Synthesis of Eupalinilide E, a Promoter of Human Hematopoietic Stem and Progenitor Cell Expansion

J Am Chem Soc. 2016 May 11;138(18):6068-73. doi: 10.1021/jacs.6b03055. Epub 2016 May 2.


Improving the ex vivo and in vivo production of hematopoietic stem and progenitor cells (HSPCs) has the potential to address the short supply of these cells that are used in the treatment of various blood diseases and disorders. Eupalinilide E promotes the expansion of human HSPCs and inhibits subsequent differentiation, leading to increased numbers of clinically useful cells. This natural product represents an important tool to uncover new methods to drive expansion while inhibiting differentiation. However, in the process of examining these effects, which occur through a novel mechanism, the natural product was consumed, which limited additional investigation. To provide renewed and improved access to eupalinilide E, a laboratory synthesis has been developed and is reported herein. The synthetic route can access >400 mg in a single batch, employing reactions conducted on useful scales in a single vessel. Key transformations enabling the approach include a diastereoselective borylative enyne cyclization and a late-stage double allylic C-H oxidation as well as adapted Luche reduction and aluminum-mediated epoxidation reactions to maximize the synthetic efficiency. Retesting of the synthetic eupalinilide E confirmed the compound's ability to expand HSPCs and inhibit differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aluminum / chemistry
  • Antigens, CD34 / biosynthesis
  • Cell Differentiation
  • Cell Proliferation
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Oxidation-Reduction
  • Sesquiterpenes / chemical synthesis*
  • Sesquiterpenes / pharmacology*
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Stereoisomerism


  • Antigens, CD34
  • Sesquiterpenes
  • eupalinilide E
  • Aluminum