The migrastatin family: Discovery of potent cell migration inhibitors by chemical synthesis

Christoph Gaul, Jón T. Njardarson, Dandan Shan, David C. Dorn, Kai Da Wu, William P. Tong, Xin Yun Huang, Malcolm A.S. Moore, Samuel J. Danishefsky

Research output: Contribution to journalArticle

149 Scopus citations

Abstract

The first asymmetric total synthesis of (+)-migrastatin (1), a macrolide natural product with antimetastatic 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.

Original languageEnglish (US)
Pages (from-to)11326-11337
Number of pages12
JournalJournal of the American Chemical Society
Volume126
Issue number36
DOIs
StatePublished - Sep 15 2004
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

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    Gaul, C., Njardarson, J. T., Shan, D., Dorn, D. C., Wu, K. D., Tong, W. P., Huang, X. Y., Moore, M. A. S., & Danishefsky, S. J. (2004). The migrastatin family: Discovery of potent cell migration inhibitors by chemical synthesis. Journal of the American Chemical Society, 126(36), 11326-11337. https://doi.org/10.1021/ja048779q