Studies on the biosynthesis of paraherquamide A. Origin of the beta-methylproline ring

The paraherquamides are potent anthelmintic alkaloids isolated from various Penicillium sp. These substances have attracted considerable attention due to their molecular complexity, intriguing biogenesis, and potential as antiparasitic drugs. The most potent member of this family is paraherquamide A (1), which contains the unusual amino acid, β-methyl-β-hydroxyproline. Recently, a Smith-Kline Beecham group reported the isolation and structural elucidation of the simpler indole alkaloid VM55599 (11) which, like compounds, contains the unusual amino acid β-methylproline. As part of a program directed primarily at elucidating the biosynthetic mechanism of formation of the unique core bicyclo[2.2.2] ring system that is common to all of these alkaloids, we have initiated studies on the biosynthesis of the unusual, functionalized proline derivatives that constitute the paraherquamide family. Herein, we report the biosynthetic incorporation of primary amino acid building blocks that constitute the core framework of this class of alkaloids.