Arene-metal complexes and carbene-chromium complexes will be developed for the specific purpose of quinone synthesis. The methods will be applied in the synthesis of aklavinone and related anthracyclinones, the new anti-tumor agent nogalamycin and its active analogs--nogalarol and nogamycin, and the mitomycins. A route to aklavinone using metalation and nucleophilic aromatic substitution promoted by the chromium tricarbonyl unit will be completed, and will demonstrate a strategy for direct synthesis of the anthracyclinones bearing the 7-hydroxy substituent in the proper orientation. Carbene-chromium complexes react with alkynes to generate arene-chromium complexes. This novel reaction will be employed in the preparation of precursors for the nucleophilic substitution onto coordinated arenes in the synthesis of the D ring of aklavinone. The same reaction, carbene-alkyne cycloaddition, offers particularly direct routes to the anthracyclinones through the synthesis of anthracene derivatives with functionalized side chains that can form the tetracyclic structures of electrophilic ring closure. The aglycone structure of nogalamycin will be approached in a very direct way using the carbene/alkyne cycloaddition in two ways. First, an intramolecular version will attach the amino sugar unit fused to the A ring, and the methods worked out for the aklavinone synthesis will be applied to the attachment of the D ring. The methods will provide access to both the natural (10-carbomythoxy) and analog structures (11-hydroxy, 10-decarboxylated) which have shown important anti-tumor activity. Amino-carbene complexes will be developed in the carbene/alkyne cycloaddition reaction, and will lead to direct syntheses of themitomycin skeleton. The scope and limitations for the amino-carbene complexes in heterocyclic synthesis will be defined, and the synthesis of specific mitomycins will be undertaken.
