Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Collective synthesis of 1,2,4-trisubstituted, meta- and ortho-substituted arene bioisosteres from bicyclobutanes

Nature Chemistry (2026)Cite this article

Subjects

Abstract

Replacing benzene rings with C(sp3)-rich bioisosteres to yield compounds with improved drug-like properties is an attractive strategy in medicinal chemistry. While many caged hydrocarbons have been validated as bioisosteres of ortho- and meta-disubstituted benzenes, 3D analogues of 1,2,4-trisubstituted benzenes—the second most prevalent benzenoid pattern in drugs—remain elusive because vector fidelity and enantioselective access are still formidable challenges. Here we report a practical route to (enantiomerically pure) 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) by cycloadditions of bicyclo[1.1.0]butanes with 1,4-dithiane-2,5-diol. This method produces cycloadducts with two and three exit vectors, which serve as promising bioisosteres for ortho-substituted and 1,2,4-trisubstituted benzenes, respectively. Moreover, the cycloadducts can be transformed into a diverse chemical space, including 1,5-disubstituted thiabicyclo[3.1.1]heptenes. Crystallographic analysis and a comparison of the pharmacokinetic properties, along with an evaluation of the biological activity of diflunisal, salicylanilide and the anticancer drug sonidegib, in relation to their 3D thia-BCHep analogues, demonstrate that the thia-BCHeps obtained can provide new surrogates for 1,2,4-trisubstituted, meta- and ortho-substituted benzene rings in drug discovery programmes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Collective and tailorable synthesis of ortho-, meta- and 1,2,4-trisubstituted benzene bioisosteres.
Fig. 2: Density functional theory calculations and proposed mechanism.
Fig. 3: Gram-scale reaction and downstream transformations.
Fig. 4: Preparation of the thia-BCHep-containing drug analogues.
Fig. 5: Geometric and physicochemical comparison of thia-BCHep scaffolds versus substituted benzenes with biological evaluation.

Similar content being viewed by others

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2470121 (for (S)-3k), 2412757 (for (R)-7a), 2412760 (for 24), 2470119 (for S9), 2412872 (for 27) and 2412761 (for 29). Copies of the data can be obtained free of charge at https://www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within the Article and its Supplementary Information, which include synthetic procedures, characterization data, nuclear magnetic resonance spectra, HPLC traces, computational details, biological studies, and evaluations of physicochemical and pharmacokinetic properties.

References

  1. Meanwell, N. A. Improving drug design: an update on recent applications of efficiency metrics, strategies for replacing problematic elements, and compounds in nontraditional drug space. Chem. Res. Toxicol. 29, 564–616 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Shearer, J., Castro, J. L., Lawson, A. D. G., MacCoss, M. & Taylor, R. D. Rings in clinical trials and drugs: present and future. J. Med. Chem. 65, 8699–8712 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ritchie, T. J. & Macdonald, S. J. F. The impact of aromatic ring count on compound developability—are too many aromatic rings a liability in drug design?. Drug Discov. Today 14, 1011–1020 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Tsien, J., Hu, C., Merchant, R. R. & Qin, T. Three-dimensional saturated C(sp3)-rich bioisosteres for benzene. Nat. Rev. Chem. 8, 605–627 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mykhailiuk, P. K. Saturated bioisosteres of benzene: where to go next?. Org. Biomol. Chem. 17, 2839–2849 (2019).

    Article  CAS  PubMed  Google Scholar 

  6. Subbaiah, M. A. M. & Meanwell, N. A. Bioisosteres of the phenyl ring: recent strategic applications in lead optimization and drug design. J. Med. Chem. 64, 14046–14128 (2021).

    Article  CAS  PubMed  Google Scholar 

  7. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Stepan, A. F. et al. Application of the bicyclo[1.1.1]pentane motif as a nonclassical phenyl ring bioisostere in the design of a potent and orally active γ-secretase inhibitor. J. Med. Chem. 55, 3414–3424 (2012).

    Article  CAS  PubMed  Google Scholar 

  9. Pellicciari, R. et al. S)-(+)-2-(3′-Carboxybicyclo[1.1.1]pentyl)-glycine, a structurally new group I metabotropic glutamate receptor antagonist. J. Med. Chem. 39, 2874–2876 (1996).

    Article  CAS  PubMed  Google Scholar 

  10. Dilmaç, A. M., Spuling, E., de Meijere, A. & Bräse, S. Propellanes-from a chemical curiosity to ‘explosive’ materials and natural products. Angew. Chem. Int. Ed. 56, 5684–5718 (2017).

    Article  Google Scholar 

  11. Ma, X. & Pham, L. N. Selective topics in the syntheses of bicyclo[1.1.1]pentane (BCP) analogues. Asian J. Org. Chem. 9, 8–22 (2020).

    Article  CAS  Google Scholar 

  12. Shire, B. R. & Anderson, E. A. Conquering the synthesis and functionalization of bicyclo[1.1.1]pentanes. JACS Au 3, 1539–1553 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gianatassio, R. et al. Strain-release amination. Science 351, 241–246 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ripenko, V. et al. Light-enabled scalable synthesis of bicyclo[1.1.1]pentane halides and their functionalizations. Nat. Synth. 3, 1538–1549 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chalmers, B. A. et al. Validating Eaton’s hypothesis: cubane as a benzene bioisostere. Angew. Chem. Int. Ed. 55, 3580–3585 (2016).

    Article  CAS  Google Scholar 

  16. Reekie, T. A., Williams, C. M., Rendina, L. M. & Kassiou, M. Cubanes in medicinal chemistry. J. Med. Chem. 62, 1078–1095 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Auberson, Y. P. et al. Improving nonspecific binding and solubility: bicycloalkyl groups and cubanes as para-phenyl bioisosteres. ChemMedChem 12, 590–598 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Levterov, V. V. et al. 2-Oxabicyclo[2.2.2]octane as a new bioisostere of the phenyl ring. Nat. Commun. 14, 5608 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao, J.-X. et al. 1,2-Difunctionalized bicyclo[1.1.1]pentanes: long-sought-after mimetics for ortho/meta-substituted aenes. Proc. Natl Acad. Sci. USA 118, e2108881118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Garry, O. L. et al. Rapid access to 2-substituted bicyclo[1.1.1]pentanes. J. Am. Chem. Soc. 145, 3092–3100 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Denisenko, A. et al. 2-Oxabicyclo[2.1.1]hexanes as saturated bioisosteres of the ortho-substituted phenyl ring. Nat. Chem. 15, 1155–1163 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Denisenko, A., Garbuz, P., Shishkina, S. V., Voloshchuk, N. M. & Mykhailiuk, P. K. Saturated bioisosteres of ortho-substituted benzenes. Angew. Chem. Int. Ed. 59, 20515–20521 (2020).

    Article  CAS  Google Scholar 

  23. Agasti, S. et al. A catalytic alkene insertion approach to bicyclo[2.1.1]hexane bioisosteres. Nat. Chem. 15, 535–541 (2023).

    Article  CAS  PubMed  Google Scholar 

  24. Levterov, V. V. et al. 2-Oxabicyclo[2.1.1]hexanes: synthesis, properties, and validation as bioisosteres of ortho- and meta-benzenes. Angew. Chem. Int. Ed. 63, e202319831 (2024).

    Article  CAS  Google Scholar 

  25. Levterov, V. V., Panasyuk, Y., Pivnytska, V. O. & Mykhailiuk, P. K. Water-soluble non-classical benzene mimetics. Angew. Chem. Int. Ed. 59, 7161–7167 (2020).

    Article  CAS  Google Scholar 

  26. Frank, N. et al. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. Nature 611, 721–726 (2022).

    Article  CAS  PubMed  Google Scholar 

  27. Iida, T. et al. Practical and facile access to bicyclo[3.1.1]heptanes: potent bioisosteres of meta-substituted benzenes. J. Am. Chem. Soc. 144, 21848–21852 (2022).

    Article  CAS  PubMed  Google Scholar 

  28. Wiesenfeldt, M. P. et al. General access to cubanes as benzene bioisosteres. Nature 618, 513–518 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Smith, E. et al. Silver(I)-catalyzed synthesis of cuneanes from cubanes and their investigation as isosteres. J. Am. Chem. Soc. 145, 16365–16373 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Son, J.-Y. et al. Exploring cuneanes as potential benzene isosteres and energetic materials: scope and mechanistic investigations into regioselective rearrangements from cubanes. J. Am. Chem. Soc. 145, 16355–16364 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Fujiwara, K. et al. Biological evaluation of isosteric applicability of 1,3-substituted cuneanes as m-substituted benzenes enabled by selective isomerization of 1,4-substituted cubanes. Chem. Eur. J. 30, e202303548 (2023).

    Article  Google Scholar 

  32. Epplin, R. C. et al. 2]-Ladderanes as isosteres for meta-substituted aromatic rings and rigidified cyclohexanes. Nat. Commun. 13, 6056 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang, M. et al. Catalytic asymmetric synthesis of meta benzene isosteres. Nature 633, 90–95 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yang, Y. et al. An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates. Nat. Chem. 13, 950–955 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang, Y. et al. Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates. Nat. Chem. 16, 285–293 (2024).

    Article  CAS  PubMed  Google Scholar 

  36. Bychek, R. & Mykhailiuk, P. K. A practical and scalable approach to fluoro-substituted bicyclo[1.1.1]pentanes. Angew. Chem. Int. Ed. 61, e202205103 (2022).

    Article  CAS  Google Scholar 

  37. Reinhold, M. et al. Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space. Chem. Sci. 14, 9885–9891 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Harmata, A. S., Spiller, T. E., Sowden, M. J. & Stephenson, C. R. J. Photochemical formal (4+2)-cycloaddition of imine-substituted bicyclo[1.1.1]pentanes and alkenes. J. Am. Chem. Soc. 143, 21223–21228 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li, Y.-J. et al. Catalytic intermolecular asymmetric [2π + 2σ] cycloadditions of bicyclo[1.1.0]butanes: practical synthesis of enantioenriched highly substituted bicyclo[2.1.1]hexanes. J. Am. Chem. Soc. 146, 34427–34441 (2024).

    Article  CAS  PubMed  Google Scholar 

  40. Nilova, A., Campeau, L.-C., Sherer, E. C. & Stuart, D. R. Analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients. J. Med. Chem. 63, 13389–13396 (2020).

    Article  CAS  PubMed  Google Scholar 

  41. Zhang, Y. et al. Photochemical intermolecular [3σ+2σ]-cycloaddition for the construction of aminobicyclo[3.1.1]heptanes. J. Am. Chem. Soc. 144, 23685–23690 (2022).

    Article  Google Scholar 

  42. Yu, T. et al. Selective [2σ+2σ] cycloaddition enabled by boronyl radical catalysis: synthesis of highly substituted bicyclo[3.1.1]heptanes. J. Am. Chem. Soc. 145, 4304–4310 (2023).

    Article  CAS  Google Scholar 

  43. Nguyen, T. V. T., Bossonnet, A., Wodrich, M. D. & Waser, J. Photocatalyzed [2σ+2σ] and [2σ+2π] cycloadditions for the synthesis of bicyclo[3.1.1]heptanes and 5- or 6-membered carbocycles. J. Am. Chem. Soc. 145, 25411–25421 (2023).

    Article  CAS  PubMed  Google Scholar 

  44. Lin, Z. et al. Synthesis of azabicyclo[3.1.1]heptenes enabled by catalyst-controlled annulations of bicyclo[1.1.0]butanes with vinyl azides. J. Am. Chem. Soc. 146, 18565–18575 (2024).

    Article  CAS  PubMed  Google Scholar 

  45. Liu, Y. et al. Pyridine-boryl radical-catalyzed [3π+2σ] cycloaddition for the synthesis of pyridine isosteres. Chem 10, 1–10 (2024).

    Article  Google Scholar 

  46. Zhou, J.-L. et al. Palladium-catalyzed ligand-controlled switchable hetero-(5+3)/enantioselective [2σ+2σ] cycloadditions of bicyclobutanes with vinyl oxiranes. J. Am. Chem. Soc. 146, 19621–19628 (2024).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, X., Gao, R. & Li, X. Catalytic asymmetric construction of chiral polysubstituted 3‑azabicyclo[3.1.1]heptanes by copper-catalyzed stereoselective formal [4π+2σ] cycloaddition. J. Am. Chem. Soc. 146, 21069–21077 (2024).

    Article  CAS  PubMed  Google Scholar 

  48. Dutta, S. et al. Formal [2σ+2σ]-cycloaddition of aziridines with bicyclo[1.1.0]butanes: access to enantiopure 2‑azabicyclo[3.1.1]heptane derivatives. J. Am. Chem. Soc. 146, 27204–27212 (2024).

    Article  CAS  PubMed  Google Scholar 

  49. Zhang, J. et al. Eu(OTf)3-catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones: access to polysubstituted 2-oxa-3-azabicyclo[3.1.1]heptanes. Angew. Chem. Int. Ed. 63, e202318476 (2024).

    Article  CAS  Google Scholar 

  50. Wu, W.-B. et al. Enantioselective formal (3+3) cycloaddition of bicyclobutanes with nitrones enabled by asymmetric Lewis acid catalysis. Nat. Commun. 15, 8005 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang, X.-G. et al. Copper-catalyzed enantioselective [4π+2σ] cycloaddition of bicyclobutanes with nitrones. J. Am. Chem. Soc. 146, 27274–27281 (2024).

    Article  CAS  PubMed  Google Scholar 

  52. George, M. et al. Double strain-release (3+3)-cycloaddition: Lewis Acid catalyzed reaction of bicyclobutane carboxylates and aziridines. Chem. Eur. J. 31, e202404099 (2024).

    Article  PubMed  Google Scholar 

  53. Chintawar, C.-C. et al. Photoredox-catalysed amidyl radical insertion to bicyclo[1.1.0]butanes. Nat. Catal. 7, 1232–1242 (2024).

    Article  CAS  Google Scholar 

  54. Golfmann, M. & Walker, J. C. L. Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis. Commun. Chem. 6, 9 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sujansky, S. J. & Ma, X. Reaction paradigms that leverage cycloaddition and ring strain to construction bicyclic aryl bioisosteres from bicyclo[1.1.0]butanes. Asian J. Org. Chem. 13, e202400045 (2024).

    Article  CAS  Google Scholar 

  56. Kleinmans, R. et al. Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer. Nature 605, 477–482 (2022).

    Article  CAS  PubMed  Google Scholar 

  57. Guo, R. et al. Strain-release [2π+2σ] cycloadditions for the synthesis of bicyclo[2.1.1]hexanes initiated by energy transfer. J. Am. Chem. Soc. 144, 7988–7994 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wang, H. et al. Dearomative ring expansion of thiophenes by bicyclobutane insertion. Science 381, 75–81 (2023).

    Article  CAS  PubMed  Google Scholar 

  59. Dhake, K. et al. Beyond bioisosteres: divergent synthesis of azabicyclohexanes and cyclobutenyl amines from bicyclobutanes. Angew. Chem. Int. Ed. 61, e202204719 (2022).

    Article  CAS  Google Scholar 

  60. Wipf, P. et al. Pericyclic cascade reactions of (bicyclo[1.1.0]butylmethyl)amines. Angew. Chem. Int. Ed. 45, 4172–4175 (2006).

    Article  CAS  Google Scholar 

  61. Ni, D. et al. Intermolecular formal cycloaddition of indoles with bicyclo[1.1.0]butanes by Lewis acid catalysis. Angew. Chem. Int. Ed. 62, e202308606 (2023).

    Article  CAS  Google Scholar 

  62. Yang, L. et al. B(C6F5)3‑catalyzed formal (n + 3) (n = 5 and 6) cycloaddition of bicyclo[1.1.0]butanes to medium bicyclo[n.1.1]alkanes. Org. Lett. 26, 4104–4110 (2024).

    Article  CAS  PubMed  Google Scholar 

  63. Hu, Q.-Q. et al. Lewis acid catalyzed cycloaddition of bicyclobutanes with ynamides for the synthesis of polysubstituted 2-aminobicyclo[2.1.1]hexenes. Angew. Chem. Int. Ed. 63, e202405781 (2024).

    Article  CAS  Google Scholar 

  64. Liu, Y. et al. Titanium catalyzed [2σ+2π] cycloaddition of bicyclo[1.1.0]-butanes with 1,3-dienes for efficient synthesis of stilbene bioisosteres. Nat. Commun. 15, 4374 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. de Robichon, M. et al. Enantioselective, intermolecular [π2+σ2] photocycloaddition reactions of 2(1H)-quinolones and bicyclo[1.1.0]butanes. J. Am. Chem. Soc. 145, 24466–24470 (2023).

    Article  Google Scholar 

  66. Fu, Q. et al. Enantioselective [2π+2σ] cycloadditions of bicyclo[1.1.0]butanes with vinylazaarenes through asymmetric photoredox catalysis. J. Am. Chem. Soc. 146, 8372–8380 (2024).

    Article  CAS  PubMed  Google Scholar 

  67. Jeong, J. et al. Divergent enantioselective access to diverse chiral compounds from bicyclo[1.1.0]butanes and α,β-unsaturated ketones under catalyst control. J. Am. Chem. Soc. 146, 27830–27842 (2024).

    Article  CAS  PubMed  Google Scholar 

  68. Reissig, H.-U. & Zimmer, R. Donor-acceptor-substituted cyclopropane derivatives and their application in organic synthesis. Chem. Rev. 103, 1151–1196 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Schneider, T. F. et al. A new golden age for donor–acceptor cyclopropanes. Angew. Chem. Int. Ed. 53, 5504–5523 (2014).

    Article  CAS  Google Scholar 

  70. Oku, A., Abe, M. & Iwamoto, M. Electron transfer profile of cyclopropanone acetals in the nonirradiated reaction with tetracyanoethylene, chloranil, and dicy anodichlorobenzoquinone. J. Org. Chem. 59, 7445–7452 (1994).

    Article  CAS  Google Scholar 

  71. Scott, K. A. & Njardarson, J. T. Analysis of US FDA‑approved drugs containing sulfur atoms. Top Curr. Chem (Z). 376, 5 (2018).

    Article  Google Scholar 

  72. Mustafa, M. & Winum, J.-Y. The importance of sulfur-containing motifs in drug design and discovery. Expert Opin. Drug Dis. 17, 501–512 (2022).

    Article  CAS  Google Scholar 

  73. Feng, M. et al. Sulfur containing scaffolds in drugs: synthesis and application in medicinal chemistry. Curr. Top. Med. Chem. 16, 1200–1216 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Pathania, S. et al. Role of sulphur-heterocycles in medicinal chemistry: An update. Eur. J. Med. Chem. 180, 486–508 (2019).

    Article  CAS  PubMed  Google Scholar 

  75. Regueiro-Ren, A. Cyclic sulfoxides and sulfones in drug design. Adv. Heterocycl. Chem. 134, 1–30 (2021).

    Google Scholar 

  76. Beno, B. R. et al. A survey of the role of noncovalent sulfur interactions in drug design. J. Med. Chem. 58, 4383–4438 (2015).

    Article  CAS  PubMed  Google Scholar 

  77. Dibchak, D. et al. General synthesis of 3-azabicyclo[3.1.1]heptanes and evaluation of their properties as saturated isosteres. Angew. Chem. Int. Ed. 62, e202304246 (2023).

    Article  CAS  Google Scholar 

  78. Wang, M. & Jiang, X. Prospects and challenges in organosulfur chemistry. ACS Sustain. Chem. Eng. 10, 671–677 (2022).

    Article  CAS  Google Scholar 

  79. Kosuge, S., Hamanaka, N. & Hayashi, M. Synthesis of thromboxane A2 analog DL-(9,11), (11,12)-dideoxa-(9,11)-methylene-(11,12)-epithio-thromboxane A2 methyl ester. Tetrahedron Lett. 22, 1345–1348 (1981).

    Article  CAS  Google Scholar 

  80. Garrido-García, P. et al. Enantioselective photocatalytic synthesis of bicyclo[2.1.1]hexanes as ortho-disubstituted benzene bioisosteres with improved biological activity. Nat. Chem. 17, 734–745 (2025).

    Article  PubMed  Google Scholar 

  81. Pitzer, L., Schäfers, F. & Glorius, F. Rapid assessment of the reaction-condition-based sensitivity of chemical transformations. Angew. Chem. Int. Ed. 58, 8572–8576 (2019).

    Article  CAS  Google Scholar 

  82. Lee, C., Yang, W. & Parr, R. G. Development of the Colle–Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev. B 37, 785–789 (1988).

    Article  CAS  Google Scholar 

  83. Becke, A. D. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys. 98, 5648–5652 (1993).

    Article  CAS  Google Scholar 

  84. Grimme, S., Antony, J., Ehrlich, S. & Krieg, H. A consistent and accurate ab initio parametrization of density functional dispersion correction (DFT-D) for the 94 elements H–Pu. J. Chem. Phys. 132, 154104 (2010).

    Article  PubMed  Google Scholar 

  85. Legault, C. Y. CYLview, 1.0b (Université de Sherbrooke, 2009).

  86. Wu, F. et al. Zinc-catalyzed enantioselective formal (3+2) cycloadditions of bicyclobutanes with imines: catalytic asymmetric synthesis of azabicyclo[2.1.1]hexanes. Angew. Chem. Int. Ed. 63, e202406548 (2024).

    Article  CAS  Google Scholar 

  87. Bickelhaupt, F. M. & Houk, K. N. Analyzing reaction rates with the distortion/interaction-activation strain model. Angew. Chem. Int. Ed. 56, 10070–10086 (2017).

    Article  CAS  Google Scholar 

  88. Lee, C.-C. et al. Discovery of 5-(2′,4′-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. Eur. J. Med. Chem. 98, 115–126 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Li, Q.-R. et al. Novel-smoothened inhibitors for therapeutic targeting of naïve and drug-resistant hedgehog pathway-driven cancers. Acta Pharmacol. Sin. 40, 257–267 (2019).

    Article  CAS  PubMed  Google Scholar 

  90. Yang, L., Xie, G., Fan, Q. & Xie, J. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 29, 469–481 (2010).

    Article  PubMed  Google Scholar 

  91. Wang, F., Stappenbeck, F. & Parhami, F. Inhibition of hedgehog signaling in fibroblasts, pancreatic, and lung tumor cells by oxy186, an oxysterol analogue with drug-like properties. Cells 8, 509 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Ma, C. et al. Molecular mechanisms involving the Sonic Hedgehog pathway in lung cancer therapy: recent advances. Front. Oncol. 12, 729088 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Della Corte, C. M. et al. SMO Gene amplification and activation of the hedgehog pathway as novel mechanisms of resistance to anti-epidermal growth factor receptor drugs in human lung cancer. Clin. Cancer Res. 21, 4686–4697 (2015).

    Article  PubMed  Google Scholar 

  94. Kenny, P. W. & Montanari, C. A. Inflation of correlation in the pursuit of drug-likeness. J. Comput. Aided Mol. Des. 27, 1–13 (2013).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (grant nos. 22471068 to J.-J.F. and 82371812 to W.Z.), Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (grant no. 2023B1212060022 to Y.Q.) and Key-Area Research and Development Program of Guangdong Province (grant no. 2022B1111050003 to Y.Q.). We acknowledge the robotic AI-Scientist platform of Chinese Academy of Sciences for its assistance with the theoretical calculations.

Author information

Author notes

  1. These authors contributed equally: Feng Wu, Ji-Jie Wang, Yuanjiu Xiao.

Authors and Affiliations

  1. State Key Laboratory of Chemo and Biosensing, Advanced Catalytic Engineering Research Center of the Ministry of Education, College of Chemistry and Chemical Engineering, Hunan University, Changsha, People’s Republic of China

    Feng Wu, Ji-Jie Wang, Yuanjiu Xiao, Quanxin Peng, Yu-Jie Li & Jian-Jun Feng

  2. State Key Laboratory of Anti-Infective Drug Discovery and Development, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China

    Keren Peng & Yu Qian

  3. School of Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China

    Qianlan Han & Wei Zhang

  4. Key Laboratory of Mesoscopic Chemistry of Ministry of Education, State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, People’s Republic of China

    Mengran Wei & Guoqiang Wang

Authors
  1. Feng Wu
    View author publications

    Search author on:PubMed Google Scholar

  2. Ji-Jie Wang
    View author publications

    Search author on:PubMed Google Scholar

  3. Yuanjiu Xiao
    View author publications

    Search author on:PubMed Google Scholar

  4. Quanxin Peng
    View author publications

    Search author on:PubMed Google Scholar

  5. Yu-Jie Li
    View author publications

    Search author on:PubMed Google Scholar

  6. Keren Peng
    View author publications

    Search author on:PubMed Google Scholar

  7. Qianlan Han
    View author publications

    Search author on:PubMed Google Scholar

  8. Mengran Wei
    View author publications

    Search author on:PubMed Google Scholar

  9. Yu Qian
    View author publications

    Search author on:PubMed Google Scholar

  10. Wei Zhang
    View author publications

    Search author on:PubMed Google Scholar

  11. Guoqiang Wang
    View author publications

    Search author on:PubMed Google Scholar

  12. Jian-Jun Feng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

J.-J.F. conceived and directed the project. F.W., J.-J.W. and Y.X. conducted the synthetic investigation. Q.P. and Y.-J.L. helped with the collection of some new compounds and data analysis. K.P. and Y.Q. conducted the osteoclast-inhibitory and antitumour activity studies. Q.H. and W.Z. conducted the COX-2 inhibitory activity assays, preliminary safety evaluations and molecular docking analyses. M.W. and G.W. performed the density functional theory calculations. J.-J.F., Y.Q., W.Z. and G.W. wrote the paper. All authors discussed the results and commented on the manuscript. F.W., J.-J.W. and Y.X. contributed equally to this work.

Corresponding authors

Correspondence to Yu Qian, Wei Zhang, Guoqiang Wang or Jian-Jun Feng.

Ethics declarations

Competing interests

The authors declare the following competing financial interests: J.-J.F. and J.-J.W. (Hunan University) are listed as inventors on Chinese patent application number CN202411347274.8, which covers the synthesis of ‘sp3-analogues of the antiresorptive agent 40 via (3 + 3) cycloadditions of bicyclobutanes with 1,4-dithiane-2,5-diol and medical uses thereof’ reported in this Article. The other authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information (download PDF )

Synthetic procedures, characterization data, nuclear magnetic resonance (NMR) spectra, HPLC traces, computational details, X-ray crystallographic data, determination of aqueous solubility, determination of lipophilicity (logD), determination of metabolic stability and biological studies, Supplementary Tables 1–21 and Supplementary Figs. 1–19.

Reporting Summary (download PDF )

Supplementary Data 1 (download ZIP )

Contains the Cartesian coordinates and energetic details used to generate potential-energy surfaces and dihedral-torsion energy profiles. A README.txt file with detailed descriptions of the folder contents is included in the zipped archive.

Supplementary Data 2 (download XLSX )

Physicochemical and pharmacokinetic property data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, F., Wang, JJ., Xiao, Y. et al. Collective synthesis of 1,2,4-trisubstituted, meta- and ortho-substituted arene bioisosteres from bicyclobutanes. Nat. Chem. (2026). https://doi.org/10.1038/s41557-026-02097-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41557-026-02097-7

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing