Polar 1,4-cycloadditions of isoquinolinium salts are highly regio- and stereospecific. The overall process disrupts the aza aromatic ring creating a polycyclic system with two new carbon-carbon bonds and up to 5 new stereocenters. Significantly, however, the potential of this reaction is essentially unexplored. The long-range objectives of this proposal are to delineate the scope and limitations of polar 1,4-cycloadditions using isoquinolinium salts and related aza aromatics and to highlight their versatility for the stereorational preparation of chemotherapeutic natural products. These goals will be illustrated in conceptually novel total syntheses of representative examples from four classes of natural products. First, control of stereochemistry and functionality will be demonstrated by total syntheses of the anthracyclinones Alpha1-rhodomycinone, 11-deoxycarminomycinone, and the recently isolated 10-carbomethoxy congeners auramycinone and sulfurmycinone. Second, a highly efficient preparation of the vindoline-type Aspidosperma alkaloid vincadifformine will extend the useful range of polar 1,4-cycloadditions to other aza aromatics. Third, methodology for the regioselective construction of aromatic systems with complex appendages will be exploited in the total synthesis of (+)-vineomycin B2 aglycone. And fourth, a new annulation procedure will be utilized to prepare the protoberberine alkaloid berberine.