Total Synthesis of Calyciphylline A - A Potent Cytotoxic Alkaloid

描述(申请人提供)：将开发具有抗癌活性的重要生物碱--帽叶碱A的全化学合成。这一高度节约原子的策略的重点将是在Ru催化的级联异构化反应中一步构建杯茶碱的[6.7.5]环系。在这一点上，过渡金属催化的级联异构化反应的发展从未完成过。此外，6环中的4环是通过异构化反应简单地形成的，这突出了一种非常有效和高度原子经济的方法来获得这种复杂的分子，只加入了两个保护基团。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合成脂肪族氨基甲酸酯保护的亚胺，以及将高官能化的炔烃加成脂肪族饱和醛。此外，一位将军 将探索过渡金属催化1，7-烯炔的[5+2]环加成反应的方法。在内部开发的方法无疑将在一般合成社区中得到广泛应用。拟议项目的成功完成将实现以下目标：1)为进一步的生物学研究提供材料，以研究S分子是一种潜在的治疗剂；2)概述合成这类分子的概念基础，并以高度原子经济性的方法合成其他类型的分子；3)开发涉及主基和过渡金属催化的新催化反应；4)完成第一次全合成 从这类有效的、结构独特的天然产品中分离出来。

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.