Biosynthetic precursors of the lipase inhibitor lipstatin

Three putative intermediates in the biosynthesis of the lipase inhibitor lipstatin were synthesized in stable isotope-labeled form and were added to fermentation cultures of Streptomyces toxytricini. Biosynthetic lipstatin was isolated and analyzed by NMR spectroscopy. 3,10,11,12-(2)H]-(3S,5Z,8Z)-3-hydroxytetradeca-5,8-dienoic acid (9) was shown to serve as a direct biosynthetic precursor of lipstatin. 7,8-(2)H(2)]Hexylmalonate (11) was also incorporated into lipstatin, albeit at a relatively low rate. The leucine moiety of (13)C-formyl,(15)N]-N-formylleucine (10) was diverted to lipstatin under loss of the (13)C-labeled formyl residue.