ja048779q_si_001.pdf (532.32 kB)

The Migrastatin Family:  Discovery of Potent Cell Migration Inhibitors by Chemical Synthesis

Download (532.32 kB)
journal contribution
posted on 15.09.2004, 00:00 by 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
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 + 321). 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 (3537). 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.