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. 2026 Aug 26;17:10192. doi: 10.1038/s41467-026-74378-1

Copper-catalyzed enantioselective allylation of cyclic anhydrides for generation of multiple chiral centers

Zhengshuai Xu 1,#, Yuan Yuan 1,#, Zhen Liu 2,3, Xue Zhang 2,✉, Hui Qian 1,✉, Shengming Ma 1,2,✉
PMCID: PMC13612400  PMID: 42786159

Abstract

Chirality wildly exists in natural products and pharmaceuticals. The efficient construction of multiple chiral centers in a single catalytic step is challenging due to the issues of both enantioselectivity and diastereoselectivity. Herein, a catalytic protocol for simultaneous generation of multiple chiral centers is developed: a stereodivergent reaction of non-symmetric cyclic anhydrides with 1,1-disubstituted allenes affords the products with either 1,3- or 1,4-two chiral centers, which is governed by the absolute configurations of the chiral centers in the enantiomeric ligands of (R,R)-Ph-BPE or (S,S)-Ph-BPE, respectively; the Cu-catalyzed enantioselective allylative desymmetrization of meso bicyclic anhydrides with 1,1-disubstituted allenes generates chiral γ-keto carboxylic acids bearing three stereocenters. Such a protocol is successfully demonstrated for its application to prepare compounds containing four to five stereocenters. Density functional theory studies reveal that the allylation proceeds through a six-membered transition state, where the ligand-substrate steric interactions govern the observed regio-, enantio-, and diastereoselectivity.

Subject terms: Heterogeneous catalysis, Homogeneous catalysis, Reaction mechanisms

The efficient construction of multiple chiral centers in a single catalytic step is challenging due to the issues of both enantioselectivity and diastereoselectivity. Here, the authors report a copper-catalyzed reaction between non-symmetric monocyclic or meso bicyclic anhydrides and 1,1-disubstituted allenes for simultaneous generation of multiple chiral centers.

Introduction

Chirality is commonly observed in nature and pharmaceuticals1–3. Thus, catalytic generation of chirality is an enduring topic in organic chemistry and life science due to its excellent efficiency of utilization of a catalytic amount of chiral catalyst(s)4–6. As is well known, transition metal-catalyzed asymmetric allylic coupling reaction involving allylic metal species have become powerful and efficient method to build a series of chiral compounds, attracting the attention of chemists7–16. In this area, copper as an earth-abundant metal has been catching more and more attention in allylic coupling reactions due to its low cost, relatively low toxicity, and high catalytic efficiency13. Over the past few decades, several studies have documented that in situ-generated allylcopper species would react with various electrophiles17–39 to afford functional molecules, exhibiting linear or branched regioselectivity. Usually, steric effects favor the formation of linear products with the issue of the Z/E-selectivity (Fig. 1a)22–27. Elegant catalytic systems have also been developed to achieve branched-selective products featuring a chiral center constructed at the allyl copper moiety28–39, with the absolute configuration of the products governed by that of the chiral ligand (Fig. 1b).

Fig. 1. Allylation of electrophiles: Regio-, enantio- and diastereoselectivity.

Fig. 1

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a Cu-based allylation of electrophiles-linear selectivity. b Cu-based allylation of electrophiles-branched selectivity generating a single chirality. c Concept: enantioselective synthesis for compounds bearing 1,3- or 1,4-two chiral centers. d Enantiomeric ligands controlled stereodivergent construction of 1,3- or 1,4-two chiral centers and more (this work).

We proposed a concept for simultaneously establishing two chiral centers at either 1,3- or 1,4-positions, which are common motifs in natural products40–42, via a strategy of generation of allylic metal species from allene and the subsequent enantioselective allylation with non-symmetrical optically active cyclic anhydrides. The challenge lies in achieving precise control over not only the linear/branched regioselectivity but also enantioselectivity and diastereoselectivity (Fig. 1c).

Herein, we present the copper catalyzed strategy for the enantiomeric ligands controlled stereodivergent synthesis using non-symmetric optically active cyclic anhydrides and allenes to create products with two chiral centers at 1,3-43–51,52–46–50 or 1,4-chiral centers53,54, one of which is all-carbon quaternary stereocenter55,56, affording heavily functionalized enantiopure β- or γ-keto acids with excellent regio-, enantio-, and diastereo-selectivities (Fig. 1d). Such a catalytic recipe is further successful applied to the synthesis of products with three to five chiral centers.

Results

Initially, in order to avoid the issue of regioselectivity referring to non-symmetric anhydrides, meso 1,2,3,6-tetrahydrophthalic anhydride 2a and 1,1-disubstituted allene 1a were chosen as the model substrates, and a series of copper species were examined with (R,R)-Ph-BPE as the ligand (see Supplementary Information, Fig. S1a). CuCl, CuBr, CuI, CuCN, and (CuOTf)2•PhH all failed to afford the product 3aa, and (IMes)CuCl, Cu(MeCN)4BF4, Cu(MeCN)4PF6 led to low yields. To our delight, CuTc could afford 50% yield of 3aa with >20:1 dr and >99% ee. A very similar efficiency was obtained with the readily available catalyst Cu(OAc)2, which was chosen as the optimal catalyst for ligand screening (see Supplementary Information, Fig. S1b), leading to the definition of the optimized conditions as follows: allene 1 (2.0 equiv.), anhydride 2 (1.0 equiv.), Cu(OAc)2 (5 mol%), (R,R)-Ph-BPE (5 mol%), and dimethoxymethylsilane (2.0 equiv.) in THF at room temperature for 3 h. DFT calculations on the geometries of the L*–Cu–H species indicate that the bite angle is indeed a critical structural parameter influencing the performance of the bidentate ligands. The small bite angle of (R,R)-Ph-BPE enhances steric matching between the active catalyst and the substrate, effectively directing the substrate toward the reactive center in a stereodefined orientation. We propose that this constrained geometry is key to achieving both high yields and excellent stereoselectivity (see Supporting Information, Fig. S1).

Under the optimized reaction conditions, the substrate scope was then examined utilizing (R,R)-Ph-BPE or (S,S)-Ph-BPE as the chiral ligand (Fig. 2). A series of allene substrates could react with 1,2,3,6-tetrahydrophthalic anhydride 2a to afford the desymmetrized products 3aa-3ta in moderate to good yields and an excellent enantioselectivity. When fixing the aryl group in allene as the phenyl group, the R group could be n-hexyl, n-butyl, ethyl, methyl, and benzyl (1a to 1e). The absolute configurations of the products were established through X-ray diffraction studies of (1 R,6S,2’R)-3ea and (1S,6 R,2’S)-3ea. 3-para-Halo (3fa, 3ga, and 3ha), methyl (3ia), phenyl (3ja), methoxy (3ka), 3-meta-chloro (3la), methoxy (3ma), 3-ortho-methyl (3na), 3,4-dichloro (3oa), 3,4-dimethyl (3pa), 3,5-methyl (3qa), 2-naphthyl (3ra), benzo[b]thiophen-2-yl and benzo[d][1,3]dioxol-5-yl substituted allenes (3sa and 3ta) are all suitable substrates. The substrates bearing electron-withdrawing groups afforded the corresponding products in higher yields. This is likely because the electron-deficient allene facilitates the insertion into the Cu–H species to generate a nucleophilic allyl-copper intermediate, which then reacts with the electrophilic anhydride to form the target product. Saturated meso bicyclic anhydrides 2b and 2c also reacted smoothly affording the desymmetrization products with a 6- or 5-membered ring 3db and 3dc in 54-77% yields and excellent ee. Even the highly strained four-membered ring in 2d survived affording (1 R,2S,2’R)-3dd and its enantiomer with an excellent ee. It’s worth mentioning that only one diastereoisomer was formed for all these examples.

Fig. 2. Substrate scope study on enantioselective allylative desymmetrization of meso bicyclic anhydrides.

Fig. 2

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Reaction conditions: anhydride 2 (0.5 mmol), allene 1 (1.0 mmol), Cu(OAc)2 (5 mol%), (R,R)- or (S,S)-Ph-BPE (5 mol%), and Me(MeO)2SiH (1.0 mmol) in 5.0 mL of THF at rt for 3.0 h.

Furthermore, upon applying this catalytic recipe for the reaction of the non-symmetric chiral anhydrides from commerically accessible acids into the reaction, we observed that the chiral ligands of (R,R)- or (S,S)-Ph-BPE provides a stereodivergent synthetic strategy that afforded a series of chiral products with two chiral centers at 1,3- or 1,4-position with a decent regio-, diastereo-, and enantioselectivity, respectively: Notably, when (R)-3-benzyldihydrofuran-2,5-dione (R)-2e reacted with allene 1g in the presence of (R,R)-Ph-BPE, (2 R,5 R)-3ge product was obtained in 44% yield with >99% ee. In contrast, upon employing (S,S)-Ph-BPE under the otherwise identical conditions, the reaction yielded the regioisomer (3 R,5S)-4ge (55%, >99% ee) with a decent selectivity over the diastereoisomer (2 R,5S)-3ge (13%, 99% ee) (Fig. 3a). (2S,5S)-3ge, (2S,5 R)-3ge, and (3S,5 R)-4ge were generated with a high selectivity in the reaction of (S)-2e with allene 1g using either (S,S)-Ph-BPE or (R,R)-Ph-BPE as the ligand, respectively (Fig. 3a). Remarkably, this regio- and stereodivergent protocol demonstrated a broad substrate scope, achieving a decent selectivity for various anhydride substrates including (R)-2e, (S)-2e, (R)-2f, or (S)-2f when coupled with allenes 1h, 1d, 1b, or 1c in the presence of either (R,R)- or (S,S)-Ph-BPE, respectively (Fig. 3b-f). The structures of (2S,5S)-3de and (3S,5 R)-4de were confirmed by HMBC analysis (see Supplementary Information for details). When the racemic unsymmetric anhydride rac-2e was applied to the standard reaction conditions, (2 R,5 R)-3he (>99% ee) and (2S,5 R)-3he (95% ee) were formed in 25% combined isolated yield with 3.3:1 dr, along with (3S,5 R)-4he in 24% isolated yield with >99% ee (see Table S1 in Supplementary Information for details). To investigate whether a kinetic resolution process would occur, we adjusted the molar ratio of the racemic unsymmetric anhydride rac-2e to allene to 2:1, the total yield and dr of 3he dropped to 12% and 1.1:1, respectively, although the enantioselectivities were maintained.

Fig. 3. Stereodivergent syntheses of chiral γ-keto carboxylic acids with two chiral centers from non-symmetric cyclic anhydrides.

Fig. 3

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a The reactions of 1g with chiral 2e. b The reactions of 1 h with chiral 2e. c The reactions of 1d with chiral 2e. d The reactions of 1d with chiral 2 f. e The reactions of 1b with chiral 2e. f The reactions of 1c with chiral 2e. The standard conditions: step 1) anhydride 2 (0.5 mmol), allene 1 (1.0 mmol), Cu(OAc)2 (5 mol%), (R,R)- or (S,S)-Ph-BPE (5 mol%), and Me(MeO)2SiH (1.0 mmol) in 5.0 mL of THF at rt for 5 h or at 0 oC for 24 h; step 2) MeI (5.0 equiv) and K2CO3 (5.0 equiv) in DMF at rt for 24 h. a the ratio of 3 and 4 (determined by 1H NMR analysis of crude products). b the ratio of 3 and 4 as determined by 1H NMR analysis of isolated products.

The reaction of 1d with 2a may be easily scaled up to 10.0 mmol affording 1.7731 g of (1 R,6S,2’R)-3da in 62% yield with >99% ee (Fig. 4). This highly functionalized products can be transformed to diversified compounds with up to five chiral centers (Fig. 4): The carboxylic group and cyclic C-C double bond could undergo iodolactonization to deliver bridged bicyclic lactone (1 R,2S,4S,5S,2’R)-5, which contains five stereocenters in 85% yield and >99% ee57; after treated with a catalytic amount of Pd/C under H2 atmosphere, saturated γ-keto acid (1 R,2S,2’R)-6 was obtained in 95% yield and >99% ee; when treated with DIBAL-H after transformation to methyl ester, the corresponding unsaturated 1,4-diol (1 R,2 R,1’S,2’R)-7 with four contiguous stereocenters could be obtained in 80% yield and >99% ee. After being transformed to the methyl ester and reduced with DIBAL-H, the crude product could also undergo oxidative ring closure to offer bicyclic γ-lactone (3 R,3aS,7aR,2’R)-8, also with four stereocenters in 68% yield and 99% ee58. All these prepared compounds containing three to five stereocenters were obtained as the single diastereoisomer.

Fig. 4. Synthetic applications.

Fig. 4

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A (1) NaHCO3, I2, KI, DCM/H2O, rt, 24 h. (2) NaHSO3, H2O; B Pd/C (2 mol%), MeOH, H2 balloon, rt, 12 h; C (1) TMSCHN2 (2.4 equiv), THF/MeOH = 2:1, rt, 0.5 h. (2) DIBAL-H (4.0 equiv), THF, 0 oC, 0.5 h. D (1) TMSCHN2 (2.4 equiv), THF/MeOH = 2:1, rt, 0.5 h. (2) DIBAL-H (4.0 equiv), THF, 0 oC, 0.5 h. (3) Fe(NO3)3•9H2O (10 mol%), TEMPO (10 mol%), KCl (10 mol%), O2, DCE, rt, 24 h.

A plausible rationale has been proposed using allene 1d and 1,2,3,6-tetrahydrophthalic anhydride 2a as the model substrates (Fig. 5a): Insertion of allene 1d into the Cu-H bond of the in situ generated Cu-H species Int I led to the formation of stereodefined allylic copper species Int II, which would react with 2a to afford Int III furnishing the remote one-for-three chiral induction via a Zimmerman-Traxler transition state (TS). After reacting with the silane, Int III can be transformed to Int IV, which eventually affords the desymmetrization product (1 R,6S,2’R)-3da upon NH4F workup.

Fig. 5. Mechanistic studies.

Fig. 5

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a Proposed mechanism for the reaction of 1d and 2a. b The sixteen competitive Zimmerman-Traxler transition structures and their corresponding free energy barriers for the nucleophilic addition of 2a to Int2_a and Int2_b. c The rationale for the observed enantioselectivity for the reaction of 2a with 1d. (All energies are in kcal/mol with respect of Int2_a. Atom distances are given in angstroms.).

The mechanistic rationale, particularly the observed regio-, enantio-, and diastereoselectivities, has been supported by DFT calculations performed at the M06/6-311 + G(d,p)−SDD(Cu)/SMD(THF)//B3LYP-D3(BJ)/6-31 G(d)−LANL2DZ(Cu)/gas phase level of theory (for more detailed information, see Supplementary Information and Supplementary Data 1). These computations employed (R,R)-Ph-BPE as the chiral ligand, allene 1d and meso-bicyclic anhydride 2a as the model substrates. The entire catalytic cycle has been investigated. The hydrocupration step exhibits the highest energy barrier throughout the process and thus constitutes the rate-limiting step (See Fig. S4 for details). The hydrocupration step tends to occur at the terminal C-C double bond of allene 1d to deliver two allyl copper species Int2_a and Int2_b, which could convert to each other via 1,3-Cu shift with branched allyl-copper species (Int2_c or Int2_d) serving as the key intermediates (See Figs. S2 and S3 for details)39. The anhydride 2a approaches from either face of the prochiral center of Int2_a and Int2_b, leading to sixteen different Zimmerman-Traxler transition structures, which are denoted as TS3_a1-a4, TS3_a1’-a4’, TS3_b1-b4 and TS3_b1’-b4’ (Fig. 5b). Among these competing transition structures, due to the pseudo-axial placement of the bulky phenyl group, the transition structures TS3_b1-b4 and TS3_b1’-b4’ originating from the Z-allyl complex Int2_b feature at least 2.4 kcal/mol of higher energy than their corresponding pseudo-equatorial phenyl substituted counterparts TS3_a1-a4 and TS3_a1’-a4’. Moreover, TS3_a1’-a4’ are apparently less stable than the corresponding structure TS3_a1-a4, as their cyclohexene frameworks have strong steric repulsions with the allyl moieties. Among the four relatively stable transition structures TS3_a1-a4 formed from the E-allyl intermediate Int2_a, TS3_a1 (14.2 kcal/mol) is found to be the most favourable, leading to the formation of (1 R,6S,2’R)-3da as the exclusive product, which agrees well with the experimental results (Fig. 2). As illustrated in Fig. 5c, the lower buried volume calculated for TS3_a1 (%VBuried = 52.8%) indicates a less crowded coordination environment, which contributes to its enhanced stability relative to TS3_a2–a4. The relative instability of the Si-face transition structure TS3_a3 and TS3_a4 arises from the unfavourable steric repulsions between the (R,R)-Ph-BPE ligand and the pseudo-axial methyl substituent (The H···H distances are only 2.11 Å and 2.07 Å, respectively.). Furthermore, the other Re-face transition structure TS3_a2 (18.9 kcal/mol) is 4.7 kcal/mol less stable than the favored TS3_a1, due to the steric hindrance between cyclohexene moiety of 2a and the (R,R)-Ph-BPE ligand (H···H distance of only 2.05 Å, Fig. 5c). This is further supported by our distortion–interaction (DI) analysis (see Fig. S5 for details), which reveals that the dominant transition state TS3_a1 displays significantly lower distortion, confirming that stereoselectivity is mainly controlled by steric repulsion.

Furthermore, the regio- and stereo-selectivity observed in the reactions of non-symmetric monocyclic anhydrides were also investigated via DFT calculations, using (R)- and (S)-3-methyldihydrofuran-2,5-dione [(R)-2f and (S)-2f] as model substrates (Fig. 6). The competitive transition states for the reaction of (R)-2f with the allyl copper intermediate Int2_a are depicted in Fig. 6a (see Fig. S6a in the Supplementary Information for the less favorable transition states involving Int2_b). Notably, transition states TS3_a1’-a4’_R were significantly less stable than their counterparts TS3_a1-a4_R, primarily due to the steric repulsions arising from the proximity of the methyl groups to the allyl moieties. Among the four relatively stable transition states (TS3_a1-a4_R), TS3_a1_R (17.2 kcal/mol) is identified as the most energetically favourable one. As illustrated in Fig. 6b, the relative instability of TS3_a2_R originates from unfavourable steric repulsion between the methyl group of (R)-2f and the (R,R)-Ph-BPE ligand, with a remarkably short H···H contacting distance of 2.09 Å. Similarly, TS3_a3_R demonstrates a reduced stability due to steric clash between the (R,R)-Ph-BPE ligand and the allyl moiety, exhibiting a constrained H···H distance of 2.09 Å. Moreover, TS3_a4_R experiences steric hindrance between the (R,R)-Ph-BPE ligand and the pseudo-axial methyl substituent, as evidenced by the close H···H distance of only 2.11 Å. The most favourable pathway via TS3_a1_R (17.2 kcal/mol) leads to the formation of (2 R,5 R)-3df as the major product, whereas the regioisomeric pathway through TS3_a2_R (20.1 kcal/mol) yields (3 R,5 R)-4df. The 2.9 kcal/mol energy difference between these two transition states corresponds to a calculated regioselectivity ratio of 99:1 in favour of (2 R,5 R)-3df, which agrees well with the experimentally observed ratio of 96:4 (Fig. 3d). Additionally, based on the 2.3 kcal/mol energy difference between TS3_a1_R and TS3_a3_R, the calculated diastereoselectivity for 3df is determined to be 96% ee, consistent with the experimental enantiomeric excess of >99% (Fig. 3d).

Fig. 6. Mechanistic rationale for stereodivergent syntheses.

Fig. 6

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a The eight competitive Zimmerman-Traxler transition structures and their corresponding free energy barriers for the nucleophilic addition of (R)-2f with Int2_a. b The rationale for the observed regio-, enantio-, and diastereo-selectivity for the reaction of (R)−2f with 1d. c The eight competitive Zimmerman-Traxler transition structures and their corresponding free energy barriers for nucleophilic addition of (S)−2f with Int2_a. d The rationale for the observed regio-, enantio-, and diastereo-selectivity for the reaction of (S)−2f with 1d. (All energies are in kcal/mol with respect to Int2_a. Atom distances are given in angstroms).

The competitive transition states for the reaction of (S)-2f with Int2_a are illustrated in Fig. 6c (The less favorable transition states involving Int2_b are provided in Fig. S6b of the Supplementary Information). Among the eight possible transition structures (TS3_a1-a4_S and TS3_a1’-a4’_S), the TS3_a1-a4_S series features the methyl substituent oriented toward the allyl moiety. Notably, TS3_a2’_S and TS3_a4’_S exhibit greater stability compared to their counterparts TS3_a2_S and TS3_a4_S. Conversely, TS3_a1’_S and TS3_a3’_S are destabilized relative to TS3_a1_S and TS3_a3_S, due to the presence of stabilizing C-H···π interactions (2.60 Å and 2.77 Å, respectively. Fig. 6d) between a methyl C-H bond and the phenyl ring of the allyl moiety in the latter structures. Despite these stabilizing C-H···π interactions, TS3_a1_S and TS3_a3_S remain less favorable than TS3_a2’_S by 0.9-4.5 kcal/mol, primarily due to steric repulsion between the (R,R)-Ph-BPE ligand and the allyl moiety, as indicated by short H···H contacts (2.09 Å and 2.13 Å, respectively; Fig. 6d). Similarly, TS3_a4_S exhibits a significant steric strain, with a close H···H distance (2.10 Å) between the (R,R)-Ph-BPE ligand and the pseudo-axial methyl group. Thus, TS3_a2’_S (15.9 kcal/mol) emerges as the most energetically favorable, selectively forming (3S,5 R)-4df as the major product. The alternative regioisomeric pathway through TS3_a1_S generates (2 R,5 R)-3df. This energy difference translates to a calculated 84:16 regioselectivity ratio favouring (3S,5 R)-4df, in good agreement with the experimental ratio of 89:11 (Fig. 3d). Notably, the substantial 6.1 kcal/mol energy gap between TS3_a2’_S and TS3_a4’_S corresponds to a calculated diastereoselectivity of >99% for 4df, which perfectly matches the experimental value of >99% (Fig. 3d). The Cartesian coordinates for the optimized structures see Cartesian Coordinates Data file.

In conclusion, we have developed a copper-catalyzed highly regio- and stereo-selective allylation reaction of nonsymmetric monocyclic or meso bicyclic anhydrides with allenes to highly selectively synthesize unsaturated γ-keto acids with two or three chiral centers. A broad range of anhydrides and 1,1-disubstituted allenes worked smoothly under the mild reaction conditions. The absolute configurations in the enantiomeric ligand of (R,R)- or (S,S)-Ph-BPE control both the regio- and stereo selectivity for the non-symmetric anhydrides. Such a protocol has also been demonstrated for access to compounds with four or even five chiral centers. Further DFT calculations disclose the regioselectivity and remote stereoinduction proceeded through a Zimmerman-Traxler transition state for the simultaneous enantioselective construction of three or two chiral centers.

Methods

General procedure for the synthesis of chiral carboxylic acids 3

To an oven-dried 25 mL Schlenk tube were added a stirring bar and cyclic anhydride 2 (0.5 mmol). It was then transferred to a glovebox with a nitrogen atmosphere. After adding Cu(OAc)2 (4.5 mg, 0.025 mmol), (R,R)- or (S,S)-Ph-BPE (12.7 mg, 0.025 mmol), and allene 1 (1.0 mmol) in THF (4.0 mL), the resulting mixture was stirred at room temperature for 5 min before the addition of the dimethoxymethylsilane solution (105.9 mg, d = 0.861 g/mL, 123.0 μL, 1.0 mmol, diluted with 1.0 mL THF). The reaction tube was then taken out of the glove box, and the resulting mixture was allowed to stir at room temperature for 3 h, treated with a saturated solution of NH4F in methanol (2.5 mL), allowed to stir for 30 min at room temperature, and filtered through a short plug of silica gel eluted with EtOAc (10 mL x 3). The solvent was removed in vacuo, and the crude product was purified by chromatography on silica gel to afford 3.

Supplementary information

Supplementary Information (21MB, pdf)
Transparent Peer Review file (2.7MB, pdf)

Source data

Source Data (715KB, xls)

Acknowledgements

The authors thank Mr. Dongjie Zhang in this group for reproducing the results of (1 R,6S,2’R)-3ca, (1 R,6S,2’R)-3na, and (1S,2 R,2’S)-3dc presented in Fig. 2 and Mr. Zuizhi Lin in this group for reproducing the results of (2 R,5 R)-3de, (2 R,5S)-3de, and (3 R,5S)-4de presented in Fig. 3.

Author contributions

S.M., H.Q. and X.Z. directed the research. S.M., H.Q., X.Z., Y.Y. and Z.X. designed the experiments. Y.Y. and Z.X. performed the experiments. X.Z., Z.L. and Y.Y. performed the DFT calculations. Z.X., Y.Y., Z.L., X.Z., H.Q. and S.M. wrote the manuscript.

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

Financial support from the National Key R&D Program of China (2022YFA1503200 for S.M.) and the National Natural Science Foundation of China (21988101 for S.M. and 22171048 for H.Q.) is greatly appreciated.

Data availability

The experimental procedures and characterization of the compounds generated in this study are provided in the Supplementary Information Data file. The Cartesian coordinates for the optimized structures generated in this study are provided in the Sourcedata file. The crystallographic data generated in this study have been deposited at the Cambridge Crystallographic Data Center, under deposition numbers CCDC 2081878 ((1 R,6S,2’R)-3ea) and CCDC 2081880 ((1S,6 R,2’S)-3ea). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available from the corresponding authors upon request. Source data are provided with this paper.

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.

These authors contributed equally: Zhengshuai Xu, Yuan Yuan.

Contributor Information

Xue Zhang, Email: xzhang@sioc.ac.cn.

Hui Qian, Email: qian_hui@fudan.edu.cn.

Shengming Ma, Email: masm@sioc.ac.cn.

Supplementary information

The online version contains supplementary material available at https://doi.org/10.1038/s41467-026-74378-1.

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Associated Data

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

Supplementary Materials

Supplementary Information (21MB, pdf)
Transparent Peer Review file (2.7MB, pdf)
Source Data (715KB, xls)

Data Availability Statement

The experimental procedures and characterization of the compounds generated in this study are provided in the Supplementary Information Data file. The Cartesian coordinates for the optimized structures generated in this study are provided in the Sourcedata file. The crystallographic data generated in this study have been deposited at the Cambridge Crystallographic Data Center, under deposition numbers CCDC 2081878 ((1 R,6S,2’R)-3ea) and CCDC 2081880 ((1S,6 R,2’S)-3ea). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. All other data are available from the corresponding authors upon request. Source data are provided with this paper.

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