Approach Towards Synthesis of Nodusmicin

E. Auer, E. Gössinger, M. Graupe, K. Zimmermann

Institut für organische Chemie der Universität Wien
1090 Vienna, Austria

In 1980 nodusmicin - a macrolide antibiotic - was isolated from cultures of Saccharopolyspora hirsuta [1]. Like the structurally related nargenicins this compound is active against Gram positive bacteria. Their activity extends to drug resistant bacteria and is coupled with low toxicity and substantial oral activity. These facts and the unusual structural features of these compounds initiated several approaches towards the synthesis of nodusmicin, which so far have culminated in the total synthesis of 18-desoxynargenicin by Kallmerten et al. [2].

The highly substituted enantiomerically pure decalinone 2 is the key intermediate of our synthetic approach. It was synthesised using an annulation method developed in our laboratory [3], starting with cheap, easily available, symmetrical compounds.

Decalinone 2 allows alternative possibilities to close the oxygen bridge and to connect with the further two parts of the macrocyclic lactone. We succeeded in producing an advanced intermediate 3 of Kallmerten's synthesis of 18-desoxynargenicin with the advantage, that in our case 3 is enantiomerically pure.

In a model study we investigated the possibility of coupling the side chain with the decalin part before closing the oxygen bridge. This we achieved by intramolecular reductive coupling of a ketoester.

The protected C-15 to C-19 part of the macrocycle was synthesised via the Evans oxazolidinone technique as the key step.



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