title: The migrastatin family: discovery of potent cell migration inhibitors by chemical synthesis.
abstract: 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.
authors.affiliation: Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Gaul
authors.forename: Jón T
authors.initials: JT
authors.lastname: Njardarson
authors.forename: Dandan
authors.initials: D
authors.lastname: Shan
authors.forename: David C
authors.initials: DC
authors.lastname: Dorn
authors.forename: Kai-Da
authors.initials: KD
authors.lastname: Wu
authors.forename: William P
authors.initials: WP
authors.lastname: Tong
authors.forename: Xin-Yun
authors.initials: XY
authors.lastname: Huang
authors.forename: Malcolm A S
authors.initials: MA
authors.lastname: Moore
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Danishefsky
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology*; D018942:Macrolides / Q000138:chemical synthesis* / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000438:Alcohols; D007659:Ketones; D007783:Lactones; D018942:Macrolides; D010881:Piperidones; C418199:migrastatin; C007864:glutarimide