Issue Date: July 20, 2009
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.
- Chemical & Engineering News
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