Kirromycin is a complex linear polyketide that acts as a protein biosynthesis inhibitor by binding to the bacterial elongation factor Tu. The kirromycin biosynthetic gene cluster was isolated from the producer, Streptomyces collinus Tü 365, and confirmed by targeted disruption of essential biosynthesis genes. Kirromycin is synthesized by a large hybrid polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) encoded by the genes kirAI-kirAVI. This complex involves some very unusual features, including the absence of internal acyltransferase (AT) domains in KirAI-KirAV, multiple split-ups of PKS modules on separate genes, and swapping in the domain organization. Interestingly, one PKS enzyme, KirAVI, contains internal AT domains. Based on in silico analysis, a route to pyridone formation involving PKS and NRPS steps was postulated. This hypothesis was experimentally proven by feeding studies with [U-13C3(15)N]beta-alanine and NMR and MS analyses of the isolated pure kirromycin.

Spirodionic acid (1), a novel microbial metabolite with a spiro[4.5]decene skeleton, the 6-ethyl-2H-pyrone 5, dihydrosarkomycin (6), and other metabolites were isolated from the strain Streptomyces sp. Tü 6077. Structural elucidation was accomplished by NMR spectroscopic and mass-spectrometric studies, and the biosyntheses of compounds 1, 5, and 6 were investigated by feeding experiments with (13)C-labeled precursors. All results indicate a biogenetic sequence with metabolite 5 and sarkomycin (7) as precursors in the formation of spirocyclus 1 through an intermolecular Diels-Alder-type reaction.

To elucidate the structure of the new natural product spirodionic acid, which has three stereogenic centers of hitherto unknown configuration, two 4-ethenylspiro[4.5]dec-6-en-1,8-diones with opposite relative configuration at C4 and C5 were prepared. The first access involved the synthesis of 3-ethenyl-2-formylcyclopentanone (8) using a three-component coupling process. A sequence of Michael addition to penten-3-one (7) and intramolecular aldol condensation then led to the highly selective formation of the 4S*,5S*-configured spirocycle 5. In contrast, a selective spiroannelation of a cyclohexenone ring was accomplished by a novel type of twofold Michael addition to the dialkenyl ketone 11 with subsequent dehydrogenation to furnish the 4S*,5R*-configured spirocycle 25. Diastereoselective methylation and oxidative degradation then completed a highly efficient synthesis of the natural product as prerequisite for the assignment of its absolute configuration.

Other natural products U 0800 Spirodionic Acid, a Novel Metabolite from Streptomyces sp. Part 1. Structure Elucidation and Diels-Alder-Type Biosynthesis. -(TEXTOR, A.; PAPASTAVROU, I.; SIEWERT, J.; MAGULL, J.; KULIK, A.; FIEDLER, H.-P.; VON ZEZSCHWITZ, P.; GROND*, S.; Chem. Eur.

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