The emergence of drug-resistant strains of Plasmodium falciparum — the major cause of severe malarial infections — has resulted in much interest in the flindersial alkaloids, which are thought to act by a different mechanism than the commonly used drug chloroquine. With a goal of further testing and developing these natural products, Ravikrishna Vallakati and Jeremy May from the University of Houston have now described a biomimetic synthesis of several members of this family of alkaloids.
Prior work on the biosynthesis of the related natural products borreverine and isoborreverine led Vallakati and May to propose that the biosynthetic origin of flinderole A is an acid-catalysed ring-opening of borrerine followed by dimerization in a formal [3+2] cycloaddition (as pictured). Acid treatment of borrerine produced flinderole A along with its diastereomer desmethylflinderole C (at the starred position) and isoborreverine. To their surprise, and contrary to the previous reports, very little borreverine itself was produced under these conditions. The results, however, reflect the fact that borreverine and the flinderoles are not found together in nature. Furthermore, the Diels–Alder reaction to form borreverine would be energetically unfavourable with respect to that forming isoborreverine.
A one-pot reaction involving methylation of borrerine prior to acid treatment gave flinderoles B and C, meaning that all of the antimalarial flindersial alkaloids can be synthesized in as few as three steps from three simple commercially available materials. This convergent synthesis should make it possible to vary each of these three components to easily make analogues of the flinderoles and thus allow their testing for antimalarial activity.
About this article
Cite this article
Davey, S. Flinderoles facilitated. Nature Chem 4, 430 (2012). https://doi.org/10.1038/nchem.1370