A stereotetrad-centered approach toward pironetin: Dead ends, Detour, and evolution of the synthetic strategy

Abstract

Pironetin is a unique α-tubulin inhibitor and has been of utmost interest in the synthetic community. Based on the enabling method to access various stereotriads and stereotetrads, we devised a new total synthesis of pironetin, a total 13 steps from commercially available (S)-Roche ester, representing one of the shortest synthetic routes reported to date. The facile fragmentation induced by the deprotonation of the pyrone ring at C4 led us to reorient the installation of the remote enone moiety prior to the lactone ring formation. Moreover, the undesired Michael addition of a phosphate reagent to the acrylate guided us to introduce a sterically demanding cinnamate motif that was also found to facilitate the selective removal of the TBDPS group. The evolution of the synthetic route underlines that the experimental execution of the reactivity of various functional groups is instrumental to devise a successful synthesis.