Scalable Synthesis of Cortistatin A and Related Structures

摘要

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 functio-nalized cortistatin A-ring embedded with a key heteroadaman-tane 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 "cortistatinone". A selective Δ~(16)-alkene reduction with Raney Ni provided cortistatin A. With this scalable and practical route, copious quantities of cortistatinone, A -cortistatin A (the equipotent direct precursor to cortistatin A), and its related analogues were prepared for further biological studies.