Two dircectional Benzyne Ring Annulation in Total Synthesis

The urgent need for the discovery and development of new pharmaceuticals for the treatment of cancer, AIDS, infectious and a lot of other diseases demands that all approaches to drug discovery are exploited aggressively. Among the possible approaches, the one from natural products has made unique and vital contributions to drug discovery. Natural selection during evolution and competition between the species has produced millions of powerful biologically active natural products, which can serve as a fruitful source of drug leads. The group of angucycline antibiotics features an interesting benz[a]anthraquinone framework with varying degree of insaturation and oxygenation, and displays a broad spectrum of biological activities including antitumor, antifungal and antiviral properties. Because of their unique combination of structural diversity and highly selective and specific biological activities they represent attractive lead-targets for the development of new and effective drugs in the battle against bacterial, viral and fungal pathogens and the emergence of microbial resistance. Unfortunately synthetic access to highly oxygenated angucyclines, the aquayamycin antibiotics, which show the therapeutically most significant and promising biological activity among angucycline antibiotics, still represents a real challenge. For this purpose the total synthesis of the aquayamycin like antifungal Sch 47554 will be undertaken to investigate a novel two-directional double furan-Diels-Alder reaction of 1,4-difluoro-2,6-dimethoxybenzene. This easy and flexible double benzyne strategy should be of general applicability and should make available intermediates and compounds of the aquayamycin class of natural products for assay as antifungal and antibiotic agents.