The research plan aims to develop new methods of organic synthesis and apply them in the synthesis of biologically-active natural products and analogs. Structures with potentially interesting biologically activity will be prepared in appropriate quantities for testing, through the National Cancer Institute and the Cornell Veterinary College. The emphasis is on new transition-metal reagents and electro-chemical techniques. Specific target molecules include quinone-based antibiotics such as granaticin, where key steps will involve carbene-metal complexes, and ionophone antibiotics such as tetronomycin, where crucial furan and pyran rings will be formed selectively with palladium-catalyzed processes. Key sections of other ionophore and macrolide antibiotics, with carefully controlled stereo-relationships of adjacent chiral centers, will be synthesized. Basic new oxidation methods will be developed, using electro-chemistry to re-cycle the key reagents. The long range goal is a set of electrode-supported oxidation catalysts based on amines. Coupling of two carbon units is the most fundamental problem in organic synthesis, and low valent metal reagents based on nickel and iron will be explored. Electro-reduction will be employed to regenerate the active catalysts. Overall, this effort will make available more powerful and more selective tools for drug synthesis, and will define specific pathways to classes of molecules of current interest in drug development.
