Enantioselective Total Synthesis of (−)-FR182877 and Evaluation of the Biological Activity of Its Pharmacophore

Abstract The details of our enantioselective total synthesis of (−)-FR182877 and evaluation of the biological activity of its pharmacophore are described. Our total synthesis features (1) the oxidation–intramolecular Diels–Alder–intramolecular hetero Diels–Alder reaction cascade, affording the tetracyclic compound including the ABCD-ring system of (−)-FR182877 as a single isomer, (2) the palladium-catalyzed intramolecular Heck reaction for the construction of the highly strained seven-membered F-ring in high yield, and (3) the iridium-mediated isomerization of the allylic alcohol to the α-methyl ketone followed by epimerization and reduction to furnish all the stereogenic centers of (−)-FR182877 in a completely stereoselective manner. The enantioselective synthesis of compounds containing the DEF-ring moiety of (−)-FR182877 was achieved using an inverse electron-demand hetero Diels–Alder reaction as the key step. The product was extremely reactive and converted into a stable hydrate during isolation, which exhibited no significant biological activity. However, the acetate of the hydrate was found to act on HeLa cells at relatively high concentrations (200 μM) and inhibit cell division in a manner like that of paclitaxel. This study demonstrates the power of organic synthesis and provides valuable information for the total synthesis and creation of bioactive polycyclic compounds.