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The Migrastatin Family: Discovery of Potent Cell Migration Inhibitors by Chemical Synthesis
journal contribution
posted on 2004-09-15, 00:00 authored 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. DanishefskyThe 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.