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Natural products

Taming reactive benzynes

Nature Chemistry volume 9, pages 504–506 (2017)Cite this article

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Natural products often serve as sources of new drugs, either directly or after synthetic modification, but site-selective functionalization of complex small molecules is challenging. Now, a method has been developed that enables selective modification of a wide range of natural products by engaging a benzyne intermediate in a variety of reaction modes.

Natural products have long been a bountiful source of drugs, but structural modification is often necessary to optimize potency, pharmacokinetics and other important parameters. Indeed, close to half of drugs approved between 1981 and 2014 are natural product derivatives, synthetic natural product mimics, or contain natural product pharmacophores1. Although the majority of these drugs are produced via chemical modification of the parent natural product, carrying out selective reactions in the presence of the diverse and dense functionalities found in natural products is notoriously challenging due to the likelihood of side reactions. In order to conduct chemoselective reactions directly on complex substrates, protecting group manipulations and/or multistep sequences are often necessary — for example in the conversion of 10-deacetylbaccatin III to docetaxel (three steps)2, epothilone B to ixabepilone (two to three steps)3, and erythromycin A to clarithromycin (six steps)4. These additional manipulations generally diminish the overall yield of the desired product and limit the practicality of such reaction sequences.

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Figure 1: Examples of the diverse reaction modes observed when complex natural products are reacted with a benzyne intermediate generated via a hexadehydro-Diels–Alder reaction.

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Authors and Affiliations

  1. Sarah Z. Tasker and Paul J. Hergenrother are in the Department of Chemistry at the University of Illinois at Urbana-Champaign, Urbana, Ilinois 61801, USA,

    Sarah Z. Tasker & Paul J. Hergenrother

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  1. Sarah Z. Tasker
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  2. Paul J. Hergenrother
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Correspondence to Paul J. Hergenrother.

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Tasker, S., Hergenrother, P. Taming reactive benzynes. Nature Chem 9, 504–506 (2017). https://doi.org/10.1038/nchem.2786

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