SYNTHESIS OF ANTHRACYCLINONES

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A general synthetic strategy, based on the reactions of chromium carbene complexes with acetylenes, is presented for the synthesis of several anthracyclinones, anthracyclines, aureolic acid aglycones, and constituents of antitumor alkaloids. The synthetic targets include 11- chlorodaunorubicin, 11-chloroaclacinomycin, and 4-fluoroaclacinomycin which are unnatural analogs of compounds either in use clinically or currently in human trials. The strategy should be flexible enough 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 and if successful, will allow for the preparation of the unnatural 11-halo analogs for testing. 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 that the key strategy, the reaction of carbene complexes with acetylenes, be examined with regard to the synthesis of several 11-deoxy anthracyclines including aklavinone, 11-deoxydaunomycinone, and 7-con-o-methylnogarol, a semisynthetic derivative of nogalamycin, which was developed by UpJohn Company. Preliminary results indicate that this strategy is flexible enough to provide for the regioselective synthesis of olivin and chromomycinone, the aglycones of the aureolic acid family of antitumor antibiotics related to the anthracyclines. It has been further found in preliminary studies that these reactions should provide for an efficient entry into the aspidospermia carbon skeleton and it is proposed that they be investigated with regard to the synthesis of several members of the aspidospermia alkaloid family including vindoline which is a constituent of the dimeric antitumor indole alkaloids vinblastine and vincristine.