Synthetic Route Development for the Laboratory Preparation of Eupalinilide E

Following the discovery
that the guaianolide natural product eupalinilide
E promotes the expansion of hematopoietic stem and progenitor cells;
the development of a synthetic route to provide laboratory access
to the natural product became a priority. Exploration of multiple
synthetic routes yielded an approach that has permitted a scalable
synthesis of the natural product. Two routes that failed to access
eupalinilide E were triaged either as a result of providing an incorrect
diastereomer or due to lack of synthetic efficiency. The successful
strategy relied on late-stage allylic oxidations at two separate positions
of the molecule, which significantly increased the breadth of reactions
that could be used to this point. Subsequent to C–H bond oxidation,
adaptations of existing chemical transformations were required to
permit chemoselective reduction and oxidation reactions. These transformations
included a modified Luche reduction and a selective homoallylic alcohol
epoxidation.