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

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.