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Bioinspired chemical synthesis of monomeric and dimeric stephacidin A congeners

Nature Chemistry volume 10, pages 38–44 (2018)Cite this article

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Abstract

Stephacidin A and its congeners are a collection of secondary metabolites that possess intriguing structural motifs. They stem from unusual biosynthetic sequences that lead to the incorporation of a prenyl or reverse-prenyl group into a bicyclo[2.2.2]diazaoctane framework, a chromene unit or the vestige thereof. To complement biosynthetic studies, which normally play a significant role in unveiling the biosynthetic pathways of natural products, here we demonstrate that chemical synthesis can provide important insights into biosynthesis. We identify a short total synthesis of congeners in the reverse-prenylated indole alkaloid family related to stephacidin A by taking advantage of a direct indole C6 halogenation of the related ketopremalbrancheamide. This novel strategic approach has now made possible the syntheses of several natural products, including malbrancheamides B and C, notoamides F, I and R, aspergamide B, and waikialoid A, which is a heterodimer of avrainvillamide and aspergamide B. Our approach to the preparation of these prenylated and reverse-prenylated indole alkaloids is bioinspired, and may also inform the as-yet undetermined biosynthesis of several congeners.

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Figure 1: Selected reverse-prenylated indole alkaloid congeners.
Figure 2: Hypotheses for the biosynthesis of stephacidin A congeners.
Figure 3: Synthetic strategy for stephacidin A and the application of C6 halogenation.
Figure 4: Syntheses of stephacidin A and congeners.
Figure 5: Conjugation possibilities for aspergamide B and avrainvillamide.

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Acknowledgements

This work is supported by a grant from the US National Institutes of Health (NIH) (NIGMS RO1 086374). We are grateful for a Japan Society for the Promotion of Science Postdoctoral Fellowship to K.M., a Science without Borders Postdoctoral Fellowship to D.P.S. (Brazil; CSF/CNPq 200205/2014-5), the US National Science Foundation (NSF) Graduate Research Fellowship Program, the American Chemical Society Division of Organic Chemistry and the Hellman Graduate Awards Program (University of California (UC) Berkeley) for awards to E.V.M.-M. and the Natural Sciences and Engineering Research Council of Canada for a Postdoctoral Fellowship to K.G.M.K. We are grateful to D. H. Sherman (University of Michigan) and R. M. Williams (Colorado State University), as well as D. Tantillo (UC Davis), for helpful discussions regarding the prenylated and reverse-prenylated indole alkaloids, and the NMR CMAD computational analysis, respectively. We thank R. Cichewicz (University of Oklahoma) for an authentic sample of waikialoid A as well as for an initial secondary metabolite screen on the producing P. aspergillus sp. A. Zeeck (Georg-August-Universität Göttingen) is graciously acknowledged for his tireless efforts to locate and obtain analytical data for the material reported by his laboratory in 1995 to be aspergamide B. X-ray crystallography instrumentation is supported by NIH Shared Instrumentation Grant S10-RR027172. The AV-600, AV-500, DRX-500, AVQ-400 and AVB-400 NMR spectrometers are partially supported by NIH Grants SRR023679A and 1S10RR016634-01 and NSF Grants CHE-9633007 and CHE-0130862. The 900 MHz NMR instrument is funded by NIH Grant GM68933. The Molecular Graphics and Computation Facility is funded by the NIH (S10OD023532). We thank K. Owens (UC Berkeley), K. Durkin (UC Berkeley) and Y. Olatunji-Ojo (UC Berkeley) for assistance with DFT computations and A. G. DiPasquale for X-ray crystallographic analysis.

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  1. Ken Mukai and Danilo Pereira de Sant'Ana: These authors contributed equally to this work.

Authors and Affiliations

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

    Ken Mukai, Danilo Pereira de Sant'Ana, Yasuo Hirooka, Eduardo V. Mercado-Marin, David E. Stephens, Kevin G. M. Kou, Sven C. Richter, Naomi Kelley & Richmond Sarpong

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Contributions

R.S., K.M. and D.P.S. designed the research with assistance from Y.H. and E.V.M.-M. All synthetic chemistry was performed by K.M., D.P.S., Y.H., E.V.M.-M., D.E.S., S.C.R. and N.K. Computational studies were conducted by D.E.S., K.G.M.K. and K.M. R.S. wrote the manuscript with contributions from all the authors; all the authors were actively engaged in the editing of the manuscript and gave their approval of the final version. K.M. and D.P.S. contributed equally to this work.

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Correspondence to Richmond Sarpong.

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Mukai, K., de Sant'Ana, D., Hirooka, Y. et al. Bioinspired chemical synthesis of monomeric and dimeric stephacidin A congeners. Nature Chem 10, 38–44 (2018). https://doi.org/10.1038/nchem.2862

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