Total Synthesis of the Antibiotic Branimycin

In view of the increasing bacterial resistance and cross resistance and the forthcoming threat of international bioterrorism the introduction of novel antibiotics is of prime interest in pharmaceutical chemistry. Although such antibitotics are basically available by fermentation chemical manipulation and eventually total synthesis is the only way to gain deeper knowledge into the biomechanism and the pharmacophoric parts of the molecule. As amply demonstrated by the penicillins permanent chemical alteration of a basic lead structure is essential to maintain antibacterial efficiency. We propose various strategies for the total synthesis of the novel antibiotic branimycin which is a promising compound with respect to biological activity and lack of side effects. Our synthesis includes trusted and novel methodology such as intramolecular Diels Alder addition, or ring closing metathesis or intramolecular 1,3-dipolar cycloaddition. Altogether 4 different approaches are suggested to minimize the risk of failure and to ensure a maximum of broadness with respect to the methodologies involved.

The increasing resistance of bacterial pathogens against standard antibiotics combined with an emerging threat of bioterrorism has led to the urgent need for developing innovative anti-infective drugs. In 2001, branimycin, an unusual member of this family has been isolated and structurally characterized by the Laatsch group in Göttingen. First biological tests have shown that branimycin is highly active against Escherichia coli, Bacillus subtilis, Streptomyces viridochromogenes (Tü 57) and Staphylococcus aureus. Furthermore it apparently combines low toxicity with a broad spectrum of high antibacterial activities combined with considerable oral availability. The fermentation so far produces only very small amounts of the material, which are not sufficient for extensive biological testing . To gain sufficient amounts and also to vary the structure and get insight into the pharmacophoric parts of the molecule, a program was launched toward the total synthesis of branimycin. This was also attractive from the purely chemical standpoint as the structure of branimycin is unusually complex, calls for the development of novel methodology and and is thus a true challenge for the organic chemist. So far the synthesis has not been finished yet. However due to the combined efforts of two postdocs, two PhD and two diploma students no less than three entirely different novel and original routes have been developed for constructing the central structural cis- decalin unit and two for the side chain, and we are thus confident to complete the synthesis in the near future.