Studies toward the total synthesis of naphthyridinomycin/bioxalomycin antitumor antibiotics

The first part of this thesis details the preparation of substituted 1,4-dihydro-2H-isoquinoline-3,5,8-triones via the thermal ring expansion and subsequent cyclization of hydroxy cyclobutenones. The syntheses proceed in four to six steps with overall yields ranging from 11–37% from commercially available starting materials. Some of the isoquinoline-3,5,8-trione compounds synthesized showed biological activity against cdc25B₂ with IC₅₀'s in the low micromolar range (work performed in collaboration with Dr. Lazo's group in the Department of Pharmacology).; The second part of this thesis details studies directed toward the total synthesis of tetrazomine, a novel antitumor antibiotic. Two fragment syntheses were completed in enantioselective fashion (the first of such for this molecule). A scalable enantioselective synthesis of the AB-ring system was accomplished in 20 steps and 4% overall yield. Key aspects included the use of Sharpless' asymmetric dihydroxylation conditions to install a benzylic stereocenter in 94% ee and an intramolecular Friedel-Crafts hydroxyalkylation of an N-allylated α-oacetamide to form the isoquinoline ring system. The D-ring synthesis was completed in 6 steps and 31% overall yield. The key reaction in this sequence was an imide-enamide conversion.; Model studies demonstrated the feasibility of the key intramolecular Heck reaction to synthesize the 3,8-diazabicyclo[3.2.1]octane moiety. However, our efforts toward the total synthesis of tetrazomine stalled due to the unsuccessful application of the intramolecular Heck reaction sequence in the real system. Several alternative reaction sequences were investigated; however, these also failed to give the desired ring system.