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An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates


Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons.

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Fig. 1: Bridged hydrocarbons and BCP syntheses.
Fig. 2: Derivatization and synthetic application of BCP boronates.

Data availability

The experimental data as well as the characterization data for all the compounds prepared in the course of these studies are provided in the Supplementary Information. The crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2062923 (16), 2062924 (20), 2062925 (26) and 2081087 (40-ester; see the X-ray crystallographic data in the Supplementary Information). Copies of the data can be obtained free of charge via


  1. 1.

    Levin, M. D., Kaszynski, P. & Michl, J. Bicyclo[1.1.1]pentanes, [n]staffanes, [1.1.1]propellanes, and tricyclo[,5]pentanes. Chem. Rev. 100, 169–234 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    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).

    Google Scholar 

  3. 3.

    Wiberg, K. B. The concept of strain in organic chemistry. Angew. Chem. Int. Ed. Engl. 25, 312–322 (1986).

    Google Scholar 

  4. 4.

    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).

    CAS  Google Scholar 

  5. 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).

    CAS  Google Scholar 

  6. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bauer, M. R. et al. Put a ring on it: application of small aliphatic rings in medicinal chemistry. RSC Med. Chem. 12, 448–471 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

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

    Google Scholar 

  14. 14.

    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).

    CAS  Google Scholar 

  15. 15.

    Wiberg, K. B. & Walker, F. H. [1.1.1]Propellane. J. Am. Chem. Soc. 104, 5239–5240 (1982).

    CAS  Google Scholar 

  16. 16.

    Jackson, J. E. & Allen, L. C. The C1–C3 bond in [1.1.1]propellane. J. Am. Chem. Soc. 106, 591–599 (1984).

    CAS  Google Scholar 

  17. 17.

    Feller, D. & Davidson, E. R. Ab initio studies of [1.1.1]- and [2.2.2]propellane. J. Am. Chem. Soc. 109, 4133–4139 (1987).

    CAS  Google Scholar 

  18. 18.

    Wu, W., Gu, J., Song, J., Shaik, S. & Hiberty, P. C. The inverted bond in [1.1.1]propellane is a charge-shift bond. Angew. Chem. Int. Ed. 48, 1407–1410 (2009).

    CAS  Google Scholar 

  19. 19.

    Wiberg, K. B., Waddell, S. T. & Laidig, K. [1.1.1]Propellane: reaction with free radicals. Tetrahedron Lett. 27, 1553–1556 (1986).

    CAS  Google Scholar 

  20. 20.

    Kaszynki, P. & Michl, J. A practical photochemical synthesis of bicyclo[1.1.1]pentane-1,3-dicarboxylic acid. J. Org. Chem. 53, 4593–4594 (1988).

    Google Scholar 

  21. 21.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Lopchuk, J. M. et al. Strain-release heteroatom functionalization: development, scope, and stereospecificity. J. Am. Chem. Soc. 139, 3209–3226 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    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).

    CAS  Google Scholar 

  24. 24.

    Kanazawa, J. & Uchiyama, M. Recent advances in the synthetic chemistry of bicyclo[1.1.1]pentane. Synlett 30, 1–11 (2019).

    CAS  Google Scholar 

  25. 25.

    Makarov, I. S., Brocklehurst, C. E., Karaghiosoff, K., Koch, G. & Knochel, P. Synthesis of bicyclo[1.1.1]pentane bioisosteres of internal alkynes and para-disubstituted benzenes from [1.1.1] propellane. Angew. Chem. Int. Ed. 56, 12774–12777 (2017).

    CAS  Google Scholar 

  26. 26.

    Kanazawa, J., Maeda, K. & Uchiyama, M. Radical multicomponent carboamination of [1.1.1]propellane. J. Am. Chem. Soc. 139, 17791–17794 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kondo, M. et al. Silaboration of [1.1.1]propellane: a storable feedstock for bicyclo[1.1.1]pentane derivatives. Angew. Chem. Int. Ed. 59, 1970–1974 (2020).

    CAS  Google Scholar 

  28. 28.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

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

    CAS  Google Scholar 

  30. 30.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

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

    CAS  Google Scholar 

  32. 32.

    Hughes, J. M. E., Scarlata, D. A., Chen, A. C.-Y., Burch, J. & Gleason, J. L. Aminoalkylation of [1.1.1]propellane enables direct access to high-value 3-alkylbicyclo[1.1.1]pentan-1-amines. Org. Lett. 21, 6800–6804 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Shelp, R. A. & Walsh, P. J. Synthesis of BCP benzylamines from 2‐azaallyl anions and [1.1.1]propellane. Angew. Chem. Int. Ed. 57, 15857–15861 (2018).

    CAS  Google Scholar 

  34. 34.

    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).

    CAS  Google Scholar 

  35. 35.

    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).

    CAS  Google Scholar 

  36. 36.

    Shin, S., Lee, S., Choi, W., Kim, N. & Hong, S. Visible-light-induced 1,3-aminopyridylation of [1.1.1]propellane with N-aminopyridinium salts. Angew. Chem. Int. Ed. 60, 7873–7879 (2021).

    CAS  Google Scholar 

  37. 37.

    Toriyama, F. et al. Redox-active esters in Fe-catalyzed C–C coupling. J. Am. Chem. Soc. 138, 11132–11135 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    VanHeyst, M. D. et al. Continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]pentane trifluoroborate salts and their utilization in metallaphotoredox cross-couplings. Org. Lett. 22, 1648–1654 (2020).

    CAS  Google Scholar 

  39. 39.

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

    CAS  Google Scholar 

  40. 40.

    Zarate, C. et al. Development of scalable routes to 1-bicyclo[1.1.1]pentylpyrazoles. Org. Process Res. Dev. 25, 642–647 (2021).

    CAS  Google Scholar 

  41. 41.

    Shelp, R. A. et al. Strain-release 2-azaallyl anion addition/borylation of [1.1.1]propellane: synthesis and functionalization of benzylamine bicyclo[1.1.1]pentyl boronates. Chem. Sci. 12, 7066–7072 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Kaleta, J. et al. Bridge-chlorinated bicyclo[1.1.1]pentane-1,3-dicarboxylic acids. J. Org. Chem. 84, 2448–2461 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Wiberg, K. B., Connor, D. S. & Lampman, G. M. The reaction of 3-bromocyclobutane-1-methyl bromide with sodium: bicyclo[1.1.1]pentane. Tetrahedron Lett. 5, 531–534 (1964).

    Google Scholar 

  48. 48.

    Padwa, A. & Alexander, E. Photochemical formation of a substituted bicyclo[1.1.1]pentane. J. Am. Chem. Soc. 89, 6376–6377 (1967).

    CAS  Google Scholar 

  49. 49.

    Srinivasan, R. & Carlough, K. H. Mercury(3P1) photosensitized internal cycloaddition reactions in 1,4-, 1,5-, and 1,6-dienes. J. Am. Chem. Soc. 89, 4932–4936 (1967).

    CAS  Google Scholar 

  50. 50.

    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).

    CAS  Google Scholar 

  51. 51.

    Meinwald, J., Szkryalo, W. & Dimmel, D. R. Bicyclo[1.1.1]pentane from mercury sensitized and unsensitized gas phase photolyses of bicyclo[2.1.1]hexan-2-one. Tetrahedron Lett. 8, 731–733 (1967).

    Google Scholar 

  52. 52.

    Wiberg, K. B. in The Chemistry of Cyclobutanes Ch. 1, 1–15 (Wiley, 2005).

  53. 53.

    Wiberg, K. B. & Connor, D. S. Bicyclo[1.1.1]pentane. J. Am. Chem. Soc. 88, 4437–4441 (1966).

    CAS  Google Scholar 

  54. 54.

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

    CAS  Google Scholar 

  55. 55.

    Barluenga, J., Tomás-Gamasa, M., Aznar, F. & Valdés, C. Metal-free carbon–carbon bond-forming reductive coupling between boronic acids and tosylhydrazones. Nat. Chem. 1, 494–499 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Préz-Aguilar, M. C. & Valdés, C. Olefination of carbonyl compounds through reductive coupling of alkenylboronic acids and tosylhydrazones. Angew. Chem. Int. Ed. 51, 5953–5957 (2012).

    Google Scholar 

  57. 57.

    Plaza, M. & Valdés, C. Stereoselective domino carbocyclizations of γ- and δ-cyano-N-tosylhydrazones with alkenylboronic acids with formation of two different C(sp3)–C(sp2) bonds on a quaternary stereocenter. J. Am. Chem. Soc. 138, 12061–12064 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Plaza, M., Paraja, M., Florentino, L. & Valdés, C. Domino synthesis of benzo-fused β,γ-unsaturated ketones from alkenylboronic acids and N-tosylhydrazone-tethered benzonitriles. Org. Lett. 21, 632–635 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Wu, G., Deng, Y., Wu, C., Zhang, Y. & Wang, J. Synthesis of α-aryl esters and nitriles via deaminative coupling of α-aminoesters and α-aminoacetonitriles with arylboronic acids. Angew. Chem. Int. Ed. 53, 10510–10514 (2014).

    CAS  Google Scholar 

  60. 60.

    Merchant, R. R. & Lopez, J. A. A general C(sp3)-C(sp3) cross-coupling of benzyl sulfonylhydrazones with alkyl boronic acids. Org. Lett. 22, 2271–2275 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Plaza, M., Parisotto, S. & Valdés, C. Heterocyclization and spirocyclization processes based on domino reactions of N‐tosylhydrazones and boronic acids involving intramolecular allylborylations of nitriles. Chem. Eur. J. 24, 14836–14843 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Arunprasath, D., Bala, B. D. & Sekar, G. Luxury of N-tosylhydrazones in transition-metal-free transformations. Adv. Synth. Catal. 361, 1172–1207 (2019).

    CAS  Google Scholar 

  63. 63.

    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).

    CAS  Google Scholar 

  64. 64.

    Tani, K. & Stoltz, B. M. Synthesis and structural analysis of 2-quinuclidonium tetrafluoroborate. Nature 441, 731–734 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Davenport, R. et al. Visible-light-driven strain-increase ring contraction allows the synthesis of cyclobutyl boronic esters. Angew. Chem. Int. Ed. 59, 6525–6528 (2020).

    CAS  Google Scholar 

  66. 66.

    Hirsch, J. A. Table of conformational energies. Top. Stereochem. 1, 199–222 (1967).

    CAS  Google Scholar 

  67. 67.

    Eliel, E. L., Wilen, S. H. & Doyle, M. P. in Basic Organic Stereochemistry 443 (Wiley, 2001).

  68. 68.

    Yang, C.-T. et al. Alkylboronic esters from copper‐catalyzed borylation of primary and secondary alkyl halides and pseudohalides. Angew. Chem. Int. Ed. 51, 528–532 (2012).

    CAS  Google Scholar 

  69. 69.

    Stymiest, J. L., Dutheuil, G., Mahmood, A. & Aggarwal, V. K. Lithiated carbamates: chiral carbenoids for iterative homologation of boranes and boronic esters. Angew. Chem. Int. Ed. 46, 7491–7494 (2007).

    CAS  Google Scholar 

  70. 70.

    Li, H. et al. Formal carbon insertion of N-tosylhydrazone into B–B and B–Si bonds: gem-diborylation and gem-silylborylation of sp3 carbon. Org. Lett. 16, 448–451 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Bonet, A., Pubill-Ulldemolins, C., Bo, C., Gulyás, H. & Fernández, E. Transition‐metal‐free diboration reaction by activation of diboron compounds with simple Lewis bases. Angew. Chem. Int. Ed. 50, 7158–7161 (2011).

    CAS  Google Scholar 

  72. 72.

    Kisan, S., Krishnakumar, V. & Gunanathan, C. Ruthenium-catalyzed anti-Markovnikov selective hydroboration of olefins. ACS Catal. 7, 5950–5954 (2017).

    CAS  Google Scholar 

  73. 73.

    Yamamoto, Y., Fujikawa, R., Umemoto, T. & Miyaura, N. Iridium-catalyzed hydro-boration of alkenes with pinacolborane. Tetrahedron 60, 10695–10700 (2004).

    CAS  Google Scholar 

  74. 74.

    Fasano, V. et al. How big is the pinacol boronic ester as a substituent? Angew. Chem. Int. Ed. 59, 22403–22407 (2020).

    CAS  Google Scholar 

  75. 75.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Zweifel, G., Arzoumanian, H. & Whitney, C. C. A convenient stereoselective synthesis of substituted alkenes via hydroboration-iodination of alkynes. J. Am. Chem. Soc. 89, 3652–3653 (1967).

    CAS  Google Scholar 

  77. 77.

    Armstrong, R. J. & Aggarwal, V. K. 50 years of Zweifel olefination: a transition-metal-free coupling. Synthesis 49, 3323–3336 (2017).

    CAS  Google Scholar 

  78. 78.

    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).

    CAS  Google Scholar 

  79. 79.

    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).

    CAS  Google Scholar 

  80. 80.

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

    Google Scholar 

  81. 81.

    Littke, A. F., Dai, C. & Fu, G. C. Versatile catalysts for the Suzuki cross-coupling of arylboronic acids with aryl and vinyl halides and triflates under mild conditions. J. Am. Chem. Soc. 122, 4020–4028 (2000).

    CAS  Google Scholar 

  82. 82.

    Dreher, S. D., Dormer, P. G., Sandrock, D. L. & Molander, G. A. Efficient cross-coupling of secondary alkyltrifluoroborates with aryl chlorides—reaction discovery using parallel microscale experimentation. J. Am. Chem. Soc. 130, 9257–9259 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Li, L., Zhao, S., Joshi-Pangu, A., Diane, M. & Biscoe, M. R. Stereospecific Pd-catalyzed cross-coupling reactions of secondary alkylboron nucleophiles and aryl chlorides. J. Am. Chem. Soc. 136, 14027–14030 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Brown, H. C., Midland, M. M. & Levy, A. B. Facile reaction of alkyl- and aryldichloroboranes with organic azides. General stereospecific synthesis of secondary amines. J. Am. Chem. Soc. 95, 2394–2396 (1973).

    CAS  Google Scholar 

  85. 85.

    Bagutski, V., Elford, T. G. & Aggarwal, V. K. Synthesis of highly enantioenriched C‐tertiary amines from boronic esters: application to the synthesis of igmesine. Angew. Chem. Int. Ed. 50, 1080–1083 (2011).

    CAS  Google Scholar 

  86. 86.

    Kuduk, S. D. & Skudlarek, J. W. 2-Pyridyloxy-3-substituted-4-nitrile orexin receptor antagonists. WO patent WO2014066196A1 (2014).

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Financial support for this work was provided by the Welch Foundation (I-2010-20190330), the National Institutes of Health (R01GM141088) and UT Southwestern Eugene McDermott Endowed Scholarship. 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 thank the Chen, Tambar, Ready, De Brabander, Smith and Falck groups (UTSW) for generous access to equipment, and helpful discussions. We are grateful to K. Campos, L.-C. Campeau, P. Fier, C. Zarate Saez and K. McClymont (Merck & Co., Inc., Kenilworth, NJ, USA) for feedback on this manuscript.

Author information




Y.Y., J.T. and T.Q. performed the experiments; J.M.E.H., B.K.P., R.R.M. and T.Q. designed and supervised the project; J.M.E.H. and B.K.P. performed the DSC experiments; Y.Y., J.T., J.M.E.H., R.R.M. and T.Q. wrote the paper.

Corresponding author

Correspondence to Tian Qin.

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Competing interests

A provisional patent application naming T.Q., Y.Y. and J.T. as inventors has been filed by the Board of Regents of the University of Texas System, which covers the synthetic method and structural motifs described in this manuscript. The remaining authors declare no competing interests.

Additional information

Peer review information Nature Chemistry thanks Varinder Aggarwal, Cara Brocklehurst and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary information

General experimental, general procedures, additional optimization of cyclizations, Suzuki cross-couplings and aminations, limitations, troubleshooting, experimental procedures and characterization data of starting materials, substrate precursors and substrates, DSC experiments, X-ray crystallographic data and NMR spectra.

Supplementary Data 1

Crystallographic data for compound 16; CCDC reference 2062923.

Supplementary Data 2

Crystallographic data for compound 20; CCDC reference 2062924.

Supplementary Data 3

Crystallographic data for compound 26; CCDC reference 2062925.

Supplementary Data 4

Crystallographic data for compound 40-ester; CCDC reference 2081087.

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

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