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Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates

Nature Chemistry volume 16, pages 285–293 (2024)Cite this article

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Abstract

Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure–activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.1]pentane (BCP) motif has increasingly received attention as a bioisosteric replacement of benzene rings due to its ability to improve the physicochemical properties of prospective drug candidates, but studying the SARs of C2-substituted BCPs has been heavily restricted by the need for multistep de novo synthesis of each analogue of interest. Here we report a programmable bis-functionalization strategy to enable late-stage sequential derivatization of BCP bis-boronates, opening up opportunities to explore the SARs of drug candidates possessing multisubstituted BCP motifs. Our approach capitalizes on the inherent chemoselectivity exhibited by BCP bis-boronates, enabling highly selective activation and functionalization of bridgehead (C3)-boronic pinacol esters (Bpin), leaving the C2-Bpin intact and primed for subsequent derivatization. These selective transformations of both BCP bridgehead (C3) and bridge (C2) positions enable access to C1,C2-disubstituted and C1,C2,C3-trisubstituted BCPs that encompass previously unexplored chemical space.

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Fig. 1: Significance, challenges and strategy for accessing multi-substituted BCPs.
Fig. 2: Preliminary chemoselectivity of BCP bis-boronates and theoretical explanation.
Fig. 3: Scope and synthesis of BCP bis-boronates.
Fig. 4: Syntheses of structurally divergent BCP compounds.
Fig. 5: PMIs between substituted BCPs and arenes.

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Data availability

Experimental data as well as characterization data for all new compounds prepared in the course of these studies are provided in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition nos. CCDC 2158998 (15), 2159002 (23), 2158995 (24), 2159016 (25), 2159001 (27), 2162135 (33), 2160325 (55), 2160336 (59) and 2162136 (76), see the 'X-ray crystallographic data' section in the Supplementary Information. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source Data are provided with this paper.

References

  1. 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 

  2. Talele, T. T. Opportunities for tapping into three-dimensional chemical space through a quaternary carbon. J. Med. Chem. 63, 13291–13315 (2020).

    Article  CAS  PubMed  Google Scholar 

  3. Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    Article  CAS  PubMed  Google Scholar 

  4. Costantino, G. et al. Synthesis and biological evaluation of 2-(3′-(1H-tetrazol-5-yl)bicyclo[1.1.1]pent-1-yl)glycine (S-TBPG), a novel mGlu1 receptor antagonist. Bioorg. Med. Chem. 9, 221–227 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Mikhailiuk, P. K. et al. Conformationally rigid trifluoromethyl‐substituted α‐amino acid designed for peptide structure analysis by solid‐state 19F NMR spectroscopy. Angew. Chem. Int. Ed. 45, 5659–5661 (2006).

    Article  CAS  Google Scholar 

  6. 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 

  7. Westphal, M. V., Wolfstaedter, B. T., Plancher, J., Gatfield, J. & Carreira, E. M. Evaluation of tert-butyl isosteres: case studies of physicochemical and pharmacokinetic properties, efficacies, and activities. ChemMedChem 10, 461–469 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Measom, N. D. et al. Investigation of a bicyclo[1.1.1]pentane as a phenyl replacement within an LpPLA2 Inhibitor. ACS Med. Chem. Lett. 8, 43–48 (2017).

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. Mikhaliuk, P. K. Saturated bioisoteres of benzene: where to go next? Org. Biomol. Chem. 17, 2839–2849 (2019).

    Article  Google Scholar 

  11. 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 

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

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Caputo, D. F. J. et al. Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes. Chem. Sci. 9, 5295–5300 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nugent, J. et al. A general route to bicyclo[1.1.1]pentanes through photoredox catalysis. ACS Catal. 9, 9568–9574 (2019).

    Article  CAS  Google Scholar 

  15. Zhang, X. et al. Copper-mediated synthesis of drug-like bicyclopentanes. Nature 580, 220–226 (2020).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Trongsiriwat, N. et al. Reactions of 2‐aryl‐1,3‐dithianes and [1.1.1]propellane. Angew. Chem. Int. Ed. 58, 13416–13420 (2019).

    Article  CAS  Google Scholar 

  17. Yu, S., Jing, C., Noble, A. & Aggarwal, V. K. 1,3-Difunctionalizations of [1.1.1]-propellane via 1,2-metalate rearrangements of boronate complexes. Angew. Chem. Int. Ed. 59, 3917–3921 (2020).

    Article  CAS  Google Scholar 

  18. Kim, J. H., Ruffoni, A., Al-Faiyz, Y. S. S., Sheikh, N. & Leonori, D. Divergent strain‐release amino‐functionalization of [1.1.1]propellane with electrophilic nitrogen‐radicals. Angew. Chem. Int. Ed. 59, 8225–8231 (2020).

    Article  CAS  Google Scholar 

  19. Garlets, Z. J. et al. Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes. Nat. Catal. 3, 351–357 (2020).

    Article  CAS  Google Scholar 

  20. 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 

  21. Yu, S., Jing, C., Noble, A. & Aggarwal, V. K. Iridium-catalyzed enantioselective synthesis of α-chiral bicyclo[1.1.1]pentanes by 1,3-difunctionalization of [1.1.1]propellane. Org. Lett. 22, 5650–5655 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. Polites, V. C., Badir, S. O., Keess, S., Jolit, A. & Molander, G. A. Nickel-catalyzed decarboxylative cross-coupling of bicyclo[1.1.1]pentyl radicals enabled by electron donor-acceptor complex photoactivation. Org. Lett. 23, 4828–4833 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nugent, J., Sterling, A. J., Frank, N., Mousseau, J. J. & Anderson, E. A. Synthesis of α-quaternary bicyclo[1.1.1]pentanes through synergistic organophotoredox and hydrogen atom transfer catalysis. Org. Lett. 23, 8628–8633 (2021).

    Article  CAS  PubMed  Google Scholar 

  24. Wong, M. L. J., Sterling, A. J., Mousseau, J. J., Duarte, F. & Anderson, E. A. Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes. Nat. Commun. 12, 1644 (2021).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pickford, H. D. et al. Twofold radical-based synthesis of N,C-difunctionalized bicyclo[1.1.1]pentanes. J. Am. Chem. Soc. 143, 9729–9736 (2021).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  27. Anderson, J. M., Measom, N. D., Murphy, J. A. & Poole, D. L. Bridge functionalisation of bicyclo[1.1.1]pentane derivatives. Angew. Chem. Int. Ed. 60, 24754–24769 (2021).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ma, X., Han, Y. & Bennett, D. J. Selective synthesis of 1-dialkylamino-2-alkylbicyclo-[1.1.1]pentanes. Org. Lett. 22, 9133–9138 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Ma, X., Sloman, D. L., Han, Y. & Bennett, D. J. A selective synthesis of 2,2-difluorobicyclo[1.1.1]pentane analogues:‘BCP-F2’. Org. Lett. 21, 7199–7203 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. 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 

  32. Applequist, D. E., Renken, T. L. & Wheeler, J. W. Polar substituent effects in 1,3-disubstituted bicyclo[1.1.1]pentanes. J. Org. Chem. 47, 4985–4995 (1982).

    Article  CAS  Google Scholar 

  33. Bychek, R. M. et al. Difluoro-substituted bicyclo[1.1.1]pentanes for medicinal chemistry: design, synthesis, and characterization. J. Org. Chem. 84, 15106–15117 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Ryan, E. M., Amber, L. T. & Edward, A. A. Synthesis and applications of polysubstituted bicyclo[1.1.0]butanes. J. Am. Chem. Soc. 143, 21246–21251 (2021).

    Article  Google Scholar 

  35. Buskes, M. J. & Blanco, M. J. Impact of cross-coupling reactions in drug discovery and development. Molecules 25, 3493–3514 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wiberg, K. B. & Williams, V. Z. Bicyclo[1.1.1]pentane derivatives. J. Org. Chem. 35, 369–373 (1970).

    Article  CAS  Google Scholar 

  37. Levin, M. D., Kaszynski, P. & Michl, J. Bicyclo[1.1.1]pentanes, [n]saffanes, [1.1.1]propellanes, and tricyclo[2.1.0.02,5]pentanes. Chem. Rev. 100, 169–223 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Jarret, R. M. & Cusumano, L. 13C–13C coupling in [1.1.1]propellane. Tetrahedron Lett. 31, 171–174 (1990).

    Article  CAS  Google Scholar 

  39. Mlynarski, S. N., Schuster, C. H. & Morken, J. P. Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling. Nature 505, 386–390 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  40. Blaisdell, T. P. & Morken, J. P. Hydroxyl-directed cross-coupling: a scalable synthesis of debromohamigeran E and other targets of interest. J. Am. Chem. Soc. 137, 8712 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu, X., Sun, C., Mlynarski, S. & Morken, J. P. Synthesis and stereochemical assignment of arenolide. Org. Lett. 20, 1898 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kaiser, D., Noble, A., Fasano, V. & Aggarwal, V. K. 1,2-Boron shifts of β-boryl radicals generated from bis-boronic esters using photoredox catalysis. J. Am. Chem. Soc. 141, 14104–14109 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fawcett, A. et al. Regio- and stereoselective homologation of 1,2-bis(boronic esters): stereocontrolled synthesis of 1,3-diols and Sch725674. Angew. Chem., Int. Ed. 55, 14663–14667 (2016).

    Article  CAS  Google Scholar 

  44. Nóvoa, L., Trulli, L., Parra, A. & Tortosa, M. Stereoselective diboration of spirocyclo-butenes: a platform for the synthesis of spirocycles with orthogonal exit vectors. Angew. Chem. Int. Ed. 60, 11763–11768 (2021).

    Article  Google Scholar 

  45. Crudden, C. M. et al. Iterative protecting group-free cross-coupling leading to chiral multiply arylated structures. Nat. Commun. 7, 11065–11071 (2016).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  46. Yang, Y. et al. Practical and modular construction of C(sp3)–rich alkyl boron compounds. J. Am. Soc. Chem. 143, 471–480 (2021).

    Article  CAS  Google Scholar 

  47. Qi, X., Kohler, D. G., Hull, K. L. & Liu, P. Energy decomposition analyses reveal the origins of catalyst and nucleophile effects on regioselectivity in nucleopalladation of alkenes. J. Am. Chem. Soc. 141, 11892–11904 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li, H., Wang, L., Zhang, Y. & Wang, J. Transition-metal-free synthesis of pinacol alkylboronates from tosylhydrazones. Angew. Chem. Int. Ed. 51, 2943–2946 (2012).

    Article  CAS  Google Scholar 

  49. Yang, C. T., Zhang, Z. Q., Liu, Y. C. & Liu, L. Copper-catalyzed cross-coupling reaction of organoboron compounds with primary alkyl halides and pseudohalides†. Angew. Chem. Int. Ed. 50, 3904–3907 (2011).

    Article  CAS  Google Scholar 

  50. Pozzi, D., Scanlan, E. M. & Renaud, P. A mild radical procedure for the reduction of B-alkylcatecholboranes to alkanes. J. Am. Chem. Soc. 127, 14204–14205 (2005).

    Article  CAS  PubMed  Google Scholar 

  51. André-Joyaux, E., Kuzovlev, A., Tappin, N. D. & Renaud, P. A general approach to deboronative radical chain reaction with pinacol alkylboronic esters. Angew. Chem. Int. Ed. 59, 13859–13864 (2020).

    Article  Google Scholar 

  52. Lima, F. et al. A Lewis base catalysis approach for the photoredox activation of boronic acids and esters. Angew. Chem. Int. Ed. 56, 15136–15140 (2017).

    Article  CAS  Google Scholar 

  53. Lima, F. et al. Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow. Chem. Commun. 54, 5606–5609 (2018).

    Article  CAS  Google Scholar 

  54. Lima, F. et al. Visible light activation of boronic esters enables efficient photoredox C(sp2)–C(sp3) cross-couplings in flow. Angew. Chem. Int. Ed. 55, 14085–14089 (2016).

    Article  CAS  Google Scholar 

  55. Tellis, J. C., Primer, D. N. & Molander, G. A. Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis. Science 345, 433–436 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gutierrez, O., Tellis, J. C., Primer, D. N., Molander, G. A. & Kozlowski, M. C. Nickel-catalyzed cross-coupling of photoredox-generated radicals: uncovering a general manifold for stereoconvergence in nickel-catalyzed cross-couplings. J. Am. Chem. Soc. 137, 4896–4899 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Primer, D. N. & Molander, G. A. Enabling the cross-coupling of tertiary organoboron nucleophiles through radical-mediated alkyl transfer. J. Am. Chem. Soc. 139, 9847–9850 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Yuan, M., Song, Z., Badir, S. O., Molander, G. A. & Gutierrez, O. On the nature of C(sp3)–C(sp2) bond formation in nickel-catalyzed tertiary radical cross-couplings: a case study of Ni/photoredox catalytic crosscoupling of alkyl radicals and aryl halides. J. Am. Chem. Soc. 142, 7225–7234 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Molander, G. A., Colombel, V. & Braz, V. A. Direct alkylation of heteroaryls using potassium alkyl- and alkoxymethyltrifluoroborates. Org. Lett. 13, 1852–1855 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Odachowski, M. et al. Development of enantiospecific coupling of secondary and tertiary boronic esters with aromatic compounds. J. Am. Chem. Soc. 138, 9521–9532 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Nykaza, T. V. et al. Intermolecular reductive C–N cross coupling of nitroarenes and boronic acids by PIII/PV=O catalysis. J. Am. Chem. Soc. 140, 15200–15205 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sadhu, K. M. & Matteson, D. S. (Chloromethyl)lithium: efficient generation and capture by boronic esters and a simple preparation of diisopropyl (chloromethyl)boronate. Organometallics 4, 1687–1689 (1985).

    Article  CAS  Google Scholar 

  63. Li, J., Grillo, A. S. & Burke, M. D. From synthesis to function via iterative assembly of N-methyliminodiacetic acid boronate building blocks. Acc. Chem. Res. 48, 2297–2307 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Blair, D. J. et al. Automated iterative Csp3–C bond formation. Nature 604, 92–97 (2022).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. Angell, R. M. et al. Biphenyl amide p38 kinase inhibitors 4: DFG-in and DFG-out binding modes. Bioorg. Med. Chem. Lett. 18, 4433–4437 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Sauer, W. H. & Schwarz, M. K. Molecular shape diversity of combinatorial libraries: a prerequisite for broad bioactivity. J. Chem. Inf. Comput. Sci. 43, 987–1003 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Prosser, K. E., Stokes, R. W. & Cohen, S. M. Evaluation of 3‑dimensionality in approved and experimental drug space. ACS Med. Chem. Lett. 11, 1292–1298 (2020). During manuscript editing process after it is accepted, several publications on synthesis of bridge-substituted BCPs and BCP boronates were reported.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Dong, W. et al. Exploiting the sp2 character of bicyclo[1.1.1]pentyl radicals in the transition-metal-free multi-component difunctionalization of [1.1.1]propellane. Nat. Chem. 14, 1068–1077 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yu, I. F. et al. Catalytic undirected borylation of tertiary C–H bonds in bicyclo[1.1.1]pentanes and bicyclo[2.1.1]hexanes. Nat. Chem. 15, 685–693 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wright, B. A. et al. Skeletal editing approach to bridge-functionalized bicyclo[1.1.1] pentanes from azabicyclo[2.1.1]hexanes. J. Am. Chem. Soc. 145, 0960–10966 (2023).

    Article  Google Scholar 

  71. 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 

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Acknowledgements

Financial support for this work was provided by the National Science Foundation (CAREER CHE-2143925 to T.Q.), National Institutes of Health (R01GM141088 to T.Q. and R35GM137797 to O.G.), Camille and Henry Dreyfus Foundation (to O.G.) and UT Southwestern Eugene McDermott Scholarship (to T.Q.). Preliminary results were made possible by the support of Welch Foundation (I-2010-20190330 to T.Q.) and American Chemistry Society Petroleum Research Fund (62223-DNI1 to T. Q.). UT Southwestern Amgen Scholars program supported a fellowship to J.B.W. We thank F. Lin (UTSW) for assistance with NMR spectroscopy; H. Baniasadi (UTSW) for HRMS; and V. Lynch (UT-Austin) for X-ray crystallographic analysis. We gratefully acknowledge the Texas A&M University HPRC resources (https://hprc.tamu.edu), UMD Deepthought2, MARCC/BlueCrab HPC clusters and XSEDE (CHE160082 and CHE160053) for computational resources. We thank the Chen, Tambar, Ready, De Brabander, Smith and Falck groups (UTSW) for generous access to equipment, and helpful discussions. We are grateful to S. W. Krska, X. Ma, and D. Levorse (Merck & Co., Inc.) for feedback on this manuscript and assistance with ADME profiling.

Author information

Author notes

  1. These authors contributed equally: Yangyang Yang, Jet Tsien.

Authors and Affiliations

  1. Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA

    Yangyang Yang, Jet Tsien, James B. Wang & Tian Qin

  2. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, USA

    Ryan Dykstra & Osvaldo Gutierrez

  3. Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, CA, USA

    Si-Jie Chen & Rohan R. Merchant

  4. Department of Process Research and Development, Merck & Co., Inc., Rahway, NJ, USA

    Jonathan M. E. Hughes & Byron K. Peters

  5. Department of Chemistry, Texas A&M University, College Station, TX, USA

    Osvaldo Gutierrez

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Contributions

Y.Y. and J.T. performed synthetic experiments; R.D., J.B.W. and O.G. performed DFT theoretical studies. S.-J.C. performed PMI and 3D score calculations. J.M.E.H., B.K.P., R.R.M. and T.Q. designed and supervised the project; Y.Y., J.T., R.D., S.-J.C., J.B.W., J.M.E.H., B.K.P., R.R.M., O.G. and T.Q. contributed to the manuscript writing.

Corresponding authors

Correspondence to Osvaldo Gutierrez or Tian Qin.

Ethics declarations

Competing interests

The authors declare the following competing financial interest(s): T.Q., Y.Y. and J.T. from UT Southwestern Medical Center are listed as inventors on US patent application no. 63/146,266, which covers the ‘synthesis of BCP bis-boronates’ in the manuscript, and on the US provisional application no. 63/321,700, which covers ‘C3-functionalization of BCP bis-boronates’ and ‘late-stage C2-functionalization of BCP boronates’ in the manuscript. The remaining authors declare no competing interests.

Peer review

Peer review information

Nature Chemistry thanks Xiaoshen Ma, Gergely Tolnai and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Selective functionalization of C2-boronate.

To achieve C2-functionalization with C3-boron retained, BCP bis-boronate 23 was firstly transformed into C3-BMIDA and BTIDA esters (109, 110), followed by oxidation and Giese-type alkylation to afford C2-functionalized products (111,112).

Extended Data Fig. 2 Synthesis and ADME study of p-38 kinase inhibitor 116 and its BCP analogue 115.

The BCP analogue 115 of arene 116, a p-38 kinase inhibitor65, was prepared via the selective functionalization sequence: 1) cyanation; 2) hydrolysis and esterification; 3) arylation; 4) hydrolyses and amide couplings. The physicochemical and ADME properties for both compounds were profiled. Fsp3, the fraction of sp3 carbon atoms; Log D, distribution coefficient; Solubility, high-throughput equilibrium solubility; MDCKII, Madin-Darby canine kidney cells; Papp, apparent permeability.

Supplementary information

Supplementary Information

General experimental; multi-gram-scale preparation of BCP bis-boronates (13, 23–27); optimization of synthesis and functionalizations of BCP bis-boronates; C2 control of selective C3-functionalization of BCP boronates; troubleshooting; general experimental procedures and characterization data of substrates in selective C3-Bpin functionalization of BCP bis-boronates; experimental procedures and characterization data of substrates in late-stage functionalization of BCP C2-Boronates; reverse reactivity of BCP bis-boronates; experimental procedures and characterization data of BCP analogue 115 and bioactive arene 116; current methods and substrates limitation; differential scanning calorimetry experiments of compounds 13, 23–26, SI-5, SI-7 and SI-16; X-ray crystallographic data for BCP compounds; computational investigation on BCP bis-boronates; procedure for compound enumeration; calculation of PMI and 3D Scores; references; NMR spectra.

Supplementary Data 1

The xyz coordinates in the calculation part of Supplementary Information.

Supplementary Data 2

Crystallographic data for compound 15; CCDC reference no. 2158998.

Supplementary Data 3

Crystallographic data for compound 23; CCDC reference no. 2159002.

Supplementary Data 4

Crystallographic data for compound 24; CCDC reference no. 2158995.

Supplementary Data 5

Crystallographic data for compound 25; CCDC reference no. 2159016.

Supplementary Data 6

Crystallographic data for compound 27; CCDC reference no. 2159001.

Supplementary Data 7

Crystallographic data for compound 33; CCDC reference no. 2162135.

Supplementary Data 8

Crystallographic data for compound 55; CCDC reference no. 2160325.

Supplementary Data 9

Crystallographic data for compound 59; CCDC reference no. 2160336.

Supplementary Data 10

Crystallographic data for compound 76; CCDC reference no. 2162136.

Source data

Source Data Fig. 2

Total energies and energy decomposition analysis values used to compute Esteric, Edisp, Eelstat and Eorb of barriers \({\mathbf{13-TS}}^{\mathbf{C}_{\mathbf 2}}\) and \({\mathbf{13-TS}}^{\mathbf{C}_{\mathbf 3}}\). Equations for Esteric, Edisp, Eelstat and Eorb found in ref. 47.

Source Data Fig. 5

Raw data file for PMI and box-whisker plots in Fig. 5.

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Yang, Y., Tsien, J., Dykstra, R. et al. Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates. Nat. Chem. 16, 285–293 (2024). https://doi.org/10.1038/s41557-023-01342-7

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