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Unified biomimetic assembly of voacalgine A and bipleiophylline via divergent oxidative couplings

Nature Chemistry volume 9, pages 793–798 (2017)Cite this article

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Abstract

Bipleiophylline is a highly complex monoterpene indole alkaloid composed of two pleiocarpamine units anchored on an aromatic spacer platform. The synthesis of bipleiophylline is considered as a mountain to climb by the organic chemistry community. Here, a unified oxidative coupling protocol between indole derivatives and 2,3-dihydroxybenzoic acid, mediated by silver oxide, has been developed to produce the core of bipleiophylline. This method also allows the independent preparation of benzofuro[2,3-b]indolenine and isochromano[3,4-b]indolenine scaffolds, depending only on the nature of the aromatic platform used. The procedure has been applied to simple indole derivatives and to more challenging monoterpene indole alkaloids, thereby furnishing natural-product-like structures. The use of scarce pleiocarpamine as the starting indole allows the first syntheses of bipleiophylline and of its biosynthetic precursor, voacalgine A. The structure of the latter has been reassigned in the course of our investigations by 2D NMR and displays an isochromano[3,4-b]indolenine motif instead of a benzofuro[2,3-b]indolenine.

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Figure 1: Biosynthesis of bipleiophylline and voacalgine A.
Figure 2: Access to the benzofuro[2,3-b]indolenine and to the isochromano[3,4-b]indolenine scaffolds.
Figure 3: DFT calculations for the isochromano[3,4-b]indolenine formation.
Figure 4: Synthesis of voacalgine A related products.
Figure 5: Access to the central polyheterocyclic core of 1.
Figure 6: Biomimetic assembly of voacalgine A and bipleiophylline with structure revision of voacalgine A.

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  • 09 March 2017

    In the version of this Article originally published, the e-mail address for Erwan Poupon was not correct. This has been corrected to erwan.poupon@u-psud.fr in the online versions of this Article.

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Acknowledgements

We gratefully acknowledge, the ANR (ANR-15-CE29-0001 and ANR-12-JS07-0002), the Université Paris-Sud and the CNRS for financial support. J.-P. Baltaze (ICMMO), J.-C. Jullian (BioCIS) and C. Dejean (BioCIS) are gratefully acknowledged for NMR assistance. M. Litaudon (ICSN) and the “Extractothèque” of ICSN are gratefully acknowledged for their support in collecting the plant material. The authors are grateful to the North Province of New Caledonia, which facilitated the field investigation. T.-S. Kam is gratefully acknowledged for spectra of bipleiophylline.

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Authors and Affiliations

  1. BioCIS, Université Paris-Sud, Université Paris-Saclay, CNRS, Châtenay-Malabry, 92290, France

    David Lachkar, Guillaume Bernadat, Kadiria Ahamada, Mehdi A. Beniddir, Karine Leblanc, Elvis Otogo N'nang, Victor Turpin, Erwan Poupon & Laurent Evanno

  2. Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), Université Paris-Sud, Université Paris-Saclay, CNRS, UMR 8182, Orsay Cedex, 91405, France

    Natacha Denizot, Régis Guillot, Cyrille Kouklovsky & Guillaume Vincent

  3. ICSN, Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Saclay, 1 avenue de la Terrasse, Gif-sur-Yvette Cedex, 91198, France

    Vincent Dumontet & Jean-François Gallard

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Contributions

L.E., E.P. and G.V. conceived the project. N.D., D. L., L.E. and G.V. performed the synthetic experimental work. N.D. and D.L. contributed equally. G.B. performed the DFT calculations, K.A. performed prospective experiments. V.D. collected bark of Alstonia balansae. D.L., E.O.N. and V.T. purified pleiocarpamine. C.K. advised on synthetic aspects of the work. M.A.B. advised on the extraction aspects of the work. J.F.G. recorded 600 MHz NMR spectra. R.G. resolved the crystal structures. K.L. developed all conditions for purifications by preparative HPLC and performed analytical HPLC. L.E., E.P. and G.V. wrote the manuscript. All authors read and commented on the manuscript.

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Correspondence to Erwan Poupon, Laurent Evanno or Guillaume Vincent.

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Supplementary information

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Supplementary information (PDF 6197 kb)

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Crystallographic data for compound 8b (CIF 1182 kb)

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Crystallographic data for compound 9a (CIF 3127 kb)

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Crystallographic data for compound 10a (CIF 273 kb)

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Crystallographic data for compound 18a (CIF 1821 kb)

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Lachkar, D., Denizot, N., Bernadat, G. et al. Unified biomimetic assembly of voacalgine A and bipleiophylline via divergent oxidative couplings. Nature Chem 9, 793–798 (2017). https://doi.org/10.1038/nchem.2735

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