Cascade Catalysis Towards Synthesis of Phorbol Architecture

描述(申请人提供)：虽然自然界分子制剂的生产，特别是那些具有生物活性的分子制剂，是在相对较少的化学转化中实现的，但合成化学家对分子的方法并不那么流畅，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取重要分子结构的能力提供宝贵的经验教训。仿生过程的发展，通过使用多个催化剂而不分离中间体来实现顺序催化操作，应该会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。在这项提案中，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。佛波醇是一种有效的肿瘤促进剂，是最重要的天然产物之一，已被用于研究其致癌机制。最近，它的衍生物显示了抗肿瘤、镇痛和抗艾滋病毒的活性。由于这些重大的生物学影响，获得佛波醇及其同系物变得非常重要。建议的合成将利用级联催化的优势，在控制对映体和非对映选择性的情况下，以一种简短、有效和深思熟虑的方式获得所需的分子结构。合成的模块化性质将使设计的策略适用于佛波醇家族的广泛分子结构。与公众健康相关：12-脱氧佛波醇酯衍生物已显示出作为抗肿瘤药物的潜力。研究有效地合成接近母体结构的12-脱氧佛波醇，将被证明对抗肿瘤药物的开发有利。

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.