English

• Bioactive sesquiterpenoids feature a variety of highly rearranged skeletons [1–4] providing an abundant resource of novel lead compounds or pharmacophores for medicinal chemistry. The structural complexity and diversity of these molecules and their wide range of bioactivities have attracted extensive interest in developing elegant and efficient synthetic strategies to prepare these molecules [5,6]. Generally, two synthetic approaches have been applied, one of which is guided by the transform-goal strategy that relies on the available toolbox of known transformations or innovative methodologies [7–9]. The other is guided by the structure-goal strategy, which involves recognition of a structurally matched moiety or skeleton that is traced back to an accessible starting material, particularly chiral-pool terpenes [10–13]. Although the wide application of chiral monoterpenes in synthesis, direct transformation of sesquiterpenoid feedstocks to obtain structural-diversified counterparts seems more attractive due to their complete C15 carbon skeleton and intrinsic stereogenicity. The recent landmark synthesis of Illicium-type sesquiterpenoids by Maimone's group showcased the efficiency of a chiral-pool-terpene navigated oxidative development strategy [14–16]. However, sophisticated skeletal manipulation and unconventional C—H functionalization still limit the widespread application of polycyclic sesquiterpenoids and alternative synthetic strategies need to be developed.

  Illihenin A (1), a novel tricyclo[6.2.2.0^1,5]sesquiterpenoid with cage-like skeleton, was isolated from the roots of Illicium henryi in trace amounts and exhibited potent antiviral activity against coxsackievirus B3 (CVB3) with an IC₅₀ value of 2.87 µmol/L [17]. The unique structure and intriguing bioactivity of 1 inspired us to synthesize this compound and further reveal the mechanism of its antiviral activity. Herein, we report the realization of a novel ring-reorganization synthetic strategy to achieve the first asymmetric synthesis of 1 from the abundant feedstock sesquiterpene (-)-α-cedrene and unveiled the inhibitory effect of 1 on the ROS production and apoptosis induced by CVB3 infection.

  Structurally, 1 is a benzoylated sesquiterpenoid which features a novel cage-like 5–7–6 tricyclic scaffold as well as six contiguous stereogenic centers, including two all-carbon-substituted quaternary carbons. A semi-synthetic approach involving the use of a readily available chiral terpene, the components and stereogenicity of which could be incorporated into the target molecule to the greatest level of efficiency, was proposed. The tricyclic sesquiterpene (-)-α-cedrene was treated as a starting material, into which a shared spiro[4.5]decane moiety was embedded along with the maintenance of the stereochemistry of the western cyclopentane substructure. Thus, the synthetic plan aims at fulfilling this unprecedented conversion from (-)-α-cedrene to 1. However, such an endeavour entailed several sophisticated transformations: (1) the selective cleavage of the undesired C5-C7 bond in the cedrene skeleton to obtain a spirocyclic framework; (2) the formation of C6-C13 bonds to cyclize the seven-membered ring, and (3) the stereoselective installation of presumed C-5 and C-13 stereocenters. To address these obstacles, we devised a unique ring-reorganization strategy (Scheme 1). Hinging on the C-7 hydroxylated cedrane 4 as a pivotal intermediate, alkoxyl-induced β-fragmentation led to 3 with requisite functionalizations at C7 and C13, followed by an array of oxidation steps, an intramolecular Aldol reaction occurs in 2 to furnish the tricyclic core of 1. The introduction of a tertiary hydroxy group into 4 was traced back to 5 via SmI₂-mediated ketone-olefin reductive coupling, which has been reported in the construction of numerous constrained bridgehead alcohols [18–21]. Finally, 5 could be prepared from the presumed (-)-α-cedrene by taking advantage of a series of redox manipulations.

  Scheme 1

  

  Scheme 1.  Outline of the ring-reorganization synthetic plan and retrosynthetic analysis of illihenin A (1).

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  We commenced our synthesis (Scheme 2) with oxidative cleavage of (-)-α-cedrene using a previous method (RuCl₃/NaIO₄) [16] to afford keto acid 6, followed by methylation to yield ester 7. Baeyer-Villiger oxidation using m-CPBA in 1,2-dichloroethane at elevated temperatures resulted in the smooth conversion of 7 to 8 in moderate yield, and subsequent LiAlH₄-reduction and PCC-oxidation led to aldehyde 9. Wittig methylenation of 9 was performed using a combination of PPh₃CH₃Br and t-BuOK to obtain alkene 10. Then, two-step, one-carbon homologation of 10 was carried out through a cross olefin metathesis between allyltrimethylsilane and 10 to afford an E/Z mixture of allylsilane 11, followed by p-toluenesulfonic acid catalyzed protodesilylation and olefin bond migration to yield the key intermediate 5. With 5 in hand, our attention was directed toward investigation of this significant reductive coupling reaction. At first, a general procedure (3.0 equiv. of SmI₂ and 3.0 equiv. of t-BuOH in THF, at room temperature) was applied, and only a trace amount of the ketone-reduced byproduct was detected. Subsequent screening of a series of reaction conditions, including different equivalents of SmI₂, the addition of an additive (HMPA), and the switch of proton donor (MeOH), all failed to afford the cyclized product, and only the ketone-reduced product was observed (see Supporting information for details). The poor reactivity of the unactivated olefin bond and the α-quaternary ketone toward 6-exo-trig cyclization was attributed to steric congestion adjacent to the ketyl reacting center, which was also reported in Molander's work [22].

  Scheme 2

  

  Scheme 2.  Synthetic trial for the key intermediate 4.

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  It was demonstrated that the hydroxy group could coordinate to the oxophilic samarium(Ⅲ) ion to facilitate ketyl radical couplings and control the stereoselectivity [23–27]. Inspired by this finding, we devised a structure of 12 (Scheme 3a), where the allyl hydroxy group may chelate to samarium(Ⅲ) ion to fix the olefin bond close to the ketyl radical center and lower the energy barrier associated with the formation of the transition state. Selective addition of vinyl magnesium bromide to aldehyde group in 9 at −78 ℃ smoothly delivered a pair of diastereoisomer of 12 in 67% yield (d.r. = 1:1). A variety of reaction conditions were screened using 12 as the substrate. Ultimately, the addition of H₂O (Scheme 3a) as a cosolvent was revealed to be indispensable for the cyclization step, affording desired cyclization product 13 in 15% yield as a mixture of diastereomers at C6 (d.r. = 5:1), together with 7-endo-trig byproduct 14 in 30% yield. Analysis of the NMR data and X-ray crystallography results unveiled that the C10 stereocenters of 13 and 14 had opposite stereochemistry, in contrast to the assumption that the racemic stereogenicity of OH-10 in 12 would unbiasedly distribute into both of coupling products. This unique association indicated that the chelation effect of the chiral hydroxy group may distinguish a more favorable transition state at the coupling stage (6-exo vs. 7-endo), leading to obvious regioselectivity.

  Scheme 3

  

  Scheme 3.  (a) Reductive coupling of diastereomeric mixture of 12 mediated by SmI₂ in THF and H₂O. (b) Reductive coupling of two separated diastereoisomers of 12 mediated by SmI₂ in THF and H₂O.

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  To test this hypothesis, two separated diastereoisomers of 12 were tested under the same conditions. As shown in Scheme 3b, the reaction of optically pure (S)-OH 12 with SmI₂ in THF and H₂O generated 6-exo-trig 13 as a major product with a highly improved yield (56%) and diastereoselectivity (d.r. = 8:1), and the originally uncharacterized (10R)−14 and its dehydrated product 15 were also isolated in 18% and 20% yield respectively. In the case of (R)-OH 12, the 7-endo-trig cyclization afforded 14 as the sole product in 92% yield. These results unambiguously verified that the regioselectivity of the coupling reaction was governed, to a large degree, by the stereogenicity of the hydroxy group near the olefin bond. Although some methods have been developed to achieve switchable regioselective cyclization mediated by SmI₂ [28], it was the first report that the stereogenicity of adjacent hydroxy group could manipulate the regioselectivity of reductive coupling between 6-exo and 7-endo, and a possible mechanism was proposed to illustrate this unique association.

  As shown in Scheme 4, a generally accepted mechanism of reductive coupling mediated by SmI₂ commences with single-electron reduction of a ketone by SmI₂ to form a ketyl radical anion intermediate, after which an allyl hydroxy group displaces one of the coordinated solvent molecules, and chelates to samarium(Ⅲ) ion to produce a cyclic ketyl radical anion intermediate. Then the ketyl radical is added to the olefin bond to forge a new C—C bond along with a newly formed alkyl radical. Subsequent reduction of the new radical intermediate lead to a Sm(Ⅲ) alkoxide, which abstracts a proton from a proton source (H₂O in this case) to afford the coupling products. When an (S)-OH moiety was engaged in the cycle ketyl radical intermediate, both conformers A and B were accessible, and the slight preference for 6-exo cyclization may originate from the steric hindrance imposed by the β-methyl group (depicted in B) when the terminal methylene approached to the ketyl radical center during the 7-endo cyclization. Moreover, the diastereoselectivity at C6 was attributed, as previously reported, to the hyperconjugation effect between the newly formed methylene radical and the alkyl group of the ketyl and/or electrostatic repulsion [29]. In the case of (R)-OH 12, 6-exo cyclization led to a twisted trans-bicyclo[3.3.1]cyclic system, in which distorting tension severely hampered the stability of intermediate E, making the 6-exo route a formidable pathway. In contrast, the relatively more flexible bicyclo[3.3.2]cyclic system (D) generated by 7-endo cyclization, could offset the ring strain, affording 14 as the sole coupling product.

  Scheme 4

  

  Scheme 4.  Proposed mechanism of OH-directed regioselective coupling mediated by SmI₂.

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  Having demonstrated the coordinative effect of the hydroxy group, we set out to develop an asymmetric synthesis route for (S)-OH 12. As shown in Scheme 5, a mixture of 12 was first treated with Dess-Martin periodinane to afford α,β-unsaturated ketone 16, and then, asymmetric reduction of the conjugated carbonyl was achieved by BH₃ in the presence of 2-Me-(R)-CBS catalyst [30], furnishing (7R*,10S)-diol 17. Selective protection of allyl hydroxy alcohol using 1.3 equiv. of TESCl at −78 ℃ in DCM/DMF led to 18 in modest yield. And the undesired 7-mono- and 7,10-disilylation byproducts were hydrolyzed under 5% TFA in THF and H₂O to recycle the substrate. After three cycles, 18 was afforded in a total 75% yield, and sequential oxidation and deprotection smoothly produced the single diastereoisomer (S)-OH 19, from which key intermediate 13 was successfully prepared at the gram scale.

  Scheme 5

  

  Scheme 5.  Synthetic route of illihenin A (1).

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  Then, the secondary hydroxy group at C-10 in 13 was proposed to be deoxygenated according to Barton's protocol [31]. Unfortunately, trials using thiocarbonates (CS₂, MeI, and NaH) led to low yield and poor reproducibility, which may be due to interference from C7-OH. After a lot of attempts, thioacylation by (thiobenzoylthio)acetic acid and NaH in refluxing THF [32] smoothly afforded thiobenzoic ester 20 which was then reduced by a combination of n-Bu₃SnH and AIBN to obtain 4 in satisfactory yield (78%, two steps). The C7-C5 bond in 4 was cleaved with a Pb(OAc)₄—Cu(OAc)₂-pyridine system, and spirocyclic 3 was successfully obtained. However, the subsequent hydroboration-oxidation of 3 to install C13-OH gave only a pair of C7 diastereoisomers 21a and 21b with an undesired R configuration at C-5, which was determined from X-ray crystallographic analyses. This overwhelming stereoselectivity may have resulted from the bulky cyclohexanone shielding the Re face of olefin bond from the BH₃ addition. To circumvent this problem, we resorted to base-catalyzed α-epimerization of aldehyde 2 in the Aldol condensation step to facilitate inversion of the stereochemistry at C-5 to the desired S configuration. Thus, the mixture of diols 21a and 21b was subjected to Dess-Martin oxidation to obtain a keto aldehyde intermediate which was used as the substate for the crucial Aldol reaction. To our satisfaction, only a pair of cyclized products 22a and 22b, which resulted from the complete stereochemical inversion of C5 (Scheme 5), were produced in 60% yield (d.r. = 1:1) after treatment with the catalytic amounts of TBD at 50 ℃, and their configurations were confirmed by NMR data (Figs. S64-S72, Tables S3 and S4 in Supporting information) of the benzoylated derivatives of 22a and 22b and the ROESY spectrum of the latter (Fig. S72). To the end, both epimers of 22a and 22b (Scheme 5, paths a or b) were tailored to be benzoylated under different conditions to afford illihenin A in a combined yield of 82%.

  DFT calculations were carried out with the VASP code (see Supporting information) to elucidate the chiral inversion in this cyclization. As shown in Fig. 1, upon catalysis of TBD, the aldehyde (5R)−2, which was prepared from 21a and 21b, could feasibly epimerize into 2 through multistep tautomerization, which was found to be exothermic by 35.6 kJ/mol. In addition, the calculated energy barrier of intramolecular cyclization for both (5R)−2 and 2 suggested the activation energy of TS1 from (5R)−2 was 101.2 kJ/mol higher than that of TS2 from 2. This may be attributed to the spatial repulsion between C5-CH₃ and the cyclohexane ring in TS1, whereas C5-CH₃ in TS2 stretched out the molecule away from the cyclohexane ring, resulting in a lower energy barrier. These calculations rationalize why S23 was not observed in the Aldol condensation step and showed the origins of chiral inversion at C-5 in 21a and 21b (Fig. 1).

  Figure 1

  

  Figure 1.  DFT calculation of aldol reaction.

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  Having achieved the synthesis of illihenin A, we evaluated the inhibitory effect of illihenin A on the replication of CVB3. As shown in Fig. 2A, illihenin A decreased the level of VP1 mRNA in a dose dependent manner in HCT-8 and Vero cells. Similarly, illihenin A treatment dose-dependently decreased virus yields in HCT-8 and Vero cells (Fig. 2B). CVB3 virus infection reportedly induces reactive oxygen species (ROS) production and apoptosis in host cells to promote virus replication [33–35], therefore, we investigated the effect of illihenin A on the production of ROS induced by CVB3.

  Figure 2

  

  Figure 2.  Antiviral activity of illihenin A against CVB3. (A, B) Vero and HCT-8 cells were infected with CVB3 (MOI = 0.1) for 1 h and then cultured in the medium supplemented with various concentrations of illihenin A for 24 h. The cells were harvested for qRT-PCR assay (A) and viral titers detection by cytopathic effect (CPE) assay (B). *P < 0.05, ** P < 0.01, and ***P < 0.001 by one-way ANOVA with Holm-Sidak multiple comparisons test, compared with control group.

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  As shown in Fig. 3A, ROS production was detected in HCT-8 cells at 12 h post CVB3 infection, while illihenin A significantly inhibited CVB3-induced ROS production. Then, we examined the effect of illihenin A on CVB3-induced apoptosis using cleaved caspase 3 as an indicator. It was found that CVB3 infection induced the activation of caspase 3 in HCT-8 cells, and illihenin A significantly inhibited the production of cleaved caspase 3 (Fig. 3B). Consistent with the observation of caspase 3 activation, we found partial chromatin condensation and nucleus lysis into fragments after CVB3 infection, which were significantly inhibited by illihenin A treatment (Fig. 3C). These results indicated that illihenin A can inhibit CVB3 replication by inhibiting the ROS production and apoptosis induced by CVB3 infection.

  Figure 3

  

  Figure 3.  Illihenin A inhibits ROS production and apoptosis induced by CVB3 infection. (A) HCT-8 cells were infected with CVB3 (MOI = 0.1) for 1 h and treated with illihenin A for 12 h. ROS production in the cells was detected with a ROS assay kit. (B, C) HCT-8 cells were infected with CVB3 (MOI = 0.1) for 1 h and treated with illihenin A for 24 h. The cells were harvested for Western blot (B) or the nucleus was stained using hochest and observed via a fluorescence microscopy (C). *P < 0.05 compared with the CVB3 group by Student's t-test.

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  In summary, we developed a novel ring-reorganization strategy for the first asymmetric synthesis of illihenin A from the commercially available terpene(-)-α-cedrene in 19 steps. The unique SmI₂-mediated regioselective cyclization controlled by intramolecular coordinative effect in this synthetic process was reported for the first time, providing an alternative method to enforce the inactivated substrate. Meanwhile, a sequential disassembly-reassembly procedure efficiently facilitated skeletal conversion and stereochemical installation. This semisynthetic endeavor demonstrated the potential of skeletal rearrangement approach, starting from an inexpensive chiral-pool feedstock, and leading to the efficient synthesis of complex natural products. Furthermore, a preliminary study revealed that the antiviral activity of the natural product results from its inhibitory effect on the ROS production and apoptosis induced by CVB3. Future studies, including investigations of potential biological target and synthesis of analogues may contribute to the development of more potent antiviral agents.

  Declaration of interest statement

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Wen-Rui Li: Writing – original draft, Validation, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Ru-Bing Wang: Writing – review & editing, Methodology, Formal analysis. Huiqiang Wang: Writing – original draft, Validation, Investigation, Data curation. Jin-Yao Yong: Formal analysis, Data curation. Yu-Huan Li: Supervision, Resources, Formal analysis. Shi-Shan Yu: Writing – review & editing, Supervision, Resources, Project administration, Formal analysis, Conceptualization. Shuang-Gang Ma: Writing – review & editing, Supervision, Resources, Project administration, Funding acquisition, Formal analysis, Conceptualization.

  Acknowledgments

  This research financially supported by the National Natural Science Foundation of China (No. 22177135) and the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2023-I2M-2-006). We are grateful to the State Key Laboratory of Natural and Biomimetic Drugs of Peking University for the X-ray crystallographic measurements and analyses.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2025.110945.

  
  
• 1. [1]

     B.M. Fraga, Nat. Prod. Rep. 29 (2012) 1334. doi: 10.1039/c2np20074k

  2. [2]

     T. Abu-Izneid, A. Rauf, M.A. Shariati, et al., Pharmacol. Res. 161 (2020) 105165. doi: 10.1016/j.phrs.2020.105165

  3. [3]

     D. Chen, J. Li, X. Xu, et al., Chin. Chem. Lett. 35 (2024) 109451. doi: 10.1016/j.cclet.2023.109451

  4. [4]

     J. Li, Z. Cui, Y. Li, et al., Chin. Chem. Lett. 35 (2022) 4257–4260.

  5. [5]

     T.J. Maimone, P.S. Baran, NatChemBio 3 (2007) 396–407. doi: 10.1038/nchembio.2007.1

  6. [6]

     A. Kanwal, M. Bilal, N. Rasool, et al., Pharmaceuticals 15 (2022) 1392. doi: 10.3390/ph15111392

  7. [7]

     X. Cheng, G.C. Micalizio, J. Am. Chem. Soc. 138 (2016) 1150–1153. doi: 10.1021/jacs.5b12694

  8. [8]

     Y. Zhu, J. Zheng, P.A. Evans, J. Am. Chem. Soc. 145 (2023) 3833–3838. doi: 10.1021/jacs.2c10923

  9. [9]

     C. Etling, G. Tedesco, A. Di Marco, et al., J. Am. Chem. Soc. 145 (2023) 7021–7029. doi: 10.1021/jacs.3c01262

  10. [10]

      Z.G. Brill, M.L. Condakes, C.P. Ting, et al., Chem. Rev. 117 (2017) 11753–11795. doi: 10.1021/acs.chemrev.6b00834

  11. [11]

      J. Kühlborn, J. Groß, T. Opatz, Nat. Prod. Rep. 37 (2020) 380–424. doi: 10.1039/c9np00040b

  12. [12]

      R.F. Lusi, M.A. Perea, R. Sarpong, Acc. Chem. Res. 55 (2022) 746–758. doi: 10.1021/acs.accounts.1c00783

  13. [13]

      C.S. Harmange Magnani, D.Q. Thach, K.T. Haelsig, et al., Acc. Chem. Res. 53 (2020) 949–961. doi: 10.1021/acs.accounts.0c00055

  14. [14]

      K. Hung, M.L. Condakes, T. Morikawa, et al., J. Am. Chem. Soc. 138 (2016) 16616–16619. doi: 10.1021/jacs.6b11739

  15. [15]

      M.L. Condakes, K. Hung, S.J. Harwood, et al., J. Am. Chem. Soc. 139 (2017) 17783–17786. doi: 10.1021/jacs.7b11493

  16. [16]

      K. Hung, M.L. Condakes, L.F.T. Novaes, et al., J. Am. Chem. Soc. 141 (2019) 3083–3099. doi: 10.1021/jacs.8b12247

  17. [17]

      J.-Y. Yong, W.-R. Li, X. Wang, et al., J. Org. Chem. 86 (2021) 2017–2022. doi: 10.1021/acs.joc.0c02727

  18. [18]

      D.J. Edmonds, D. Johnston, D.J. Procter, Chem. Rev. 104 (2004) 3371–3404. doi: 10.1021/cr030017a

  19. [19]

      K.C. Nicolaou, S.P. Ellery, J.S. Chen, Angew. Chem. Int. Ed. 48 (2009) 7140–7165. doi: 10.1002/anie.200902151

  20. [20]

      M. Szostak, N.J. Fazakerley, D. Parmar, et al., Chem. Rev. 114 (2014) 5959–6039. doi: 10.1021/cr400685r

  21. [21]

      Y. Gao, D. Ma, Nat. Synth. 1 (2022) 275–288. doi: 10.1038/s44160-022-00046-z

  22. [22]

      G.A. Molander, J.A. McKie, J. Org. Chem. 60 (1995) 872–882. doi: 10.1021/jo00109a018

  23. [23]

      M. Kawatsura, F. Matsuda, H. Shirahama, J. Org. Chem. 59 (1994) 6900–6901. doi: 10.1021/jo00102a010

  24. [24]

      F. Matsuda, J. Syn. Org. Chem. Jpn. 53 (1995) 987–998. doi: 10.5059/yukigoseikyokaishi.53.987

  25. [25]

      F. Matsuda, M. Kawatsura, K. Hosaka, et al., Chem. Eur. J. 5 (1999) 3252–3259. doi: 10.1002/(SICI)1521-3765(19991105)5:11<3252::AID-CHEM3252>3.0.CO;2-D

  26. [26]

      T. Kan, S. Nara, T. Ozawa, et al., Angew. Chem. Int. Ed. 39 (2000) 355–357. doi: 10.1002/(SICI)1521-3773(20000117)39:2<355::AID-ANIE355>3.0.CO;2-U

  27. [27]

      T. Kan, S. Hosokawa, S. Nara, et al., J. Org. Chem. 69 (2004) 8956–8958. doi: 10.1021/jo049203m

  28. [28]

      T.K. Hutton, K.W. Muir, D.J. Procter, Org. Lett. 5 (2003) 4811–4814. doi: 10.1021/ol0358399

  29. [29]

      A.L.J. Beckwith, Tetrahedron 37 (1981) 3073–3100. doi: 10.1016/S0040-4020(01)98839-8

  30. [30]

      E.J. Corey, C.J. Helal, Angew. Chem. Int. Ed. 37 (1998) 1986–2012. doi: 10.1002/(SICI)1521-3773(19980817)37:15<1986::AID-ANIE1986>3.0.CO;2-Z

  31. [31]

      S.W. McCombie, W.B. Motherwell, M.J. Tozer, The Barton-McCombie reaction, in: S. E. Denmark, Organic Reactions, John Wiley & Sons, 2012, pp. 161–432.

  32. [32]

      D.H.R. Barton, M. Bolton, P.D. Magnus, et al., J. Chem. Soc., Perkin Trans. 1 (1973) 1574–1579.

  33. [33]

      J. Chi, S. Yu, C. Liu, et al., Biochem. Biophys. Res. Commun. 503 (2018) 1641–1644. doi: 10.1016/j.bbrc.2018.07.093

  34. [34]

      B. Han, T. Wang, Z. Xue, et al., Int. J. Nanomed. 16 (2021) 6035–6048. doi: 10.2147/ijn.s327094

  35. [35]

      W. Li, M. Chen, L. Xu, et al., RSC Adv. 9 (2019) 1222–1229. doi: 10.1039/c8ra08662a

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  Scheme 1  Outline of the ring-reorganization synthetic plan and retrosynthetic analysis of illihenin A (1).

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  Scheme 2  Synthetic trial for the key intermediate 4.

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  Scheme 3  (a) Reductive coupling of diastereomeric mixture of 12 mediated by SmI₂ in THF and H₂O. (b) Reductive coupling of two separated diastereoisomers of 12 mediated by SmI₂ in THF and H₂O.

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  Scheme 4  Proposed mechanism of OH-directed regioselective coupling mediated by SmI₂.

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  Scheme 5  Synthetic route of illihenin A (1).

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  Figure 1  DFT calculation of aldol reaction.

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  Figure 2  Antiviral activity of illihenin A against CVB3. (A, B) Vero and HCT-8 cells were infected with CVB3 (MOI = 0.1) for 1 h and then cultured in the medium supplemented with various concentrations of illihenin A for 24 h. The cells were harvested for qRT-PCR assay (A) and viral titers detection by cytopathic effect (CPE) assay (B). *P < 0.05, ** P < 0.01, and ***P < 0.001 by one-way ANOVA with Holm-Sidak multiple comparisons test, compared with control group.

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  Figure 3  Illihenin A inhibits ROS production and apoptosis induced by CVB3 infection. (A) HCT-8 cells were infected with CVB3 (MOI = 0.1) for 1 h and treated with illihenin A for 12 h. ROS production in the cells was detected with a ROS assay kit. (B, C) HCT-8 cells were infected with CVB3 (MOI = 0.1) for 1 h and treated with illihenin A for 24 h. The cells were harvested for Western blot (B) or the nucleus was stained using hochest and observed via a fluorescence microscopy (C). *P < 0.05 compared with the CVB3 group by Student's t-test.

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