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.
Subscribe to Journal
Get full journal access for 1 year
only $3.83 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Nusim, S. H. (ed.) Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation 2nd edn, Vol. 205 of Drugs and the Pharmaceutical Sciences (CRC Press, 2009)
Schaefer, B. Natural Products in the Chemical Industry 209–518 (Springer, 2014)
Farina, V. Reeves, J. T., Senanayake, C. H. & Song, J. J. Asymmetric synthesis of active pharmaceutical ingredients. Chem. Rev. 106, 2734–2793 (2006)
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)
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)
Hudlický, T. & Reed, J. W. The Way of Synthesis (Wiley-VCH, 2007)
Service, R. F. Race for molecular summits. Science 285, 184–187 (1999)
Negishi, E.-i. Magical power of transition metals: past, present, and future (Nobel lecture). Angew. Chem. Int. Ed. 50, 6738–6764 (2011)
White, M. C. C–H bond functionalization and synthesis in the 21st century: a brief history and prospectus. Synlett 23, 2746–2748 (2012)
Kwok, R. Five hard truths for synthetic biology. Nature 463, 288–290 (2010)
MacMillan, J. & Beale, M. H. Diterpene biosynthesis. Compr. Nat. Prod. Chem. 2, 217–243 (1999)
Koehn, F. E. & Carter, G. T. The evolving role of natural products in drug discovery. Nature Rev. Drug Discov. 4, 206–220 (2005)
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)
Chan, T. Y. K. Aconite poisoning. Clin. Toxicol. 47, 279–285 (2009)
Catterall, W. A. et al. Voltage-gated ion channels and gating modifier toxins. Toxicon 49, 124–141 (2007)
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)
Vakhitova, Yu. V. et al. A study of the mechanism of the antiarrhythmic action of allapinin. Russ. J. Bioorg. Chem. 39, 92–101 (2013)
Nishiyama, Y., Han-ya, Y., Yokoshima, S. & Fukuyama, T. Total synthesis of (−)-lepenine. J. Am. Chem. Soc. 136, 6598–6601 (2014)
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)
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)
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)
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)
Marx, J. N., Cox, J. H. & Norman, L. R. 2-Carbomethoxycyclopent-2-enone. J. Org. Chem. 37, 4489–4491 (1972)
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)
Yokota, S. & Miyamoto, S. Insecticide. Japanese patent 2008-024670 (2008)
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)
Quideau, S. et al. Iodine-mediated and electrochemical oxidative transformations of 2-methoxy- and 2-methylphenols. ARKIVOC 2003(vi), 106–119 (2003)
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)
Fürstner, A. & Davies, P. W. Catalytic carbophilic activation: catalysis by platinum and gold π acids. Angew. Chem. Int. Ed. 46, 3410–3449 (2007)
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)
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)
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)
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)
Wiesner, K. Total synthesis of racemic talatisamine. Pure Appl. Chem. 41, 93–112 (1975)
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)
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)
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)
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)
Corey, E. J. & Cheng, X.-M. The Logic of Chemical Synthesis 43–44 (Wiley, 1989)
Hoffmann, R. W. Elements of Synthesis Planning (Springer, 2009)
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)
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)
Legault, C. Y. CYLview, 1.0b. http://www.cylview.org (Université de Sherbrook, 2009)
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.
The authors declare no competing financial interests.
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.
About this article
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
Angewandte Chemie International Edition (2020)
Organic & Biomolecular Chemistry (2020)
Angewandte Chemie (2020)
Chinese Chemical Letters (2020)
Angewandte Chemie (2019)