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August 30, 2011

Indole Changeup Yields Elusive Alkaloid

ACS Meeting News: Cyclization and nitrene insertion star in synthesis

Carmen Drahl

Indole Reinvented: Rejiggering indole's reactivity helped researchers construct a complex alkaloid. View Enlarged Image
Indole Reinvented Rejiggering indole's reactivity helped researchers construct a complex alkaloid.
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By turning a heterocycle’s reactivity on its head, chemists have achieved the first total synthesis of the natural product (–)-N-methylwelwitindolinone C isothiocyanate. The indole-containing alkaloid reverses pump-protein-mediated resistance to anticancer drugs in tumor cells, so it represents a potential lead for treating drug-resistant cancers. The research was presented on Aug. 30 in the Division of Organic Chemistry at the American Chemical Society national meeting in Denver (J. Am. Chem. Soc., DOI: 10.1021/ja206538k).

Only two welwitindolinones, which are found in blue-green algae, have succumbed to total synthesis. And the ones with densely packed [4.3.1] bicyclic cores, including N-methylwelwitindolinone C isothiocyanate, have proved especially tricky to make than the others. For University of California, Los Angeles, assistant professor Neil K. Garg and colleagues, the key to forging that core was in reversing indole’s inherent reactivity.

Normally, indoles make excellent nucleophiles, but in 2009 Garg’s team found a way to make them behave like electrophiles instead, by generating a reactive intermediate called an indolyne (Org. Lett., DOI: 10.1021/ol802958a). An indolyne cyclization features prominently in Garg’s route to N-methylwelwitindolinone C isothiocyanate, as does a late-stage nitrene insertion to functionalize a congested carbon. Indolyne chemistry “opens the door to somewhat unconventional strategies for building indole alkaloids,” Garg told C&EN.

He added that this is only the second total synthesis of a [4.3.1] bicyclic member of the welwitindolinone family, after the University of Chicago’s Viresh H. Rawal’s synthesis of N-methylwelwitindolinone D isonitrile (J. Am. Chem. Soc., DOI: 10.1021/ja201834u).

“Garg’s construction of the [4.3.1] bicycle is a beautiful example of indolyne chemistry in an extremely complex setting,” said Sarah E. Reisman of Caltech, who has synthesized related a natural product but did not attend the meeting.

“A synthesis of the welwitindolinones has been pursued by a number of groups and welwitindolinone C in particular has proven very challenging,” said indole natural product expert John L. Wood of Colorado State University. “The endgame transformations certainly required considerable experimentation to work out, and thus the efficiency of the indolyne chemistry in providing sufficient material was key to the success.”

In Denver, Garg discussed how his group recently swapped deuterium for a key hydrogen atom improved the yield of the nitrene insertion. “The immediate plans are to make the other welwitindolinones and hopefully send them off for biological testing,” he told C&EN.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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