NEW METHODS FOR THE SYNTHESIS OF PHORBOXAZOLE

Phorboxaza是一种有趣的新天然产品，显示出 显著的抗癌活性。在针对NCI的小组肿瘤的测试中 细胞系，例如，它被发现抑制结肠的生长 肿瘤细胞HCT-116的GI50为4.36×10~(-10)M 对人类实体肿瘤的效力可与最有效的 到目前为止已知的试剂，并使苯并恶唑A的合成成为一种高 优先开发新的抗癌药物。苯并恶唑A和 B是从海绵Phorbos sp.中分离到的。在0.040%和 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 支持广泛的抗癌评估或制备结构 类比。呋喃唑甲及其制剂评价的进一步研究进展 癌症化疗的类似物将取决于 其全合成的有效途径。 我们提出了一种高度收敛的合成呋喃甲恶唑的方法。 发现了一种酯的还原乙酰化和Prins环化 立体选择性地给出一个四氢吡喃。这一反应的范围 将被研究，其中两个四氢吡喃环在 用这种方法将制备并恶唑类化合物。侧链A和 大环B将通过砜烷基化反应偶联 灵感来自莱伊的作品。个人光学纯品的合成 碎片是基于可靠的和既定的方法。整体而言 合成路线是收敛的，非常适合制备 类比。

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.