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Process Chemistry

Chemists cut in half the number of steps needed to synthesize phorbol

Nineteen-step enantioselective synthesis opens up avenues to previously inaccessible analogs of this biologically active compound

by Bethany Halford
March 24, 2016 | A version of this story appeared in Volume 94, Issue 13

Three chemists show a synthetic strategy on a white board.
Credit: Scripps Research Institute California
Scripps chemists (from left) Baran, Chu, and Kawamura show the team’s 19-step synthesis of phorbol, which includes a cascade transformation of 13 different chemical events that take place in one pot.

For the first time, chemists have completed an enantioselective total synthesis of the complex natural product (+)-phorbol. And they did it with a route that requires only 19 steps. That’s a dramatic cut in chemical transformations from previous approaches, which took 40 to 52 steps to make a racemic mixture of the compound.

Since its discovery more than 80 years ago, densely functionalized, polycyclic phorbol has intrigued both chemists and biologists. One source of phorbol is the sap of the manchineel tree, native to the Caribbean. The sap can cause skin to blister on contact. Certain derivatives, known as phorbol esters, encourage tumors to grow rapidly. But compounds in the phorbol family have also shown promise as immune-modulating, antiviral, and anticancer therapies.

Phorbol and its derivatives are frequently made via semisynthesis, where a compound with much of phorbol’s skeleton is extracted from a natural source and then synthetically transformed. But this approach makes it impossible to make certain phorbol analogs. Seeking access to those compounds, Phil S. Baran, Shuhei Kawamura, and Hang Chu of Scripps Research Institute California and Jakob Felding of LEO Pharma developed a new enantioselective synthesis of phorbol (Nature 2016, DOI: 10.1038/nature17153).

Baran, who led the project, notes that strategy was the key to this synthesis, as opposed to cutting-edge chemistry. “Everything that’s in this paper could have been done in 1978,” he says. The crucial insight, Baran notes, was to recognize that a key intermediate his group had previously used to make the anticancer compound ingenol could be diverted to make phorbol—much like what happens biosynthetically.

“The synthesis of phorbol, once considered a formidable if not impossible challenge, has attracted creative strategies from many laboratories,” comments Stanford University’s Paul Wender, whose lab reported the first racemic total synthesis of phorbol in 1989. The Baran lab now builds “impressively” on this body of earlier work and “cleverly introduces, among other noteworthy features, a C–H activation process that greatly enhances the step economy of this new route,” Wender adds. “One looks forward to ‘phorbol version 3.0’ that will surely be inspired by this and earlier research.”



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