We propose a course of research, involving the use of sequential nitrone cyclo-addition reactions, in concert with highly stereoselective deamination procedures, to synthesize a structural unit present in a large array of terpenoid derivatives. This methodology promises to provide an entry to the germacrolide class of sesquiterpene lactones. Specifically, approaches to germacrene B, inunolide, and tulipinolide are considered in detail. This approach is also applicable to other such lactones (e.g., costunolide, eupatolide, eupaserrin, and deacetyleupaserrin). The novel approach suggested involves the cycloaddition of selectively alkylated cyclobutylated nitrones onto properly functionalized dienes. The resultant isoxazolidines will be cleaved oxidatively to generate a second nitrone with regiospecificity. This intermediate will be induced to undergo a further cycloaddition onto the remaining double bond of the original diene to generate a polycyclic isoxazolidine capable of ultimate stereoselective deamination via the corresponding diazene. The germacrolide will result directly from this process. A wide array of germacrolide sesquiterpene lactones have been found to possess cytotoxic or antitumor activity. Both costunolide and tulipinolide show inhibitory activity against the KB cell culture of human carcinoma of the nasopharynx. Eupaserrin and deacetyleupaserrin, oxygenated derivatives related to tulipinolide, show significant in vivo antileukemic activity (P-388) in mice. We plan to submit all relevant intermediates to the National Cancer Institute for the appropriate physiological screens.
