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Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions

Nature Chemistry volume 10, pages 85–90 (2018)Cite this article

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Abstract

The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C–H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si–H bonds to yield an oxophilic silylium (R3Si+) equivalent along with a reducing (H–) equivalent. Together, these reactive intermediates enable the reduction of multiple functional groups. Exogenous phosphine Lewis bases further modify the catalyst speciation and attenuate aggressive silylium ions for the selective modification of complex natural products. Manipulation of the catalyst, silane reagent and the reaction conditions provides experimental control over which site is modified (and how). Applying this catalytic method to complex bioactive compounds (natural products or drugs) provides a powerful tool for studying structure–activity relationships.

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Figure 1: Natural products display diverse structures and bioactivity.
Figure 2: Fluoroarylborane catalysts can use the Piers silane-activation mechanism to activate C–O bonds and enable the functionalization of complex natural products.
Figure 3: Chemoselective amide reductions in complex environments are enabled by mixed fluoroarylalkylborane catalysts.
Figure 4: To test the fluoroarylborane methodology on a new natural product class, several selective modifications of 10-deacetoxybaccatin III were demonstrated.

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References

  1. Wright, P. M., Seiple, I. B. & Myers, A. G. The evolving role of chemical synthesis in antibacterial drug discovery. Angew. Chem. Int. Ed. 53, 8840–8869 (2014).

    CAS  Google Scholar 

  2. Barnes, E. C., Kumar, R. & Davis, R. A. The use of isolated natural products as scaffolds for the generation of chemically diverse screening libraries for drug discovery. Nat. Prod. Rep. 33, 372–381 (2016).

    CAS  PubMed  Google Scholar 

  3. Fischbach, M. A. & Walsh, C. T. Antibiotics for emerging pathogens. Science 325, 1089–1093 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Galloway, W. R. J. D., Isidro-Llobet, A. & Spring, D. R. Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. Nat. Commun. 1, 80 (2010).

    PubMed  Google Scholar 

  5. Lachance, H., Wetzel, S., Kumar, K. & Waldmann, H. Charting, navigating, and populating natural product chemical space for drug discovery. J. Med. Chem. 55, 5989–6001 (2012).

    CAS  PubMed  Google Scholar 

  6. Clemons, P. A. et al. Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles. Proc. Natl Acad. Sci. USA 107, 18787–18792 (2010).

    CAS  PubMed  Google Scholar 

  7. Hann, M. M., Leach, A. R. & Harper, G. Molecular complexity and its impact on the probability of finding leads for drug discovery. J. Chem. Inf. Comput. Sci. 41, 856–864 (2001).

    CAS  PubMed  Google Scholar 

  8. 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).

    CAS  PubMed  Google Scholar 

  9. Wilcock, B. C. et al. Electronic tuning of site-selectivity. Nat. Chem. 4, 996–1003 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Huigens, R. W. III et al. A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products. Nat. Chem. 5, 195–202 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. He, J., Hamann, L. G., Davies, H. M. L. & Beckwith, R. E. J. Late-stage C–H functionalization of complex alkaloids and drug molecules via intermolecular rhodium-carbenoid insertion. Nat. Commun. 6, 5943 (2015).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  13. Lewis, C. A. & Miller, S. J. Site-selective derivatization and remodeling of erythromycin A by using simple peptide-based chiral catalysts. Angew. Chem. Int. Ed. 45, 5616–5619 (2006).

    CAS  Google Scholar 

  14. Balthaser, B. R., Maloney, M. C., Beeler, A. B., Porco, J. A. & Snyder, J. K. Remodelling of the natural product fumagillol employing a reaction discovery approach. Nat. Chem. 3, 969–973 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Galloway, W. R. J. D. & Spring, D. R. Is synthesis the main hurdle for the generation of diversity in compound libraries for screening? Expert Opin. Drug Discov. 4, 467–472 (2009).

    CAS  PubMed  Google Scholar 

  16. Kim, K.-C. et al. Crystallographic evidence for a free silylium ion. Science 297, 825–827 (2002).

    CAS  PubMed  Google Scholar 

  17. Reed, C. A. The silylium ion problem, R3Si+. Bridging organic and inorganic chemistry. Acc. Chem. Res. 31, 325–332 (1998).

    CAS  Google Scholar 

  18. Klare, H. F. T. & Oestreich, M. Silylium ions in catalysis. Dalton Trans. 39, 9176–9184 (2010).

    CAS  PubMed  Google Scholar 

  19. Houghton, A. Y., Hurmalainen, J., Mansikkamäki, A., Piers, W. E. & Tuononen, H. M. Direct observation of a borane–silane complex involved in frustrated Lewis-pair-mediated hydrosilylations. Nat. Chem. 6, 983–988 (2014).

    CAS  PubMed  Google Scholar 

  20. Rendler, S. & Oestreich, M. Conclusive evidence for an SN2-Si mechanism in the B(C6F5)3-catalyzed hydrosilylation of carbonyl compounds: implications for the related hydrogenation. Angew. Chem. Int. Ed. 47, 5997–6000 (2008).

    CAS  Google Scholar 

  21. Sakata, K. & Fujimoto, H. Quantum chemical study of B(C6F5)3-catalyzed hydrosilylation of carbonyl group. J. Org. Chem. 78, 12505–12512 (2013).

    CAS  PubMed  Google Scholar 

  22. Chatterjee, I., Porwal, D. & Oestreich, M. B(C6F5)3-catalyzed chemoselective defunctionalization of ether-containing primary alkyl tosylates with hydrosilanes. Angew. Chem. Int. Ed. 56, 3389–3391 (2017).

    CAS  Google Scholar 

  23. Piers, W. E., Marwitz, A. J. V. & Mercier, L. G. Mechanistic aspects of bond activation with perfluoroarylboranes. Inorg. Chem. 50, 12252–12262 (2011).

    CAS  PubMed  Google Scholar 

  24. Oestreich, M., Hermeke, J. & Mohr, J. A unified survey of Si–H and H–H bond activation catalysed by electron-deficient boranes. Chem. Soc. Rev. 44, 2202–2220 (2015).

    CAS  PubMed  Google Scholar 

  25. Parks, D. J. & Piers, W. E. Tris(pentafluorophenyl)boron-catalyzed hydrosilation of aromatic aldehydes, ketones, and esters. J. Am. Chem. Soc. 118, 9440–9441 (1996).

    CAS  Google Scholar 

  26. Gevorgyan, V., Rubin, M., Benson, S., Liu, J.-X. & Yamamoto, Y. A novel B(C6F5)3-catalyzed reduction of alcohols and cleavage of aryl and alkyl ethers with hydrosilanes. J. Org. Chem. 65, 6179–6186 (2000).

    CAS  PubMed  Google Scholar 

  27. Drosos, N. & Morandi, B. Boron-catalyzed regioselective deoxygenation of terminal 1,2-diols to 2-alkanols enabled by the strategic formation of a cyclic siloxane intermediate. Angew. Chem. Int. Ed. 54, 8814–8818 (2015).

    CAS  Google Scholar 

  28. Drosos, N., Ozkal, E. & Morandi, B. Catalytic selective deoxygenation of polyols using the B(C6F5)3/silane system. Synlett 27, 1760–1764 (2016).

    CAS  Google Scholar 

  29. Gandhamsetty, N., Park, S. & Chang, S. Selective silylative reduction of pyridines leading to structurally diverse azacyclic compounds with the formation of sp3 C–Si bonds. J. Am. Chem. Soc. 137, 15176–15184 (2015).

    CAS  PubMed  Google Scholar 

  30. Gandhamsetty, N. et al. Chemoselective silylative reduction of conjugated nitriles under metal-free catalytic conditions: β-silyl amines and enamines. Angew. Chem. Int. Ed. 54, 6832–6836 (2015).

    CAS  Google Scholar 

  31. Chandrasekhar, S., Chandrashekar, G., Reddy, M. S. & Srihari, P. A facile and chemoselective conjugate reduction using polymethylhydrosiloxane (PMHS) and catalytic B(C6F5)3 . Org. Biomol. Chem. 4, 1650–1652 (2006).

    CAS  PubMed  Google Scholar 

  32. Tiddens, M. R., Klein Gebbink, R. J. M. & Otte, M. The B(C6F5)3-catalyzed tandem Meinwald rearrangement–reductive amination. Org. Lett. 18, 3714–3717 (2016).

    CAS  PubMed  Google Scholar 

  33. Mack, D. J., Guo, B. & Njardarson, J. T. Synthesis of allylic and homoallylic alcohols from unsaturated cyclic ethers using a mild and selective C–O reduction approach. Chem. Commun. 48, 7844–7846 (2012).

    CAS  Google Scholar 

  34. Zhang, Q., Fu, M.-C., Yu, H.-Z. & Fu, Y. Mechanism of boron-catalyzed N-alkylation of amines with carboxylic acids. J. Org. Chem. 81, 6235–6243 (2016).

    CAS  PubMed  Google Scholar 

  35. Porwal, D. & Oestreich, M. B(C6F5)3-catalyzed reduction of aromatic and aliphatic nitro groups with hydrosilanes. Eur. J. Org. Chem. 2016, 3307–3309 (2016).

    CAS  Google Scholar 

  36. Lee, P. T. K. & Rosenberg, L. Scope and selectivity of B(C6F5)3-catalyzed reactions of the disilane (Ph2SiH)2 . J. Organomet. Chem. 809, 86–93 (2016).

    CAS  Google Scholar 

  37. Huang, P.-Q., Lang, Q.-W. & Wang, Y.-R. Mild metal-free hydrosilylation of secondary amides to amines. J. Org. Chem. 81, 4235–4243 (2016).

    CAS  PubMed  Google Scholar 

  38. Adduci, L. L., Bender, T. A., Dabrowski, J. A. & Gagné, M. R. Chemoselective conversion of biologically sourced polyols into chiral synthons. Nat. Chem. 7, 576–581 (2015).

    CAS  PubMed  Google Scholar 

  39. Bender, T. A., Dabrowski, J. A., Zhong, H. & Gagné, M. R. Diastereoselective B(C6F5)3-catalyzed reductive carbocyclization of unsaturated carbohydrates. Org. Lett. 18, 4120–4123 (2016).

    CAS  PubMed  Google Scholar 

  40. Bender, T. A., Dabrowski, J. A. & Gagné, M. R. Delineating the multiple roles of B(C6F5)3 in the chemoselective deoxygenation of unsaturated polyols. ACS Catal. 6, 8399–8403 (2016).

    CAS  Google Scholar 

  41. Palacios, D. S., Dailey, I., Siebert, D. M., Wilcock, B. C. & Burke, M. D. Synthesis-enabled functional group deletions reveal key underpinnings of amphotericin B ion channel and antifungal activities. Proc. Natl Acad. Sci. USA 108, 6733–6738 (2011)

    CAS  PubMed  Google Scholar 

  42. Volmer, A. A., Szpilman, A. M. & Carreira, E. M. Synthesis and biological evaluation of amphotericin B derivatives. Nat. Prod. Rep. 27, 1329–1349 (2010).

    CAS  PubMed  Google Scholar 

  43. Palacios, D. S., Anderson, T. M. & Burke, M. D. A post-PKS oxidation of the amphotericin B skeleton predicted to be critical for channel formation is not required for potent antifungal activity. J. Am. Chem. Soc. 129, 13804–13805 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Shimano, M., Nagaoka, H. & Yamada, Y. Synthesis of gibberellin A1, A5. A55 and A60. Metal–ammonia reduction of gibberellic acid and its derivatives. Chem. Pharm. Bull. 38, 276–278 (1990).

    CAS  Google Scholar 

  45. Soomro, S. et al. Design of novel artemisinin-like derivatives with cytotoxic and anti-angiogenic properties. J. Cell. Mol. Med. 15, 1122–1135 (2011).

    CAS  PubMed  Google Scholar 

  46. Heiden, Z. M. & Lathem, A. P. Establishing the hydride donor abilities of main group hydrides. Organometallics 34, 1818–1827 (2015).

    CAS  Google Scholar 

  47. Kim, Y. & Chang, S. Borane-catalyzed reductive α-silylation of conjugated esters and amides leaving carbonyl groups intact. Angew. Chem. Int. Ed. 55, 218–222 (2016).

    CAS  Google Scholar 

  48. Hoveyda, A. H., Evans, D. A. & Fu, G. C. Substrate-directable chemical reactions. Chem. Rev. 93, 1307–1370 (1993).

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  50. Stephan, D. W. & Erker, G. Frustrated Lewis pairs: metal-free hydrogen activation and more. Angew. Chem. Int. Ed. 49, 46–76 (2009).

    Google Scholar 

  51. Chen, D., Leich, V., Pan, F. & Klankermayer, J. Enantioselective hydrosilylation with chiral frustrated Lewis pairs. Chem. Eur. J. 18, 5184–5187 (2012).

    CAS  PubMed  Google Scholar 

  52. Parks, D. J., von H. Spence, R. E. & Piers, W. E. Bis(pentafluorophenyl)borane: synthesis, properties, and hydroboration chemistry of a highly electrophilic borane reagent. Angew. Chem. Int. Ed. 34, 809–811 (1995).

    CAS  Google Scholar 

  53. Volkov, A., Tinnis, F., Slagbrand, T., Trillo, P. & Adolfsson, H. Chemoselective reduction of carboxamides. Chem. Soc. Rev. 45, 6685–6697 (2016).

    CAS  PubMed  Google Scholar 

  54. Mukherjee, D., Shirase, S., Mashima, K. & Okuda, J. Chemoselective reduction of tertiary amides to amines catalyzed by triphenylborane. Angew. Chem. Int. Ed. 55, 13326–13329 (2016).

    CAS  Google Scholar 

  55. Kingston, D. G. I. The shape of things to come: structural and synthetic studies of taxol and related compounds. Phytochemistry 68, 1844–1854 (2007).

    CAS  PubMed  Google Scholar 

  56. Gao, F., Yu, M., Chen, Q.-H. & Wang, F.-P. A selective intramolecular transacylation of taxoids accompanying with the oxetane ring opening. Chem. Pharm. Bull. 60, 415–418 (2012).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was exclusively supported by the Department of Energy (Basic Energy Sciences, DE-FG02-05ER15630). T.A.B. is grateful for a University of North Carolina Dissertation Completion Fellowship.

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  1. Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Trandon A. Bender, Philippa R. Payne & Michel R. Gagné

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Contributions

T.A.B. and M.R.G. conceived and designed the experiments; T.A.B. performed the experiments; P.R.P. prepared Lewis acid catalysts; T.A.B. and M.R.G. participated in the process of data analysis and the writing of the paper.

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Correspondence to Michel R. Gagné.

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Bender, T., Payne, P. & Gagné, M. Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions. Nature Chem 10, 85–90 (2018). https://doi.org/10.1038/nchem.2863

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