The primary objective of this research program is to continue to develop a combination of novel synthetic methods and new strategies for the synthesis of bioactive heterocycles and heterocyclic natural products. Emphasis will be placed upon producing and refining methodology having potentially broad applicability which will be of practical value to both organic and medicinal chemists involved in synthesis of cancer chemotherapeutic agents. In addition, studies will be conducted on total synthesis of a number of structurally unique and complex nitrogen-containing natural products, many of which have significant cytotoxic activity. A major goal involves utilization of our novel intramolecular allenylsilane imino ene reaction, discovered in previous years of this grant, as a pivotal step in total synthesis of the cytotoxic Lycopodium alkaloid lyconadin A. Total syntheses of the structurally unique cytotoxic marine natural products perophoramidine and the communesins will be completed using a halogen-selective tandem Heck/carbonylation strategy as a key strategic step. A total synthesis of the unusual cyclopropane-containing alkaloid lundurine A is in progress and will be completed, as will a new stereoselective total synthesis of the immunosuppressant agent FR901483.
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