Synthese von Alternaria-Metaboliten und Graphislactonen (English shop)

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Metabolites of the mould genus Alternaria have so far been insufficiently investigated. These fungi are distributed worldwide and pose an incalculable risk to humans and animals. In order to carry out metabolism studies or toxicological tests with individual metabolites, synthetic access to these molecules is of great advantage. Alternaria ssp. produce these metabolites in varying composition and small amounts. The structurally related graphislactones and ulocladol are produced by script lichens or endophytic fungi, and their metabolism appears to be closely related to that of the Alternaria metabolites.

The aim of this work was to develop an efficient, flexible access to these compounds. All substances possess a resorcylic acid lactone as their basic skeleton, which can be retrosynthetically cleaved into two fragments. A Suzuki–Miyaura cross-coupling was envisaged as the key step of the syntheses, for which an aromatic boronic acid ester was developed as coupling partner. The reaction conditions could be optimised for this sterically demanding, ortho-substituted system.

For the preparation of altenuene, isoaltenuene, neoaltenuene and 4-epi-neoaltenuene, diastereomerically pure iodinated cyclohexenols were required as coupling partners, which could be synthesised starting from ()-quinic acid. By means of this first total synthesis of altenuene and isoaltenuene it was possible to elucidate the absolute configuration of the two natural products with the aid of a crystal structure, optical rotation values and CD spectra. With only one further transformation, such as hydrogenation or selective oxidation, further isomers of altenuene could be prepared. In this way the structure reported in the literature for dihydroaltenuene B could be corrected.

The highly substituted aromatic precursors required for the total synthesis of graphislactones C–F and ulocladol could be obtained from vanillin by a short synthetic sequence in four to five steps. While graphislactones C and D and ulocladol were in agreement with the published analytical data, this was not the case for graphislactones E and F. Owing to the flexible synthetic route it was possible to construct the presumed corrected structures of these graphislactones in a few steps. The correction of the structures could be confirmed by NOESY experiments and comparison of the analytical data.

Overall, ten natural products, two corrected structures and three previously unknown epimers could be prepared in this work.