Studies on the biosynthesis of paraherquamide. Construction of the amino acid framework

It has been previously established in this laboratory that the β-methyl-β-hydroxyproline moiety of the potent anthelmintic agent paraherquamide A, is biosynthetically derived from l-isoleucine. The downstream events from l-Ile to paraherquamide A have now been investigated. The synthesis of [1-13C]-labeled l-β-methylproline is described by means of a Hoffman–Loeffler–Freytag reaction sequence from [1-13C]-l-Ile. This amino acid is shown to be a direct biosynthetic precursor to paraherquamide A by feeding and incorporation experiments in growing cultures of Penicillium fellutanum. Three tryptophan-containing dipeptides of l-β-methylproline have been constructed: [13C2]-2-(1,1-dimethyl-2-propenyl)-l-tryptophanyl-3(S)-methyl-l-proline; [13C2]-3(S)-methyl-l-prolyl-2-(1,1-dimethyl-2-propenyl)-l-tryptophan and [13C2]-cyclo-2-(1,1-dimethyl-2-propenyl)-l-tryptophan-3(S)-methyl-l-proline. [α-15N, 1-13C]-2-(1,1-Dimethyl-2-propenyl)-l-tryptophan was also prepared but none of these substances were found to serve as biosynthetic precursors to paraherquamide A.