SYNTHESIS OF ANTHRACYCLINONES

基于铬卡宾反应的一般合成策略 与乙炔的络合物被提出用于合成几个 蒽环酮类、蒽环类、金酸苷元及其组合物 抗肿瘤生物碱。合成目标包括11个- 氯柔比星、11-氯阿克拉霉素和4-氟阿克拉霉素 是临床上使用的或目前正在使用的化合物的非天然类似物 人体试验。战略应该足够灵活，以考虑到 11-氧基和11-脱氧并芳香酮类化合物的合成 建议在此基础上发展出这两个专业的融合 如果成功，将允许 测试用非天然11晕类似物的制备。11-脱氧 由于这一发现，人们最近对蒽环己酮类药物感兴趣 这一类中的一些成员具有与阿霉素类似的活性 但心脏毒性水平有所降低。有人建议，关键是 策略，卡宾络合物与乙炔的反应，被研究 关于几种11-脱氧蒽环类化合物的合成 阿克拉维酮、11-脱氧柔红霉素酮和7-酮-o-甲基橙花酚，a 由Upjohn开发的诺加拉霉素的半合成衍生物 结伴。初步结果表明，该策略具有一定的灵活性。 足以提供区域选择性合成橄榄素和 金黄色葡萄糖酸家族的苷元--色霉酮 与蒽环类药物有关的抗生素。它被进一步发现在 初步研究表明，这些反应应该提供一种有效的 进入无精症的碳骨架，并提出了它们 就几个成员的合成进行调查 无精症生物碱家族，包括长春花碱，它是 抗肿瘤二聚体吲哚生物碱长春花碱和长春新碱。

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.