Alkaloid Acetylaranotin Made After 40-Year Quest

Elemental sulfur has helped bring an end to chemists’ 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 help scientists get 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 graduate student Julian A. Codelli and postdoc 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’s Scripps Research Institute team (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 related molecules. Williams adds that the complete retention of stereochemistry the team observed during the epidisulfide installation was “stunning.”

“Our plan right now is to dive in and figure out what’s responsible for that stereoselectivity,” Reisman says.