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Chemoselective methylene oxidation in aromatic molecules

Nature Chemistry volume 11, pages 213–221 (2019)Cite this article

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Abstract

Despite significant progress in the development of site-selective aliphatic C–H oxidations over the past decade, the ability to oxidize strong methylene C–H bonds in the presence of more oxidatively labile aromatic functionalities remains a major unsolved problem. Such chemoselective reactivity is highly desirable for enabling late-stage oxidative derivatizations of pharmaceuticals and medicinally important natural products that often contain such functionality. Here, we report a simple manganese small-molecule catalyst Mn(CF3–PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive. Preparative remote methylene oxidation is obtained in 50 aromatic compounds housing medicinally relevant halogen, oxygen, heterocyclic and biaryl moieties. Late-stage methylene oxidation is demonstrated on four drug scaffolds, including the ethinylestradiol scaffold where other non-directed C–H oxidants that tolerate aromatic groups effect oxidation at only activated tertiary benzylic sites. Rapid generation of a known metabolite (piragliatin) from an advanced intermediate is demonstrated.

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Fig. 1: Enzymatic and small-molecule approaches for C–H oxidation.
Fig. 2: Chemoselective methylene C–H oxidation.
Fig. 3: Late-stage methylene hydroxylation of synthetic and natural product, aromatic drugs derivatives.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition nos. CCDC 1869257 for (S,S)-5, CCDC 1869258 for 73, CCDC 1869259 for 74 and CCDC 1869260 for (R,R)-S2. Copies of the data can be obtained free of charge from www.ccdc.cam.ac.uk/structures/. All other data supporting the findings of this study are available within the Article and its Supplementary Information, or from the corresponding author upon reasonable request.

References

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

    Article  CAS  Google Scholar 

  2. Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

    Article  CAS  Google Scholar 

  3. McMurray, L., O’Hara, F. & Gaunt, M. J. Recent developments in natural product synthesis using metal-catalysed C–H bond functionalisation. Chem. Soc. Rev. 40, 1885–1898 (2011).

    Article  CAS  Google Scholar 

  4. Ford, M. C. & Ho, P. S. Computational tools to model halogen bonds in medicinal chemistry. J. Med. Chem. 59, 1655–1670 (2016).

    Article  CAS  Google Scholar 

  5. Ortiz de Montellano, P. R. (ed.) Cytochrome P450: Structure, Mechanism, and Biochemistry (Springer, Berlin, 2015).

  6. Mack, J. B. C., Gipson, J. D., Du Bois, J. & Sigman, M. S. Ruthenium-catalyzed C–H hydroxylation in aqueous acid enables selective functionalization of amine derivatives. J. Am. Chem. Soc. 139, 9503–9506 (2017).

    Article  CAS  Google Scholar 

  7. Ottenbacher, R. V., Samsonenko, D. G., Talsi, E. P. & Bryliakov, K. P. Highly efficient, regioselective, and stereospecific oxidation of aliphatic C–H groups with H2O2, catalyzed by aminopyridine manganese complexes. Org. Lett. 14, 4310–4313 (2012).

    Article  CAS  Google Scholar 

  8. Adams, A. M., Du Bois, J. & Malik, H. A. Comparative study of the limitations and challenges in atom-transfer C–H oxidations. Org. Lett. 17, 6066–6069 (2015).

    Article  CAS  Google Scholar 

  9. Chen, M. S. & White, M. C. A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

    Article  CAS  Google Scholar 

  10. Chen, M. S. & White, M. C. Combined effects on selectivity in Fe-catalyzed methylene oxidation. Science 327, 566–571 (2010).

    Article  CAS  Google Scholar 

  11. Gormisky, P. E. & White, M. C. Catalyst-controlled aliphatic C–H oxidations with a predictive model for site-selectivity. J. Am. Chem. Soc. 135, 14052–14055 (2013).

    Article  CAS  Google Scholar 

  12. White, M. C. Adding aliphatic C–H bond oxidations to synthesis. Science 335, 807–809 (2012).

    Article  CAS  Google Scholar 

  13. White, M. C. & Zhao, J. Aliphatic C–H oxidations for late-stage functionalization. J. Am. Chem. Soc. 140, 13988–14009 (2018).

    Article  CAS  Google Scholar 

  14. Paradine, S. M. et al. A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp 3) –H amination. Nat. Chem. 7, 987–994 (2015).

    Article  CAS  Google Scholar 

  15. Padwa, A. et al. Ligand effects on dirhodium(ii) carbene reactivities. Highly effective switching between competitive carbenoid transformations. J. Am. Chem. Soc. 115, 8669–8680 (1993).

    Article  CAS  Google Scholar 

  16. Quinn, R. K. et al. Site-selective aliphatic C–H chlorination using N-chloroamides enables a synthesis of chlorolissoclimide. J. Am. Chem. Soc. 138, 696–702 (2016).

    Article  CAS  Google Scholar 

  17. Asensio, G., Castellano, G., Mello, R. & González Núñez, M. E. Oxyfunctionalization of aliphatic esters by methyl(trifluoromethyl)dioxirane. J. Org. Chem. 61, 5564–5566 (1996).

    Article  CAS  Google Scholar 

  18. Kawamata, Y. et al. Scalable, electrochemical oxidation of unactivated C–H bonds. J. Am. Chem. Soc. 139, 7448–7451 (2017).

    Article  CAS  Google Scholar 

  19. Yosca, T. H. et al. Iron(iv)hydroxide pK a and the role of thiolate ligation in C–H bond activation by cytochrome P450. Science 342, 825–829 (2013).

    Article  CAS  Google Scholar 

  20. Guroff, G. et al. Hydroxylation-induced migration. The NIH shift: recent experiments reveal an unexpected and general result of enzymatic hydroxylation of aromatic compounds. Science 157, 1524–1530 (1967).

    Article  CAS  Google Scholar 

  21. Jeon, S. & Bruice, T. C. Redox chemistry of water-soluble iron, manganese, and chromium metalloporphyrins and acid–base behavior of their lyate axial ligands in aqueous solution: influence of electronic effects. Inorg. Chem. 31, 4843–4848 (1992).

    Article  CAS  Google Scholar 

  22. Chen, J. et al. Tuning the reactivity of mononuclear nonheme manganese(iv)-oxo complexes by triflic acid. Chem. Sci. 6, 3624–3632 (2015).

    Article  CAS  Google Scholar 

  23. White, M. C., Doyle, A. G. & Jacobsen, E. N. A synthetically useful, self-assembling MMO mimic system for catalytic alkene epoxidation with aqueous H2O2. J. Am. Chem. Soc. 123, 7194–7195 (2001).

    Article  CAS  Google Scholar 

  24. Bigi, M. A., Reed, S. A. & White, M. C. Directed metal (oxo) aliphatic C–H hydroxylations: overriding substrate bias. J. Am. Chem. Soc. 134, 9721–9726 (2012).

    Article  CAS  Google Scholar 

  25. Miao, C. et al. Proton-promoted and anion-enhanced epoxidation of olefins by hydrogen peroxide in the presence of nonheme manganese catalysts. J. Am. Chem. Soc. 138, 936–943 (2016).

    Article  CAS  Google Scholar 

  26. Mas-Ballesté, R. & Que, L.Jr. Iron-catalyzed olefin epoxidation in the presence of acetic acid: insights into the nature of the metal-based oxidant. J. Am. Chem. Soc. 129, 15964–15972 (2007).

    Article  Google Scholar 

  27. Marson, C. M. New and unusual scaffolds in medicinal chemistry. Chem. Soc. Rev. 40, 5514–5533 (2011).

    Article  CAS  Google Scholar 

  28. Howell, J. M., Feng, K., Clark, J. R., Trzepkowski, L. J. & White, M. C. Remote oxidation of aliphatic C–H bonds in nitrogen-containing molecules. J. Am. Chem. Soc. 137, 14590–14593 (2015).

    Article  CAS  Google Scholar 

  29. Osberger, T. J., Rogness, D. C., Kohrt, J. T., Stepan, A. F. & White, M. C. Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature 537, 214–219 (2016).

    Article  CAS  Google Scholar 

  30. Rennhack, A. et al. Synthesis of a potent photoreactive acidic gamma-secretase modulator for target identification in cells. Bioorg. Med. Chem. 20, 6523–6532 (2012).

    Article  CAS  Google Scholar 

  31. Obach, R. S. Pharmacologically active drug metabolites: impact on drug discovery and pharmacotherapy. Pharmacol. Rev. 65, 578–640 (2013).

    Article  CAS  Google Scholar 

  32. Sarabu, R. et al. Discovery of piragliatin—first glucokinase activator studied in type 2 diabetic patients. J. Med. Chem. 55, 7021–7036 (2012).

    Article  CAS  Google Scholar 

  33. Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs from 1981 to 2014. J. Nat. Prod. 79, 629–661 (2016).

    Article  CAS  Google Scholar 

  34. D’Accolti, L., Fusco, C., Lampignano, G., Capitelli, F. & Curci, R. Oxidation of natural targets by dioxiranes. Part 6: On the direct regio- and site-selective oxyfunctionalization of estrone and of 5α-androstane steroid derivatives. Tetrahedron Lett. 49, 5614–5617 (2008).

    Article  Google Scholar 

  35. Breslow, R., Zhang, X. & Huang, Y. Selective catalytic hydroxylation of a steroid by an artificial cytochrome P-450 enzyme. J. Am. Chem. Soc. 119, 4535–4536 (1997).

    Article  CAS  Google Scholar 

  36. See, Y. Y., Herrmann, A. T., Aihara, Y. & Baran, P. S. Scalable C–H oxidation with copper: synthesis of polyoxypregnanes. J. Am. Chem. Soc. 137, 13776–13779 (2015).

    Article  CAS  Google Scholar 

  37. Font, D. et al. Readily accessible bulky iron catalysts exhibiting site selectivity in the oxidation of steroidal substrates. Angew. Chem. Int. Ed. 55, 5776–5779 (2016).

    Article  CAS  Google Scholar 

  38. Nanjo, T., de Lucca, E. C. Jr & White, M. C. Remote, late-stage oxidation of aliphatic C–H bonds in amide-containing molecules. J. Am. Chem. Soc. 139, 14586–14591 (2017).

    Article  CAS  Google Scholar 

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Acknowledgements

Financial support for this work was provided by the NIH NIGMS Maximizing Investigators’ Research Award MIRA (R35 GM122525). The authors acknowledge The Uehara Memorial Foundation for a fellowship to T.N. and Conselho Nacional de Desenvolvimento Científico e Tecnológico for a fellowship to E.C.L. (proc. no. 234643/2014-5). The authors thank L. Zhu for assistance with NMR spectroscopy, D. Gray and T. Woods for X-ray crystallographic studies, and C. Delaney for preliminary studies on basic nitrogen-containing compounds. The authors also thank C. Wendell, K. Feng and W. Liu for checking the procedures. The data reported in this paper are tabulated in the Supplementary Information.

Author information

Authors and Affiliations

  1. Department of Chemistry, Roger Adams Laboratory, University of Illinois, Urbana, IL, USA

    Jinpeng Zhao & M. Christina White

  2. Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, Japan

    Takeshi Nanjo

  3. Institute of Chemistry, University of Campinas, Campinas/SP, Brazil

    Emilio C. de Lucca Jr

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Contributions

M.C.W. and J.Z. conceived and designed the project and wrote the manuscript. J.Z., T.N. and E.C.L. conducted the experiments and analysed the data. All authors provided comments on the experiments and manuscript during its preparation.

Corresponding author

Correspondence to M. Christina White.

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Competing interests

The University of Illinois has filed a patent application on the Mn(CF3–PDP) catalyst for methylene oxidation in aromatic molecules.

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Supplementary information

Supplementary Information

Supplementary experimental data, synthetic procedures, chemical compound characterization data and Supplementary Figs 1–4

Crystallographic data

CIF for compound S2. CCDC reference 1869260

Crystallographic data

CIF for compound 5. CCDC reference 1869257

Crystallographic data

CIF for compound 73. CCDC reference 1869258

Crystallographic data

CIF for compound 74. CCDC reference 1869259

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Zhao, J., Nanjo, T., de Lucca, E.C. et al. Chemoselective methylene oxidation in aromatic molecules. Nature Chem 11, 213–221 (2019). https://doi.org/10.1038/s41557-018-0175-8

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