The proposed program is directed at a total synthesis of a wide range of biologically active medium-sized carbocyclic and heterocyclic natural products. Our objective includes the development and refinement of general synthetic methods which would allow the convenient preparation of natural products and their synthetic derivatives for biological testing. The new key methods include (1) the (4 + 3) cycloadditions of cyclic oxyallyls and heteroatom-substituted oxyallyls; and (2) the low-valent titanium-mediated cyclopropanations of carboxylic acid derivatives and related coupling of imides; subsequent elaboration includes a cascade of free-radical cyclizations. Specific target molecules include the tigliane, daphnane, and ingenane diterpenes of the phorbol family (e.g., phorbol (Ia), prostratin (II), resiniferatoxin (III), or ingenol (IVa)) which possess potent cocarcinogenic, tumor inhibitory, anti-HIV, or analgesic activity; ophiobolins (Va-c) which show interesting inhibitory activities of Ca(2+)-binding calmodulins or angiotensin II receptor binding; tropoloisoquinoline alkaloids of the colchicine family (e.g., gradirubrine (VI), isoimerubrine (VII), and imerubrine (VIII)), which are antimitotic inhibitors; sarains A-C (IXA-IXC), structurally fascinating marine alkaloids, which exhibit antitumor, antibacterial, and insecticidal activity; Cephalotaxus alkaloids (e.g., cephalotaxine (X) and homoharringtonine (XI) having significant antitumor activity); and mitomycin alkaloids (e.g., mitomycin C (XIIC) and FR900482 (XV)) which are clinically important antitumor agents. The target compounds are chosen not only for their useful biological activities, but also to demonstrate the preparative power of the underlying synthetic methodologies that have successfully been developed in our laboratories. Concurrent with these new foci, we will also bring to a successful conclusion some ongoing research projects.
