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

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作者：

C Gaul，Njardarson, JT，D Shan，Dorn, DC，Wu, KD，Tong, WP，Huang, XY，Moore, MAS，Danishefsky, SJ

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摘要：

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 + 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 CF(3)-alcohol 71 as promising anti-metastatic agents.

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关键词：

TRANSFORMED NIH/3T3 CELLS RING-CLOSING METATHESIS XESTOSPONGIA-EXIGUA KIRKPATRICK STREPTOMYCES SP MK929-43F1 ANGIOGENESIS INHIBITOR ANTIFUNGAL ANTIBIOTICS ABSOLUTE-CONFIGURATION BIOLOGICAL-ACTIVITY ORGANIC-SYNTHESIS ENANTIOSELECTIVE SYNTHESIS