Two Directional Benzyne Ring Annulation in the Total Synthesis of Sch 47554

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Synthetic organic chemistry is a discipline of paramount importance to biomedical research and pharmaceutical innovation. It impacts directly on all stages of the discovery and development process for new medicines. The discovery of new hit active compounds and their optimisation to produce pharmaceutical lead structures depend on drug design, iterative synthesis and biological evaluation. What may be less apparent in 2006 is the vital importance of natural product isolation, total synthesis and semi-synthesis for the discovery of the commercially successful drugs of the future. In the area of infectious disease, over 31% of the drugs in current use in medicine are derived either directly or via semi-synthesis from natural product lead structures. In addition, natural products constitute over 20% of all drugs in all areas of medicine with major emphasis on drugs to treat cancer and in transplant surgery. There is considerable alarm amongst the medical profession regarding fungal disease. Pathogens such as Candida albicans, Cryptococcus neoformans, Pneumocystis carinii and Aspergillus fumigatus are the cause of considerable morbidity and mortality in immuno-compromised patients. These include patients with fully blown AIDS, recipients of transplant surgery, who need to be treated for life with immuno-suppressants to prevent tissue rejection, and patients undergoing cancer chemotherapy, whose immune system is impaired by the side effects of their anti-cancer drugs. Current therapies for the treatment of serious systemic fungal infection are deficient since there now are resistance problems with azole fungistatic agents and the more potent fungicidal polyene drugs are toxic. As such, there is urgent need for novel therapies for serious fungal disease and for the management of the legions of topical fungal infections. The grant applicant is seeking funding to support the research by one postdoctoral research associate who will carry out the total synthesis of both Sch 47554 and Sch 47555, which are potent antifungal agents. Both compounds show activities against the pathogens Candida albicans, C. tropicalis, C. stellatoidea, Trichophyton mentagrophytes, T. rubrum, T. tonsurans and Microsporum canis with the greater activity shown by Sch 47554. These bioactive natural products are closely related to the aquayamycins, which show antitumour effects, antiviral activities, are inhibitors of tryptophan 5-monooxygenase and tyrosine hydrolase and display inhibition of blood platelet aggregation. As such, Sch 47554 and Sch 47555 are excellent hit chemical structure on which to base the design of new antifungal agents for the treatment of fungal infections in man. In order to achieve these goals, it is necessary to develop new synthetic chemistry for the elaboration of the highly functionalised core structures of the natural products. The new methodology should be amenable for the synthesis of analogues structures and be of general use in pharmaceutical synthesis and discovery.