This application outlines a program for the continued development of a unified synthetic approach to the quinocarcin and naphthyridinomycin families of DNA reactive isoquinoline alkaloids. These substances along with the recently isolated tetrazomine, hold promise as potential antineoplastic agents because of their ability to inhibit nucleic acid synthesis at the DNA template level. In this context, practical asymmetric routes to these substances and their congeners in enantiomerically pure form are required for further investigation and eventual exploitation of their interaction with native nucleic acid sequences. Specific aims for the next funding period include: 1. Exploration of the photochemistry of thioimide-conjugated aziridines and the cycloaddition behavior of the resultant unsymmetrical azomethine ylides. 2. The evaluation of intramolecular imide/thioimide olefination as a new general method for the asymmetric synthesis of 1-substituted dihydroisoquinolines. 3. Asymmetric synthesis and structure elucidation of tetrazomine, a new antitumor antibiotic which resembles quinocarcin in both its structure and antitumor activity. 4. Optimization of the intramolecular cycloaddition strategy (i.e. rational tether modification) in support of the proposed naphthyridinomycin synthetic studies. 5. Completion of an asymmetric synthesis of cyanocycline A and naphthyridinomycin based on this intramolecular 1,3-dipolar cycloaddition protocol. 6. The design (molecular modelling), asymmetric synthesis, and evaluation of a new class of C2-symmetric DNA cross-linking agents based on quinocarcin.