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Design of catalysts for site-selective and enantioselective functionalization of non-activated primary C–H bonds

Nature Chemistry volume 10, pages 1048–1055 (2018)Cite this article

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Abstract

C–H functionalization represents a promising approach for the synthesis of complex molecules. Instead of relying on modifying the functional groups present in a molecule, the synthetic sequence is achieved by carrying out selective reactions on the C–H bonds, which traditionally would have been considered to be the unreactive components of a molecule. A major challenge is to design catalysts to control both the site- and stereoselectivity of the C–H functionalization. We have been developing dirhodium catalysts with different selectivity profiles in C–H functionalization reactions with donor/acceptor carbenes as reactive intermediates. Here we describe a new dirhodium catalyst capable of the functionalization of non-activated primary C–H bonds with high levels of site selectivity and enantioselectivity.

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Fig. 1: Catalyst-controlled C–H functionalization.
Fig. 2: Catalyst optimization studies.
Fig. 3: Catalyst-controlled C–H functionalization of chiral substrates.
Fig. 4: Catalyst-controlled C–H functionalization of the steroid, stigmasteryl acetate.
Fig. 5: Structural information about dirhodium catalyst I.
Fig. 6: Optimized transition structures for carbene insertion into the primary C–H bond.

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References

  1. Godula, K. & Sames, D. C–H bond functionalization in complex organic synthesis. Science 312, 67–72 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Wencel-Delord, J. & Glorius, F. C–H bond activation enables the rapid construction and late-stage diversification of functional molecules. Nat. Chem. 5, 369–375 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Fier, P. S. & Hartwig, J. F. Synthesis and late-stage functionalization of complex molecules through C–H fluorination and nucleophilic aromatic substitution. J. Am. Chem. Soc. 136, 10139–10147 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Noisier, A. F. & Brimble, M. A. C–H functionalization in the synthesis of amino acids and peptides. Chem. Rev. 114, 8775–8806 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Romero, N. A., Margrey, K. A., Tay, N. E. & Nicewicz, D. A. Site-selective arene C–H amination via photoredox catalysis. Science 349, 1326–1330 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Cuthbertson, J. D. & MacMillan, D. W. The direct arylation of allylic sp 3 C–H bonds via organic and photoredox catalysis. Nature 519, 74–77 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jin, J. & MacMillan, D. W. Alcohols as alkylating agents in heteroarene C–H functionalization. Nature 525, 87–90 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Davies, H. M. L. & Hansen, T. Asymmetric intermolecular carbenoid C−H insertions catalyzed by rhodium(ii) (S)-N-(p-dodecylphenyl)sulfonylprolinate. J. Am. Chem. Soc. 119, 9075–9076 (1997).

    Article  CAS  Google Scholar 

  10. Davies, H. M. L., Antoulinakis, E. G. & Hansen, T. Catalytic asymmetric synthesis of syn-aldol products from intermolecular C−H insertions between allyl silyl ethers and methyl aryldiazoacetates. Org. Lett. 1, 383–386 (1999).

    Article  CAS  Google Scholar 

  11. Davies, H. M. L. & Antoulinakis, E. G. Asymmetric catalytic C−H activation applied to the synthesis of syn-aldol products. Org. Lett. 2, 4153–4156 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Chan, K. H., Guan, X., Lo, V. K. & Che, C. M. Elevated catalytic activity of ruthenium(ii)-porphyrin-catalyzed carbene/nitrene transfer and insertion reactions with N-heterocyclic carbene ligands. Angew. Chem. Int. Ed. 53, 2982–2987 (2014).

    Article  CAS  Google Scholar 

  13. Li, Y., Huang, J. S., Zhou, Z. Y., Che, C. M. & You, X. Z. Remarkably stable iron porphyrins bearing nonheteroatom-stabilized carbene or (alkoxycarbonyl)carbenes: isolation, X-ray crystal structures, and carbon atom transfer reactions with hydrocarbons. J. Am. Chem. Soc. 124, 13185–13193 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Suematsu, H. & Katsuki, T. Iridium(iii) catalyzed diastereo- and enantioselective C−H bond functionalization. J. Am. Chem. Soc. 131, 14218–14219 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Axten, J. M., Ivy, R., Krim, L. & Winkler, J. D. Enantioselective synthesis of d-threo-methylphenidate. J. Am. Chem. Soc. 121, 6511–6512 (1999).

    Article  CAS  Google Scholar 

  16. Davies, H. M. L., Hansen, T., Hopper, D. W. & Panaro, S. A. Highly regio-, diastereo-, and enantioselective C−H insertions of methyl aryldiazoacetates into cyclic N-Boc-protected amines. Asymmetric synthesis of novel C2-symmetric amines and threo-methylphenidate. J. Am. Chem. Soc. 121, 6509–6510 (1999).

    Article  CAS  Google Scholar 

  17. Lyons, T. W. & Sanford, M. S. Palladium-catalyzed ligand-directed C–H functionalization reactions. Chem. Rev. 110, 1147–1169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Simmons, E. M. & Hartwig, J. F. Catalytic functionalization of unactivated primary C–H bonds directed by an alcohol. Nature 483, 70–73 (2012).

    Article  CAS  PubMed  Google Scholar 

  19. Liu, Y. J. et al. Overcoming the limitations of directed C–H functionalizations of heterocycles. Nature 515, 389–393 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dick, A. R., Hull, K. L. & Sanford, M. S. A highly selective catalytic method for the oxidative functionalization of C−H bonds. J. Am. Chem. Soc. 126, 2300–2301 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Desai, L. V., Malik, H. A. & Sanford, M. S. Oxone as an inexpensive, safe, and environmentally benign oxidant for C−H bond oxygenation. Org. Lett. 8, 1141–1144 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Kalyani, D. & Sanford, M. S. Regioselectivity in palladium-catalyzed C−H activation/oxygenation reactions. Org. Lett. 7, 4149–4152 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Hwang, S. J., Cho, S. H. & Chang, S. Synthesis of condensed pyrroloindoles via Pd-catalyzed intramolecular C–H bond functionalization of pyrroles. J. Am. Chem. Soc. 130, 16158–16159 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. McQuaid, K. M. & Sames, D. C–H bond functionalization via hydride transfer: Lewis acid catalyzed alkylation reactions by direct intramolecular coupling of sp 3 C–H bonds and reactive alkenyl oxocarbenium intermediates. J. Am. Chem. Soc. 131, 402–403 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. He, G., Zhao, Y., Zhang, S., Lu, C. & Chen, G. Highly efficient syntheses of azetidines, pyrrolidines, and indolines via palladium catalyzed intramolecular amination of C(sp 3)−H and C(sp 2)−H bonds at gamma and delta positions. J. Am. Chem. Soc. 134, 3–6 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Doyle, M. P., Duffy, R., Ratnikov, M. & Zhou, L. Catalytic carbene insertion into C−H bonds. Chem. Rev. 110, 704–724 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Doyle, M. P., Kalinin, A. V. & Ene, D. G. Chiral catalyst controlled diastereoselection and regioselection in intramolecular carbon−hydrogen insertion reactions of diazoacetates. J. Am. Chem. Soc. 118, 8837–8846 (1996).

    Article  CAS  Google Scholar 

  28. Taber, D. F. & Stiriba, S. E. Synthesis of natural products by rhodium-mediated intramolecular C−H insertion. Chem. Eur. J. 4, 990–992 (1998).

    Article  CAS  Google Scholar 

  29. Breslow, R. & Gellman, S. H. Intramolecular nitrene carbon–hydrogen insertions mediated by transition-metal complexes as nitrogen analogs of cytochrome P-450 reactions. J. Am. Chem. Soc. 105, 6728–6729 (1983).

    Article  CAS  Google Scholar 

  30. Espino, C. G., Wehn, P. M., Chow, J. & Du Bois, J. Synthesis of 1,3-difunctionalized amine derivatives through selective C−H bond oxidation. J. Am. Chem. Soc. 123, 6935–6936 (2001).

    Article  CAS  Google Scholar 

  31. Sigman, M. S. & Werner, E. W. Imparting catalyst control upon classical palladium-catalyzed alkenyl C−H bond functionalization reactions. Acc. Chem. Res. 45, 874–884 (2012).

    Article  CAS  PubMed  Google Scholar 

  32. Hickman, A. J. & Sanford, M. S. Catalyst control of site selectivity in the Pdii/iv-catalyzed direct arylation of naphthalene. ACS Catal. 1, 170–174 (2011).

    Article  CAS  Google Scholar 

  33. Hartwig, J. F. Catalyst-controlled site-selective bond activation. Acc. Chem. Res. 50, 549–555 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Dydio, P. et al. An artificial metalloenzyme with the kinetics of native enzymes. Science 354, 102–106 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Thu, H. Y., Yu, W. Y. & Che, C. M. Intermolecular amidation of unactivated sp 2 and sp 3 C–H bonds via palladium-catalyzed cascade C–H activation/nitrene insertion. J. Am. Chem. Soc. 128, 9048–9049 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Espino, C. G., Fiori, K. W., Kim, M. & Du Bois, J. Expanding the scope of C–H amination through catalyst design. J. Am. Chem. Soc. 126, 15378–15379 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Bois, J. D. Rhodium-catalyzed C–H amination—an enabling method for chemical synthesis. Org. Process Res. Dev. 15, 758–762 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Huang, X., Bergsten, T. M. & Groves, J. T. Manganese-catalyzed late-stage aliphatic C–H azidation. J. Am. Chem. Soc. 137, 5300–5303 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Sharma, A. & Hartwig, J. F. Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization. Nature 517, 600–604 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chen, H., Schlecht, S., Semple, T. C. & Hartwig, J. F. Thermal, catalytic, regiospecific functionalization of alkanes. Science 287, 1995–1997 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Schmidt, V. A., Quinn, R. K., Brusoe, A. T. & Alexanian, E. J. Site-selective aliphatic C–H bromination using N-bromoamides and visible light. J. Am. Chem. Soc. 136, 14389–14392 (2014).

    Article  CAS  PubMed  Google Scholar 

  42. Davies, H. M. & Manning, J. R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion. Nature 451, 417–424 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Davies, H. M. & 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).

    Article  CAS  PubMed  Google Scholar 

  44. 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, 7602–7606 (2016).

    Article  CAS  Google Scholar 

  45. 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 

  46. Thu, H. Y. et al. Highly selective metal catalysts for intermolecular carbenoid insertion into primary C–H bonds and enantioselective C−C bond formation. Angew. Chem. Int. Ed. 47, 9747–9751 (2008).

    Article  CAS  Google Scholar 

  47. Davies, H. M. L. & Venkataramani, C. Kinetic resolution and double stereodifferentiation in catalytic asymmetric C−H activation of 2-substituted pyrrolidines. Org. Lett. 3, 1773–1775 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Liao, K. et al. Site-selective carbene-induced C–H functionalization catalyzed by dirhodium tetrakis(triarylcyclopropanecarboxylate) complexes. ACS Catal. 8, 678–682 (2018).

    Article  CAS  Google Scholar 

  49. Hansen, J. H., Autsbach, J. & Davies, H. M. L. Computational study on the selectivity of donor/acceptor-substituted rhodium carbenoids. J. Org. Chem. 74, 6555–6563 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Financial support was provided by the National Science Foundation (NSF) via the CCI Center for Selective C–H Functionalization (CHE-1700982). D.G.M. acknowledges NSF MRI-R2 grant CHE-0958205 and the use of the resources of the Cherry Emerson Center for Scientific Computation. Funds to purchase the NMR and X-ray spectrometers used in these studies were supported by the NSF (CHE 1531620 and CHE 1626172). The authors thank J. Bacsa for the X-ray structure determinations.

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Authors and Affiliations

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

    Kuangbiao Liao, Djamaladdin G. Musaev & Huw M. L. Davies

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

    Yun-Fang Yang, Yingzi Li, Jacob N. Sanders & K. N. Houk

  3. College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, Zhejiang, P.R. China

    Yun-Fang Yang

  4. Cherry L. Emerson Center for Scientific Computation, Emory University, Atlanta, GA, USA

    Djamaladdin G. Musaev

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Contributions

K.L. and H.M.L.D. designed the synthetic experiments, K.L. performed the synthetic experiments, Y.-F.Y., Y.L., J.S., D.G.M. and K.N.H. conducted the computational studies, and K.L., K.N.H and H.M.L.D. prepared 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 March 10, 2015). The other authors declare no competing interests.

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Supplementary information

Supplementary information

Supplementary experimental and computational details

Crystallographic data

CIF for compound 11; CCDC reference: 1551026

Crystallographic data

Structure factors for compound 11; CCDC reference 1551026

Crystallographic data

CIF for catalyst F; CCDC reference: 1552206

Crystallographic data

Structure factors for catalyst F; CCDC reference 1552206

Computational data

Calculated C2 symmetric structure for catalyst I

Computational data

Calculated C4 symmetric structure for catalyst I

Computational data

Calculated C4a symmetric structure for catalyst I

Computational data

Calculated D2 symmetric structure for catalyst I

Computational data

Calculated C2 symmetric carbene structure

Computational data

Calculated C4 symmetric carbene structure for catalyst

Computational data

Calculated transition state TS1

Computational data

Calculated transition state TS2

Computational data

Calculated transition state TS3

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Liao, K., Yang, YF., Li, Y. et al. Design of catalysts for site-selective and enantioselective functionalization of non-activated primary C–H bonds. Nature Chem 10, 1048–1055 (2018). https://doi.org/10.1038/s41557-018-0087-7

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