The research program described herein is directed toward the development of general synthetic approaches to natural products, which either exhibit anticancer activity or are closely related to natural products possessing anticancer properties. Specifically, the syntheses of taxusin, a taxane diterpene related structurally to the anticancer agents taxol (NSC 125973) and cephalomannine; sesbanimide, a potent antitumor substance isolated from Sesbania drummodii seeds; and the novel anticancer antibiotic bactobolin (NSC 325014), which is isolated from a Pseudomonas, as well as the structurally similar antibiotic actinobolin. The proposed syntheses of these substances will be sufficiently efficient and flexible so that analogs may be readily prepared for a study of structure-activity relationships. Selected compounds will be submitted to the National Cancer Institute for biological screening as potential anticancer agents. During the synthesis of any structurally complex or functionally rich natural product, as is the case with the targets of these investigations, it is necessary to invent and develop new synthetic methods and strategies. Of particular importance to the present task is the development of techniques for the stereoselective introduction of oxygen functionality on cyclic and acyclic arrays. New synthetic applications of furan chemistry to the construction of carbocycles and hydropyrans will also be investigated, and further developments of the intramolecular cycloadditions of nitrile oxides will be examined. Finally, attention will be accorded to the use of methods of asymmetric synthesis for the application to the enantioselective syntheses of the targeted natural products.
