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Synthesis

When less yields more

J. Am. Chem. Soc. 134, 13577–13579 (2012)

Artemisinin is a critical compound in the treatment of malaria. At the moment, commercial availability of this molecule relies on extraction from natural sources, but the high cost of its isolation limits global usage. Several synthetic routes to access this compound have been reported, and engineered microbes are able to make the artemisinin precursor artemisinic acid, but Zhu and Cook wondered whether a fully synthetic approach using inexpensive precursors might provide a scalable route to the terpene-based natural product. To investigate, the authors devised a five-pot strategy beginning with cyclohexenone that avoids protecting groups and uses cascade or one-pot reactions to quickly build molecular complexity. Clever application of a [4+2] reaction to form the second ring allowed the authors to focus on controlling the reaction pathway but not fret over the stereochemical outcome, as the relevant stereocenters were set in subsequent steps. The introduction of crotyl bromide set the stage for the final step (shown) in which both the seven-membered ring and the peroxide bridge would be formed; testing of a variety of oxidative rearrangement strategies identified singlet oxygen (formed via decomposition of H2O2) as the necessary reagent. This sequence, conducted at the gram scale, provides new ideas for managing malaria.

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Goodman, C. When less yields more. Nat Chem Biol 8, 808 (2012). https://doi.org/10.1038/nchembio.1073

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