760988-63-4Relevant academic research and scientific papers
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.
, p. 11326 - 11337 (2007/10/03)
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.
