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

• Published in: Journal of the American Chemical Society Vol. 126; no. 36; pp. 11326 - 11337
• Main Authors: Gaul, Christoph, Njardarson, Jón T, Shan, Dandan, Dorn, David C, Wu, Kai-Da, Tong, William P, Huang, Xin-Yun, Moore, Malcolm A. S, Danishefsky, Samuel J
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 15-09-2004
• Subjects: Alcohols - chemical synthesis; Alcohols - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; Cell Movement - drug effects; Chemistry; Chemotherapy; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Humans; Ketones - chemical synthesis; Ketones - pharmacology; Lactones - chemical synthesis; Lactones - pharmacology; Macrolides - chemical synthesis; Macrolides - pharmacology; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - pathology; Medical sciences; Mice; Organic chemistry; Pharmacology. Drug treatments; Piperidones - chemical synthesis; Piperidones - chemistry; Piperidones - pharmacology; Preparations and properties; Structure-Activity Relationship; Antineoplastic agent; Catalytic reaction; Condensation reaction; Asymmetric synthesis; Polyenic compound; Antimetastatic agent; Oxygen heterocycle; Macrolide; Biological activity; Total synthesis
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja048779q

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 CF3-alcohol 71 as promising anti-metastatic agents.