Asymmetric Synthesis of Bioactive Natural Products

生物活性天然产物的不对称合成

• 批准号: 8265929
• 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/8265929
• 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(由申请者提供)：该项目寻求开发和实施新的策略，用于全合成具有良好生物活性的复杂天然产物。在这项资助下将合成的目标结构是：1)萨拉戈齐酸C，角鲨烯合成酶抑制剂；2)紫霉素，抗生素；3)亮绿球菌素B，集落刺激因子诱导剂。这三种结构独特的天然产物共享高水平的官能团和立体化学复杂性，使它们成为新反应发现的有吸引力的平台。拟议研究的一个基本原则是，碳骨架的建立必须与引入立体化学信息相一致，以实现最大效率；因此，级联反应是计划合成路线的主要内容。这些战略尤其寻求利用一种新开发的试剂的独特反应性：叔丁基叔丁基二甲基硅基乙醛。这是一种偶联剂，连接了互补的亲核和亲电反应伙伴，通常对伴随着碳骨架建立的立体中心具有高水平的立体控制。在每一个拟议的合成中，关键步骤是一个新的、机械引导的多加成反应，该反应在一次操作中引入了相当大一部分的分子复杂性。这些反应被配置为使关键官能团在适当的氧化状态下被引入，最大限度地减少了下游操作的浪费。与公共健康相关：本研究中目标为合成的分子都显示出强大的生物活性，这可能对小分子疗法的发展具有重要意义。这些化合物的有效制备是任何未来生物医学应用的必要前提。