SYNTHESIS OF ANTHRACYCLINONES

本文提出了一种通用的合成策略， 基于铬卡宾络合物与 乙炔。 合成的靶点包括柔红霉素的糖苷配基 和阿霉素，它们是重要的化疗剂， 治疗多种人类癌症。 该战略灵活， 允许合成11-氧基和11-脱氧 蒽环酮，我们建议从它开发一个收敛合成 这两种主要的蒽环类化合物 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。 建议合成 阿克拉霉素和7-con-o-methylnogarol（一种半合成 由UpJohn公司开发的诺加霉素的衍生物。 这 一种现在被称为menogarol的化合物最近被批准用于第二阶段 人体临床试验的结果 初步结果表明，这一战略 具有足够的灵活性以提供几种 阿克拉维酮的非天然单氟衍生物。

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.