A General Route to Anti-tumor Angucycline/Angucyclinones

说明(申请人提供)：本提案中概述的研究目标是调查使用1，3-二卤代-2-(三烷基硅基)苯作为1，3-苯并二炔前体的范围，以此作为通向苯并菲核心的一般路线。使用一次性的系链将环加成反应呈现在分子内，这将控制苯并炔环加成反应的区域化学。生产的本茨[a]蒽核将进一步精制成天然产物鲁比吉酮B1、乌丹西酮B和IB-00208，这些化合物是来自安古环素/安古西酮系列天然产品的有效抗肿瘤化合物。该反应将被研究，并将扩大1，3-苯二炔的环加成反应的范围，使用生成所需的苯并二炔中间体的正交方法。这将允许苯并yne的受控生成和反应，以生产适当官能化的苯并[a]蒽核。使用所提出的3-苯二炔方法通过灵活的路线进行有效的化学合成将为合成大量结构相似的安古环素/安古西酮天然产物提供一般的合成策略，这些天然产物已被确定为在癌症、抗菌药物、抗病毒药物和酶抑制剂治疗领域的潜在药物。

DESCRIPTION (provided by applicant): The goal of the research outlined in this proposal is to investigate the scope of using 1,3-dihalo-2- (trialkylsilyl) benzenes as 1,3-benzadiyne precursors as a general route to the benz[a]anthracene core. Using disposable tethers to render the cycloadditions intramolecular will control the regiochemistry of the benzyne cycloadditions. The benz[a]anthracene cores produced will be further elaborated into the natural products rubiginone B1, urdamycinone B, and IB-00208, which are potent antitumor compounds from the angucycline/angucyclinone family of natural products. The reaction will be investigated and will expand the scope of 1,3-benzadiyne cycloadditions by using orthogonal methods of generating the requisite benzyne intermediates. This will allow for a controlled generation and reaction of benzyne to produce appropriately functionalized benz[a]anthracene cores. Efficient chemical syntheses by flexible routes using the proposed, 3-benzadiyne methodology will provide a general synthetic strategy for the synthesis of a multitude of structurally similar angucycline/angucyclinone natural products, which have been identified as potential pharmaceuticals in the therapeutic areas of cancer, anti-bacterials, anti-virals, and enzyme inhibitors.