SYNTHESES OF NATURAL ANTI-CANCER AGENTS AND ANALOGS

芳烃金属络合物和卡宾铬络合物将用于 对苯二酚合成的具体目的。这些方法将应用于 新型抗癌药物阿克拉维酮及其相关的蒽环酮类化合物的合成 抗肿瘤药物诺加拉霉素及其活性类似物--诺加罗尔和 诺伽霉素和丝裂霉素。使用金属化合成阿拉维酮 三羰基铬促进的亲核芳香族取代反应 该单元将完成，并将展示直接 含7-羟基取代基的蒽环酮类化合物的合成 正确的定位。卡宾-铬配合物与炔烃反应生成 生成芳烃铬络合物。这种新的反应将被用于 亲核取代前驱体的制备 阿拉维酮D环合成中的配位芳烃。相同 卡宾-炔环加成反应提供了特别直接的路线 通过合成蒽衍生物来合成蒽环己酮类化合物 具有官能化的侧链，可以形成四环结构 亲电密封圈。诺加拉霉素的苷元结构将是 以非常直接的方式使用卡宾/炔的环加成反应 两种方式。首先，分子内版本将连接氨基糖 单元融合到A环上，并给出了计算阿拉维酮的方法 合成将应用于D环的连接。这些方法 将提供对天然(10-甲氧基)和类似物的访问 已显示出重要的结构(11-羟基、10-脱羧基) 抗肿瘤活性。氨基卡宾络合物将在 卡宾/炔的环加成反应，并将导致直接合成 丝裂霉素骨架。氨基卡宾的应用范围和局限性 定义了杂环合成中的络合物，并介绍了杂环化合物的合成 将进行特定的丝裂霉素试验。

Arene-metal complexes and carbene-chromium complexes will be developed for the specific purpose of quinone synthesis. The methods will be applied in the synthesis of aklavinone and related anthracyclinones, the new anti-tumor agent nogalamycin and its active analogs--nogalarol and nogamycin, and the mitomycins. A route to aklavinone using metalation and nucleophilic aromatic substitution promoted by the chromium tricarbonyl unit will be completed, and will demonstrate a strategy for direct synthesis of the anthracyclinones bearing the 7-hydroxy substituent in the proper orientation. Carbene-chromium complexes react with alkynes to generate arene-chromium complexes. This novel reaction will be employed in the preparation of precursors for the nucleophilic substitution onto coordinated arenes in the synthesis of the D ring of aklavinone. The same reaction, carbene-alkyne cycloaddition, offers particularly direct routes to the anthracyclinones through the synthesis of anthracene derivatives with functionalized side chains that can form the tetracyclic structures of electrophilic ring closure. The aglycone structure of nogalamycin will be approached in a very direct way using the carbene/alkyne cycloaddition in two ways. First, an intramolecular version will attach the amino sugar unit fused to the A ring, and the methods worked out for the aklavinone synthesis will be applied to the attachment of the D ring. The methods will provide access to both the natural (10-carbomythoxy) and analog structures (11-hydroxy, 10-decarboxylated) which have shown important anti-tumor activity. Amino-carbene complexes will be developed in the carbene/alkyne cycloaddition reaction, and will lead to direct syntheses of themitomycin skeleton. The scope and limitations for the amino-carbene complexes in heterocyclic synthesis will be defined, and the synthesis of specific mitomycins will be undertaken.