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Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products

Nature Chemistry volume 9, pages 523–530 (2017)Cite this article

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Abstract

An important question in organic chemistry concerns the extent to which benzynes—one of the classical reactive intermediates in organic chemistry—can react in discriminating fashion with trapping reagents. In particular, whether these species can react selectively with substrates containing multiple functional groups and possible sites of reactivity has remained unanswered. Natural products comprise a palette of multifunctional compounds with which to address this question. Here, we show that benzynes produced by the hexadehydro-Diels–Alder (HDDA) reaction react with many secondary metabolites with a preference for one among several pathways. Examples demonstrating such selectivity include reactions with: phenolics, through dearomatizing ortho-substitution; alkaloids, through Hofmann-type elimination; tropolone and furan, through cycloaddition; and alkaloids, through three-component fragmentation–coupling reactions. We also demonstrate that the cinchona alkaloids quinidine and quinine give rise to products (some in as few as three steps) that enable subsequent and rapid access to structurally diverse polyheterocyclic compounds. The results show that benzynes are quite discriminating in their reactivity—a trait perhaps not broadly enough appreciated.

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Figure 1: The two-stage HDDA cascade.
Figure 2: Different modes of reaction between a benzyne (2 or 8) and various phenolics.
Figure 3: Reactions with tertiary amines.
Figure 4: Three-component reactions involving complex alkaloids.
Figure 5: Net cycloaddition reactions between benzynes and conjugated π-systems.
Figure 6: Quinidine and quinine derivatizations via benzynes.

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Acknowledgements

These studies were supported by the US Department of Health and Human Services [National Institute of General Medical Sciences (GM-65597) and National Cancer Institute (CA-76497)]. The computational portions were carried out using software and hardware provided by the University of Minnesota Supercomputing Institute (MSI). NMR spectra were obtained using an instrument purchased with a grant from the NIH Shared Instrumentation Grant program (S10OD011952).

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  1. Department of Chemistry, University of Minnesota, 207 Pleasant Street, SE, Minneapolis, 55455, Minnesota, USA

    Sean P. Ross & Thomas R. Hoye

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  1. Sean P. Ross
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S.P.R. and T.R.H. conceived the experiments, interpreted the data, co-wrote the manuscript, and agreed to the content of the final submission. S.P.R. executed the experiments and collected the data.

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Correspondence to Thomas R. Hoye.

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Ross, S., Hoye, T. Reactions of hexadehydro-Diels–Alder benzynes with structurally complex multifunctional natural products. Nature Chem 9, 523–530 (2017). https://doi.org/10.1038/nchem.2732

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