Synthesis of (+)-cortistatin A |
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Authors: | Shenvi Ryan A Guerrero Carlos A Shi Jun Li Chuang-Chuang Baran Phil S |
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Institution: | Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. |
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Abstract: | 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. |
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