STEREOCONTROLLED SYNTHESIS OF BIOACTIVE ALKALOIDS

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The proposal describes plans for the development of general strategies for stereoselective synthesis of a wide range of alkaloids, including those from the Strychnos, Aspidosperma, Corynantheine, Pleiocarpamine, Akuammiline, and Sarpagine families. Many of these structurally complex natural products exhibit potent biological activities, while the properties of many others have not been investigated. The synthetic routes that will be developed during these investigations are expected to result in concise (many just 5-8 steps) and high yielding syntheses of many natural products, so that sizable quantities of the final targets can be prepared and submitted for evaluation of their biological activity. The research plan has been divided into three broad sections. The first part describes new strategies for the synthesis of Strychnos and related alkaloids. These strategies will be extend to the Aspidosperma family of natural products. In particular, the PI is to develop efficient syntheses of vincadifformine, vindorosine and vindoline, the latter representing the lower part of the potent and clinically important anticancer agent vinblastine. The third part describes the application of some of the newly developed chemistry to a wide range of natural products that are derived biogenetically from geissoschizine. The syntheses have been designed to complete the target in a minimum number of steps, to explore and develop chemistry that will be of general use to organic and medicinal chemists, and to incorporate chemistry that can be adapted to asymmetric synthesis. The syntheses will offer the opportunity to explore the scope and usefulness of Heck-type reactions in complex alkaloid synthesis. Overall, these investigations are expected to result in not only efficient syntheses of a wide range of indole alkaloids, but also to the development of methodology, particularly palladium catalyzed processes, that should prove useful to other synthetic endeavors.