Strategies and Methods for Complex Alkaloid Synthesis

复杂生物碱合成的策略和方法

• 批准号: 7089993
• 负责人: Erik J. Sorensen
• 金额: $ 27.91万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7089993
• 关键词: alkaloids; alkenes; biological products; chemical reaction; chemical synthesis; cyclization; indoles; intermolecular interaction; kinesin; stereochemistry; technology /technique development

DESCRIPTION (provided by applicant): The objective of this research program is to develop powerful strategies and reactions to transform simple, commercially available compounds into structurally complex, nitrogen-containing molecules with high efficiency and in a practical fashion. By undertaking syntheses of biologically active alkaloids having a high level of architectural and/or stereochemical complexity, our ultimate goal is to extend the capabilities of chemical synthesis through the development of innovative strategies and efficient bond-forming reactions. The methods section of the research plan is divided into 5 parts. The first part describes the evolution of our design for synthesizing acutumine, a unique, chlorine-containing plant alkaloid that enhances memory in rats and inhibits human T-cell proliferation with moderate potency. The development of a 5-step synthesis of the complex molecular framework of acutumine will provide the foundation for an eventual total synthesis of this alkaloid and related nitrogen-containing compounds. The second part describes our effort to develop a concise synthesis of terpendole E featuring a novel cation-olefin cascade cyclization process. Terpendole E, a complex indole diterpene, is the only known natural product inhibitor of the motor activity of the human mitotic kinesin Eg5 and is a potential anti-cancer agent. Parts 3 and 4 describe our plans for developing unconventional photochemical cyclizations in the context of syntheses of the scarce, architecturally remarkable marine alkaloids chartelline A and chartellamide A. The final part describes our ongoing effort to develop metal-catalyzed, cis-selective chloroaminations of alkenes for use in a total synthesis of the potent immunosuppressive and cytotoxic alkaloid palau'amine. The structurally novel, biologically active alkaloids described in this grant application are attractive objectives for chemical research because successful strategies for their synthesis do not yet exist. These molecules provide rich opportunities to invent powerful strategies and broadly useful methods for complex chemical synthesis.

描述（由申请人提供）：该研究计划的目标是开发强大的策略和反应，以高效且实用的方式将简单的市售化合物转化为结构复杂的含氮分子。通过合成具有高水平结构和/或立体化学复杂性的生物活性生物碱，我们的最终目标是通过开发创新策略和有效的成键反应来扩展化学合成的能力。研究计划的方法部分分为5部分。第一部分描述了我们合成 acutumine 的设计的演变，acutumine 是一种独特的含氯植物生物碱，可增强大鼠的记忆力并以中等效力抑制人类 T 细胞增殖。尖碱复杂分子框架的五步合成的开发将为这种生物碱和相关含氮化合物的最终全合成奠定基础。第二部分描述了我们开发萜烯 E 的简明合成方法的努力，该合成方法具有新颖的阳离子-烯烃级联环化工艺。 Terpendole E 是一种复杂的吲哚二萜，是唯一已知的人类有丝分裂驱动蛋白 Eg5 运动活性的天然产物抑制剂，也是一种潜在的抗癌剂。第 3 部分和第 4 部分描述了我们在合成稀有的、结构上引人注目的海洋生物碱 Chartelline A 和 Chartellamide A 的背景下开发非常规光化学环化的计划。最后部分描述了我们正在努力开发金属催化的、顺式选择性的烯烃氯胺化，用于强效免疫抑制和细胞毒性的全合成。 生物碱帕劳胺。该资助申请中描述的结构新颖、具有生物活性的生物碱对于化学研究来说是有吸引力的目标，因为尚不存在成功的合成策略。这些分子为发明复杂化学合成的强大策略和广泛有用的方法提供了丰富的机会。