Project Summary/Abstract The primary objective of this research program is to continue to develop a combination of novel synthetic methods and new strategies for the synthesis of bioactive heterocycles and alkaloid natural products. Emphasis will be placed upon producing and refining methodology having potentially broad applicability which will be of practical value to both organic and medicinal chemists involved in synthesis of bioactive compounds. In addition, studies will be conducted on target oriented total syntheses of a number of structurally unique and complex nitrogen-containing natural products. Goals involve completing ongoing enantioselective total syntheses of the cytotoxic Lycopodium alkaloid (+)-lyconadin A and the cytotoxic marine alkaloid (-)- haouamine A, which are currently well advanced. Enantioselective total syntheses of the structurally unique cytotoxic marine natural products perophoramidine and the communesins will also be completed using asymmetric intramolecular Heck reactions or tandem Heck reactions/carbonylations as key strategic steps. Studies will be conducted on the use of intramolecular Michael additions of vinylnitroso compounds in enantioselective total syntheses of the core of the stemofoline alkaloids, as well as the unique indole alkaloid actinophyllic acid, a potent inhibitor of the enzyme carboxypeptidase U. Intermolecular conjugate additions of carbon nucleophiles to vinylnitroso compounds will constitute key steps in total syntheses of the vallesamine class of indole alkaloids including (Z)-vallesamine, angustilobine A and angustilodine. New synthetic methodology involving inter- and intramolecular conjugate additions to vinylnitroso compounds will be explored in order to generate quaternary carbon centers as well as spirocycles bearing quaternary centers. Finally, methodology will be investigated for effecting catalytic enantioselective conjugate additions of vinylnitroso compounds.