A General Route to Anti-tumor Angucycline/Angucyclinones

描述（由申请人提供）：本提案中概述的研究目标是研究使用1,3-二卤-2-（三烷基硅基）苯作为1,3-苯并二苯胺前体作为苯并[a]蒽核心的一般途径的范围。利用一次性系绳将环加成物呈现在分子内，可以控制苯基环加成物的区域化学。所制得的苯并[a]蒽芯将进一步发展为天然产物rubiginone B1、urdamycinone B和IB-00208，它们是安环素/安环素家族天然产物中有效的抗肿瘤化合物。该反应将被研究，并将扩大1,3-苯并苯胺环加成的范围，使用正交法产生必要的苯中间体。这将允许一个受控的生成和反应的苯，以产生适当功能化的苯[a]蒽核心。利用所提出的3-苯并二炔方法，通过灵活的路线进行高效的化学合成，将为合成大量结构相似的安古霉素/安古霉素天然产物提供一种通用的合成策略，这些天然产物已被确定为癌症、抗菌、抗病毒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.