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

It has been previously established in this laboratory that the beta -methyl-beta -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-(13)C]-labeled L-beta -methylproline is described by means of a Hoffman-Loeffler-Freytag reaction sequence from [1-(13)C]-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 Penicillum fellutanum. Three tryptophan-containing dipeptides of L-beta -methylproline have been constructed: [(13)C(2)]-2-(l,1-dimethyl-2-propenyl)-L-tryptophanyl-3(S)-methyl-L-proline [(13)C(2)]-3(S)-methyl-L-prolyl-2-(l,1-dimethyl-2-propenyl)-L-tryptophan and [(13)C(2)]-cyclo-2-(l,1-dimethyl-2-propenyl)-L-tryptophan-3(S)-methyl-L-proline. [alpha-(15)N, 1-(13)C]-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. (C) 2001 Elsevier Science Ltd. All rights reserved.