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Alkaloid Acetylaranotin Made After 40-Year Quest

Caltech chemists make fungal natural product with help from rhodium catalysis, elemental sulfur

by Carmen Drahl
November 7, 2011 | A version of this story appeared in Volume 89, Issue 45

Elemental sulfur has helped bring an end to a 40-year quest to synthesize (–)-acetyl­aranotin, an intricately structured alkaloid first isolated from fungi (J. Am. Chem. Soc., DOI: 10.1021/ja209354e). The synthesis could provide scientists more details about how acetylaranotin and its relatives exhibit their anticancer and antiviral activities. Acetylaranotin is a dimeric epidithiodi­ketopiperazine natural product. Although chemists have synthesized some natural products in this family, acetylaranotin and molecules most closely resembling it have eluded synthesis. Caltech’s Sarah E. Reisman zeroed in on acetylaranotin’s seven-membered dihydrooxepine ring because its sensitivity to multiple reaction conditions foiled prior synthesis attempts. With Julian A. Codelli and Angela L. A. Puchlopek, Reisman generated the ring through a rhodium-catalyzed cyclo­isomerization followed by chloride elimination. Taking a page from a 2011 synthesis by K. C. Nicolaou and coworkers of Scripps Research Institute (J. Am. Chem. Soc., DOI: 10.1021/ja2032635), Reisman tweaked a 1970s-era protocol to install acetylaranotin’s epidisulfide moiety with elemental sulfur. “Reisman and her lab knocked this one out of the park,” says Robert M. Williams of Colorado State University, who has worked toward synthesis of related alkaloids.


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