Cascade Catalysis Towards Synthesis of Phorbol Architecture

描述（由申请人提供）：虽然分子试剂，特别是具有生物活性的那些分子试剂的自然生产是在相对短的化学转化次数中实现的，但合成化学家对分子的方法不是流线型的，因此既不高效也不有效。模拟自然界的生物合成过程将为提高化学家获得重要分子结构的能力提供宝贵的经验。仿生过程的发展，其中连续的催化操作是通过利用多种催化剂而不分离中间体来实现的，应该增强化学家以更有效的方式接近生物活性分子结构的能力。在这个提议中，级联催化的适用性将在佛波醇结构的背景下进行测试，特别是在12-脱氧佛波醇的全合成中。佛波醇（Phorbol）是一种强有力的肿瘤促进剂，是研究肿瘤发生机制的重要天然产物之一。最近，它的衍生物已被证明具有抗肿瘤、镇痛和抗HIV活性。由于这些重要的生物影响，获得佛波醇及其同系物变得非常重要。“拟议的合成将利用级联催化，以一种简短、有效和谨慎的方式获得所需的分子结构，并控制对映体和非对映体的选择性。合成的模块化性质将允许设计的策略适用于佛波醇家族内的广泛的分子结构。与公共卫生的相关性：12-脱氧佛波醇酯衍生物已被证明具有作为抗肿瘤剂的潜力。有效合成母体结构12-脱氧佛波醇的研究将证明有利于开发抗肿瘤药物。

DESCRIPTION (provided by applicant): While nature's production of molecular agents, especially those with biological activity, are achieved in a relatively short number of chemical transformations, synthetic chemists' approaches to molecules are not as streamlined and thus neither as efficient nor effective. Emulation of nature's biosynthetic processes will provide valuable lessons for advancing the capability of chemists to access molecular structures of importance. The development of a biomimetic process, where sequential catalytic manipulations are achieved through utilization of multiple catalysts without isolation of intermediates, should enhance the chemist's ability to approach architectures of biologically active molecules in a more effective fashion. In this proposal, the applicability of cascade catalysis will be tested in the context of the phorbol architecture, specifically in the total synthesis of 12-deoxy phorbol. Phorbol, a potent tumor promoter, has been one of the most important natural products that has been used in studies to decipher the mechanism of the carcinogenesis. More recently, its derivatives have demonstrated anti-tumor, analgesic, and anti-HIV activities. Due to these significant biological implications, access to phorbol and its congeners have become very important. "The proposed synthesis will take advantage of cascade catalysis to access the desired molecular architecture in a short, efficient, and deliberate manner with control of enantio- and diastereoselectivity. The modular nature of the synthesis will allow the devised strategy to be applicable towards a wide range of the molecular structures within the phorbol family. Relevance to public health: 12-deoxy phorbol ester derivatives have demonstrated potential as anti-tumor agents. Studies of efficient synthetic access to the parent structure, 12-deoxy phorbol, will prove beneficial towards development of anti-tumor medicines.