SYNTHESIS OF ANTHRACYCLINONES

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A general synthetic strategy is presented for the synthesis of several anthracyclinones based on the reactions of chromium carbene complexes with acetylenes. The synthetic targets include the aglycones of daunorubicin and adriamycin which are important chemotherapeutic agents for the treatment of a broad range of human cancers. The strategy is flexible to allow for the synthesis of both the 11-oxy and the 11-deoxy anthracyclinones and we propose to develop from it a convergent synthesis for these two major classes of anthracyclinones. The 11-deoxy anthracyclinones have been of more recent interest due to the finding that some members of this class have comparable activity to that of adriamycin but with a reduced level of cardiotoxicity. It is proposed to synthesize the aglycone of aclacinomycin and 7-con-o-methylnogarol, a semi-synthetic derivative of nogalamycin, which was developed by UpJohn Company. This compound, now known as menogarol, has recently been approved for phase II of human clinical trials. Preliminary results indicate that this strategy is flexible enough to provide for the regioselective synthesis of several unnatural mono fluoro derivatives of aklavinone.