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

Christoph Gaul, Jon 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

141 Citations (Scopus)

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

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Aldehydes
Cell Movement
Oxazolidinones
Lewis Acids
Macrolides
Alkenes
Biological Products
Olefins
Tumors
Condensation
Assays
Alcohols
Cells
Acids
migrastatin
Neoplasms
glutarimide

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

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

In: Journal of the American Chemical Society, Vol. 126, No. 36, 15.09.2004, p. 11326-11337.

Research output: Contribution to journalArticle

Gaul, C, Njardarson, JT, Shan, D, Dorn, DC, Wu, KD, Tong, WP, Huang, XY, Moore, MAS & Danishefsky, SJ 2004, 'The migrastatin family: Discovery of potent cell migration inhibitors by chemical synthesis', Journal of the American Chemical Society, vol. 126, no. 36, pp. 11326-11337. https://doi.org/10.1021/ja048779q
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. / The migrastatin family : Discovery of potent cell migration inhibitors by chemical synthesis. In: Journal of the American Chemical Society. 2004 ; Vol. 126, No. 36. pp. 11326-11337.
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