Asymmetric Synthesis of Bioactive Natural Products

生物活性天然产物的不对称合成

• 批准号: 8038260
• 负责人: Jeffrey S Johnson
• 金额: $ 25.09万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038260
• 关键词: 3-hydroxybutanal; Antibiotics; Biological; Biological Factors; Carbon; Colony-Stimulating Factors; Complex; Coupling; Development; Exhibits; Felis catus; Future; Glyoxylates; Goals; Grant; Health; Laboratories; Lactones; Molecular; Oximes; Pactamycin; Preparation; Reaction; Reagent; Reducing Agents; Research; Route; Scheme; Skeleton; Squalene Synthetase; Structure; Therapeutic; Vertebral column; functional group; glyoxylate; inhibitor/antagonist; leustroducsin B; operation; oxidation; preconditioning; small molecule; zaragozic acid C

DESCRIPTION (provided by applicant): This project seeks to develop and implement new tactics for the total synthesis of complex natural products that exhibit promising biological activities. Targeted structures that will be synthesized under the aegis of this grant are: 1) zaragozic acid C, a squalene synthase inhibitor; 2) pactamycin, an antibiotic; 3) leustroducsin B, a colony-stimulating factor inducer. These three structurally unique natural products share a high level of functional group and stereochemical complexity that renders them attractive platforms for new reaction discovery. An underlying principle of the proposed research is that buildup of the carbon skeleton must coincide with introduction of stereochemical information for maximum efficiency; therefore, cascade reactions are a staple of the projected synthetic routes. The strategies in particular seek to harness the unique reactivity of a newly developed reagent: tert-butyl tert-butyldimethylsilyl glyoxylate. This is a coupling reagent that conjoins complementary nucleophilic and electrophilic reaction partners, often with high levels of stereocontrol for the stereogenic centers that are concomitantly built up with the carbon skeleton. In each proposed synthesis, the key step is a new, mechanistically guided poly-addition reaction that introduces a significant fraction of the molecular complexity in a single operation. The reactions are configured such that the key functional groups are introduced in the proper oxidation state, minimizing wasteful downstream operations. PUBLIC HEALTH RELEVANCE: The molecules that are targeted for synthesis in this study all exhibit potent biological activities that could hold significance in the development of small molecule therapeutics. The efficient preparation of these compounds is a necessary precondition for any future biomedical applications.

描述（由申请人提供）：该项目旨在开发和实施新的策略来全合成具有有前景的生物活性的复杂天然产物。在本次资助的支持下将合成的目标结构是：1) 萨拉哥酸 C，一种角鲨烯合酶抑制剂； 2) 帕大霉素，一种抗生素； 3) leustroducsin B，一种集落刺激因子诱导剂。这三种结构独特的天然产物具有高水平的官能团和立体化学复杂性，这使得它们成为新反应发现的有吸引力的平台。该研究的基本原则是碳骨架的构建必须与立体化学信息的引入相一致，以实现最大效率；因此，级联反应是预计合成路线的主要内容。这些策略特别寻求利用新开发的试剂的独特反应性：叔丁基二甲基甲硅烷基乙醛酸酯。这是一种偶联试剂，可连接互补的亲核和亲电反应伙伴，通常对与碳骨架一起构建的立体中心具有高水平的立体控制。在每个提出的合成中，关键步骤是一种新的、机械引导的加聚反应，该反应在单个操作中引入了分子复杂性的很大一部分。反应的配置使得关键官能团以适当的氧化态引入，从而最大限度地减少下游操作的浪费。公共健康相关性：本研究中合成的目标分子均表现出有效的生物活性，对小分子疗法的开发具有重要意义。这些化合物的有效制备是任何未来生物医学应用的必要先决条件。