The objective of this proposal is to develop a new synthetic approach to the naphthyridinomycin and quinocarcin families of isoquinoline alkaloids. Since these substances inhibit DNA synthesis they are potential antineoplastic agents. Methodology will be explored that allows for the stereoselective assembly of these structurally complex targets from chiral, nonracemic precursors. Thus asymmetric syntheses of the requisite phenylglycinol derivatives will be investigated first. These starting materials will be incorporated into a scheme that relies on a novel 1,3-dipolar cycloaddition reaction to construct the 3,8- diazabicyclo(3.2.1)octane moiety common to both target families. In this context, complimentary photochemical and thermal routes to azomethine ylides will be explored. The latter method would involve a novel valence tautomerization of enamines for ylide generation. Both inter- and intramolecular variations of this key addition will be investigated in detail, with complete stereocontrol as a goal. Subsequent Hoesch cyclization (isoquinoline formation) sets the stage for the final sequence of events that should lead to the desired targets and analogues thereof. As mentioned above, these target substances have been shown to inhibit DNA synthesis and (at least for naphthyridinomycin) this seems to occur as a result of irreversible binding to the deoxyguanidylic acid - deoxycytidylic acid base pairs. A logical extension of the proposed synthetic work would be an investigation into the exact nature of this binding to DNA and the chemical events (ie. activation of the antibiotic) that precede it. Such studies would be useful for the rational design of new antineoplastic agents with minimal unwanted side effects. More importantly perhaps, work of this nature could lead to a better understanding (and thus control) of DNA synthesis at the cellular level and the medical problems associated with the malfunction of this process.