SYNTHESIS OF ANTHRACYCLINONES

基于铬卡宾反应的一般合成策略 络合物与乙炔，提出了几个合成 蒽环类、蒽环类、金酸苷元及其成分 抗肿瘤生物碱。 合成目标包括11- 氯柔红霉素、11-氯阿克拉霉素和4-氟阿克拉霉素， 是临床上或目前使用的化合物的非天然类似物 人体试验 该战略应具有足够的灵活性， 合成了11-氧代和11-脱氧蒽环酮， 我建议从它发展一个收敛综合这两个主要的 蒽环类，如果成功，将允许 制备用于测试的非天然11-卤代类似物。 11-脱氧 蒽环类化合物最近受到关注，因为发现 该类中的一些成员具有与阿霉素相当的活性 但心脏毒性降低。 建议关键 策略，卡宾络合物与乙炔的反应，被检查 关于几种11-脱氧蒽环类抗生素的合成， Aklavinone，11-deoxydaunomycinone和7-con-o-methylnogarol，a 诺加霉素的半合成衍生物，由UpJohn开发 公司 初步结果表明，该策略是灵活的 足以提供橄榄石的区域选择性合成， 色霉素酮，抗肿瘤的金酸家族的糖苷配基 与蒽环类抗生素有关的抗生素。 它已被进一步发现， 初步研究表明，这些反应应该提供一个有效的 进入spidospermia碳骨架，并提出，他们 关于几个成员的合成进行调查， spidospermia生物碱家族，包括vindoline，其是 二聚抗肿瘤吲哚生物碱长春碱和长春新碱。

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.