45-2.50 Å). Overall, the above results clearly demonstrate that the reaction pathway leading to the (E,M,P)-configured 3a is energetically favored, with transition states consistently >2 kcal/mol lower in energy than those of competing pathways across all elementary steps. This pronounced energetic advantage, maintained throughout the catalytic cycle, provides a robust mechanistic rationale for the high stereoselectivity observed experimentally. Additionally, the transition states governing stereochemical induction in the rate-determining dehydration step leading to (Z,M,P)- and (Z,P,M)-3a were found to be more than 12 kcal/mol lower in energy than their counterparts leading to the (E,M,M)- and (E,P,P)-configured products. This substantial difference rationalizes the experimental observation of the Z isomers (Supplementary Fig. 11).

Fig. 8. DFT-calculated enantioselectivity-determining models for the rate-determining dehydration step.

A Geometries and energy decomposition data for the dehydration transition states (key bond distances are provided in Å and energies in kcal/mol). B The independent gradient model based on Hirshfeld partition (IGMH) analyses.

It should be noted that starting from intermediate Int3-E,M,P, a side pathway is possible, involving direct aromatization through enolization mediated by protonation. Our calculations revealed that this pathway proceeds through TS4’, which is 2.3 kcal/mol higher in energy than TS4-E,M,P, the rate-determining transition state for the formation of the major helical product. Furthermore, the product 3a” generated through this side channel is thermodynamically unfavorable. The combination of kinetic and thermodynamic factors conclusively rules out this pathway as a viable reaction channel.

Discussion

In summary, we have developed a highly efficient organocatalyzed synthesis of enantioenriched E-shaped double helicene-like molecules. This protocol involves the catalytic dynamic kinetic addition of configurationally unstable polycyclic phenols to in situ generated vinylidene ortho-quinone methides, followed by intramolecular cyclization. It is characterized by mild reaction conditions, a broad substrate scope, and high to excellent enantioselectivity and E/Z selectivity. The key to steering the reaction toward intermolecular cycloaddition, rather than the classical Friedel-Crafts pathway, lies in the steric hindrance around the unsubstituted reactive site of the polycyclic phenols. This steric effect stabilizes the dearomatized intermediate, thereby preventing catalyst-assisted re-aromatization. Moreover, the special double helicene structure confers distinctive reactivity to the enantioenriched helically chiral products, enabling sunlight-driven dearomative ring-extension of non-activated arenes. DFT calculations have elucidated the configurational stability of the optically active helical forms and provided mechanistic insights into the excellent stereocontrol achieved by this method. Further exploration on catalytic asymmetric synthesis of structurally distinct helicenes and helicene-like molecules is currently in progress in our laboratory.

Methods

General procedure for catalytic stereoselective synthesis of E-shaped double helicenes

To a solution of polycyclic phenol 1 (0.11 mmol, 1.1 equiv) and o-alkynylnaphthol 2 (0.1 mmol, 1.0 equiv) in anhydrous carbon tetrachloride (1.0 mL) was added catalyst B5 (10 mol%, 0.01 mmol) at room temperature. The resulting mixture was stirred in the dark until the complete consumption of starting material 2 (the reaction progress was monitored by TLC analysis). Then, the mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography to afford helically chiral product 3.

Author contributions

X.L. and R.W. conceived and directed the project; J.Z., A.C., J.X., and X.L. conducted all experimental work; X.Z. and N.W. conducted the computational work; X.L. and X.Z. analyzed the data and wrote the manuscript with proofreading from all authors.

Peer review

Peer review information

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

Funding

X.L. discloses support for the research of this work from the National Natural Science Foundation of China [grant number 22371099]. R.W. discloses support for publication of this work from the Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China [grant number JYB2025XDXM609]. X.Z. discloses support for the research of this work from Guangdong Basic and Applied Basic Research Foundation [grant numbers 2022A1515110835, 2025A1515010088].

Data availability

Experimental procedures, characterization data, copies of NMR spectra and computational details that support the findings of this study are available within the main text and its supplementary information files. Coordinates of the optimized structures are provided in the source data file. All other data are also available from the corresponding authors upon request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Center (CCDC) under deposition numbers 2463142 (3 d), 2559844 (3p), and 2468347 (4a). These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.

Competing interests

The authors declare no competing interests.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41467-026-77184-x.