SYNTHESES OF NATURAL ANTI-CANCER AGENTS AND ANALOGS

将开发芳烃-金属络合物和卡宾-铬络合物， 醌合成的具体目的。 这些方法将应用于 阿克拉维酮和相关蒽环酮的合成， 抗肿瘤剂诺加霉素及其活性类似物诺加洛尔， 野霉素和丝裂霉素。 使用金属化和 三羰基铬促进的亲核芳香取代反应 单位将完成，并将展示一个战略， 7-羟基取代蒽环酮的合成 正确的方向。 卡宾-铬络合物与炔反应， 生成芳烃-铬络合物。 这种新的反应将被用于 亲核取代前体的制备 在阿克拉维酮D环的合成中使用配位芳烃。 相同的 卡宾-炔环加成反应提供了特别直接的途径 通过蒽衍生物的合成， 具有官能化的侧链，所述侧链可以形成以下四环结构： 亲电环闭合 诺加霉素的糖苷配基结构将是 以一种非常直接的方式使用卡宾/炔环加成， 两种方式。 首先，分子内的形式将氨基糖 单位融合到A环，并为aklavinone制定了方法 合成将应用于D环的连接。 的方法 将提供天然（10-甲氧羰基）和类似物 结构（11-羟基，10-脱羧），已显示出重要的 抗肿瘤活性。 氨基-卡宾络合物将在2008年开发。 碳烯/炔环加成反应，并将导致直接合成 丝裂霉素骨架。 氨基卡宾的范围和限制 杂环化合物的合成将被定义，和合成 将使用特定的丝裂霉素。

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.