This grant will continue a research program to investigate the fundamental chemistry of recently discovered, biologically active natural products. Our plans include three major areas for study. 1. Lankacidins: The Synthesis of Large Ring Carbocycles. The lankacidins exhibit important in vivo antimicrobial and antitumor activities with low toxicity. In our continuing development of this program, we have constructed a fully functionalized six-membered lactone, which provides a constricted platform for ring closure of the carbon macrocycle. Several strategies are discussed for macrocycle formation, and conversions to lankacidin derivatives. 2. Funiculosin: Novel Anti-Infective Cyclitols. Funiculosin is a structurally unique Penicillium metabolite, which displays antiviral and antitumor effects. It is most valuable as a novel antifungal with in vivo potency comparable to griseofulvin with very low toxicity. Our synthetic studies will approach the target as an unusual C-linked nucleoside. A convergent approach will seek to prepare the "all-syn"-cyclopentanetetrol, and effect formation of the 4-hydroxy-2-pyridinone through an intramolecular condensation. The dihydropyranyl ring will be a focal point our study of internal Michael reactions, which may be a relevant chemical feature for bioactivity. 3. Zoanthamine: A New Class of Marine Alkaloids. Zoanthamine is a remarkable alkaloidal structure offering an array of novel chemical features. Limited information reports antiinflamatory activity and analgesic effects. Our proposed chemistry will investigate intramolecular Pd(O) cross-coupling reactions of aryl halides with allylic alcohols. Secondly, studies of the Michael reaction will be explored for ring annulation. Finally, new methodology for carbanions in nitrogen-containing, chiral synthons will be detailed.