Network-analysis-guided synthesis of weisaconitine D and liljestrandinine

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.

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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.

Author information

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.

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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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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