Scalable Synthesis of Cortistatin A and Related Structures

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• 作者：Jun Shi ; Georg Manolikakes ; Chien-Hung Yeh ; Carlos A. Guerrero ; Ryan A. Shenvi ; Hiroki Shigehisa ; Phil S. Baran
• 刊名：Journal of the American Chemical Society
• 出版年：2011
• 出版时间：May 25, 2011
• 年：2011
• 卷：133
• 期：20
• 页码：8014-8027
• 全文大小：1757K
• 年卷期：v.133,no.20(May 25, 2011)
• ISSN：1520-5126

文摘

Full details are provided for an improved synthesis of cortistatin A and related structures as well as the underlying logic and evolution of strategy. The highly functionalized cortistatin A-ring embedded with a key heteroadamantane was synthesized by a simple and scalable five-step sequence. A chemoselective, tandem geminal dihalogenation of an unactivated methyl group, a reductive fragmentation/trapping/elimination of a bromocyclopropane, and a facile chemoselective etherification reaction afforded the cortistatin A core, dubbed 鈥渃ortistatinone鈥? A selective 螖¹⁶-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, 螖¹⁶-cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies.