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.
Subscribe to Journal
Get full journal access for 1 year
We are sorry, but there is no personal subscription option available for your country.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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.
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).
Wiberg, K. B. The concept of strain in organic chemistry. Angew. Chem. Int. Ed. 25, 312–322 (1986).
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).
Kanazawa, J. & Uchiyama, M. Recent advances in the synthetic chemistry of bicyclo[1.1.1]pentane. Synlett 30, 1–11 (2019).
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).
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).
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).
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).
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).
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).
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).
Wiberg, K. B. & Connor, D. S. Bicyclo[1.1.1]pentane. J. Am. Chem. Soc. 88, 4437–4441 (1966).
Wiberg, K. B. & Waddell, S. T. Reactions of [1.1.1]propellane. J. Am. Chem. Soc. 112, 2194–2216 (1990).
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).
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).
Kanazawa, J., Maeda, K. & Uchiyama, M. Radical multicomponent carboamination of [1.1.1]propellane. J. Am. Chem. Soc. 139, 17791–17794 (2017).
Gianatassio, R. et al. Strain-release amination. Science 351, 241–246 (2016).
Lopchuk, J. M. et al. Strain-release heteroatom functionalization: development, scope, and stereospecificity. J. Am. Chem. Soc. 139, 3209–3226 (2017).
Della, E. W. & Taylor, D. K. Synthesis of some bridgehead–bridgehead-disubstituted bicyclo[1.1.1]pentanes. J. Org. Chem. 59, 2986–2996 (1994).
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).
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).
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).
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).
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).
Ni, S. et al. A general amino acid synthesis enabled by innate radical cross-coupling. Angew. Chem. Int. Ed. 57, 14560–14565 (2018).
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).
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).
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).
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).
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).
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).
Wiberg K. B. & Williams, V. Z. Jr. Bicyclo[1.1.1]pentane derivatives. J. Org. Chem. 35, 366–369 (1970).
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).
Gutekunst, W. R. & Baran, P. S. C–H Functionalization logic in total synthesis. Chem. Soc. Rev. 40, 1976–1991 (2011).
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).
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).
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).
Liao, K. et al. Site-selective and stereoselective functionalization of non-activated tertiary C–H bonds. Nature 551, 609–613 (2017).
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).
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).
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).
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).
Auberson, Y. P. et al. Improving nonspecific binding and solubility: bicycloalkyl groups and cubanes as para-phenyl bioisosteres. ChemMedChem 12, 590–598 (2017).
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
2-Phenyl-2-(4-phenylphenyl)ethanamine Section 6 (PubChem, acessed 7 November 2018); https://pubchem.ncbi.nlm.nih.gov/compound/44719858#section=BioAssay-Results
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).
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).
Wiberg, K. B. & McMurdie, N. Formation and reactions of bicyclo[1.1.1]pentyl-1 cations. J. Am. Chem. Soc. 116, 11990–11998 (1994).
Wiberg, K. B. & McMurdie, N. Mechanism of the solvolysis of bicyclo[1.1.1]pentyl-1 derivatives. J. Org. Chem. 58, 5603–5604 (1993).
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.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Garlets, Z.J., Sanders, J.N., Malik, H. et al. Enantioselective C–H functionalization of bicyclo[1.1.1]pentanes. Nat Catal (2020). https://doi.org/10.1038/s41929-019-0417-1