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Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes

Nature Catalysis volume 3, pages 351–357 (2020)Cite this article

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Abstract

Bicyclo[1.1.1]pentanes (BCPs) are highly strained carbocycles that have fascinated the chemical community for decades because of their unique structure. Despite the immense interest in this scaffold and extensive synthetic efforts, the construction of BCP derivatives still relies substantially on the manipulation of dimethyl bicyclo[1.1.1]pentane-1,3-dicarboxylate. Furthermore, BCPs that contain a proximal stereocentre are underrepresented in the literature and their generation requires stoichiometric chiral auxiliaries. Here we explore enantioselective C–H functionalization of BCPs as a conceptually innovative strategy that provides access to chiral substituted BCPs. For this purpose, enantioselective intermolecular sp3 C–H insertion reactions of donor/acceptor diazo compounds catalysed by the chiral dirhodium complex, Rh2(TCPTAD)4, were employed to forge new C–C bonds at the tertiary position of a variety of BCPs. This work also establishes that highly strained molecules can undergo direct C–H insertion without losing the integrity of their carbocyclic framework.

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Fig. 1: Applications and synthesis of BCPs related to the current work.
Fig. 2: Structures and applications of other dirhodium catalysts for site-selective functionalization of unactivated C–H bonds.
Fig. 3: Evaluation of the optimization catalysts for C–H functionalization of BCPs.
Fig. 4: Scope of the reaction with respect to substrates and aryldiazoacetates.
Fig. 5: Synthesis of analogues of known biologically active compounds and a comparison of solubility and microsomal stability.
Fig. 6: Computational analysis of C–H insertion into BCPs.

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Data availability

Crystallographic data for the structures reported in this Letter have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. 1906391 and 1906395. Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif. Complete experimental procedures and compound characterization data are available in the Supplementary Information; any other data is available from the authors on request.

References

  1. Levin, M. D., Kaszynski, P. & Michl, J. Bicyclo[1.1.1]pentanes, [n]staffanes, [1.1.1]propellanes, and tricyclo[2.1.0.02,5]pentanes. Chem. Rev. 100, 169–234 (2000).

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  3. Locke, G. M., Bernhard, S. S. R. & Senge, M. O. Nonconjugated hydrocarbons as rigid-linear motifs: isosteres for material sciences and bioorganic and medicinal Chemistry. Chem. Eur. J. 25, 4590-4647 (2018).

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

    CAS  Google Scholar 

  5. 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  Google Scholar 

  6. Westphal, M. V., Wolfstädter, B. T., Plancher, J.-M., 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  Google Scholar 

  7. 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 

  8. Barbachyn, M. R. et al. U-87947E, a protein quinolone antibacterial agent incorporating a bicyclo[1.1.1]pent-1-yl (BCP) subunit. Bioorg. Medicinal Chem. Lett. 3, 671–676 (1993).

    CAS  Google Scholar 

  9. Goh, Y. L., Cui, Y. T., Pendharkar, V. & Adsool, V. A. Toward resolving the resveratrol conundrum: synthesis and in vivo pharmacokinetic evaluation of BCP–resveratrol. ACS Med. Chem. Lett. 8, 516−520 (2017).

  10. 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  Google Scholar 

  11. Kaszynski, P., Friedli, A. & Michl, J. Toward a molecular-size tinkertoy construction set. Preparation of terminally functionalized [n]staffanes from [1.1.1]propellane. J. Am. Chem. Soc. 114, 601–620 (1992).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  13. Wiberg, K. B. & Waddell, S. T. Reactions of [1.1.1]propellane. J. Am. Chem. Soc. 112, 2194–2216 (1990).

    CAS  Google Scholar 

  14. Bunker, K. D., Sach, N. W., Huang, Q. & Richardson, P. F. Scalable synthesis of 1-bicyclo[1.1.1]pentylamine via a hydrohydrazination reaction. Org. Lett. 13, 4746–4748 (2011).

    CAS  PubMed  Google Scholar 

  15. Goh, Y. L. et al. A new route to bicyclo[1.1.1]pentan-1-amine from 1-azido-3- iodobicyclo[1.1.1]pentane. Org. Lett. 16, 1884–1887 (2014).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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 

  19. Della, E. W. & Taylor, D. K. Synthesis of some bridgehead–bridgehead-disubstituted bicyclo[1.1.1]pentanes. J. Org. Chem. 59, 2986–2996 (1994).

    CAS  Google Scholar 

  20. Rehm, J. D. D., Ziemer, B. & Szeimies, G. A facile route to bridgehead disubstituted bicyclo[1.1.1]pentanes involving palladium-catalyzed cross-coupling reactions. Eur. J. Org. Chem. 1999, 2079–2085 (1999).

  21. Messner, M., Kozhushkov, S. I. & de Meijere, A. Nickel- and palladium-catalyzed cross-coupling reactions at the bridgehead of bicyclo[1.1.1]pentane derivatives—a convenient access to liquid crystalline compounds containing bicyclo[1.1.1]pentane moieties. Eur. J. Org. Chem. 2000, 1137–1155 (2000).

  22. Matos, J. L. M., Vásquez-Céspedes, S., Gu, J., Oguma, T. & Shenvi, R. A. Branch-selective addition of unactivated olefins into imines and aldehydes. J. Am. Chem. Soc. 140, 16976–16981 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 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 

  24. Schelp, R. A. & Walsh, P. J. Synthesis of BCP benzylamines from 2-azaallyl anions and [1.1.1]propellane. Angew. Chem. Int. Ed. 55, 15857–15861 (2018).

  25. Ni, S. et al. A general amino acid synthesis enabled by innate radical cross-coupling. Angew. Chem. Int. Ed. 57, 14560–14565 (2018).

    CAS  Google Scholar 

  26. 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).

    CAS  PubMed  Google Scholar 

  27. Pritz, S., Pätzel, M., Szeimies, G., Dathe, M. & Bienert, M. Synthesis of a chiral amino acid with bicyclo[1.1.1]pentane moiety and its incorporation into linear and cyclic antimicrobial peptides. Org. Biomol. Chem. 5, 1789–1794 (2007).

    CAS  PubMed  Google Scholar 

  28. Filosa, R. et al. Design, synthesis and biological evaluation of novel bicyclo[1.1.1]pentane-based omega-acidic amino acids as glutamate receptors ligands. Bioorg. Medicinal Chem. 17, 242–250 (2009).

    CAS  Google Scholar 

  29. Kokhan, S. O. et al. Design, synthesis, and application of an optimized monofluorinated aliphatic label for peptide studies by solid-state 19F NMR spectroscopy. Angew. Chem. Int. Ed. 55, 14788–14792 (2016).

    CAS  Google Scholar 

  30. 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 

  31. Wong, M. L. J., Mousseau, J. J., Mansfield, S. J. & Anderson, E. A. Synthesis of enantioenriched α-chiral bicyclo[1.1.1]pentanes. Org. Lett. 7, 2408–2411 (2019).

  32. Wiberg K. B. & Williams, V. Z. Jr. Bicyclo[1.1.1]pentane derivatives. J. Org. Chem. 35, 366–369 (1970).

    Google Scholar 

  33. Della, E. W., Grob, C. A. & Taylor, D. K. Bridgehead carbocations: a solvolytic study of 1-bromobicyclo[1.1.1]pentane and its bridgehead-substituted derivatives. J. Am. Chem. Soc. 116, 6159–6166 (1994).

    CAS  Google Scholar 

  34. Gutekunst, W. R. & Baran, P. S. C–H Functionalization logic in total synthesis. Chem. Soc. Rev. 40, 1976–1991 (2011).

    CAS  PubMed  Google Scholar 

  35. Davies, H. M. L. & Morton, D. Guiding principles for site selective and stereoselective intermolecular C–H functionalization by donor/acceptor rhodium carbenes. Chem. Soc. Rev. 40, 1857–1869 (2011).

    CAS  PubMed  Google Scholar 

  36. Guptill, D. M. & Davies, H. M. L. 2,2,2-Trichloroethyl aryldiazoacetates as robust reagents for the enantioselective C–H functionalization of methyl ethers. J. Am. Chem. Soc. 136, 17718–17721 (2014).

    CAS  PubMed  Google Scholar 

  37. Liao, K., Negretti, S., Musaev, D. G., Bacsa, J. & Davies, H. M. L. Site-selective and stereoselective functionalization of unactivated C–H bonds. Nature 533, 230–234 (2016).

    CAS  PubMed  Google Scholar 

  38. Liao, K. et al. Site-selective and stereoselective functionalization of non-activated tertiary C–H bonds. Nature 551, 609–613 (2017).

    CAS  PubMed  Google Scholar 

  39. Liao, K. et al. Design of catalysts for site-selective and enantioselective functionalization of non-activated primary C–H bonds. Nat. Chem. 10, 1048–1055 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Liu, W. et al. Catalyst-controlled selective functionalization of unactivated C–H bonds in the presence of electronically activated C–H bonds. J. Am. Chem. Soc. 140, 12247–12255 (2018).

    CAS  PubMed  Google Scholar 

  41. Fu, J., Ren, Z., Bacsa, J., Musaev, D. G. & Davies, H. M. L. Desymmetrization of cyclohexanes by site- and stereoselective C–H functionalization. Nature 564, 395–399 (2018).

    CAS  PubMed  Google Scholar 

  42. Qin, C. & Davies, H. M. L. Role of sterically demanding chiral dirhodium catalysts in site-selective C–H functionalization of activated primary C–H bonds. J. Am. Chem. Soc. 136, 9792–9796 (2014).

    CAS  PubMed  Google Scholar 

  43. 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  Google Scholar 

  44. Biphenyl-4-yl(phenyl)acetic Acid Section 7 (PubChem, accessed 7 November 2018); https://pubchem.ncbi.nlm.nih.gov/compound/226171#section=Biological-Test-Results

  45. 2-Phenyl-2-(4-phenylphenyl)ethanamine Section 6 (PubChem, acessed 7 November 2018); https://pubchem.ncbi.nlm.nih.gov/compound/44719858#section=BioAssay-Results

  46. Davies, H. M. L., Hansen, T. & Churchill, M. R. Catalytic asymmetric C–H activation of alkanes and tetrahydrofuran. J. Am. Chem. Soc. 122, 3063–3070 (2000).

    CAS  Google Scholar 

  47. Della, E. W. & Schiesser, C. H. Hyperconjugation in strained bridgehead cyclobutyl cations: an ab initio study of bicyclo[1.1.1]pent-1-yl cubyl and norcubyl cations. J. Chem. Soc. Chem. Commun. 1994, 417–419 (1994).

    Google Scholar 

  48. Wiberg, K. B. & McMurdie, N. Formation and reactions of bicyclo[1.1.1]pentyl-1 cations. J. Am. Chem. Soc. 116, 11990–11998 (1994).

    CAS  Google Scholar 

  49. Wiberg, K. B. & McMurdie, N. Mechanism of the solvolysis of bicyclo[1.1.1]pentyl-1 derivatives. J. Org. Chem. 58, 5603–5604 (1993).

    CAS  Google Scholar 

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Acknowledgements

This work was supported by the NSF under the Center for C–H Functionalization (grant no. CHE-1700982) and the NIGMS of the NIH under award nos. F32GM130020 (Z.J.G.) and F32GM122218 (J.N.S.). The content is solely the responsibility of the authors and does not necessarily represent the views of the NSF or NIH. Additional financial support was provided by Novartis. Instrumentation used in this work was supported by the National Science Foundation (grant nos. CHE 1531620 and CHE 1626172). Computational resources were provided by the UCLA Institute for Digital Research and Education (IDRE). We wish to thank the members of the NSF Center for C–H Functionalization (grant no. CHE-1700982), especially J.Du. Bois . and N. Chiappini, for helpful discussions regarding this work. We thank J. Bacsa and T. Pickel at the Emory X-ray Crystallography Facility for the X-ray structural analysis. We thank S. Skolnik and J. Poirier at the Novartis Institutes for BioMedical Research for carrying out solubility and logD measurements.

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Authors and Affiliations

  1. Department of Chemistry, Emory University, Atlanta, GA, USA

    Zachary J. Garlets & Huw M. L. Davies

  2. Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA

    Jacob N. Sanders & K. N. Houk

  3. Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA

    Hasnain Malik & Christian Gampe

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Contributions

Z.J.G. performed the synthetic experiments. J.N.S. and K.N.H. conducted the computational studies. H.M. and C.G. evaluated the biologically relevant compounds and conducted the comparison studies. Z.J.G. and H.M.L.D. designed and analysed the synthetic experiments and prepared the manuscript. All authors contributed to the final draft of the manuscript.

Corresponding author

Correspondence to Huw M. L. Davies.

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Competing interests

H.M.L.D. is a named inventor on a patent entitled ‘Dirhodium catalyst compositions and synthetic processes related thereto’ (US 8,974,428, issued 10 March 2015). The other authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Methods, Figs. 1–3, Tables 1–16 and references.

Compound 8d

Crystallographic Data for Compound 8d.

Compound 29

Crystallographic Data for Compound 29.

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Garlets, Z.J., Sanders, J.N., Malik, H. et al. Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes. Nat Catal 3, 351–357 (2020). https://doi.org/10.1038/s41929-019-0417-1

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