Cascade Catalysis Towards Synthesis of Phorbol Architecture

佛波醇结构合成的级联催化

• 批准号: 7420931
• 负责人: HAHN KIM
• 金额: $ 4.68万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7420931
• 关键词: Address; Analgesics; Architecture; Biological; Biological Factors; Biological Process; Biomimetics; Cancer Biology; Carcinogenesis Mechanism; Catalysis; Chemicals; Dependence; Development; Energy Metabolism; Engineering; Event; Family; Individual; Investments; Laboratories; Learning; Medicine; Molecular; Molecular Structure; Nature; Numbers; Object Attachment; Parents; Phorbol; Phorbol Esters; Phorbols; Process; Production; Protein Kinase C; Public Health; Range; Reaction; Reporting; Science; Series; Skeleton; Structure; Testing; Time; Tumor Promoters; antitumor agent; catalyst; chemical synthesis; concept; cost; desire; success; tumor

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.

描述（由申请人提供）：虽然自然界分子制剂的生产，特别是那些具有生物活性的，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精简，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教训。仿生过程的发展，通过使用多种催化剂而不分离中间体来实现顺序催化操作，应该提高化学家以更有效的方式接近生物活性分子结构的能力。在本提案中，级联催化的适用性将在基团结构的背景下进行测试，特别是在12-脱氧基团的全合成中。佛波是一种强效的肿瘤促进剂，是研究肿瘤发生机制最重要的天然产物之一。最近，其衍生物已被证明具有抗肿瘤、镇痛和抗艾滋病毒活性。由于这些重要的生物学意义，获得象素及其同系物变得非常重要。“拟议的合成将利用级联催化以短、高效和慎重的方式获得所需的分子结构，并控制对映体和非对映体选择性。合成的模块化性质将允许设计的策略适用于广泛的phobol家族内的分子结构。与公共卫生相关：12-脱氧磷酯衍生物已被证明具有抗肿瘤药物的潜力。对母体结构12-脱氧佛波的高效合成途径的研究，将有助于抗肿瘤药物的开发。