Total Synthesis of Iejimalide A-D and Assessment of the Remarkable Actin-Depolymerizing Capacity of These Polyene Macrolides
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- 作者：Alois Fü ; rstner ; Cristina Nevado ; Mario Waser ; Martin Tremblay ; Carine Chevrier ; Filip Tepl
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- 刊名：Journal of the American Chemical Society
- 出版年：2007
- 出版时间：July 25, 2007
- 年：2007
- 卷：129
- 期：29
- 页码：9150 - 9161
- 全文大小：379K
- 年卷期：v.129,no.29(July 25, 2007)
- ISSN：1520-5126
文摘
A concise and convergent total synthesis of the highly cytotoxic marine natural products iejimalideA-D (1-4) is reported, which relies on an effective ring-closing metathesis (RCM) reaction of a cyclizationprecursor containing no less than 10 double bonds. Because of the exceptional sensitivity of thispolyunsaturated intermediate and its immediate precursors toward acid, base, and even gentle warming,the assembly process hinged upon the judicious choice of protecting groups and the careful optimizationof all individual transformations. As a consequence, particularly mild protocols for Stille as well as Suzukireactions of elaborate coupling partners have been developed that hold considerable promise for applicationsin other complex settings. Moreover, a series of non-natural "iejimalide-like" compounds has been prepared,differing from the natural lead in the polar head groups linked to the macrolide's N-terminus. With the aidof these compounds it was possible to uncover the hitherto unknown effect of iejimalide and analogues onthe actin cytoskeleton. Their capacity to depolymerize this microfilament network rivals that of the latrunculinswhich constitute the standard in the field. Structural modifications of the peptidic terminus in 2 are therebywell accommodated, without compromising the biological effects. The iejimalides hence constitute animportant new class of probe molecules for chemical biology in addition to their role as promising leadstructures for the development of novel anticancer agents.