The Migrastatin Family: Discovery of Potent Cell Migration Inhibitors by Chemical Synthesis.
In: Journal of the American Chemical Society, Jg. 126 (2004-09-15), Heft 36, S. 11326-11336
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Zugriff:
The first asymmetric total synthesis of (+)-migrastatin (1), a macrolide natural product with anti-metastatic properties, has been accomplished. Our concise and flexible approach utilized a Lewis acid-catalyzed diene aldehyde condensation (LACDAC) to install the three contiguous stereocenters and the trisubstituted (Z)-alkene of migrastatin (2 + 3 → 21). Construction of the two remaining stereocenters and incorporation of the glutarimide-containing side chain was achieved by an anti-selective aldol addition of propionyl oxazolidinone 28 to angelic aldehyde 27, followed by a Horner-Wadsworth-Emmons (HWE) coupling of 32 with glutarimide aldehyde 5. Finally, the assembly of the macrocycle was realized by a highly (E)-selective ring-closing metathesis (35 → 37). Utilizing the power of diverted total synthesis (DTS), a series of otherwise inaccessible analogues was prepared and evaluated for their potential as tumor cell migration inhibitors in several in vitro assays. These studies revealed a dramatic increase in activity when the natural motif was considerably simplified, presenting macrolactones 45 and 48, as well as macrolactam 55, macroketone 60, and CF3-alcohol 71 as promising anti-metastatic agents. [ABSTRACT FROM AUTHOR]
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The Migrastatin Family: Discovery of Potent Cell Migration Inhibitors by Chemical Synthesis.
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Autor/in / Beteiligte Person: | Gaul, Christoph ; Njardarson, Jon T. ; Shan, Dandan ; Dorn, David C. ; Wu, Kai-Da ; Tong, William P. ; Huang, Xin-Yun ; Moore, Malcolm A. S. ; Danishefsky, Samuel J. |
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Zeitschrift: | Journal of the American Chemical Society, Jg. 126 (2004-09-15), Heft 36, S. 11326-11336 |
Veröffentlichung: | 2004 |
Medientyp: | academicJournal |
ISSN: | 0002-7863 (print) |
DOI: | 10.1021/ja048779q |
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