Asymmetric Total Synthesis of Vilmotenitine A and Structural Revision of Hemsleyaconitine F

The first asymmetric total synthesis of the diterpenoid alkaloid (+)-vilmotenitine A has been accomplished. Strategically, we employed an enantioselective Michael addition to construct the C4 all-carbon quaternary stereocenter and an oxidative dearomatization/Diels-Alder cycloaddition for assembly of the A/B-ring system. Initial attempts to install the E-ring via hydrodealkenylative fragmentation/reductive amination in the presence of the D-ring, or conversely, to construct the D-ring via a Robinson-type annulation with the E-ring in place, were fruitless. The successful route ultimately relied on a hydrodealkenylative fragmentation/Mannich cyclization sequence to forge the E-ring as well as a biogenetically inspired Grob fragmentation to access the complete framework through cleavage of the C7-C17 bond and formation of the requisite C7-C8 double bond. The successful Grob fragmentation provides support for the proposed biosynthetic pathway. This work also leads to definitive revision of the structure originally assigned to hemsleyaconitine F.