ASYMMETRIC SYNTHESIS OF ANTITUMOR POLYKETIDES

拟议研究的具体目标是建立 相关接收和绝对配置，并执行 极其有效的抗肿瘤药物海绵抑素。归根结底，也许更少 这种强效抗肿瘤药物的复杂衍生物具有类似或更好的 可以准备生物档案。在这个过程中， 不对称合成的一般方法学研究 开发含天然产物聚乙酸酯和螺环酮。 这种方法也适用于抗肿瘤药物Bryostatin 11。 海绵抑素1被发现对一种 组成NCI小组的各种高度耐药的肿瘤类型 在60个人类癌细胞系中。人类黑色素瘤、肺、脑和浣熊 研究发现，癌症患者对海绵抑素特别敏感。这个 海绵抑素活性与微管类型密切相关 交互反子学。因为可获得的资源极其有限 天然来源的海绵抑素[400 kg湿重的海绵提供 只有13.8毫克(3.4x10-7%的产率)的海绵抑素合成可能 为生物提供足够量的物质所必需的 研究，结构-活性关系，甚至协助 完全的相对和绝对立体化学的阐明 重要的化合物。 包括Bryostatin 11在内的Bryostatin也被证明拥有 显著的抗肿瘤活性，包括对淋巴细胞的活性 白血病和癌肉瘤。 这里描述的聚醋酸酯碎片的不对称方法应该 在多种生物重要化合物的合成中的应用 化合物。这些方法也可以扩展以允许制备 通过加入额外的甲基来制备聚丙酸酯碎片 与平衡策略相结合的替代。 海绵抑素和Bryostatin中的不对称聚酮片段和 将使用螺环酮模板构建以控制大部分 立体化学。用作立体化学品的螺酮烯类化合物 控制元件将通过金属化合物的亲核加成来构建 从吡喃酮到醛。由此得到的三角洲-羟基吡喃可以环化。 在酸催化下对螺环酮类化合物有抑制作用。选择性螺环酮环断裂 反应也将在这些合成的背景下进行。

The specific objectives of the proposed research are to establish the relateive and absolute configuration and to execute a synthesis of the extremely potent antitumor agent spongistatin. Ultimately, perhaps less complex derivatives of this potent antitumor agent with similar or better biological profiles can be prepared. During the course of the investigation, general methodology for the asymmetric synthesis of polyacetate and spiroketal containing natural products will be developed. This methodology can also be applied to the antitumor agent bryostatin 11. Spongistatin 1 has been found to be extra ordinarily effective against a variety of highly chemoresistant tumor types which comprise the NCI panel of 60 human cancer cell lines. Human melanoma, lung, brain, and coon cancers were found to be especially sensitive to spongistatin. The activity of spongistatin correlates well with the class of microtubule interactive antimitotics. Because of the extremely limited availability of spongistatin from natural sources [400kg wet weight of Spongia sp. provided only 13.8 mg (3.4 x 10-7% yield) of spongistatin] synthesis may be essential for providing adequate quantities of the substance for biological studies, structure-activity relationships and even to assist in the elucidation of the complete relative and absolute stereochemistry of this important compound. The bryostatins including bryostatin 11 have also been shown to possess significant antitumor activity including activity against lymphocytic leukemia and carcinosarcoma. The asymmetric approaches to polyacetate fragments described herein should find application in the synthesis of a variety of biologically important compounds. These methods can also be extended to allow the preparation of polypropionate fragments by the incorporation of additional methyl substitution in combination with equilibration strategies. The asymmetric polyketide fragments within spongistatin and bryostatin and will be constructed utilizing spiroketal templates to control much of the stereochemistry. The spiroketal enones to be used as stereochemical control elements will be constructed by nucleophilic addition of metallated pyrones to aldehydes. The resulting delta-hydroxypyrones can be cyclized to spiroketals under acid catalysis. Selective spiroketal ring cleavage reactions will also be developed in the context of these syntheses.