Total Synthesis of Calyciphylline A - A Potent Cytotoxic Alkaloid

强效细胞毒性生物碱 Calyciphylline A 的全合成

• 批准号: 8312035
• 负责人: Craig Evan Stivala
• 金额: $ 4.71万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-07 至 2015-06-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8312035
• 关键词: Aldehydes; Alkaloids; Alkynes; Biological; Biological Factors; Carbamates; Catalysis; Communities; Complex; Development; Foundations; Imines; Methods; Reaction; Reporting; Research; Ruthenium; System; Therapeutic Agents; Time; Transition Elements; Zinc; anticancer activity; catalyst; chemical synthesis; cycloaddition; cytotoxic; design; novel; programs

DESCRIPTION (provided by applicant): The total chemical synthesis of calyciphylline A, an important alkaloid with anticancer activity, will be developed. The focus of this highly atom-economical strategy will be a ruthenium-catalyzed cascade of isomerization reactions to construct the [6.7.5] ring system of the Calyciphylline alkaloids in a single step. At this point i time, the development of a cascade of transition-metal-catalyzed isomerization reactions has never been done. Furthermore, 4 of the rings 6 rings of calyciphylline A are formed simply by isomerization reactions, highlighting an extremely efficient and highly atom-economical approach to this complex molecule with the incorporation of only two protecting groups. Additionally, this research program is designed to stimulate development of pre-existing methods in main group and transition-metal catalysis. These studies will explore novel zinc catalyzed ProPhenol alkynylations to saturated aliphatic carbamate-protected imines, as well as additions of highly functionalized alkynes to aliphatic saturated aldehydes. In addition, a general method for transition-metal-catalyzed [5+2] cycloadditions of 1,7-enynes will be explored. The methods developed within will undoubtedly attain widespread application amongst the general synthetic community. Successful completion of the proposed project would achieve the following: 1) Provide material for further biological studies in order to investigate the molecule s a potential therapeutic agent, 2) Outline a conceptual foundation for a synthetic, and highly atom-economical approach to other molecules of this type, 3) Develop new catalytic reactions involving both main group and transition-metal catalysis, 4) Culminate in the first total synthesis from this subclass of potent, structurally unique natural products.

描述（由申请人提供）：将开发具有抗癌活性的重要生物碱calyciphylline A的全化学合成。这种高度原子经济策略的重点将是在单一步骤中构建Calyciphylline生物碱的[6.7.5]环系统的异构化反应的顺丁烯二酸盐催化级联。在这一点上，过渡金属催化的异构化反应的级联的发展从来没有做过。此外，calyciphylline A的6个环中的4个环简单地通过异构化反应形成，突出了这种复杂分子的极其有效和高度原子经济的方法，仅引入两个保护基团。此外，该研究计划旨在促进主族和过渡金属催化中已有方法的发展。这些研究将探索新的锌催化ProPhenol炔基化饱和脂肪族氨基甲酸酯保护的亚胺，以及添加高度官能化的炔脂肪族饱和醛。此外，一名将军 探索了过渡金属催化1，7-烯炔[5+2]环加成反应的方法。其中开发的方法无疑将在一般合成社区中获得广泛应用。成功完成拟议项目将实现以下目标：1）为进一步的生物学研究提供材料，以研究该分子作为潜在的治疗剂，2）概述合成这种类型的其他分子的高度原子经济的方法的概念基础，3）开发涉及主族和过渡金属催化的新的催化反应，4）在第一次全合成中达到高潮 从这一类结构独特的强效天然产物中分离出来