Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Network-analysis-guided synthesis of weisaconitine D and liljestrandinine

Nature volume 528, pages 493–498 (2015)Cite this article

Subjects

This article has been updated

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  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)

    Article  CAS  Google Scholar 

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

Download references

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.

Author information

Author notes

  1. C. J. Marth, G. M. Gallego, J. C. Lee, T. P. Lebold & S. Kulyk

    Present address: † Present addresses: The University of Chicago Law School, 1111 East 60th Street, Chicago, Illinois 60637, USA (C.J.M.); Department of Chemistry, Pfizer Pharmaceuticals, La Jolla Laboratories, 10770 Science Center Drive, La Jolla, California 92121, USA (G.M.G.); Worldwide Medicinal Chemistry, Groton Laboratories, Pfizer Inc. Eastern Point Road, Groton, Connecticut 06340, USA (J.C.L.); Janssen Research & Development, LLC, 3210 Merryfield Row, San Diego, California, 92121-1126, USA (T.P.L.); Theravance Biopharma US Inc., 901 Gateway Boulevard, South San Francisco, California 94080, USA (S.K.).,

  2. C. J. Marth and G. M. Gallego: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, University of California, Berkeley, 94720, California, USA

    C. J. Marth, G. M. Gallego, J. C. Lee, T. P. Lebold, S. Kulyk, K. G. M. Kou & R. Sarpong

  2. Cadre Research Labs, Chicago, 60654, Illinois, USA

    J. Qin & R. Lilien

Authors
  1. C. J. Marth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. M. Gallego
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. C. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. P. Lebold
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Kulyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K. G. M. Kou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. R. Lilien
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R. Sarpong
    View author publications

    You can also search for this author in PubMed Google Scholar

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 (19 → 21), the formal hydromethoxylation sequence (21 → 23) and the development of robust conditions for the aryl conjugate addition (7 → 12; with K.G.M.K.) and Hofmann rearrangement (13 → 14). 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 (7 → 12) and establishing the sequence described for the conversion of 23 → 2 and 15 → 28. 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 (7 → 12; with C.J.M.) and the construction of piperidine 16.

Corresponding author

Correspondence to R. Sarpong.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

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.

Supplementary information

Supplementary Information

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

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature16440

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing