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（由申请人提供）：将开发出具有抗癌活性的重要生物碱的Calyciphylline A的总化学合成。这种高度原子 - 经济策略的重点将是一系列的异构化反应的氟化级联反应，以在单一步骤中构建钙含糖性生物碱的[6.7.5]环系统。在这一点上，从未做过一系列过渡金属催化异构化反应的级联反应的发展。此外，在钙齐林A的6环中，有4个仅通过异构反应形成，突出了一种极有效且高度原子的经济方法，仅掺入了两个保护基团。此外，该研究计划旨在刺激主要组和过渡金属催化中现有方法的发展。这些研究将探索新型的锌催化预知酸性烯醇化为饱和脂肪族氨基甲酸盐保护的亚胺，并添加高度功能化的炔烃与脂肪族饱和醛的醛。另外，一般 将探索1,7-Enynes的过渡金属催化方法[5+2]环载的方法。毫无疑问，内部开发的方法将在一般合成界之间得到广泛的应用。拟议项目的成功完成将实现以下内容：1）为进一步的生物学研究提供材料，以研究该分子是一种潜在的治疗剂，2）概述了对这种类型的其他分子的合成和高度原子经济学方法的概念基础，3）涉及新的催化反应，涉及主要的催化反应，涉及主要的群体和过渡中的猫脉管，最初是catalsyss的总和。 从这种有效的，结构独特的天然产品的子类中。