The proposed study is directed at total syntheses of a wide range of biologically active natural products containing medium-sized carbocycles and heterocycles. The specific aims are the development and applications of general methods or strategies that would allow expedient preparation of structurally complex natural products and synthetic derivatives for biological testing. The synthetic strategies are chosen to provide efficient and stereoselective entries to target compounds in their natural absolute configuration. Toward these objectives, we recently developed two key synthetic methods: (1) diastereoselective [4 + 3] cycloadditions of cyclic oxyallyls and heteroatom-substituted oxyallyls; and (2) Iow-valent titanium-mediated cyclopropanation reactions of carboxylic acid derivatives and related coupling of imides. Among specific target molecules for the next budget period are ingenol (la), as a prominent member of the ingenane, tigliane, and daphnane diterpenes [e.g., other prototypical members of this family include phorbol (lla), prostratin (III), resiniferatoxin (IV)] which possess potent cocarcinogenic, tumor inhibitory, anti-HIV, or analgesic activity; sarains A-C (V-VII), structurally fascinating marine alkaloids, which have been reported to display antitumor, antibacterial, and insecticidal activity; Cephalotaxus alkaloids [e.g., cephalotaxine (VIII) and homoharringtonine (IX)] having significant antileukemic activity; histrionicotoxin (X) which is known to function as a noncompetitive inhibitor of the nicotinic acetylcholine receptors; ophiobolins (Xla-c) which show interesting inhibitory activities of Ca2+-binding calmodulins or angiotension II receptor binding; and erinacines (Xll and XlII), the cyathane-type diterpenoids that possess potent stimulating activity of nerve growth factors; and mitomycin alkaloids [e.g., mitomycin C (XlVc)] which are clinically important antitumor agents.