NEW METHODS FOR THE SYNTHESIS OF PHORBOXAZOLE

Phorboxazole A是一种有趣的新天然产物， 显著的抗癌活性。 在针对国家癌症研究所的小组肿瘤的测试中， 例如，发现细胞系抑制结肠的生长， 肿瘤细胞HCT-116，GI_（50）为4.36 × 10 ~（-10）M。 这种例外 对人实体瘤的效力与最有效的 试剂的日期，并使合成的phorboxazole A高 优先开发新的抗癌药物。甲恶唑和 B是从一种海绵中分离得到的， 0.017%的干重，这提供了足够的材料 结构测定和初步生物学评价，但不会 支持广泛的抗癌评价或制备结构 类似物 甲恶唑及其代谢物评价的新进展 用于癌症化疗的类似物将取决于 为全合成提供了有效途径。 我们提出了一个高度收敛的合成phorboxazole使用我们的新的 发现了酯的还原乙酰化和Prins环化， 立体选择性地得到四氢吡喃。 这种反应的范围 将被调查，和两个四氢吡喃环中的 将使用该方法制备Phorboxazole。 侧链A和 大环B将使用砜烷基化反应偶联 受到Ley工作的启发单个光学纯的合成 片段是基于可靠和既定的方法。 整体 合成路线是收敛的，非常适合于制备 类似物

Phorboxazole A is an interesting new natural product that shows remarkable anticancer activity. In tests against the NCI's panel tumor cell lines it was found, for example, to inhibit the growth of colon tumor cells HCT-116 with a GI50 of 4.36 X 10-10 M. Such exceptional potency against human solid tumors is comparable with the most potent agents known to date, and makes the synthesis of phorboxazole A a high priority in the development of new anticancer agents. Phorboxazole A and B were isolated from a marine sponge, Phorbos sp. in 0.040 percent and 0.017 percent of the dry weight, which provided enough material for structure determination and initial biological evaluation, but will not support extensive anticancer evaluation or the preparation of structural analogs. Further progress in the evaluation of phorboxazole A and its analogs for cancer chemotherapy will depend upon the development of effective routes for its total synthesis. We propose a highly convergent synthesis of phorboxazole using our newly discovered reductive acetylation and Prins cyclization of an ester to give a tetrahydropyran stereoselectively. The scope of this reaction will be investigated, and two of the tetrahydropyran rings in the phorboxazoles will be prepared using this method. The side chain A and macrocycle B will be coupled using a sulfone alkylation reaction inspired by Ley's work. Syntheses of the individual optically pure fragments are based on reliable and established methods. The overall synthetic route is convergent and is well suited for the preparation of analogs.