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Network-analysis-guided synthesis of weisaconitine D and liljestrandinine

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Abstract

General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here we present a method to establish a strategy for such syntheses, which uses network analysis. This approach has led to the identification of a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, and the core of gomandonine. We also developed a web-based graphing program that allows network analysis to be easily performed on molecules with complex frameworks. The diterpenoid alkaloids comprise some of the most architecturally complex and functional-group-dense secondary metabolites isolated. Consequently, they present a substantial challenge for chemical synthesis. The synthesis approach described here is a notable departure from other single-target-focused strategies adopted for the syntheses of related structures. Specifically, it affords not only the targeted natural products, but also intermediates and derivatives in the three subfamilies of diterpenoid alkaloids (C-18, C-19 and C-20), and so provides a unified synthetic strategy for these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites.

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Figure 1: Molecules referenced in this work and design strategy.
Figure 2: Synthesis of weisaconitine D.
Figure 3: Synthesis of liljestrandinine and enantioselective cycloaddition.
Figure 4: Selected illustrations for network analysis graphing program.

Change history

  • 23 December 2015

    Minor changes were made to the text.

References

  1. Nusim, S. H. (ed.) Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation 2nd edn, Vol. 205 of Drugs and the Pharmaceutical Sciences (CRC Press, 2009)

  2. Schaefer, B. Natural Products in the Chemical Industry 209–518 (Springer, 2014)

  3. Farina, V. Reeves, J. T., Senanayake, C. H. & Song, J. J. Asymmetric synthesis of active pharmaceutical ingredients. Chem. Rev. 106, 2734–2793 (2006)

    CAS  Article  Google Scholar 

  4. dos Santos Pinheiro, E., Antunes, O. A. C. & Fortunak, J. M. D. A survey of the syntheses of active pharmaceutical ingredients for antiretroviral drug combinations critical to access in emerging nations. Antiviral Res. 79, 143–165 (2008)

    Article  Google Scholar 

  5. Shenvi, R. A., O’Malley, D. P. & Baran, P. S. Chemoselectivity: the mother of invention in total synthesis. Acc. Chem. Res. 42, 530–541 (2009)

    CAS  Article  Google Scholar 

  6. Hudlický, T. & Reed, J. W. The Way of Synthesis (Wiley-VCH, 2007)

  7. Service, R. F. Race for molecular summits. Science 285, 184–187 (1999)

    CAS  Article  Google Scholar 

  8. Negishi, E.-i. Magical power of transition metals: past, present, and future (Nobel lecture). Angew. Chem. Int. Ed. 50, 6738–6764 (2011)

    CAS  Article  Google Scholar 

  9. White, M. C. C–H bond functionalization and synthesis in the 21st century: a brief history and prospectus. Synlett 23, 2746–2748 (2012)

    CAS  Google Scholar 

  10. Kwok, R. Five hard truths for synthetic biology. Nature 463, 288–290 (2010)

    CAS  Article  Google Scholar 

  11. MacMillan, J. & Beale, M. H. Diterpene biosynthesis. Compr. Nat. Prod. Chem. 2, 217–243 (1999)

    CAS  Article  Google Scholar 

  12. Koehn, F. E. & Carter, G. T. The evolving role of natural products in drug discovery. Nature Rev. Drug Discov. 4, 206–220 (2005)

    CAS  Article  Google Scholar 

  13. Corey, E. J., Howe, W. J., Orf, H. W., Pensak, D. A. & Petersson, G. General methods of synthesis analysis. Strategic bond disconnections for bridged polycyclic structures. J. Am. Chem. Soc. 97, 6116–6124 (1975)

    CAS  Article  Google Scholar 

  14. Chan, T. Y. K. Aconite poisoning. Clin. Toxicol. 47, 279–285 (2009)

    CAS  Article  Google Scholar 

  15. Catterall, W. A. et al. Voltage-gated ion channels and gating modifier toxins. Toxicon 49, 124–141 (2007)

    CAS  Article  Google Scholar 

  16. Anger, T., Madge, D. J., Mulla, M. & Riddall, D. Medicinal chemistry of neuronal voltage-gated sodium channel blockers. J. Med. Chem. 44, 115–137 (2001)

    CAS  Article  Google Scholar 

  17. Vakhitova, Yu. V. et al. A study of the mechanism of the antiarrhythmic action of allapinin. Russ. J. Bioorg. Chem. 39, 92–101 (2013)

    CAS  Article  Google Scholar 

  18. Nishiyama, Y., Han-ya, Y., Yokoshima, S. & Fukuyama, T. Total synthesis of (−)-lepenine. J. Am. Chem. Soc. 136, 6598–6601 (2014)

    CAS  Article  Google Scholar 

  19. Shi, Y., Wilmot, J. T., Nordstrøm, L. U., Tan, D. S. & Gin, D. Y. Total synthesis, relay synthesis, and structural confirmation of the C18-norditerpenoid alkaloid neofinaconitine. J. Am. Chem. Soc. 135, 14313–14320 (2013)

    CAS  Article  Google Scholar 

  20. Wiesner, K., Tsai, T. Y. R., Huber, K., Bolton, S. E. & Vlahov, R. Total synthesis of talatisamine, a delphinine type alkaloid. J. Am. Chem. Soc. 96, 4990–4992 (1974)

    CAS  Article  Google Scholar 

  21. Cherney, E. C., Lopchuk, J. M., Green, J. C. & Baran, P. S. A unified approach to ent-atisane diterpenes and related alkaloids: synthesis of (−)-methyl atisenoate, (−)-isoatisine, and the hetidine skeleton. J. Am. Chem. Soc. 136, 12592–12595 (2014)

    CAS  Article  Google Scholar 

  22. Prabhakaran, J., Lhermitte, H., Das, J., Sasi-Kumar, T. K. & Grierson, D. S. The synthesis of a sulfone containing analogue of the esperamicin-A1 aglycone: a hetero Diels–Alder approach. Synlett 5, 658–662 (2000)

    Google Scholar 

  23. Marx, J. N., Cox, J. H. & Norman, L. R. 2-Carbomethoxycyclopent-2-enone. J. Org. Chem. 37, 4489–4491 (1972)

    CAS  Article  Google Scholar 

  24. Bandyopadhyaya, A. K. et al. Neurosteroid analogues. 15. A comparative study of the anesthetic and GABAergic actions of alphaxalone, Δ16-alphaxalone and their corresponding 17-carbonitrile analogues. Bioorg. Med. Chem. Lett. 20, 6680–6684 (2010)

    CAS  Article  Google Scholar 

  25. Yokota, S. & Miyamoto, S. Insecticide. Japanese patent 2008-024670 (2008)

  26. Lee, J., Kim, M., Chang, S. & Lee, H.-Y. Anhydrous hydration of nitriles to amides using aldoximes as the water source. Org. Lett. 11, 5598–5601 (2009)

    CAS  Article  Google Scholar 

  27. Quideau, S. et al. Iodine-mediated and electrochemical oxidative transformations of 2-methoxy- and 2-methylphenols. ARKIVOC 2003(vi), 106–119 (2003)

    Google Scholar 

  28. Cheng, H., Xu, L., Chen, D.-L., Chen, Q.-H. & Wang, F.-P. Construction of the functionalized B/C/D ring system of C19-diterpenoid alkaloids via intramolecular Diels–Alder reaction followed by Wagner–Meerwein rearrangement. Tetrahedron 68, 1171–1176 (2012)

    CAS  Article  Google Scholar 

  29. Fürstner, A. & Davies, P. W. Catalytic carbophilic activation: catalysis by platinum and gold π acids. Angew. Chem. Int. Ed. 46, 3410–3449 (2007)

    Article  Google Scholar 

  30. Evans, D. A., Fu, G. C. & Hoveyda, A. H. Rhodium(I)-catalyzed hydroboration of olefins. The documentation of regio- and stereochemical control in cyclic and acyclic systems. J. Am. Chem. Soc. 110, 6917–6918 (1988)

    CAS  Article  Google Scholar 

  31. Isayama, S. & Mukaiyama, T. Novel method for the preparation of triethylsilyl peroxides from olefins by the reaction with molecular oxygen and triethylsilane catalyzed by bis(1,3-diketonato)cobalt(II). Chem. Lett. 18, 573–576 (1989)

    Article  Google Scholar 

  32. Isayama, S. An efficient method for the direct peroxygenation of various olefinic compounds with molecular oxygen and triethylsilane catalyzed by a cobalt(II) complex. Bull. Chem. Soc. Jpn 63, 1305–1310 (1990)

    CAS  Article  Google Scholar 

  33. Cuerva, J. M. et al. Water: the ideal hydrogen-atom source in free-radical chemistry mediated by TiIII and other single-electron transfer metals? Angew. Chem. Int. Ed. 45, 5522–5526 (2006)

    CAS  Article  Google Scholar 

  34. Wiesner, K. Total synthesis of racemic talatisamine. Pure Appl. Chem. 41, 93–112 (1975)

    CAS  Article  Google Scholar 

  35. Schotes, C. & Mezzetti, A. Asymmetic Diels–Alder reactions of unsaturated β-ketoesters catalyzed by chiral ruthenium PNNP complexes. J. Am. Chem. Soc. 132, 3652–3653 (2010)

    CAS  Article  Google Scholar 

  36. Schotes, C., Althaus, M., Aardoom, R. & Mezzetti, A. Asymmetric Diels–Alder and Ficini reactions with alkylidene β-ketoesters catalyzed by chiral ruthenium PNNP complexes: mechanistic insight. J. Am. Chem. Soc. 134, 1331–1343 (2012)

    CAS  Article  Google Scholar 

  37. Oyama, H., Orimoto, K., Niwa, T. & Nakada, M. Highly enantioselective catalytic asymmetric Mukaiyama–Michael reactions of cyclic α-alkylidene-β-oxo imides. Tetrahedr. Asymm. 26, 262–270 (2015)

    CAS  Article  Google Scholar 

  38. Orimoto, K., Oyama, H., Namera, Y., Niwa, T. & Nakada, M. Catalytic asymmetric [4 + 2] cycloadditions and Hosomi–Sakurai reactions of α-alkylidene β-keto imides. Org. Lett. 15, 768–771 (2013)

    CAS  Article  Google Scholar 

  39. Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis 43–44 (Wiley, 1989)

  40. Hoffmann, R. W. Elements of Synthesis Planning (Springer, 2009)

  41. Steinbeck, C. et al. The chemistry development kit (CDK): an open-source Java library for chemo- and bioinformatics. J. Chem. Inform. Comput. Sci. 43, 493–500 (2003)

    CAS  Article  Google Scholar 

  42. Steinbeck, C. et al. Recent developments of the chemistry development kit (CDK) – an open-source Java library for chemo- and bioinformatics. Curr. Pharm. Des. 12, 2111–2120 (2006)

    CAS  Article  Google Scholar 

  43. Legault, C. Y. CYLview, 1.0b. http://www.cylview.org (Université de Sherbrook, 2009)

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Acknowledgements

This project was supported by award no. RO1 GM084906 from the National Institute of General Medical Sciences. C.J.M. acknowledges a National Science Foundation graduate fellowship. G.M.G. is grateful to the NIH (5F31GM095238) for a graduate fellowship. T.P.L. and K.G.M.K. acknowledge postdoctoral fellowships from the NSERC (Canada). We are grateful to X.-Y. Liu for copies of 1H and 13C NMR spectra for liljestrandinine (3). X-ray crystallography was performed by A. DiPasquale (NIH Shared Instrumentation Grant S10-RR027172). The AV-600, AV-500, DRX-500 and AVB-400 NMR instruments were partially supported by NIH grant SRR023679A, NIH grant 1S10RR016634-01, NSF grant CHE 9633007 and NSF grant CHE-0130862, respectively. We acknowledge E. Fisher (Pfizer) for contributions toward a practical synthesis of diene 8. We thank K. Owens for help with generating ‘.sdf’ files, and A. Chen, N. Kelly and K. Evens for the preparation of starting materials. We acknowledge M. Weber for computational calculations pertaining to allylic alcohol 21 and its isomer.

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Contributions

R.S. wrote the manuscript and all authors contributed to the reading and editing of the manuscript. C.J.M., G.M.G., J.C.L., T.P.L., S.K. and K.G.M.K. conducted the chemical reactions. S.K., K.G.M.K. and C.J.M. compiled the Supplementary Information. T.P.L. and G.M.G. made revisions and contributions to the Supplementary Information. J.Q., R.L. and R.S. conceptualized the graphing program, which was executed by J.Q. and R.L. J.Q., R.L. and R.S. prepared the portion of the Supplementary Information describing the graphing program. C.J.M. completed the synthesis and characterization of weisaconitine D, including the conversion of the [2.2.2] to the [3.2.1] bicycle (1921), the formal hydromethoxylation sequence (2123) and the development of robust conditions for the aryl conjugate addition (712; with K.G.M.K.) and Hofmann rearrangement (1314). G.M.G. developed steps 3–17 in the synthesis of [2.2.2] bicycle 19, including establishing a large-scale synthesis of 10, synthesis of piperidine 16, Diels–Alder cycloaddition of 17 and stereoselective reduction of ketone 18. J.C.L. completed the synthesis of liljestrandinine, including conceptualization of the nitrile as a nitrogen atom surrogate, developing conditions for the conjugate addition of the functionalized arene (712) and establishing the sequence described for the conversion of 232 and 1528. T.P.L. contributed to the conceptualization of the synthetic route with substantial synthetic contributions made to the early portion of the synthesis including the establishment of a large-scale synthesis of 10. S.K. developed the enantioselective Diels–Alder reaction (synthesis of 32) and completed the optimization, scale-up and characterization of liljestrandinine. K.G.M.K. completed the optimization, scale-up and characterization of weisaconitine D, and optimized the conjugate addition (712; with C.J.M.) and the construction of piperidine 16.

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Correspondence to R. Sarpong.

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Additional information

Crystallographic data can be obtained free of charge from the Cambridge Crystallographic Data Centre (CCDC; https://summary.ccdc.cam.ac.uk/structure-summary-form, reference numbers 1402704, 1402818, 1402820 and 1403763). The web-based graphing program we developed is available at http://www.cadrerl.com/maxbridge.

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This file contains Supplementary Figures 1-2 and Supplementary Text and Data – see contents page for details. (PDF 8866 kb)

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Marth, C., Gallego, G., Lee, J. et al. Network-analysis-guided synthesis of weisaconitine D and liljestrandinine. Nature 528, 493–498 (2015). https://doi.org/10.1038/nature16440

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