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: 8510477
• 负责人: Craig Evan Stivala
• 金额: $ 4.92万
• 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/8510477
• 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（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是钌催化的异构化反应级联，以一步构建Calyciphylline生物碱的[6.7.5]环系统。目前，过渡金属催化异构化反应级联的开发尚未完成。此外，calyciphylline A 的 4 个环 6 个环是通过异构化反应简单形成的，这突显了仅掺入两个保护基团即可极其有效且高度原子经济地制备这种复杂分子的方法。此外，该研究计划旨在促进主族和过渡金属催化中现有方法的发展。这些研究将探索新型锌催化的苯酚炔基化反应生成饱和脂肪族氨基甲酸酯保护的亚胺，以及将高度官能化的炔烃加成到脂肪族饱和醛上。此外，一般 将探索过渡金属催化的1,7-烯炔的[5+2]环加成方法。其中开发的方法无疑将在一般合成界得到广泛应用。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）概述对其他分子进行合成和高度原子经济的方法的概念基础这种类型，3）开发涉及主族和过渡金属催化的新催化反应，4）最终实现首次全合成 来自这一有效的、结构独特的天然产品的子类。