Strategies and Methods for Complex Alkaloid Synthesis

描述(申请人提供)：该研究计划的目标是开发强大的策略和反应，以高效和实用的方式将简单的、商业上可用的化合物转化为结构复杂的含氮分子。通过进行具有高度结构和/或立体化学复杂性的生物活性生物碱的合成，我们的最终目标是通过开发创新的策略和高效的成键反应来扩大化学合成的能力。研究计划的方法部分分为5个部分。第一部分描述了我们合成乌头胺的设计的演变，这是一种独特的含氯植物生物碱，可以增强大鼠的记忆，并以中等效力抑制人类T细胞的增殖。五步合成乌头胺复杂分子框架的发展将为最终全合成该生物碱和相关的含氮化合物提供基础。第二部分描述了我们致力于开发一种具有新型阳离子-烯烃级联环化过程的萜烯醇E的简明合成方法。藜芦醇E是一种复杂的吲哚二萜化合物，是唯一已知的人有丝分裂激动素EG5运动活性的天然产物抑制剂，是一种潜在的抗癌药物。第三部分和第四部分描述了我们在合成稀有的、具有结构意义的海洋生物碱查尔特林A和查特莱胺A的背景下开发非传统光化学环化反应的计划。最后一部分描述了我们正在进行的开发金属催化的、顺式选择性的烯烃氯胺化反应的工作，用于全合成有效的免疫抑制和细胞毒性生物碱帕劳胺。在这项赠款申请中描述的结构新颖、具有生物活性的生物碱是具有吸引力的化学研究目标，因为它们的成功合成策略尚不存在。这些分子为复杂的化学合成提供了丰富的机会来发明强大的策略和广泛有用的方法。

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.