ASYMMETRIC SYNTHESIS OF ANTITUMOR POLYKETIDES

拟议研究的具体目标是建立 相对和绝对配置，并执行 非常有效的抗肿瘤剂海绵他汀。 最终，也许更少 这种有效的抗肿瘤剂的复合衍生物， 可以制备生物学图谱。 过程中 研究，不对称合成的一般方法， 将开发含有聚醋酸酯和螺缩酮的天然产品。 这种方法也可以应用于抗肿瘤剂苔藓抑素11。 已经发现海绵抑素1对抗肿瘤特别有效。 多种高度耐药肿瘤类型，包括NCI组 60种人类癌细胞系的基因。 人类黑色素瘤，肺，脑，和浣熊 发现癌症对海绵抑素特别敏感。 的 Spongistatin的活性与微管的种类密切相关 交互式抗有丝分裂剂。 由于可获得的 天然来源的海绵抑素[提供400 kg湿重的海绵属物种 仅可合成13.8mg（3.4 × 10-7%产率）的海绵抑素]， 对于提供足够数量的生物活性物质至关重要 研究，结构-活性关系，甚至帮助 阐明了该化合物的完全相对和绝对立体化学， 重要化合物。 包括苔藓抑素11在内的苔藓抑素还显示具有 显著抗肿瘤活性，包括抗淋巴细胞活性 白血病和癌肉瘤。 本文所述的聚乙酸酯片段的不对称方法应 在合成多种生物学上重要的 化合物. 这些方法也可以扩展到允许制备 聚丙酸酯片段通过掺入额外的甲基 替代与平衡策略相结合。 海绵抑素和苔藓抑素内的不对称聚酮片段， 将利用螺缩酮模板来控制大部分的 立体化学 螺缩酮烯酮用作立体化学 控制元件将通过金属化的亲核加成来构造， 吡喃酮转化为醛。 得到的δ-羟基吡喃酮可以环化 在酸催化下转化为螺缩酮。 选择性螺缩酮环断裂 也将在这些合成的背景下开发反应。

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.