Synthesis of (+)-cortistatin A.
Cortistatin A is a marine steroid with highly selective and perhaps mechanistically unique antiangiogenic activity. Herein we report a synthesis of this natural product by way of "cortistatinone", an intermediate ideally suited for investigating the key pharmacophore of the cortistatin family. The synthesis begins with a terrestrial steroid and traverses a route to cortistatin A through the discovery of unique chemical reactivity. Specifically, we demonstrate the first example of a directed, geminal C-H bisoxidation, a new fragmentation cascade to access expanded B-ring steroid systems, a chemoselective cyclization to install the hallmark oxabicycle of the cortistatin family, and a remarkably selective hydrogenation reaction, which should find extensive use in future syntheses of the cortistatins and designed analogues. The synthesis displays a level of brevity, efficiency, and practicality that will be crucial in evaluating the medicinal potential of this fascinating class of marine steroids.
Shenvi
Ryan A
RA
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Guerrero
Carlos A
CA
Shi
Jun
J
Li
Chuang-Chuang
CC
Baran
Phil S
PS
D000731:Androstanes / Q000138:chemical synthesis*; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis; D011241:Prednisone / Q000737:chemistry; D013237:Stereoisomerism
D000731:Androstanes; D020533:Angiogenesis Inhibitors; D011241:Prednisone