A PRACTICAL SYNTHETIC ROUTE TO THE TETRACYCLINES

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DESCRIPTION: (Principal Investigator's Abstract) The objective of this proposal is to develop the first practical, efficient, and enantioselective laboratory synthetic route(s) to the tetracycline antibiotics. The goal is to devise a route of twelve or fewer synthetic steps, perhaps as few as eight steps, beginning with benzoic acid as a starting material. A constraint that the synthetic route be versatile is also imposed, allowing for the introduction of substantive structural variability at a late stage, particularly within the C and D rings of the tetracycline structure, where prior research has shown that there is great opportunity for antibiotic development. Synthesis of a wide range of new tetracyclines for evaluation as improved antibiotics and, potentially antitumor agents is proposed. A particular focus is the development of effective antibiotics against tetracycline-resistant microorganisms. Adaptation and/or modification of these synthetic routes to target new tetracycline structures with antitumor activity, such as SF-2575 (TAN-1518 X) will also be attempted.