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A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine

Nature Chemistry volume 5, pages 126–131 (2013)Cite this article

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Abstract

The yohimbinoid alkaloids continue to receive considerable attention from the synthetic community because of their interesting chemical structures and varied biological activity. Although there are several elegant syntheses of certain members of this group of alkaloids, a truly unified approach has yet to be developed. In short, general approaches to this compound class are hampered by a lack of complete control in setting the C(3) stereocentre at a late stage. Herein, we report that a functionalized hydrindanone enables a divergent strategy that builds on existing precedent to address this long-standing challenge. Utilizing an aminonitrile intermediate, the stereochemistry at C(3) of the yohimbinoid skeleton can be controlled effectively in a Pictet–Spengler reaction. We applied this approach to the first total syntheses of the C(3) epimeric natural products venenatine and alstovenine.

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Figure 1: Classic approaches to the synthesis of reserpine, and selected yohimbine and berbane alkaloids.
Figure 2: Retrosynthetic plan and synthesis of the aminonitrile Pictet-Spengler substrates.
Figure 3: Plausible reaction pathways for the thermal cyclization.
Figure 4: Synthesis of venenatine and alstovenine.

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Acknowledgements

The authors are grateful to the National Institutes of Health (NIGMS RO1 084906), the National Science Foundation (NSF) (CHE-0957416 and CHE-030089) and the American Cancer Society (RSG-09-017-01 CDD) for support of this work. R.S. is a Camille Dreyfus Teacher-Scholar. T.P.L. thanks the Natural Sciences and Engineering Research Council (Canada) for a postdoctoral fellowship. J.D. thanks the NSF for a predoctoral fellowship and J.L.W. thanks Chevron for a departmental fellowship. C. Kraml and N. Byrne from Lotus Separations are thanked for the separation of the enantiomers of the Diels–Alder adduct 18.

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Authors and Affiliations

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

    Terry P. Lebold, Jessica L. Wood, Josh Deitch & Richmond Sarpong

  2. Department of Chemistry, University of California, Davis, Davis, 95616, California, USA

    Michael W. Lodewyk & Dean J. Tantillo

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  1. Terry P. Lebold
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Contributions

T.P.L., J.L.W. and R.S. conceived and designed the synthetic experiments. T.P.L., J.L.W. and J.D. carried out the synthetic work. M.W.L. and D.J.T. carried out the computational work. T.P.L., J.L.W. and R.S. co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Richmond Sarpong.

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Supplementary information

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Crystallographic data for compound 16b. (CIF 30 kb)

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Crystallographic data for compound 23b. (CIF 30 kb)

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Lebold, T., Wood, J., Deitch, J. et al. A divergent approach to the synthesis of the yohimbinoid alkaloids venenatine and alstovenine. Nature Chem 5, 126–131 (2013). https://doi.org/10.1038/nchem.1528

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