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Synfacts 2009(6): 0581-0581  
DOI: 10.1055/s-0029-1216673
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of (+)-Cortistatin A

Contributor(s):Philip Kocienski, Arndt W. Schmidt
H. M. Lee, C. Nieto-Oberhuber, M. D. Shair*
Harvard University, Cambridge, USA
Enantioselective Synthesis of (+)-Cortistatin A, a Potent and Selective Inhibitor of Endothelial Cell Proliferation
J. Am. Chem. Soc.  2008,  130:  16864-16866  
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Publication History

Publication Date:
25 May 2009 (online)

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Key words

cortistatin A - aza-Prins cyclization -

Significance

Cortistatin A was isolated together with structurally related molecules from the sponge Corticium simplex. It shows potent anti-angiogenetic activity with a high selectivity towards several human and murine cancer cell lines. The focal step of the synthesis is a highly stereoselective aza-Prins cyclization to complete the steroid-like carbon framework (G → H).

Comment

Thermal loss of bromide from C and cyclopropyl opening followed by fluoride-induced desilylation of the resulting pentadienyl cation leads to vinyl bromide D. Using the less electrophilic TMS group gave a cycloheptadiene via deprotonation  at  C6  by fluoride.  Hydrogenation of the C16/C17 double bond in I could only be achieved  in low yield using diimide generated from J.

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