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Finally, Haplophytine

Elusive alkaloid target succumbs to carefully optimized synthesis

by Carmen Drahl
July 20, 2009 | A version of this story appeared in Volume 87, Issue 29

More than 50 years after its discovery, the heterodimeric indole alkaloid haplophytine has yielded to total synthesis. Originally isolated from the dried leaves of a Mexican shrub, haplophytine is an active ingredient in "la hierba de la cucaracha," a natural insecticide in use since Aztec times. It comprises two heterocyclic segments and features a crowded quaternary carbon center.

Chemists had made both wings of haplophytine, but the complete molecule had evaded synthesis. Now, Tohru Fukuyama of the University of Tokyo; Hidetoshi Tokuyama of Tohoku University, in Japan; and coworkers have made the naturally occurring enantiomer of haplophytine in 29 steps and with 0.20% overall yield for the longest linear sequence (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200902192).

The team forged the quaternary center with a Friedel-Crafts alkylation and later took advantage of a skeletal rearrangement that occurs in natural haplophytine to make the left segment, which includes a rare bicyclic skeleton. A painstakingly optimized Fischer indole synthesis linked the two segments.

"The completed work is a masterpiece of heterocyclic chemistry that captures the essence of complex molecule synthesis," says Albert Padwa of Emory University, who has also worked toward haplophytine.


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