Scalable synthesis of cortistatin A and related structures

  • J Am Chem Soc. 2011 May 25;133(20):8014-27. doi: 10.1021/ja202103e.
Jun Shi  1 ,  Georg Manolikakes ,  Chien-Hung Yeh ,  Carlos A Guerrero ,  Ryan A Shenvi ,  Hiroki Shigehisa ,  Phil S Baran
Affiliations
  • 1. Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
PMID: 21539314 DOI: 10.1021/ja202103e
Abstract

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

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